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Summary: Chloroplasts play a crucial role in plant defense against pathogens, making them primary targets for pathogen effectors that suppress host immunity. This study characterizes the Plasmopara viticola CRN‐like effector, PvCRN20, which interacts with DEG5 in the cytoplasm but not with its interacting protein, DEG8, which is located in the chloroplast.By transiently overexpressing in tobacco leaves, we show that PvCRN20 could inhibit INF1‐ and Bax‐triggered cell death. Constitutive expression of PvCRN20 suppresses the accumulation of reactive oxygen species (ROS) and promotes pathogen colonization. PvCRN20 reduces DEG5 entry into chloroplasts, thereby disrupting DEG5 and DEG8 interactions in chloroplasts.Overexpression of VvDEG5 and VvDEG8 induces ROS accumulation and enhances grapevine resistance to P. viticola, whereas knockout of VvDEG8 represses ROS production and promotes P. viticola colonization. Consistently, ectopic expression of VvDEG5 and VvDEG8 in tobacco promotes chloroplast‐derived ROS accumulation, whereas co‐expression of PvCRN20 counteracted this promotion by VvDEG5. Therefore, DEG5 is essential for the virulence function of PvCRN20. Although PvCRN20 is located in both the nucleus and cytoplasm, only cytoplasmic PvCRN20 suppresses plant immunity and promotes pathogen infection.Our results reveal that PvCRN20 dampens plant defenses by repressing the chloroplast import of DEG5, thus reducing host ROS accumulation and facilitating pathogen colonization. [ABSTRACT FROM AUTHOR]

Summary Activity‐based sensing probes are powerful tools for monitoring enzymatic activities in complex biological samples such as cellular and live animals; however, their application in plants remains challenging. Herein, fourteen activity‐based fluorescent probes were assayed against Arabidopsis O‐methyltransferases (AtOMTs). One probe, 3‐BTD, displayed a high selectivity, reactivity, and fluorescence response toward AtOMTs especially the isoform AtCCoAOMT. We further characterized the features of this probe and explored whether it could be used to detect OMT activities in living plant cells. Our results show that 3‐BTD can be used to visualize OMT activity in Arabidopsis, and no fluorescent signal was observed in the comt/ccoaomt double mutant, indicating that it has good specificity. Interestingly, in contrast to the observation that AtCCoAOMT‐YFP accumulated in both cytoplasm and nucleus, OMT enzymatic activity tracked by 3‐BTD probe was found only in the cytoplasm. This underscores the importance of activity‐based sensing in studying protein function. Moreover, 3‐BTD can be successfully applied in OMT visualization of different plants. This study indicates that 3‐BTD can serve as a potential probe for in situ monitoring the real activity of OMT in multiple plants and provides a strategy for visualizing the activity of other enzymes in plants. [ABSTRACT FROM AUTHOR]

Beryllium sulfate (BeSO4) can cause inflammation through the mechanism, which has not been elucidated. Mitochondrial DNA (mtDNA) is a key contributor of inflammation. With mitochondrial damage, released mtDNA can bind to specific receptors (e.g., cGAS) and then activate related pathway to promote inflammatory responses. To investigate the mechanism of mtDNA in BeSO4‐induced inflammatory response in 16HBE cells, we established the BeSO4‐induced 16HBE cell inflammation model and the ethidium bromide (EB)‐induced ρ016HBE cell model to detect the mtDNA content, oxidative stress‐related markers, mitochondrial membrane potential, the expression of the cGAS‐STING pathway, and inflammation‐related factors. Our results showed that BeSO4 caused oxidative stress, decline of mitochondrial membrane potential, and the release of mtDNA into the cytoplasm of 16HBE cells. In addition, BeSO4 induced inflammation in 16HBE cells by activating the cGAS‐STING pathway. Furthermore, mtDNA deletion inhibited the expression of cGAS‐STING pathway, IL‐10, TNF‐α, and IFN‐β. This study revealed a novel mechanism of BeSO4‐induced inflammation in 16HBE cells, which contributes to the understanding of the molecular mechanism of beryllium and its compounds‐induced toxicity. In this study, the inflammation and ρ0 cells model based on 16HBE cells was established to detect the mtDNA content, mitochondrial function‐related markers, the expression of the cGAS‐STING pathway, and inflammation. We found that BeSO4 caused oxidative stress, mitochondrial membrane potential decline, and the release of mtDNA into cytoplasm. The cGAS‐STING pathway was activated in inflamed 16HBE cells. mtDNA deletion inhibited the expression of cGAS‐STING pathway and inflammation. Our results contribute to the understanding of the molecular mechanism of BeSO4‐induced toxicity. [ABSTRACT FROM AUTHOR]

Granular cell tumors (GCTs) are rare, indolent neoplasms classically characterized by eosinophilic granular cytoplasm, infiltrations of polygonal cells in the collagenous stroma, and pustulo‐ovoid bodies of Milian. We describe a case of a 10‐year‐old female presenting with a GCT of the upper arm, remarkable for positive Melan‐A expression without additional melanocytic features. The differentiation between granular cells versus melanocytic neoplasms carries significant implications for clinical management, and such diagnoses should be considered carefully in the setting of unusual immunophenotypes. [ABSTRACT FROM AUTHOR]

Objective: This study investigates the effects of ZNF862 on the proliferation and apoptosis of human gingival fibroblasts and their related mechanisms. Background: As a major transcription factor family, zinc finger proteins (ZFPs) regulate cell differentiation, growth, and apoptosis through their conserved zinc finger motifs, which allow high flexibility and specificity in gene regulation. In our previous study, ZNF862 mutation was associated with hereditary gingival fibromatosis. Nevertheless, little is known about the biological function of ZNF862. Therefore, this study was aimed to reveal intracellular localization of ZNF862, the influence of ZNF862 on the growth and apoptosis of human gingival fibroblasts (HGFs) and its potential related mechanisms. Methods: Immunohistochemistry, immunofluorescence staining, and western blotting were performed to determine the intracellular localization of ZNF862 in HGFs. HGFs were divided into three groups: ZNF862 overexpression group, ZNF862 interference group, and the empty vector control group. Then, the effects of ZNF862 on cell proliferation, migration, cell cycle, and apoptosis were evaluated. qRT‐PCR and western blotting were performed to further explore the mechanism related to the proliferation and apoptosis of HGFs. Results: ZNF862 was found to be localized in the cytoplasm of HGFs. In vitro experiments revealed that ZNF862 overexpression inhibited HGFs proliferation and migration, induced cell cycle arrest at the G0/G1‐phase and apoptosis. Whereas, ZNF862 knockdown promoted HGFs proliferation and migration, accelerated the transition from the G0/G1 phase into the S and G2/M phase and inhibited cell apoptosis. Mechanistically, the effects of ZNF862 on HGFs proliferation and apoptosis were noted to be dependent on inhibiting the cyclin‐dependent kinase inhibitor 1A (p21)‐retinoblastoma 1 (RB1) signaling pathway and enhancing the B‐cell lymphoma‐extra‐large (Bcl‐xL)‐Caspase 3 signaling pathway. Conclusion: Our results for the first time reveal that ZNF862 is localized in the cytoplasm of HGFs. ZNF862 can inhibit the proliferation of HGFs by inhibiting the p21‐RB1 signaling pathway, and it also promotes the apoptosis of HGFs by enhancing the Bcl‐xL‐Caspase 3 signaling pathway. [ABSTRACT FROM AUTHOR]

