Biology Direct[JOURNAL]
Sun
200 papers
A phospho-switch to trigger mitotic chromosome condensation.
Borsellini A
Biol Direct · 2026 Jan · PMID 41501934 · Full text
One of the most eye-catching events in cell biology is the condensation of chromosomes. During mitosis, the diffuse interphase chromatin rearranges into compact, rod-shaped chromosomes that can be precisely segregated be...
One of the most eye-catching events in cell biology is the condensation of chromosomes. During mitosis, the diffuse interphase chromatin rearranges into compact, rod-shaped chromosomes that can be precisely segregated between the daughter cells. This drastic reorganization of the DNA relies on condensin I and II complexes, large ring-shaped ATPases that extrude and stabilize loops of DNA. Since condensin II is always present in the nucleous its activity is repressed by the protein MCPH1 during interphase. But what are the molecular mechanisms regulating the activation of condensin II? New evidence suggests that this activation depends on the interaction between the condensin II subunit CAP-G2 with the centromeric protein M18BP1. Both the repressor and the activator bind on the same subunit of condensin II and their alternative binding is regulated by phosphorylation, which acts as the signal to trigger DNA condensation by condensin II.
A novel synergistic action of phage vB_PaeP_GZMU_A1002 with allicin against carbapenem-resistant Pseudomonas aeruginosa.
Fu Y, Liu J, Yin Y … +9 more , Yuan K, Zhou Z, Xu L, Dou S, Cai B, He Z, Wang W, Xiao Q, Chen P
Biol Direct · 2026 Jan · PMID 41495838 · Full text
The increasing problem of bacterial resistance to antibiotics necessitates the exploration of innovative antimicrobial strategies. Phage therapy is a promising solution; however, naturally occurring phages targeting resi...
The increasing problem of bacterial resistance to antibiotics necessitates the exploration of innovative antimicrobial strategies. Phage therapy is a promising solution; however, naturally occurring phages targeting resistant pathogens remain limited. This study aimed to isolate and identify phages that lyse carbapenem-resistant Pseudomonas aeruginosa (CRPA) from sewage and investigate the synergistic antimicrobial effects of phage therapy combined with allicin. A novel phage, vB_PaeP_GZMU_A1002, was successfully isolated and characterized, revealing a double-stranded DNA genome of 63,770 bp with no virulence or resistance genes, indicating its safety for application. This phage demonstrated good stability across various temperatures and pH levels, effectively inhibited the CRPA growth within 12 h, and achieved a biofilm clearance rate of about 50%. Notably, the combination of phage and allicin significantly enhanced antimicrobial efficacy, reducing effective concentrations of both agents. The synergistic action was likely due to increased damage to bacterial cell membranes and reduced cell surface hydrophobicity. This research highlights the potential of phage therapy, particularly when combined with natural compounds like allicin, as a viable approach to combat antibiotic-resistant infections.
Integrative multi-omics analysis widens annotation and functional insights into long non-coding RNAs of Arabidopsis thaliana.
Vivek AT, Kiran H, Sahu N … +2 more , Kalakoti G, Kumar S
Biol Direct · 2026 Jan · PMID 41491960 · Full text
BACKGROUND: Long non-coding RNAs (lncRNAs) play key roles in regulating plant growth, development, and stress responses. Despite their increasing identification in plant transcriptomes, a systematic characterization of l...
BACKGROUND: Long non-coding RNAs (lncRNAs) play key roles in regulating plant growth, development, and stress responses. Despite their increasing identification in plant transcriptomes, a systematic characterization of lncRNAs is still lacking, leaving a significant knowledge gap. To address this, we systematically identified and characterized Arabidopsis lncRNAs through integrative analysis of strand-specific RNA sequencing data and multi-omics datasets, revealing their genomic features, regulatory interactions, and evolutionary characteristics. RESULTS: Using a custom pipeline applied to hundreds of stranded RNA-seq datasets, we assembled a comprehensive catalog of 4,772 intergenic and antisense Arabidopsis lncRNAs. In comparing multiple key features of lncRNAs with those of protein-coding genes, we found that intergenic lncRNAs contain high transposable element-derived fragments and display broader TE diversity. Distinct DNA methylation and histone modification signatures further distinguished lncRNAs from protein-coding genes. We additionally uncovered R-loop connections and associations with sRNAs involved in post-transcriptional regulation and RNA-directed DNA methylation, with a minor subset classified as Pol V–transcribed. Of note, our results revealed lncRNAs mediating stress-responsive cis interactions and others linked to trait-associated loci. Probing further, an experimental evidence resource confirmed small peptide production from multiple lncRNA loci. Extending our investigation, comparative analyses across Brassicaceae species revealed syntenic lncRNAs enriched for shared sequence motifs despite substantial sequence divergence. CONCLUSIONS: This study provides a valuable and extensively annotated catalog of Arabidopsis lncRNAs, revealing their diverse genomic features, regulatory interactions, and evolutionary characteristics. Altogether, our work advocates for multi-omics integrative analysis as a potent strategy to efficiently enhance lncRNA annotation, providing insights into functionality and addressing annotation limitations. Our comprehensive bioinformatic analyses of Arabidopsis lncRNAs pave the way for future functional characterization of these transcripts.