N6‐methyladenosine (m6A), as the most abundant and well‐studied RNA modification, can be reversibly added or removed by m6A methyltransferase and demethylase. The further molecular and biological function of m6A is achieved by the recognition of its binding protein. m6A functions in the diverse progress of RNA processing, including transcription regulation, splicing, nuclear export, stability, and translation, to regulate the fate of cells. Although been extensively studied in various animal cell systems, research on m6A's regulatory functions in plant cells lags. In recent years, with a deepening understanding of the functions of m6A and the development of various sequencing technologies, researches on m6A in plant cells have gradually increased. In this review, we focused on discussing the molecular functions of m6A in the nucleus and cytoplasm, aiming to elucidate the specific molecular mechanisms by which m6A regulates the fate of RNAs in plants. Finally, we provide some perspectives on future investigations of the detailed molecular mechanism of m6A‐mediated regulation in plants, which might provide insights into future strategies for achieving multiple growth regulatory processes in crops. [ABSTRACT FROM AUTHOR]

Identification of markers associated with fertility restoration (Rf) genes is essential because they can streamline the breeding of new CMS lines and production of commercial hybrid seeds. Therefore, in the present study, F2 populations (M31‐2A × DSMR 8) was utilized to identify markers linked to Rf loci on maldandi (A4) cytoplasm through bulk segregant analysis (BSA). The F2 population was analysed for seed set percentage. Chi‐square (χ2) analysis showed that the fertility restoration trait followed expected digenic ratio. By BSA, simple sequence repeats (SSRs) markers, namely, Xtxp 34 and Xtxp 69 located on chromosome 3 and SB 3956 and Xtxp 312 located on chromosome 7, showed clear polymorphism between two groups of fertile and sterile bulks. The genomic region harbouring Rf locus on chromosome 3 (2.61 Mbp) predicted to encode five pentatricopeptide repeat (PPR) genes whereas, on chromosome 7, the gene SORBI_3007G047400 predicted to encode MYB (myeloblastosis) domain containing proteins. These predicted genes could be the candidate for restoring fertility on A4 cytoplasm. This finding will be fundamental in the production and rapid selection of novel restorer lines. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the inheritance pattern of fertility restoration in hybrids resulting from crosses between a male sterile line (M31‐2A), a maldandi cytoplasm, and two promising restorers (DSMR‐4 and DSMR‐8). The evaluation of hybrids was conducted in two sets of experiments, including the F2, BC1F1 and F2, F3 generations. The segregation pattern was analysed in the F2 and BC1F1 generations, resulting in a 54:10 ratio of fertile to sterile plants and a 1:1 ratio of fertile to sterile plants, respectively. This indicated the involvement of three genes, at least two of which must be in a dominant condition for restoration to occur, acting in a duplicate complementary manner. In the F3 generation, both crosses were grown to confirm the stability of restorers, and they segregated in the ratio of 10 true‐breeding families and 44 segregating families, which was consistent with the F2 ratio. Additionally, this study observed the influence of rainfall on the partial restoration pattern over seasons, as restorer genes are up or down‐regulated depending on the availability of water. [ABSTRACT FROM AUTHOR]

Objectives: To identify the molecular etiology of distinct dental anomalies found in eight Thai patients and explore the mutational effects on cellular functions. Materials and Methods: Clinical and radiographic examinations were performed for eight patients. Whole exome sequencing, mutant protein modelling, qPCR, western blot analysis, scratch assays, immunofluorescence, confocal analysis, in situ hybridization, and scanning electron micrography of teeth were done. Results: All patients had molars with multiple supernumerary cusps, single‐cusped premolars, and a reduction in root number. Mutation analysis highlighted a heterozygous c.865A>G; p.Ile289Val mutation in CACNA1S in the patients. CACNA1S is a component of the slowly inactivating L‐type voltage‐dependent calcium channel. Mutant protein modeling suggested that the mutation might allow leakage of Ca2+ or other cations, or a tightening, to restrict calcium flow. Immunohistochemistry analysis showed expression of Cacna1s in the developing murine tooth epithelium during stages of crown and root morphogenesis. In cell culture, the mutation resulted in abnormal cell migration of transfected CHO cells compared to wildtype CACNA1S, with changes to the cytoskeleton and markers of focal adhesion. Conclusions: The malformations observed in our patients suggest a role for calcium signaling in organization of both cusps and roots, affecting cell dynamics within the dental epithelium. [ABSTRACT FROM AUTHOR]

Living organisms experience a range of stresses. To cope effectively with these stresses, eukaryotic cells have evolved a sophisticated mechanism involving the formation of stress granules (SGs), which play a crucial role in protecting various types of RNA species under stress, such as mRNAs and long non‐coding RNAs (lncRNAs). SGs are non‐membranous cytoplasmic ribonucleoprotein (RNP) granules, and the RNAs they contain are translationally stalled. Importantly, SGs have been thought to contribute to the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD). SGs also contain multiple RNA‐binding proteins (RBPs), several of which have been implicated in AD progression. SGs are transient structures that dissipate after stress relief. However, the chronic stresses associated with aging lead to the persistent formation of SGs and subsequently to solid‐like pathological SGs, which could impair cellular RNA metabolism and also act as a nidus for the aberrant aggregation of AD‐associated proteins. In this paper, we provide a comprehensive summary of the physical basis of SG‐enriched RNAs and SG‐resident RBPs. We then review the characteristics of AD‐associated gene transcripts and their similarity to the SG‐enriched RNAs. Furthermore, we summarize and discuss the functional implications of SGs in neuronal RNA metabolism and the aberrant aggregation of AD‐associated proteins mediated by SG‐resident RBPs in the context of AD pathogenesis. Geriatr Gerontol Int 2024; 24: 7–14. [ABSTRACT FROM AUTHOR]

Autophagy is a process in which cells degrade intracellular substances and play a variety of roles in cells, such as maintaining intracellular homeostasis, preventing cell overgrowth, and removing pathogens. It is highly conserved during the evolution of eukaryotic cells. So far, the study of autophagy is still a hot topic in the field of cytology. Ferroptosis is an iron‐dependent form of cell death, accompanied by the accumulation of reactive oxygen species and lipid peroxides. With the deepening of research, it has been found that ferroptosis, like autophagy, is involved in the occurrence and development of cardiovascular diseases. The relationship between autophagy and ferroptosis is complex, and the association between the two in cardiovascular disease remains to be clarified. This article reviews the mechanism of autophagy and ferroptosis and their correlation, and discusses the relationship between them in cardiovascular diseases, which is expected to provide new and important treatment strategies for cardiovascular diseases. Significance statement: Autophagy and ferroptosis are hot topics in the field of cell biochemistry, both of which are closely related to the occurrence and development of cardiovascular diseases. As the molecular mechanisms of autophagy and ferroptosis become more clear in cells, the two seem to intersect in some places, especially in related studies of cardiovascular diseases. If the interaction between autophagy and ferroptosis can be clarified, it will provide novel therapeutic strategies for alleviating related diseases. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to investigate the clinical and prognostic relevance of the Hippo‐YAP transactivators YAP1 and TAZ in oral squamous cell carcinoma, and their possible relationship with PI3K/mTOR pathway activation. Materials and Methods: Immunohistochemical analysis of YAP1, TAZ, PIK3CA (p110α), p‐AKT (Ser473), and p‐S6 (Ser235) was performed in paraffin‐embedded tissue specimens from 165 OSCC patients. Correlations between protein expression and clinical data were further assessed. Results: YAP1 expression was detected in both cytoplasm and nucleus of tumor cells, whereas TAZ expression was only found in the nucleus. Nuclear YAP1 was significantly associated with tumor size (p = 0.03), neck lymph node metastasis (p = 0.02), TNM stage (p = 0.02), and poor differentiation (p = 0.04). Nuclear TAZ was associated with tobacco (p = 0.03) and alcohol consumption (p = 0.04), and poor tumor differentiation (p = 0.04). There was a positive significant correlation between nuclear and cytoplasmic YAP1, nuclear TAZ, p110α expression, and mTORC1 activation p‐S6 (S235). Combined expression of nuclear and cytoplasmic YAP1 was prognostic in both univariate and multivariate analyses. Active nuclear YAP1 was significantly and independently associated with poor disease‐specific (p = 0.005, HR = 2.520; 95% CI = 1.319–4.816) and overall survival (p = 0.015, HR = 2.126; 95% CI = 1.155–3.916). Conclusion: Nuclear YAP1 is an independent predictor of poor survival in oral squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Objective: Multisystem proteinopathy type 3 (MSP3) is an inherited, pleiotropic degenerative disorder caused by a mutation in heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), which can affect the muscle, bone, and/or nervous system. This study aimed to determine detailed histopathological features and transcriptomic profile of HNRNPA1‐mutated skeletal muscles to reveal the core pathomechanism of hereditary inclusion body myopathy (hIBM), a predominant phenotype of MSP3. Methods: Histopathological analyses and RNA sequencing of HNRNPA1‐mutated skeletal muscles harboring a c.940G > A (p.D314N) mutation (NM_031157) were performed, and the results were compared with those of HNRNPA1‐unlinked hIBM and control muscle tissues. Results: RNA sequencing revealed aberrant alternative splicing events that predominantly occurred in myofibril components and mitochondrial respiratory complex. Enrichment analyses identified the nuclear pore complex (NPC) and nucleocytoplasmic transport as suppressed pathways. These two pathways were linked by the hub genes NUP50, NUP98, NUP153, NUP205, and RanBP2. In immunohistochemistry, these nucleoporin proteins (NUPs) were mislocalized to the cytoplasm and aggregated mostly with TAR DNA‐binding protein 43 kDa and, to a lesser extent, with hnRNPA1. Based on ultrastructural observation, irregularly shaped myonuclei with deep invaginations were frequently observed in atrophic fibers, consistent with the disorganization of NPCs. Additionally, regarding the expression profiles of overall NUPs, reduced expression of NUP98, NUP153, and RanBP2 was shared with HNRNPA1‐unlinked hIBMs. Interpretation: The shared subset of altered NUPs in amyotrophic lateral sclerosis (ALS), as demonstrated in prior research, HNRNPA1‐mutated, and HNRNPA1‐unlinked hIBM muscle tissues may provide evidence regarding the underlying common nuclear pore pathology of hIBM, ALS, and MSP. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 55-year-old female diagnosed with myelodysplastic syndromes (MDS) progressing to acute myelocytic leukemia (AML), revealing a novel fusion gene detected through transcriptome sequencing. Topics discussed include the clinical history of the patient, molecular characterization of the fusion gene, and the potential implications of non-coding Ribonucleic Acid (RNA) involvement in leukemia pathogenesis.