Organelle-specific regulation of ferroptosis.
Zhang Y, Liu M, Li M … +6 more , Wu Y, Xie M, Liu X, Lu H, Zhai X, Yang Y
Biol Direct · 2026 Jan · PMID 41484993 · Full text
Ferroptosis, an iron-dependent form of regulatory cell death driven by lipid peroxidation, has emerged as a key factor in several pathological conditions. At the organelle level, ferroptosis involves complex interactions...
Ferroptosis, an iron-dependent form of regulatory cell death driven by lipid peroxidation, has emerged as a key factor in several pathological conditions. At the organelle level, ferroptosis involves complex interactions between mitochondria, lysosome, endoplasmic reticulum (ER), Golgi apparatus, Nucleus, autophagosome, lipid droplet and peroxisome. Each of them plays a unique role in the ferroptosis cascade. Although the molecular mechanisms of ferroptosis have been extensively studied, the role of specific organelles in this process has not been fully explored. This review aims to summarize the latest advances in organelle-level changes during ferroptosis.
Spatiotemporal dynamics of neuronal subtypes and their interactions with glia following intracortical electrode implantation.
Zhao Z, Duan X, Luo J … +6 more , He Z, Zhang Y, Wang M, Qin J, Lin S, Chen H
Biol Direct · 2025 Dec · PMID 41462297 · Full text
BACKGROUND: Chronically implanted electrodes offer a promising approach for treating neurological disorders via brain-computer interfaces, yet their long-term efficacy is compromised by the neuroinflammatory foreign body...
BACKGROUND: Chronically implanted electrodes offer a promising approach for treating neurological disorders via brain-computer interfaces, yet their long-term efficacy is compromised by the neuroinflammatory foreign body response. While neurons are central to both electrode function and inflammatory regulation, their specific responses post-implantation remain poorly characterized. Here, we combined single-nucleus RNA sequencing (snRNA-seq) and immunofluorescence to delineate the spatiotemporal dynamics of neuronal subtypes in the rat motor cortex at 3, 25, and 50 days after electrode implantation. RESULTS: We identified 22 distinct neuronal subpopulations, among which clusters 5, 6, and 8 emerged as injury-responsive subtypes during the acute phase (3 days), exhibiting a specific upregulation of Tmsb4x, a key regulator of neuronal plasticity and repair. Furthermore, our analysis revealed activated signaling pathways mediating neuron-glia communication, most notably the Ptn-Sdc4 and Il34/Csf1-Csf1R axes between neurons and astrocytes. CONCLUSIONS: These findings provide a high-resolution map of neuronal adaptation to intracortical implants, uncovering previously unknown repair-associated neuronal subtypes and specific ligand-receptor pairs that coordinate the neuroinflammatory microenvironment, which offers novel insights and potential therapeutic targets for improving the biocompatibility and long-term stability of neural electrodes.
Partial inhibition of viral replication machinery enhances recombination in herpes simplex viruses.
Ralph-Altman M, Avhar D, Altman Y … +6 more , Cohen I, Azulay H, Korner T, Sweed S, Tomer E, Kobiler O
Biol Direct · 2025 Dec · PMID 41444614 · Full text
BACKGROUND: Herpes simplex viruses (HSV-1 and HSV-2) are widespread human pathogens, most commonly causing oral and genital lesions. These DNA viruses use recombination as a major driver of evolution. Intragenomic and in...
BACKGROUND: Herpes simplex viruses (HSV-1 and HSV-2) are widespread human pathogens, most commonly causing oral and genital lesions. These DNA viruses use recombination as a major driver of evolution. Intragenomic and intergenomic recombination events can be detected both in vivo and in vitro. As viral recombination is tightly linked to replication, deciphering mechanisms that specifically effect recombination remains a challenge. RESULTS: We employed a triple-fluorescent color recombination assay to identify homology mediated and non-canonical recombination events between co-infecting HSV-1 strains. We developed a deep learning model that detects and classifies progeny plaques according to their colors. This setup enabled us to perturb the infection process using small molecule inhibitors targeting either viral or host proteins. We identified that inhibitors that reduce infectious viral progeny, increased viral homology mediated recombination. The antiviral drugs, including acyclovir, also increased recombination between HSV-1 and HSV-2 and aberrations in the progeny viral genomes. CONCLUSIONS: Our results indicate that relatively low yet clinically relevant concentration of commonly used anti-herpes drugs increase intraspecies and interspecies recombination rates and genetic rearrangements. Thus, partial inhibition of the herpes replication complex can promote viral diversification, with potential implications for HSV evolution and drug resistance. CLINICAL TRIAL NUMBER: Not applicable.