Transport of macromolecules from the nucleus to the cytoplasm is essential for nearly all cellular and developmental events, and when mis‐regulated, is associated with diseases, tumor formation/growth, and cancer progression. Nuclear Envelope (NE)‐budding is a newly appreciated nuclear export pathway for large macromolecular machineries, including those assembled to allow co‐regulation of functionally related components, that bypasses canonical nuclear export through nuclear pores. In this pathway, large macromolecular complexes are enveloped by the inner nuclear membrane, transverse the perinuclear space, and then exit through the outer nuclear membrane to release its contents into the cytoplasm. NE‐budding is a conserved process and shares many features with nuclear egress mechanisms used by herpesviruses. Despite its biological importance and clinical relevance, little is yet known about the regulatory and structural machineries that allow NE‐budding to occur in any system. Here we summarize what is currently known or proposed for this intriguing nuclear export process. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor receptor‐associated factor 6 (TRAF6) is a vital molecule of inflammatory signaling pathways in innate immune response against pathogens. To elucidate its role in defense against Edwardsiella tarda infection in teleost fish, TRAF6 homologue was identified from obscure puffer (Takifugu obscurus) and functionally analyzed in this study. The obscure puffer TRAF6 (ToTRAF6) is a protein of 565 amino acids containing conserved RING domain, zinc finger‐TRAF and MATH_TRAF6 domain. ToTRAF6 mRNA distributed in various healthy tissues of obscure puffer and was upregulated in the immune related tissues after E. tarda infection. ToTRAF6 protein was localized in the cytoplasm and aggregate as dots around the nuclei in FHM cells. The overexpression of ToTRAF6 in FHM cells decreased the quantity of E. tarda and induced the significant upregulation of downstream MAPK signaling pathway genes. These data suggest that ToTRAF6 is a key molecule of MAPK signaling pathway in defense against E. tarda infection. [ABSTRACT FROM AUTHOR]

Autophagy is a highly conserved intracellular pathway that is essential for survival in all eukaryotes. In healthy cells, autophagy is used to remove damaged intracellular components, which can be as simple as unfolded proteins or as complex as whole mitochondria. Once the damaged component is captured, the autophagosome engulfs it and closes, isolating the content from the cytoplasm. The autophagosome then fuses with the late endosome and/or lysosome to deliver its content to the lysosome for degradation. Formation of the autophagosome, sequestration or capture of content, and closure all require the ATG proteins, which constitute the essential core autophagy protein machinery. This brief 'nutshell' will highlight recent data revealing the importance of small membrane‐associated domains in the ATG proteins. In particular, recent findings from two parallel studies reveal the unexpected key role of α‐helical structures in the ATG8 conjugation machinery and ATG8s. These studies illustrate how unique membrane association modules can control the formation of autophagosomes. [ABSTRACT FROM AUTHOR]

Nuclear pore complexes (NPCs) are sophisticated multiprotein assemblies embedded within the nuclear envelope and controlling the exchanges of molecules between the cytoplasm and the nucleus. In this review, we summarize the mechanisms by which these elaborate complexes are built from their subunits, the nucleoporins, based on our ever‐growing knowledge of NPC structural organization and on the recent identification of additional features of this process. We present the constraints faced during the production of nucleoporins, their gathering into oligomeric complexes, and the formation of NPCs within nuclear envelopes, and review the cellular strategies at play, from co‐translational assembly to the enrolment of a panel of cofactors. Remarkably, the study of NPCs can inform our perception of the biogenesis of multiprotein complexes in general – and vice versa. [ABSTRACT FROM AUTHOR]

Polymer science has applications in biomedical engineering, prosthetics, surgical implants, and prospective pharmaceutical excipients for drug delivery. "Intelligent or Smart Polymers" are created for drug targeting either by derivatization of natural polymers or controlled radical polymerization of electrolytes. Their mode of action is governed by the environmental stimuli viz. temperature, pH, ionic concentration, magnetism, and so on. pH‐responsive polymers, because of their self‐assembling behavior, alter their solubility, conformation, surface activity, and hydrophilicity when exposed to a specific pH. The physiological pH varies from acidic nuclei to alkaline cytoplasm and highly acidic gastric juice to slightly alkaline plasma; thus, various polymers are under study for delivering small molecules, genes, peptides, enzymes, growth factors, and antibodies. The non‐invasive drug delivery routes like oral, ocular, nasal, pulmonary, transdermal, and rectal routes can be explored for targeting recombinant proteins, monoclonal antibodies, and small molecules with particular emphasis on the individual's physiological and pathological state. Further, these polymers can be designed into various architectures like dendrimers, liposomes, micelles, and metallic nanoparticles that can serve as drug reservoirs for sustaining drug release. The challenges in this field are the selection of biocompatible polymers with ease of synthesis and scale‐up, ensuring effective drug‐loading, and stability aspects, producing robust pharmacological data, and timely regulatory approvals. This review exclusively explores the physicochemical characteristics of pH‐responsive polymers, their categorization, various architectural entities, recent studies and patents, and their emerging applications concerning specific diseases. [ABSTRACT FROM AUTHOR]