IGF2 regulates proliferation, differentiation, and mitochondrial bioenergetics in human satellite cells.
Voshtani R, Hou P, Liu Z … +5 more , Cao L, Feng C, Shao C, Shi Y, Fang J
Biol Direct · 2025 Dec · PMID 41430340 · Full text
Insulin-like growth factors (IGFs) are key regulators of the stem cell niche, playing critical roles in the proliferation and differentiation of stem cells into various lineages, including skeletal muscle. While IGF2 is...
Insulin-like growth factors (IGFs) are key regulators of the stem cell niche, playing critical roles in the proliferation and differentiation of stem cells into various lineages, including skeletal muscle. While IGF2 is known to influence muscle development, its specific effects and mechanisms in human skeletal muscle remain incompletely understood. In this study, we demonstrate that IGF2 is a key regulator of human satellite cell (huSC) proliferation, differentiation, and mitochondrial bioenergetics. Using primary huSCs cultured under defined myogenic conditions, we show that IGF2 significantly enhances myoblast proliferation and promotes differentiation via upregulation of myogenic regulatory factors and activation of the IGF1 receptor (IGF1R) pathway. Knockdown of endogenous IGF2 impaired these processes, while exogenous supplementation restored myogenic potential. Notably, IGF2 also improved mitochondrial function, evidenced by increased oxygen consumption rate, mitochondrial mass, oxidative phosphorylation protein expression, and intracellular ATP production. These effects were primarily mediated through IGF1R signaling, with IGF2R playing a modulatory role in regulating IGF2 availability. Our findings reveal that IGF2 not only initiates structural differentiation but also drives metabolic reprogramming in huSCs, highlighting its dual role in supporting muscle regeneration and energy homeostasis. These insights highlight IGF2 as a promising therapeutic target for muscle-wasting conditions such as muscular dystrophy and age-related sarcopenia and suggest its broader potential in regenerative medicine strategies.
Ecological determinants of altruism in prokaryote antivirus defense.
Biba DA, Makarova KS, Wolf YI … +3 more , Waldron L, Koonin EV, Rochman ND
Biol Direct · 2025 Dec · PMID 41422249 · Full text
Prokaryote evolution is driven in large part by the incessant arms race with viruses. Genomic investments in antivirus defense can be coarsely classified into two categories, immune systems that abrogate virus reproducti...
Prokaryote evolution is driven in large part by the incessant arms race with viruses. Genomic investments in antivirus defense can be coarsely classified into two categories, immune systems that abrogate virus reproduction resulting in clearance, and programmed cell death (PCD) systems. Prokaryotic defense systems are enormously diverse, as revealed by an avalanche of recent discoveries, but the basic ecological determinants of defense strategy remain poorly understood. Through mathematical modeling of defense against lytic virus infection, we identify two principal determinants of optimal defense strategy and, through comparative genomics, we test this model by measuring the genomic investment into immunity vs. PCD among diverse bacteria and archaea. First, as viral pressure grows, immunity becomes the preferred defense strategy. Second, as host population size grows, PCD becomes the preferred strategy. We additionally predict that, although optimal strategy typically involves investment in both PCD and immunity, investment in immunity can also result in antagonism, increasing the likelihood that a PCD-competent cell will lyse due to infection. Together, these findings indicate that, generally, PCD is preferred at low multiplicity of infection (MOI) and immunity is preferred at high MOI. Finally, we demonstrate that PCD, which is typically considered to be an altruistic trait, is in some cases neutral and can be maintained in an unstructured population over an evolutionary timescale. Our work shows that the landscape of prokaryotic antivirus defense is substantially more complex than previously suspected.
Platelet-activating factor induces ferroptosis by binding to ATF3 and inhibiting the SLC7A11/GPX4 axis to suppress the progression of endometrial carcinoma.
Pan F, Qiu Y, Huang Z … +12 more , Zheng Y, Chen Y, Song Y, Chen ZS, Guo L, Wang J, Liu X, Tao Z, Liu Y, Xuan X, Gong K, Shi K
Biol Direct · 2025 Dec · PMID 41398593 · Full text
BACKGROUND: Endometrial carcinoma (EC) is an aggressive gynecological malignancy with high recurrence rates and limited treatment options. Patients with EC exhibit elevated serum levels of lyso-platelet-activating factor...