Objective: Transport and Golgi Organization protein 1 (TANGO1) is a protein that regulates the export of procollagen from the endoplasmic reticulum and has a role in the organization of exit sites for general protein export. What regulates the expression of TANGO1 and the role of TANGO1 in fibrosis is poorly understood and has never been studied in the setting of systemic sclerosis (SSc). We undertook this study to determine the role of TANGO1 in SSc fibrosis. Methods: SSc (n = 15) and healthy (n = 12) primary fibroblast lung cell lines were investigated for the expression of TANGO1. Histologic analyses for TANGO1 were performed on lung biopsy samples (n = 12 SSc patient samples and n = 8 healthy control samples). Results: SSc fibroblasts showed increased expression of TANGO1 protein in cultured fibroblasts. TANGO1 colocalizes with α‐smooth muscle actin (α‐SMA)–positive cells in SSc lung tissue and is highly up‐regulated in the neointima of SSc vessels. TANGO1 expression was dependent on the inflammasome activation of caspase 1. It was also dependent on signaling from the interleukin‐1 (IL‐1) and transforming growth factor β (TGFβ) receptors. The decrease in TANGO1 down‐regulated export of larger cargos including collagen and laminin. Reduced TANGO1 protein had no effect on smaller molecular weight cargoes; however, the secretion of elastin was significantly reduced. Conclusion: TANGO1 is markedly increased in SSc fibroblasts and was found to be elevated in lung tissue in association with α‐SMA–positive cells. TANGO1 expression is driven by inflammasome‐dependent caspase 1 activation and is mediated by IL‐1 and TGFβ downstream signaling. These observations suggest that during fibrosis, caspase 1 promotes the up‐regulation of TANGO1 and the organization of endoplasmic reticulum exits sites, ultimately contributing to procollagen export and fibrosis. [ABSTRACT FROM AUTHOR]

Background: Worldwide, cervical cancer (CC) remains the most prevalent malignancy of the female reproductive system, posing a threat to women's life and health, and increasing the medical and economic burden on society. Therefore, the search for tumor biomarkers for CC remains an important research direction. Immunotherapy has significantly improved patient outcomes, and genes related to tumor immune infiltration have been clinically relevant and highly reproducible biomarkers that affect the prognosis and response to treatment of CC. 2,4‐dienoyl‐CoA reductase 1 (DECR1) was considered to be an oncogene in a previous study, but relationship between DECR1 and immune infiltration was not mentioned. Our study aimed to reveal the clinical value of DECR1 in CC and to investigate its relationship with immune infiltration. Methods: Human Protein Atlas was used to identify the localization of DECR1. The Ualcan database, TCGA, and IHC were used to assess the prognostic value of DECR1. GSEA was used to assess the possible signaling pathways of DECR1 in CC. The TIMER database was applied to reveal the relevance between DECR1 and immune infiltration. GEPIA was conducted to detect the co‐relationship among DECR1, immune markers, and typical molecules of apoptosis. Results: DECR1 was mainly distributed in the cytoplasm and overlapped with the endoplasmic reticulum. DECR1 was downregulated in CC compared to adjacent tissue. Survival analysis showed that patients with lower expression of DECR1 have a worse prognosis in CC. GSEA suggested that DECR1 was closely related to apoptosis signaling. TIMER showed that DECR1 was positively correlated with CD8+ T cell and CD4+ T cell but not with B cell in CC. Conclusion: DECR1 may be a potential cancer suppressor in CC and may be involved in apoptotic pathways and associated with immune infiltration. [ABSTRACT FROM AUTHOR]

Inflammasomes are a group of protein complex located in cytoplasm and assemble in response to a wide variety of pathogen‐associated molecule patterns, damage‐associated molecule patterns, and cellular stress. Generally, the activation of inflammasomes will lead to maturation of proinflammatory cytokines and pyroptotic cell death, both associated with inflammatory cascade amplification. A sensor protein, an adaptor, and a procaspase protein interact through their functional domains and compose one subunit of inflammasome complex. Under physiological conditions, inflammasome functions against pathogen infection and endogenous dangers including mtROS, mtDNA, and so on, while dysregulation of its activation can lead to unwanted results. In recent years, advances have been made to clarify the mechanisms of inflammasome activation, the structural details of them and their functions (negative/positive) in multiple disease models in both animal models and human. The wide range of the stimuli makes the function of inflammasome diverse and complex. Here, we review the structure, biological functions, and therapeutic targets of inflammasomes, while highlight NLRP3, NLRC4, and AIM2 inflammasomes, which are the most well studied. In conclusion, this review focuses on the activation process, biological functions, and structure of the most well‐studied inflammasomes, summarizing and predicting approaches for disease treatment and prevention with inflammasome as a target. We aim to provide fresh insight into new solutions to the challenges in this field. [ABSTRACT FROM AUTHOR]

Background: Glucose transporters (GLUTs) are highly expressed in various cancers. However, the implications of these variable expression patterns are unclear. This study aimed to clarify the correlation between class I GLUT expression patterns and clinical outcomes in non‐small cell lung cancer (NSCLC), including their potential role in inflammatory signaling. Methods: Biopsy tissues from 132 patients with NSCLC (92 adenocarcinomas [ADC] and 40 squamous cell carcinomas [SQCC]) were analyzed. mRNA expression levels of class I GLUTs (solute carrier 2A [SLC2A]1, SLC2A2, SLC2A3, and SLC2A4) and inflammation‐related molecules (toll‐like receptors TLR4, RelA/p65, and interleukins IL8 and IL6) were measured. Cellular localization of GLUT3 and GLUT4 was investigated using immunofluorescence. Results: Single, combined, and negative GLUT (SLC2A) expression were observed in 27/92 (29.3%), 27/92 (29.3%), and 38/92 (41.3%, p < 0.001) of ADC and 8/40 (20.0%), 29/40 (72.5%, p < 0.001), and 3/40 (7.5%) of SQCC, respectively. In ADC, the single SLC2A3‐expressed group had a significantly poorer prognosis, whereas the single SLC2A4‐expressed group had a significantly better prognosis. The combined expression groups showed no significant difference. SLC2A expression was not correlated with SQCC prognosis. SLC2A4 expression correlated with lower IL8 expression. GLUT3 and GLUT4 expressions were localized in the tumor cytoplasm. Conclusions: In lung ADC, single SLC2A3 expression correlated with poor prognosis, whereas single SLC2A4 expression correlated with better prognosis and lower IL8 expression. GLUT3 expression, which is increased by IL8 overexpression, may be suppressed by increasing the expression of GLUT4 through decreased IL8 expression. [ABSTRACT FROM AUTHOR]

Background and Aims: Neurodegeneration underpins the pathological processes of younger‐onset dementia (YOD) and has been implicated in primary psychiatric disorders (PSYs). Cerebrospinal fluid (CSF) neurofilament light (NfL) has been used to investigate neurodegeneration severity through correlation with structural brain changes in various conditions, but has seldom been evaluated in YOD and PSYs. Methods: This retrospective study included patients with YOD or PSYs with magnetic resonance imaging (MRI) of the brain and CSF NfL analysis. Findings from brain MRI were analysed using automated volumetry (volBrain) to measure white matter (WM), grey matter (GM) and whole brain (WB) volumes expressed as percentages of total intracranial volume. Correlations between NfL and brain volume measurements were computed whilst adjusting for age. Results: Seventy patients (47 with YOD and 23 with PSY) were identified. YOD types included Alzheimer disease and behavioural variant frontotemporal dementia. PSY included schizophrenia and major depressive disorder. MRI brain sequences were either fast spoiler gradient‐echo (FSPGR) or magnetization‐prepared rapid acquisition gradient‐echo (MPRAGE). In the total cohort, higher NfL was associated with reduced WB in the FSPGR and MPRAGE sequences (r = −0.402 [95% confidence interval (CI), −0.593 to −0.147], P = 0.008 and r = −0.625 [95% CI, −0.828 to −0.395], P < 0.001, respectively). Higher NfL was related to reduced GM in FSPGR (r = 0.385 [95% CI, −0.649 to −0.014], P = 0.017) and reduced WM in MPRAGE (r = −0.650 [95% CI, −0.777 to −0.307], P < 0.001). Similar relationships were seen in YOD, but not in PSY. Conclusion: Higher CSF NfL is related to brain atrophy in YOD, further supporting its use as a nonspecific marker of neurodegeneration severity. [ABSTRACT FROM AUTHOR]

Introduction: The assessment of neutrophil dysplasia features in peripheral blood is very helpful for the early screening and diagnosis of myelodysplastic neoplasms (MDS). Cell population data (CPD) parameters generated by automated hematology analyzers can reflect morphological characteristics of blood cells. This study aimed to investigate the clinical significance of CPD parameters neutrophil (Neu) X, NeuY and NeuZ in assessing neutrophil dysplasia. Methods: 218 MDS patients were divided into two subgroups according to neutrophil morphology. The differences of neutrophil research parameters between the two MDS subgroups and the control group, consisting of 210 healthy individuals, were compared, the correlation among neutrophil research parameters and the relationship between these parameters and cell morphology in MDS patients were analyzed, and receiver operating characteristic analysis were performed. Results: The median values of neutrophil research parameters NeuX and NeuZ in MDS with granulocyte dysplasia group were significantly lower than those in MDS without granulocyte dysplasia group and control group (p < 0.001), and they were positively correlated (r = 0.878, p < 0.001). The area under the receiver operating characteristic curve of NeuX and NeuZ was 0.720 (95% CI: 0.643–0.796, p < 0.001) and 0.738 (95% CI: 0.665–0.811, p < 0.001), respectively. In addition, with the decrease of NeuX value, neutrophils gradually show decreased nuclear segment and/or cytoplasmic granules. Conclusions: Combining NeuX and NeuZ can predict neutrophil dysplasia features of MDS in peripheral blood, and this can be an easier method to screen for the neutrophil dysplasia cases, as compared with the microscopic examination of peripheral blood and/or bone marrow smears. [ABSTRACT FROM AUTHOR]

Objective: Photosensitivity is one of the most common manifestations of systemic lupus erythematosus (SLE), yet its pathogenesis is not well understood. The normal‐appearing epidermis of patients with SLE exhibits increased ultraviolet B (UVB)–driven cell death that persists in cell culture. Here, we investigated the role of epigenetic modification and Hippo signaling in enhanced UVB‐induced apoptosis seen in SLE keratinocytes. Methods: We analyzed DNA methylation in cultured keratinocytes from SLE patients compared to keratinocytes from healthy controls (n = 6/group). Protein expression was validated in cultured keratinocytes using immunoblotting and immunofluorescence. An immortalized keratinocyte line overexpressing WWC1 was generated via lentiviral vector. WWC1‐driven changes were inhibited using a large tumor suppressor kinase 1/2 (LATS1/2) inhibitor (TRULI) and small interfering RNA (siRNA). The interaction between the Yes‐associated protein (YAP) and the transcriptional enhancer associate domain (TEAD) was inhibited by overexpression of an N/TERT cell line expressing a tetracycline‐inducible green fluorescent protein–tagged protein that inhibits YAP–TEAD binding (TEADi). Apoptosis was assessed using cleaved caspase 3/7 and TUNEL staining. Results: Hippo signaling was the top differentially methylated pathway in SLE versus control keratinocytes. SLE keratinocytes (n = 6) showed significant hypomethylation (Δβ = −0.153) and thus overexpression of the Hippo regulator WWC1 (P = 0.002). WWC1 overexpression increased LATS1/2 kinase activation, leading to YAP cytoplasmic retention and altered proapoptotic transcription in SLE keratinocytes. Accordingly, UVB‐mediated apoptosis in keratinocytes could be enhanced by WWC1 overexpression or YAP–TEAD inhibition, mimicking SLE keratinocytes. Importantly, inhibition of LATS1/2 with either the chemical inhibitor TRULI or siRNA effectively eliminated enhanced UVB‐apoptosis in SLE keratinocytes. Conclusion: Our work unravels a novel driver of photosensitivity in SLE: overactive Hippo signaling in SLE keratinocytes restricts YAP transcriptional activity, leading to shifts that promote UVB apoptosis. [ABSTRACT FROM AUTHOR]

Periodontitis is an oral inflammatory disease characterised by the destruction of periodontal soft tissue and alveolar bone resorption, mainly triggered by plaque microbial infection. Pyroptosis is an inflammatory form of programmed cell death mediated by the pore‐forming gasdermin proteins, which resist the invasion of pathogens into the body's immune system. Many studies have found that pyroptosis is closely related to the occurrence and development of periodontitis. At present, most of these studies focused on the canonical pathway mediated by caspase‐1. Moreover, Gram‐negative bacteria's lipopolysaccharide has been shown to activate a new form of the non‐canonical inflammasome by directly binding to human caspase‐4/5 and mouse caspase‐11 in the cytosol. However, most of the functions of non‐canonical inflammasome are still gradually being studied. Therefore, in this review, we have summarised and analysed the existence and regulation mechanism of the non‐canonical inflammasome in periodontitis. [ABSTRACT FROM AUTHOR]

The cytomorphological features of benign mesenchymal tumours of the tongue have rarely been reported. Herein, we present the cytomorphological features of adult‐type rhabdomyoma, which occurred in the tongue of a female patient, and granular cell tumour (GCT), which occurred in the tongue of a male patient; both patients were in their mid‐50s. The cytological features of the adult‐type rhabdomyoma case included large polygonal to ovoid cells with abundant and granular cytoplasm with predominantly peripherally located, uniform, round to oval nuclei and small nucleoli. Cross‐striation and crystalline intracytoplasmic structures were not seen. The cytological features of the GCT case included large cells with abundant granular pale cytoplasm, small round nuclei and small distinct nucleoli. The cytological differential diagnoses of these tumours overlap; thus, the cytological findings of the different entities included in their differential diagnoses are discussed. [ABSTRACT FROM AUTHOR]

Mitochondria are the powerhouse of the cell and function at pH ∼8.0. Dysfunctions of mitochondria, includes mitochondrial damage, leading to pH alteration. Hence, researchers aim to develop efficient pH probes for tracking mitochondrial pH dynamics. Herein, we developed a PET‐based fluorescent probe for pH monitoring during mitochondrial dysfunctions. Three derivatives were synthesized with a variable spacer's length in pentacyclic pyridinium fluorophores (PM‐C2, PM‐C3, and PM‐C6). An efficient electron transfers from the receptor (tertiary amine) was observed in the case of PM‐C2 compared to the other two derivatives. This PET process was inhibited when tertiary amine was protonated in acidic pH. However, PM‐C3 showed minimal fluorescence intensity at similar conditions and almost negligible change in case of PM‐C6, suggesting poor PET process for both the derivatives. Furthermore, DFT/TD‐DFT quantum chemical calculation well supported this optical phenomena and PET process. Biocompatible, photostable, and mitochondria‐specific PM‐C2 could monitor pH dynamics during mitochondrial damage which were engulfed by lysosome, also known as mitophagy. This mitophagy process were induced by rapamycin and starvation, which can be monitored by turn‐on fluorescence enhancement. This process was further validated by tracking Parkin‐protein translocation from cytoplasm to damaged mitochondria using our developed probe. [ABSTRACT FROM AUTHOR]