BACKGROUND: Endometrial carcinoma (EC) is an aggressive gynecological malignancy with high recurrence rates and limited treatment options. Patients with EC exhibit elevated serum levels of lyso-platelet-activating factor (lyso-PAF), a biologically inactive product generated during the hydrolysis of PAF by PAF-acetylhydrolase (II) (PAF-AH2). Nevertheless, the biological function of PAF in EC progression and the relationship between abnormal lyso-PAF levels and EC progression remain unclear. RESULTS: In this study, we identified the bioactive phospholipid mediator–PAF, which effectively suppress tumor growth both in vitro and in patient-derived organoid models. By combining the cellular thermal shift assay, drug affinity responsive target stability approach, molecular docking simulation, and surface plasmon resonance analysis, we identified activating transcription factor 3 (ATF3) as the direct binding target of PAF with a Kd of 3 0.24 µM. Mechanistically, PAF enhanced ATF3 stability through deubiquitination. In addition, ATF3 knockdown partially reversed the effects of PAF-induced SLC7A11 and GPX4 transcriptional inhibition. In vivo studies using a nude mouse xenograft model confirmed the ferroptosis-mediated tumor-suppressive effects of PAF, as evidenced by hematoxylin and eosin staining and immunohistochemical analysis. Clinically, proteomic analysis revealed upregulation of PAF-AH2 expression in EC tissues derived from patients. Subsequent analysis of EC tissue microarrays revealed that high PAF-AH2 expression is associated with poor survival. CONCLUSIONS: In conclusion, this study demonstrates that PAF inhibits EC tumor growth by inducing ferroptosis and that the underlying mechanisms of its action involve the targeting of ATF3. These findings suggest that PAF metabolism may be a promising direction for EC diagnostics and therapeutics.
KIF4A in disease pathogenesis and therapeutics: from molecular mechanisms to clinical translation.
Liu Y, Li Y, Tang C … +4 more , Wen H, Tang J, Chen G, Wu Y
Biol Direct · 2025 Dec · PMID 41361459 · Full text
Kinesin family member 4 A (KIF4A) is a multifunctional motor protein essential for chromosome condensation, spindle dynamics, and cytokinesis. Beyond its classical mitotic functions, emerging evidence positions KIF4A as...
Kinesin family member 4 A (KIF4A) is a multifunctional motor protein essential for chromosome condensation, spindle dynamics, and cytokinesis. Beyond its classical mitotic functions, emerging evidence positions KIF4A as a central regulator of tumorigenesis, therapy resistance, metabolic reprogramming, and immune modulation across diverse cancer types. However, no comprehensive review has integrated its molecular mechanisms with its roles in both oncological and non-oncological diseases, nor clarified its context-dependent behavior, including paradoxical tumor-suppressive effects in cervical cancer. In this review, we synthesize current advances spanning structural biology, transcriptional and post-translational regulation, and pathway-level interactions involving PI3K/AKT, TGF-β/Smad, Hippo-YAP, metabolic remodeling, and DNA damage response networks. We summarize KIF4A's expression and functions across more than 30 malignant tumors and multiple non-neoplastic conditions-including neurodevelopmental disorders, autoimmune diseases, viral infections, fibrotic diseases, and congenital anomalies-highlighting shared molecular themes and disease-specific distinctions. A notable finding is KIF4A's context dependency: while generally oncogenic, high KIF4A expression in cervical cancer correlates with improved survival, suggesting HPV-specific transcriptional rewiring, altered phosphorylation states, or compensatory genome stabilization as potential mechanisms.We further evaluate the translational implications of KIF4A as a biomarker for diagnosis, prognosis, and treatment response, and we critically examine therapeutic strategies targeting KIF4A-ranging from small-molecule inhibitors and gene-silencing approaches to miRNA therapeutics, exosome-based delivery systems, and neoantigen-directed immunotherapy. Finally, we outline major challenges to clinical translation, including its essential roles in mitosis and neuronal integrity, the need for tumor-selective delivery platforms, and incomplete understanding of its tissue-specific functions. Collectively, this review provides a unified mechanistic and translational framework for understanding KIF4A across human diseases, identifies key knowledge gaps, and proposes future research directions to enable safe and effective targeting of this biologically indispensable protein.
Effect of pesticides on breast cancer tumor.
Marcoccia D, Palomba S, Brajon G … +13 more , Baldi A, Galli FS, Servadei F, Palumbo V, Bonfiglio R, Treglia M, Marsella LT, Botti F, Shi Y, Candi E, Melino G, Mauriello A, Scimeca M
Biol Direct · 2025 Dec · PMID 41361320 · Full text
Breast cancer is the most common malignancy among women worldwide. Increasing evidence suggests that chronic exposure to pesticides, many of which act as endocrine-disrupting chemicals, represents a significant and under...
Breast cancer is the most common malignancy among women worldwide. Increasing evidence suggests that chronic exposure to pesticides, many of which act as endocrine-disrupting chemicals, represents a significant and underappreciated determinant for both cancer origin and progression. In this review, we reported the most recent epidemiological data, exposure pathways, and mechanistic insights linking major pesticide classes, including persistent organochlorines, organophosphates, triazines, carbamates, pyrethroids, neonicotinoids, and glyphosate-based herbicides, to breast carcinogenesis. These compounds are ubiquitous, detectable in food, water, household dust, and occupational environments, and display high lipophilicity that enables long-term bioaccumulation in adipose-rich breast tissue. Therefore, recognition of pesticides as modifiable environmental determinants of breast cancer should prompt strengthened regulation, improved biomonitoring, and public-health strategies aimed at reducing chronic exposure.