Background: Circular RNAs (circRNAs) have been reported to play vital roles in the progression of diverse human cancers, including non‐small cell lung cancer (NSCLC). The purpose of this study was to explore the exact role and underlying mechanism of circ_PLXND1 in NSCLC progression. Methods: Quantitative real‐time polymerase chain reaction (qRT‐PCR) assay was performed to determine the expression levels of circ_PLXND1, microRNA (miR)‐1287‐5p and human epidermal growth factor receptor 3 (ERBB3). The localization of circ_PLXND1 in NSCLC cells was tested by subcellular fractionation and localization assay. Cell angiogenesis, proliferation, apoptosis, migration and invasion were evaluated by tube formation assay, 5‐ethynyl‐2′‐deoxyuridine (EdU) incorporation assay, 3‐(4, 5‐dimethylthiazol‐2‐yl)‐2, 5‐diphenyltetrazolium bromide (MTT) assay, flow cytometry and transwell assay. Dual‐luciferase reporter assay was utilized to confirm the interaction between miR‐1287‐5p and circ_PLXND1 or ERBB3. Western blot assay was exploited to examine the expression of proteins. Results: Circ_PLXND1 and ERBB3 were upregulated while miR‐1287‐5p was downregulated in NSCLC tissues and cells. Circ_PLXND1 was a stable circRNA and mainly located in cytoplasm. Circ_PLXND1 silencing suppressed the proliferation, angiogenesis, migration and invasion of NSCLC cells in vitro. For mechanism analysis, circ_PLXND1 could positively regulate ERBB3 expression via sponging miR‐1287‐5p. The inhibitory impacts of circ_PLXND1 knockdown on the malignant behaviors of NSCLC cells were overturned by miR‐1287‐5p inhibitor. Overexpression of miR‐1287‐5p repressed the malignant phenotypes of NSCLC cells by targeting ERBB3. Furthermore, circ_PLXND1 interference inhibited tumor growth in vivo. Conclusions: Circ_PLXND1 knockdown impeded NSCLC progression through modulating the miR‐1287‐5p/ERBB3 axis, indicating a promising molecular target for NSCLC treatment. [ABSTRACT FROM AUTHOR]

Introduction: Multiple myeloma (MM) is a fatal hematological malignancy and does not have adequate prognostic indicators. Previous studies indicate that CEP72 is closely related to tumorigenesis and tumor progression. However, the expression and function of CEP72 in multiple myeloma have yet to be elucidated. Methods: In this study, we explored the correlation between CEP72 expression and clinicopathological characteristics as well as the impacts of CEP72 expression on the survival of MM patients. In addition, PPI, GSEA and Chemotherapy drug resistance analysis identified the possible mechanism. Results: CEP72 is overexpressed in both MM patients and MM cell lines. Clinically, patients in the CEP72high subgroup were significantly older than those in the CEP72low subgroup (p = 0.003). Up‐regulation of CEP72 was related to poor overall survival and event‐free survival. PPI network showed that CEP72 was related to PCM1, KIZ, OFD1, etc. GSEA analysis showed that CEP72 was enriched in cell cycle, oocyte meiosis, protein export, lysosome and N‐glycan biosynthesis pathways. Drug resistance analysis indicated that there was a positive correlation between the CEP72 expression and the IC50 values of 6‐mercaptopurine, 8‐chloro‐adenosine, clofarabine, fludarabine and allopurinol. Conclusion: High CEP72 expression was a poor prognostic factor in patients diagnosed with multiple myeloma. [ABSTRACT FROM AUTHOR]

Introduction: A peripheral blood smear is a basic test for hematological disease diagnosis. This test is performed manually in many places worldwide, which requires both time and qualified staff. Large laboratories are equipped with digital morphology analyzers, some of which are based on deep learning methods. However, it is difficult to explain to scientists how they work. In this paper, we proposed to add an explanatory factor to enhance the interpretability of deep learning models in leukocyte classification. Methods: 10 297 single images of leukocytes obtained from peripheral blood smears were included in this study. Pre‐trained and fully trained VGG16 and VGG19 models were used to classify the leukocytes, and Shapley Additive Explanations (SHAP) DeepExplainer was applied to visualize the area of cells that were significant for classification. The output images from the DeepExplainer were compared with cellular elements that are essential to laboratory practice. Results: The accuracy of our fully trained models was 99.81% for VGG16 and 99.79% for VGG19. It achieved slightly better results than the partially trained model, which scored 98.67% for VGG16 and 98.33% for VGG19. Their SHAP explanations indicated the significance of cellular structures in microscopic examination. Explanations in the pre‐trained models have proved the cell and nucleus contours to be relevant to classification, while explanations in the fully trained models pointed to the cytoplasm area. Conclusion: Despite different SHAP DeepExplainer explanations for fully and partially trained models, this method appears to be helpful for the verification of leukocyte classification in automated peripheral blood smear examination. [ABSTRACT FROM AUTHOR]

Copper avidly binds thiols and is redox active, and it follows that one element of copper toxicity may be the generation of undesirable disulfide bonds in proteins. In the present study, copper oxidized the model thiol N‐acetylcysteine in vitro. Alkaline phosphatase (AP) requires disulfide bonds for activity, and copper activated reduced AP both in vitro and when it was expressed in the periplasm of mutants lacking their native disulfide‐generating system. However, AP was not activated when it was expressed in the cytoplasm of copper‐overloaded cells. Similarly, this copper stress failed to activate OxyR, a transcription factor that responds to the creation of a disulfide bond. The elimination of cellular disulfide‐reducing systems did not change these results. Nevertheless, in these cells, the cytoplasmic copper concentration was high enough to impair growth and completely inactivate enzymes with solvent‐exposed [4Fe‐4S] clusters. Experiments with N‐acetylcysteine determined that the efficiency of thiol oxidation is limited by the sluggish pace at which oxygen regenerates copper(II) through oxidation of the thiyl radical–Cu(I) complex. We conclude that this slow step makes copper too inefficient a catalyst to create disulfide stress in the thiol‐rich cytoplasm, but it can still impact the few thiol‐containing proteins in the periplasm. It also ensures that copper accumulates intracellularly in the Cu(I) valence. [ABSTRACT FROM AUTHOR]

Background: Esophageal cancer is a malignant tumor with a poor prognosis and high incidence. Circular RNAs (circRNAs) have been shown to be involved in the pathogenesis of cancers, including esophageal cancer. Here, we explored the precise role of circ_0003340 in esophageal cancer development. Methods: The expression levels of circ_0003340, miR‐874‐3p and enabled homolog (ENAH) were detected by quantitative real‐time polymerase chain reaction and western blot. Subcellular localization and RNase R assays were used to characterize circ_0003340. Cell Counting Kit 8, flow cytometry, transwell assays were used to analyze cell proliferation, apoptosis, migration and invasion. The effect of circ_0003340 on tumor growth was assessed by tumor experiments in vivo. Dual‐luciferase reporter assay was used to analyze the relationship between miR‐874‐3p and circ_0003340 or ENAH. Results: Circ_0003340 was mainly located in the cytoplasm and was upregulated in esophageal cancer tissues and cells. Circ_0003340 knockdown inhibited cell proliferation, migration, invasion, glucose consumption, and lactate production and induced cell apoptosis in esophageal cancer cells. Moreover, circ_0003340 knockdown suppressed tumor growth in vivo. MiR‐874‐3p was reduced in esophageal cancer tissues and cells, and it was a molecular mediator of circ_0003340 function in esophageal cancer cells. ENAH was identified as a direct and functional target of miR‐874‐3p in esophageal cancer cells. The promotion effect of circ_0003340 on ENAH was ameliorated by miR‐874‐3p. Conclusion: The data demonstrated that circ_0003340 promoted the progression of esophageal cancer through miR‐874‐3p/ENAH axis, which might provide novel therapeutic targets for esophageal cancer intervention. [ABSTRACT FROM AUTHOR]

Aminopeptidase I (Ape1) is one of the major cargoes of the cytoplasm‐to‐vacuole targeting (Cvt) pathway, which is a kind of selective autophagy, in Saccharomyces cerevisiae. After synthesis, the Ape1 precursor (prApe1) undergoes phase separation to form liquid droplets, termed Ape1 droplets, in the cytoplasm. In this study, we found that cells expressing prApe1‐GFP exhibited temperature‐sensitive formation of Ape1 droplets, which affected its transport. Moreover, we showed that endogenous Ape1 transport was defective at high temperatures in various laboratory strains due to the defect in the formation of Ape1 droplets at these temperatures. Finally, we found that gene disruptants showing heat‐tolerant growth suppressed the temperature sensitivity of the Ape1 transport. The formation of Ape1 droplets might be an indicator of cytoplasmic integrity at high temperature. [ABSTRACT FROM AUTHOR]

A 16‐year‐old female spayed domestic shorthaired cat was examined for lameness and a mass on the fourth digit of the right hindlimb. Cytologic examination of an aspirate of the mass revealed large discrete cells admixed with low numbers of well‐granulated mast cells. The discrete cells contained single to many variably sized light pink to purple granules in their cytoplasm and had pleomorphic nuclei, with intranuclear cytoplasmic inclusions. Karyomegalic, binucleated and multinucleated cells were seen. Histologic examination of formalin‐fixed sections of the excised mass showed a mildly infiltrative, unencapsulated, multinodular dermal mass that extended into the subcutis and consisted of similar discrete cells. On immunohistochemical staining, the tumor cells expressed ionized calcium‐binding adapter molecule 1 (Iba1) and CD18. The tumor cells did not express CD3, CD20, CD117, pancytokeratin (AE1/AE3), melanoma antigen (Melan‐A), multiple myeloma oncogene‐1 (MUM1), melanoma‐associated antigen (PNL‐2), and S‐100. Low numbers of tumor cells expressed CD204 and protein gene product 9.5 (PGP9.5). Granules were variably positive for Periodic‐acid Schiff (PAS) and Alcian blue. On transmission electron microscopy, the cells contained filopodia, abundant endoplasmic reticulum, and moderate numbers of low‐density membrane‐bound granules. This case documents a previously undescribed granular variant of a histiocytic tumor in a cat. [ABSTRACT FROM AUTHOR]

B Cover Illustration b FKBP25 is ubiquitously expressed throughout the cytoplasm and nucleus of C2C12 myotubes (Blue: Nuclei, Red: FKBP25). Cover image is from the study by Tabitha Cree, John T. Price, Craig A. Goodman and colleagues included in this issue, pages 4660-4678. [Extracted from the article]

By altering the reaction ratio of precursor Ir2(ppy)4Cl2 and bridging ligand of 4,4‐bipyridine (bpy), a series of phosphorescent cyclometalated iridium(III) complexes of mono‐, di‐, and tetranuclear have been successfully obtained and characterized for the first time. The dissociation of bpy ligand can be accelerated by light irradiation or placing these complexes in glutathione (GSH) abundant aqueous solution, bpy releasing rate follows the order Ir1 > Ir2 > Ir3 > Ir4, and with an addition of histidine, a significant blue shift from orange to green phosphorescence was observed. Herein, the cellular dissociation of bpy can be monitored by an orange‐to‐green phosphorescent blue shift, and nuclei of living cells can be lighted up by a set of probes with two phosphorescent channels, and subsequent cellular uptake translocation from cytoplasm to nucleus of Ir complexes could be observed by confocal imaging within 4 h. Besides, the changes of cellular phosphorescence intensity in two fluorescent channels recorded by flow cytometry could reflect different speed of bpy release in human normal and cancer cells. Besides, Ir1–4 exert significant anticancer effect in the dark with low photocytotoxicity, by effectively inducing reactive oxygen species generation, mitochondrial membrane potential depletion, and interacting with biomolecules, and they eventually induce late apoptosis of Hela cell. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the potential role of miR‐26 family members in periodontal pathogenesis by assessing innate immune responses to periopathic bacteria and regulation of cytoskeletal organization. Materials and Methods: Expression of miR‐26a‐5p and miR‐26b‐5p was quantified in gingival biopsies derived from healthy and periodontally diseased subjects before and after non‐surgical (scaling and root planing) therapy by RT‐qPCR. Global pathway analysis and luciferase assays were performed for target identification and validation. Cytokine expression was assessed in miR‐26a‐5p transfected human oral keratinocytes upon stimulation with either live Porphyromonas gingivalis (Pg), Aggregatibacter actinomycetemcomitans or Pg lipopolysaccharide (LPS). Wound closure assays were performed in cells transfected with miR‐26a‐5p, while the impact on cytoskeletal organization was assessed by F‐actin staining. Results: miR‐26a‐5p and miR‐26b‐5p were downregulated in diseased gingiva and restored 4–6 weeks post‐therapy to levels comparable with healthy subjects. Target validation assays identified phospholipase C beta 1 as a bona fide novel target exhibiting antagonistic expression pattern in disease and post‐therapy cohorts. miR‐26a‐5p transfected cells secreted higher levels of cytokine/chemokines upon stimulation with periopathogens and demonstrated impaired cell migration and cytoskeletal rearrangement. Conclusions: Downregulated miR‐26a‐5p levels in periodontal inflammation may interfere with key cellular functions that may have significant implications for host defence and wound healing. [ABSTRACT FROM AUTHOR]

Cutaneous melanocytic tumor with CRTC1::TRIM11 fusion (CMCT) is a recently described entity with only 13 cases reported in the literature. Histopathologically, the neoplasm consists of atypical epithelioid to spindled cells that form a well‐circumscribed nodule usually confined to the dermis and subcutis with cytological features including large vesicular nuclei with prominent nucleoli and abundant eosinophilic cytoplasm. Immunohistochemistry shows variable expressivity of melanocytic markers. Currently, there are limited data regarding long‐term outcomes of this newly described entity. Most cases have done well, but there is one case reported with an adverse event. Hence, further studies are needed to accurately classify this tumor. Definitive diagnosis is made by laboratory evidence of CMCT. Herein, we report the first case of CMCT with epidermal involvement in the youngest patient known to be affected to date. [ABSTRACT FROM AUTHOR]

A 39‐year‐old man had an intracranial tumour without infiltration into the surrounding cerebral tissue. The tumour recurred seven times in 11 years but maintained a well‐demarcated character. Histopathological examination of the 4th surgical specimens showed nests of tumour cells surrounding small blood vessels. The tumour cells harboured amphophilic cytoplasm and small round nuclei with fine chromatin, and perinuclear haloes and clear borders were frequently observed, which was unclassifiable histology. By the Deutsches Krebsforschungszentrum methylation classifier, the tumour was not classified into any of the methylation classes. mRNA sequencing identified a novel SREBF1::NACC1 gene fusion. This intracranial tumour could be a novel tumour entity with NACC1 rearrangement showing characteristic histological and diagnostic imaging findings. [ABSTRACT FROM AUTHOR]

The article focuses on the identification of giant platelets with disorganized granules, which can suggest ACTB gene mutation associated with actinomyopathy-associated syndromic thrombocytopenia (ACTBAST). It describes the clinical manifestations and genetic investigations of a case involving thrombocytopenia, large platelets, and platelet morphological abnormalities, it highlights the impact of ACTB gene variants on platelet cytoskeleton and megakaryopoiesis.