Integrating rna structure and protein interactions to uncover the mechanisms of viral and cellular ires function.
Delli Ponti R, Vandelli A, Broglia L … +1 more , Tartaglia GG
Biol Direct · 2025 Dec · PMID 41354934 · Full text
BACKGROUND: RNAs fold into complex structures that critically influence gene expression. A prominent class of regulatory elements resides in the 5' untranslated region (5' UTR), where internal ribosome entry sites (IRESs...
BACKGROUND: RNAs fold into complex structures that critically influence gene expression. A prominent class of regulatory elements resides in the 5' untranslated region (5' UTR), where internal ribosome entry sites (IRESs) promote cap-independent translation by directly engaging the ribosome. First discovered in viral genomes, IRESs have been classified into four types according to their structural compactness and factor requirements. While viral IRESs are well studied, cellular IRESs remain poorly understood: they display limited sequence conservation, reduced structural compactness, and variable dependence on auxiliary RNA-binding proteins known as IRES trans-acting factors (ITAFs). Whether their activity relies mainly on RNA structure or protein assistance remains unresolved. Here, we present a computational framework that combines in silico mutagenesis and RNA-protein interaction profiling to investigate IRES mechanisms and guide the design of synthetic elements. RESULTS: Using the Hepatitis C Virus (HCV) IRES as a benchmark, we performed systematic single-nucleotide mutagenesis coupled with structural predictions. Mutations were classified as synonymous or non-synonymous based on their effect on the secondary structure. The HCV IRES showed overall robustness, but the domain interacting with eIF3 was particularly sensitive, consistent with its essential role in translation initiation. Extending this approach to other viral IRES families revealed distinct profiles of resilience: Aphthoviruses retained structural integrity despite extensive sequence variation, whereas Cripaviruses displayed higher variability. We then applied the same analysis to cellular IRESs, which proved to be more structurally sensitive, suggesting stronger reliance on cofactor support. To probe this connection, we used the catRAPID approach to predict interactions with translation-related proteins. The method distinguished IRESs with known ITAF binding, such as PTBP1, and highlighted stability-promoting mutations that increased the predicted affinity for translation factors. CONCLUSIONS: Our in silico analysis indicates that mutational tolerance mirrors IRES cofactor dependence: compact viral IRESs are structurally robust, whereas non-viral IRESs are more reliant on protein interactions. By linking structure prediction with interaction profiling, we identify variants that both stabilize IRESs and improve binding to ITAFs or translation factors. This framework provides mechanistic insight into sequence-structure-function relationships and supports the rational design of synthetic IRES elements for therapeutic and biotechnological applications.
Autophagy and mitophagy in dermatological disease: a comprehensive review from molecular pathways to therapeutic frontiers.
D'Ambrosio L, Greco ME, Forte M … +19 more , Vecchio D, Schiavon S, Nonno FD, Tahir S, Picchio V, Cozzolino C, Sarto G, Bernardi M, Spadafora L, Simeone B, Vinciguerra M, Sciarretta S, Frati G, Greco E, Potenza C, Proietti I, Morroni J, Dietrich E, Schirone L
Biol Direct · 2025 Dec · PMID 41353197 · Full text
Autophagy - the cell's built-in recycling and quality-control programme - touches every layer of cutaneous biology. In keratinocytes it sculpts the cornified envelope; in melanocytes it balances pigment synthesis and oxi...
Autophagy - the cell's built-in recycling and quality-control programme - touches every layer of cutaneous biology. In keratinocytes it sculpts the cornified envelope; in melanocytes it balances pigment synthesis and oxidative stress; in immune and appendageal cells it fine-tunes defence, repair and hair-follicle cycling. When this choreography falters, skin disorders emerge. This review journeys from basic mechanisms (ULK1 signalling, Beclin-1/VPS34 nucleation, LC3B lipidation, selective mitophagy) to their fingerprints in health and disease. We dissect how autophagy malfunctions drive psoriasis hyper-proliferation, atopic-dermatitis barrier leakiness, vitiligo depigmentation and the metabolic rewiring of melanoma. Non-melanoma cancers, infectious dermatoses, wound repair, ageing and photo-damage are mapped onto the same autophagic atlas. Therapeutically, the pathway is a double-edged sword. mTOR or caloric-restriction mimetics jump-start a protective flux; chloroquine derivatives and ULK1 blockers clip tumour survival circuits; cannabinoids, photodynamic therapy and immune-checkpoint combinations exploit context-specific toggling between induction and brake. Emerging biomarkers (LC3B-II, p62, AMBRA1) promise patient-stratified interventions. By weaving together molecular detail, pre-clinical insight and clinical translation, we show why autophagy is no longer a backstage process but a star player in dermatology - and how targeting its switches could reshape future treatment algorithms.
ssDNA phage FLiP resides in dsDNA form in resistant Flavobacterium host.
Mäkelä K, Penttinen R, Ravantti J … +2 more , Laanto E, Sundberg LR
Biol Direct · 2025 Dec · PMID 41345956 · Full text
BACKGROUND: Bacteria in the genus Flavobacterium play a key role in organic matter decomposition in the aquatic environment. Phages infecting these bacteria regulate the host populations and thereby the ecosystem functio...
BACKGROUND: Bacteria in the genus Flavobacterium play a key role in organic matter decomposition in the aquatic environment. Phages infecting these bacteria regulate the host populations and thereby the ecosystem functions. However, bacterial resistance against phage may cause changes in bacterial phenotypic characteristics. The single stranded DNA phage Finnlakevirus FLiP infects three known environmental Flavobacterium sp. isolates: B330, B167, and B114. Building on our previous FLiP-host interaction studies, we investigated resistance mechanisms from the host perspective, aiming to understand how Flavobacterium strains resist FLiP and related phages. RESULTS: We assessed the fitness effects of phage resistance by comparing growth dynamics between ancestral and resistant variants. In the absence of phage, no significant differences in growth was observed, indicating that resistance to single stranded DNA phage FLiP does not impose a detectable fitness cost under laboratory conditions. Next, we screened host genomes for anti-phage systems and compared host genomes across strains and between ancestral and resistant variants. Genomic comparisons revealed resistance-related mutations, although no single mutation or anti-phage system consistently explained FLiP resistance across strains. Furthermore, we evaluated the possibility of lysogeny and superinfection immunity using sequence analysis, PCR, and nuclease treatments. Notably, resistant B114 host harbored the FLiP genome as a circular extrachromosomal double stranded DNA element, suggesting potential for lysogeny. Surprisingly, low levels of FLiP sequences were detected in bacterial populations not exposed to FLiP in the laboratory. CONCLUSIONS: Our findings suggest that FLiP-type phages may persist in host populations as extrachromosomal double stranded DNA elements in a subset of cells. This strategy could allow phages to endure unfavorable conditions and regulate infection timing. As detected in previous experiments, rather than requiring optimal conditions, FLiP is capable of productive infection even under stress, with infection stalling only when host growth is severely limited. The constant persistence within the host population, and capability to start particle production as soon as conditions improve, may represent an evolutionary adaptation for survival and transmission in fluctuating environments.
Cryptochrome interaction networks across different tissues in Drosophila melanogaster.
Damulewicz M, Gregoris F, Colaianni D … +4 more , Cendron F, Biscontin A, Minervini G, Mazzotta GM
Biol Direct · 2025 Nov · PMID 41316449 · Full text
BACKGROUND: Drosophila CRYPTOCHROME (dCRY) is a blue light-sensitive protein involved in various biological processes, including photoreception, circadian rhythm regulation, synaptic plasticity, and magnetoreception. Its...
BACKGROUND: Drosophila CRYPTOCHROME (dCRY) is a blue light-sensitive protein involved in various biological processes, including photoreception, circadian rhythm regulation, synaptic plasticity, and magnetoreception. Its circadian function is strictly connected with light: upon light exposure, dCRY undergoes a conformational change, becoming active and binding to various proteins. However, it can also form complexes in the absence of light, with its function varying depending on the cell type in which it is expressed. RESULTS: Here, we use an experimental approach based on co-immunoprecipitation followed by mass spectrometry analysis, obtaining the in vivo interactome of dCRY in two distinct cell populations - retina photoreceptors and glial cells - at two specific time points: just before lights-on (ZT0) and one hour after lights-on (ZT1). To gain deeper insights into the functional dynamics of dCRY, we constructed reliable protein-protein interaction networks in both cell types and across the two experimental conditions, revealing a complex landscape of interactions. Additionally, we explored the biological pathways associated with the identified dCRY interactors, highlighting several tissue- and time-specific enrichments. We focused on RNA-related pathways, indicating that dCRY and its interactors are involved in regulating RNA metabolism in photoreceptors at ZT0 and in glial cells at ZT1. Finally, as a case study, we further investigated the functions of the RNA-binding protein SQUID, found to interact with dCRY in both tissues. Notably, the impaired circadian locomotor behavior exhibited by Squid mutant flies accounts for the involvement of this hnRNP in the generation of the circadian rhythmicity. CONCLUSIONS: In conclusion, our work provides the first tissue- and time-specific dCRY interactome, offering valuable insights into previously unrecognized biological processes in which it may be involved. Specifically, its potential role in the regulation of RNA metabolism contributes crucial evidence concerning the relationship between the circadian clock and RNA metabolism, thereby laying the groundwork for future research in this area.
The role of TRIM proteins in the pathogenesis of mycobacterium tuberculosis.
Di Rienzo M, Zuchegna C, Perri V … +3 more , Piacentini M, Falasca L, Romagnoli A
Biol Direct · 2025 Nov · PMID 41316292 · Full text
Mycobacterium tuberculosis (Mtb) is an intracellular pathogen responsible for tuberculosis (TB), a disease that remains the leading infectious cause of death worldwide. Several host cell proteins have been reported to pl...