Summary: Land plant spermatozoids commonly possess characteristic structures such as the spline, which consists of a microtubule array, the multilayered structure (MLS) in which the uppermost layer is a continuum of the spline, and multiple flagella. However, the molecular mechanisms underpinning spermatogenesis remain to be elucidated.We successfully identified candidate genes involved in spermatogenesis, deeply divergent BLD10s, by computational analyses combining multiple methods and omics data. We then examined the functions of BLD10s in the liverwort Marchantia polymorpha and the moss Physcomitrium patens.MpBLD10 and PpBLD10 are required for normal basal body (BB) and flagella formation. Mpbld10 mutants exhibited defects in remodeling of the cytoplasm and nucleus during spermatozoid formation, and thus MpBLD10 should be involved in chromatin reorganization and elimination of the cytoplasm during spermiogenesis.We identified orthologs of MpBLD10 and PpBLD10 in diverse Streptophyta and found that MpBLD10 and PpBLD10 are orthologous to BLD10/CEP135 family proteins, which function in BB assembly. However, BLD10s evolved especially quickly in land plants and MpBLD10 might have acquired additional functions in spermatozoid formation through rapid molecular evolution. [ABSTRACT FROM AUTHOR]

HMGA2 overexpression is found in 10–15% of leiomyomas (LM). HMGA2 overexpression is common in variants of hydropic, intravenous and lipoLM. Cellular or highly cellular LM (CLM) is a LM variant with a less well-defined molecular nature. In this study, we identified and examined 52 hypercellular LM with sclerotic collagen, herein defined as cellular leiomyoma with sclerosis (CLM-S). CLM-S shows large tumour size (average 12.2 cm) and characteristic histology of tumour cells, arranged in cellular fascicles, sheets and trabeculae with abundant dense, pink sclerotic extracellular matrix in bands and nodules and increased vascularity. Tumour cells are uniform with small, round–oval nuclei and scant, pale–eosinophilic to vacuolated cytoplasm reminiscent of pericytes. The differential diagnosis of CLM-S includes conventional CLM, endometrial stromal tumours and perivascular epithelioid cell tumour. Immunohistochemical profile [HMGA2, fumarate hydratase, smooth muscle markers, Melan A and HMB-45] and molecular alterations [by HMGA2 mRNA reverse transcription–polymerase chain reaction (RT–PCR), HMGA2 fluorescence in-situ hybridisation and MED12 sequencing] were analysed in comparison to matched myometrium and CLM controls. Remarkably, 96% (50 of 52) of CLM-S demonstrated diffuse positive immunoreactivity for HMGA2 and up to an 80-fold increase in HMGA2 mRNA, determined by RT–PCR. FISH analysis with breakpart probes at intron 3 and the 5’ UTR detected HMGA2 rearrangements in 47% (18 of 38) of CLM-S. All CLM-S retained expression of fumarate hydratase. No MED12 mutations were found in any CLM-S. Our findings show that CLM-S has unique and characteristic histomorphology probably driven by HMGA2 overexpression. [ABSTRACT FROM AUTHOR]

Summary: Initially discovered in yeast, mitochondrial retrograde signalling has long been recognised as an essential in the perception of stress by eukaryotes. However, how to maintain the optimal amplitude and duration of its activation under natural stress conditions remains elusive in plants.Here, we show that TaSRO1, a major contributor to the agronomic performance of bread wheat plants exposed to salinity stress, interacted with a transmembrane domain‐containing NAC transcription factor TaSIP1, which could translocate from the endoplasmic reticulum (ER) into the nucleus and activate some mitochondrial dysfunction stimulon (MDS) genes. Overexpression of TaSIP1 and TaSIP1‐∆C (a form lacking the transmembrane domain) in wheat both compromised the plants' tolerance of salinity stress, highlighting the importance of precise regulation of this signal cascade during salinity stress.The interaction of TaSRO1/TaSIP1, in the cytoplasm, arrested more TaSIP1 on the membrane of ER, and in the nucleus, attenuated the trans‐activation activity of TaSIP1, therefore reducing the TaSIP1‐mediated activation of MDS genes. Moreover, the overexpression of TaSRO1 rescued the inferior phenotype induced by TaSIP1 overexpression.Our study provides an orchestrating mechanism executed by the TaSRO1–TaSIP1 module that balances the growth and stress response via fine tuning the level of mitochondria retrograde signalling. [ABSTRACT FROM AUTHOR]

Blood‐based biomarkers for identifying Alzheimer's disease (AD) pathology have been of considerable interest over the past decade and can offer a significant advantage over the currently available and validated cerebrospinal fluid and positron emission tomography biomarkers in terms of cost, invasiveness and accessibility. This review explores the role of three blood‐based biomarkers; plasma amyloid β, tau and neurofilament light chain, and their combination, in the identification of AD pathology and how they may be utilised in clinical practice. [ABSTRACT FROM AUTHOR]

Na+,K+‐ATPase (NKA) is one of the most important members of the P‐type ion‐translocating ATPases and plays a pivotal role in establishing electrochemical gradients for Na+ and K+ across the cell membrane. Presented here is a 3.3 Å resolution structure of NKA in the E2·2K+ state solved by cryo‐electron microscopy. It is a stable state with two occluded K+ after transferring three Na+ into the extracellular medium and releasing inorganic phosphate bound to the cytoplasmic P domain. We describe how the extracellular ion pathway wide open in the E2P state becomes closed and locked in E2·2K+, linked to events at the phosphorylation site more than 50 Å away. We also show, although at low resolution, how ATP binding to NKA in E2·2K+ relaxes the gating machinery and thereby accelerates the transition into the next step, that is, the release of K+ into the cytoplasm, more than 100 times. [ABSTRACT FROM AUTHOR]

Breast cancer is becoming a common life‐threatening disease, especially in women, along with higher incidence and mortality. MicroRNA (miR)−506 was reported to participate in breast cancer progression, while the role of miR‐506 in breast cancer‐induced osteolytic bone metastasis is unclear. In the present study, we found significant downregulation of miR‐506 in breast cancer tissues and cell lines. Overexpression of miR‐506 notably reduced the proliferative, migratory and invasive rates of MCF7 and MDA‐MB‐231 cells, and reduced the production of inflammatory factors IL‐6 and TNF‐α in MCF7 cells. Moreover, overexpression of miR‐506 obviously inhibited tumor growth in an in vivo animal model. In addition, overexpression of miR‐560 efficiently attenuated breast cancer‐induced osteolysis in vivo, which was characterized by increased bone volume/total volume (BT/TV), trabecular number (Tb. N), and trabecular thickness (Tb. Th), as well as the reduced trabecular separation (Tb. Sp). The nuclear factor of activated T cell cytoplasmic 1 (NFATc1) was identified as a downstream target of miR‐506, and overexpression of miR‐506 could inhibit breast cancer progression by targeting NFATc1. Furthermore, our results showed that NFATc‐1 might participate in the inhibition of miR‐506 on breast cancer‐induced osteolysis. In conclusion, our findings provide insights into understanding the pathogenesis of breast cancer and breast cancer‐induced osteolytic bone metastasis, and miR‐506 might serve as a novel biomarker for this disease. Highlights: 1.MicroRNA (miR)‐506 inhibited the proliferation, migration and invasion of breast cancer cells.2.Nuclear factor of activated T cell cytoplasmic 1 (NFATc1) was a direct target gene of miR‐506.3.miR‐506 inhibited the development of breast cancer.4.miR‐506 efficiently inhibited breast cancer‐induced osteolytic bone. [ABSTRACT FROM AUTHOR]

Background: Actin, alpha, skeletal muscle 1 (ACTA1) is one of the causative genes of nemaline myopathy (NM) and congenital fiber‐type disproportion (CFTD). CFTD is characterized by type 1 fiber atrophy and distinguished from NM in the absence of rods. Eight patients with CFTD, including one patient with dilated cardiomyopathy (DCM), have previously been reported. Herein, we report the case of a 10‐year‐old boy presenting with CFTD and DCM. Methods: We performed exome sequencing and analyzed the effect of Met327Lys mutations on cultured C2C12 muscle cells compared with that seen in the wild type (WT, ACTA1) and previously identified Asp294Val mutations associated with a severe phenotype of CFTD without cardiomyopathy. Results: Exome sequencing revealed a de novo mutation, c.980 T > A, p.(Met327Lys), in ACTA1 (NM_001100.4). C2C12 cells transfected with the WT plasmid expressed ACTA1 in the nucleus and cytoplasm. Cells with the Asp294Val mutant showed needle‐like structures in the cytoplasm, whereas the expression of the Met327Lys mutant resulted in few aggregations but many apoptotic cells. Conclusion: Apoptosis induced in Met327Lys‐transfected muscle cells supports the pathogenicity of the mutation and can be implicated as one of the histopathological features associated with CFTD, as in NM. [ABSTRACT FROM AUTHOR]