Mycobacterium tuberculosis (Mtb) is an intracellular pathogen responsible for tuberculosis (TB), a disease that remains the leading infectious cause of death worldwide. Several host cell proteins have been reported to play a significant role in regulating Mtb infection and replication. Among these, TRIM proteins are a large family of E3 ubiquitin ligases that have been described as being involved in host defence against Mtb, by controlling two important cellular processes: autophagy and the inflammatory response. Autophagy is a highly conserved cellular process deputed to the degradation of damaged or unnecessary components, such as organelles and protein aggregates. Autophagy is induced by a variety of stress stimuli, including nutrient deprivation, hypoxia, infection, oxidative stress and DNA damage, to maintain cellular homeostasis and survival. Autophagy plays a crucial role in host defense against infections by selectively targeting and delivering intracellular pathogens, like bacteria, viruses, and parasites to the lysosomes for degradation. Inflammation is a biological coordinated cellular process involving the secretion of cytokines and chemokines by innate immune cells, that can be triggered by various factors, including damaged cells, toxins and pathogens. Pathogen-Associated Molecular Patterns (PAMPs), found on microbes, are recognized by pattern recognition receptors (PRRs) on immune cells, which trigger signaling pathways leading to pro-inflammatory responses and the elimination of the pathogen. Danger-Associated Molecular Patterns (DAMPs) are host-derived molecules released from damaged cells that activate the same PRRs to initiate or perpetuate inflammation. In this review, we discuss the emerging role played by TRIM proteins in regulating autophagy and pro-inflammatory response during Mtb infection, pointing out the crucial role of TRIM in the complex crosstalk between these processes.Clinical trial number Not applicable.
NAMPT modulates muscle fiber type transition in PAD myopathy via the cGMP-PKG signaling pathway.
Yang Q, Shi Y, Li W … +3 more , Xiong X, Chen Q, Zheng M
Biol Direct · 2025 Nov · PMID 41310770 · Full text
BACKGROUND: Peripheral artery disease (PAD), caused by atherosclerosis resulting in reduced blood flow in the lower extremities, impairs both skeletal muscle mass and function in humans, and its molecular mechanism is no...
BACKGROUND: Peripheral artery disease (PAD), caused by atherosclerosis resulting in reduced blood flow in the lower extremities, impairs both skeletal muscle mass and function in humans, and its molecular mechanism is not clear. Recent studies have demonstrated that Nicotinamide phosphoribosyl transferase (NAMPT) influences skeletal muscle mass and function by modulating NAD levels and cellular Ca²⁺ homeostasis. However, its role in muscle fiber type transition remains to be elucidated. RESULTS: NAMPT is downregulated in ischemic skeletal muscle and CoCl-treated C2C12 myotubes. NAMPT enhances the functional performance of ischemic limbs, reduces apoptosis, increases the formation of oxidative muscle fibers, and improves mitochondrial function. The cGMP‒PKG pathway is activated by NAMPT in ischemic limbs. Exogenous inhibition of cGMP-PKG signaling inhibits the formation of oxidative muscle fibers induced by NAMPT. CONCLUSIONS: NAMPT protects against ischemic limb injury via the cGMP‒PKG signaling pathway, suggesting that it is a promising therapeutic and predictive target for myopathy associated with PAD. CLINICAL TRIAL NUMBER: Not applicable.
CLOCK-mediated acetylation of NF-κB p65 drives immune evasion in breast cancer.
Quan X, Li N, Huang J … +1 more , Duan Y
Biol Direct · 2025 Nov · PMID 41261416 · Full text
BACKGROUND: Disruption of circadian rhythm (DCR) has been connected with breast cancer (BC) susceptibility; whereas it is unclear whether status of key clock genes could be used in predicting BC prognosis, tumor immune m...
BACKGROUND: Disruption of circadian rhythm (DCR) has been connected with breast cancer (BC) susceptibility; whereas it is unclear whether status of key clock genes could be used in predicting BC prognosis, tumor immune microenvironment, and immunotherapy responses. RESULTS: Circadian clock genes demonstrate significant dysregulation in BC, where elevated CLOCK expression emerges as an independent prognostic factor strongly correlated with adverse clinical outcomes. CLOCK-overexpressing BC cells exhibit enhanced proliferative ability and strong resistance to chemotherapy drugs doxorubicin and gemcitabine. High CLOCK expression correlates with reduced CD8 T cell infiltration and increased M2 macrophage polarization, consistent with increased immune checkpoint molecule PD-L1 expression in the TCGA BC dataset. Additionally, patients with high CLOCK expression display lower Tumor Immune Dysfunction and Exclusion (TIDE) score. Mechanistically, RNA-sequencing identified suppressed NF-κB, TNF, MAPK pathways, and PD-L1 expression in sh-CLOCK MCF-7 cells. Subsequent in vitro validation demonstrated that CLOCK mediates NF-κB p65 acetylation at K56 site, potentiating its transcriptional activation of PD-L1, thereby facilitating immune evasion in BC. CONCLUSIONS: CLOCK functions as a critical prognostic biomarker in BC by promoting tumor proliferation, chemoresistance, and immune evasion. Mechanistically, CLOCK mediates NF-κB p65 acetylation to enhance PD-L1 transcription, promoting immune evasion in BC.
Comparative analysis of human Mesenchymal Stromal Cells from Adipose Tissue and Dental Pulp: phenotypic characterization and secretome profiling.
Ventura A, Libonati A, Marcozzi S … +15 more , Ucci MA, Salvatore G, Galgani A, Pirrò S, Massimiani M, Picozza M, Russo R, Vumbaca S, Farini D, Chambery A, Borsellino G, De Felici M, Klinger FG, Campanella V, Camaioni A
Biol Direct · 2025 Nov · PMID 41233824 · Full text
BACKGROUND: In tissue regeneration, as well as in post-traumatic recovery or in treating pathological alterations, mesenchymal stromal cells (MSCs) and their products for cell-free treatments are increasingly attractive...
BACKGROUND: In tissue regeneration, as well as in post-traumatic recovery or in treating pathological alterations, mesenchymal stromal cells (MSCs) and their products for cell-free treatments are increasingly attractive and applicable. For this reason, there is an urgent need to thoroughly investigate MSCs of different origins, especially those readily available and with no ethical concerns obtained from healthy donors. METHODS: Human MSCs were derived from discarded adipose tissue of four donors (ADSCs; 8 cell populations isolated by enzymatic digestion and mechanical fragmentation) and dental pulp of two donors (DPSCs; 4 cell populations from radicular and coronal compartments by mechanical fragmentation). Cells were characterized by differentiation, proliferation, and morphological features. Conditioned media (CM) were collected, and the secretome profile analyzed. RESULTS: The trilineage differentiation assay and CD immunophenotyping showed that all primary cell lines possessed typical MSC characteristics, apart from the inability of DPSCs to perform adipogenesis. Significant CD differences were found mainly due to tissue source and regional compartments regarding coronal vs. radicular dental pulp. Notably, DPSCs were consistently smaller, Nestin-positive, and had a higher proliferation rate than ADSCs. Secretome analysis regarding anti-inflammatory and pro-inflammatory cytokines, chemokines, and growth factors accumulating in the CM throughout the culture showed significant variations among MSC lines from the two tissues and within ADSCs obtained with different extraction methods. All MSC populations release a comparable number of extracellular vesicles (EVs), although ADSCs appeared to produce a significantly higher number of smaller exosomes than DPSCs. Depending on the tissue of origin, MSCs released specific sets of microRNAs, either free or enclosed in EVs, impacting many cellular processes. The microRNAs more expressed from DPSCs are mainly involved in oxidative stress and apoptosis pathways, while those of ADSCs play a regulatory role in cell cycle and proliferation. CONCLUSIONS: The results support the notion that, despite their common characteristics, MSCs can differ in many aspects related to their ontogeny, extraction method, and, to a lesser extent, regionalization and donor heterogeneity. These findings pose challenges for the clinical translation of MSCs, their CMs, and derivatives and underline the importance of standardizing protocols to obtain MSC products from their secretome.
Oral intake of aripiprazole compromises male fertility in Drosophila.
Mukherjee A, Hurcomb JD, Loh SHY … +1 more , Martins LM
Biol Direct · 2025 Nov · PMID 41219990 · Full text
Antipsychotics have reported off-target effects, but their impact on subcellular organelles and cellular homeostasis in various organ systems is poorly understood. This study explored the off-target effects of aripiprazo...
Antipsychotics have reported off-target effects, but their impact on subcellular organelles and cellular homeostasis in various organ systems is poorly understood. This study explored the off-target effects of aripiprazole on the male reproductive system using Drosophila as a model. Aripiprazole binds nonspecifically to mitochondrial complex I, and here we investigated the effect of an aripiprazole-containing diet on spermatogenesis. We showed that aripiprazole increases the level of mitochondrial reactive oxygen species (ROS) and disrupts the homeostasis of germ cell development in the testes. The cyst cells surrounding the spermatogonia showed an increase in JNK signalling, while there was enhanced LysoTracker staining of spermatogonial cysts and defects in the later stages of spermatid individualisation. Our results revealed a connection between mitochondrial complex I dysfunction and increased germ cell loss by lysosomal degradation, resulting in decreased fertility. We conclude that aripiprazole-induced mitochondrial toxicity in germ cells results in increased loss of spermatogonial cysts and defects in spermatogenesis. We showed that diets supplemented with antioxidants or the expression of mitochondrial superoxide dismutase in spermatogonial cells can alleviate excess mitochondrial ROS-induced defects.
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