Gene Reports

Abstract Aim: Low chemotherapy response is a major risk factor for early mortality in cancer patients; it is one of the biggest challenges in cancer treatment. Main aim of this study is to identify chemotherapy non-responder, prognostic significance of pre-chemotherapy baseline variables in survival, distinguish most effective anti-cancer drug classes and formulation. Methods: In this multi-center retrospective cohort (n=2459) patients deceased with NSCLC and received anti-cancer drugs were included for analyses. To identify chemotherapy non-responder, patient population was divided into three sub-groups based on chemotherapy prescription frequency [1-15] as group-A, [16-30] as group-B, and [[&ge;]31] as group-C. Multivariate analysis was performed to identify risk of 1-year mortality in these groups. To prognose chemotherapy response in resected and unresected NSCLC patients, 0-7 days pre-chemotherapy white blood cell (WBC) count total five-ranges were compared as per overall survival in abnormal Vs normal WBC counts. Results: Post-stratification in group-A there were (n=1289) patients, in group-B (n=648) patients, and in group-C (n=522) patients. In group-A (n=301) patients 23% were found to have no new metastasis post-diagnosis significantly less p-value (0.004) compared to Group-B (n=125) 19.3%, and group-C (n=110) 19.2% patients p-value (0.008). Metastasis during chemotherapy was found significantly less in 20% patients of group-A, compared to (33%) in group-B, and (43%) in group-C p-value (<0.001). Post-chemotherapy initiation OS in group-A patients were significantly less 9 months (95% CI 9.3 - 9.6) compared to group-B 19 months (95% CI 17.7 - 20.2) and group-C 36.6 months (95% CI 34.6 - 38.5) patients p-value (<0.0001). Despite of low new metastasis and post chemo metastasis, group-A patients survived significantly less based on these outcomes group-A patients were considered as chemotherapy non-responder. Males and NSCLC stage III/IV patients were at higher risk; clinical benefits are corelated to surgery and radiotherapy for chemotherapy non-responder. Leukocytosis in both resected/unresected NSCLC group-A (13%) patients were found to be bad prognostic factor of survival in unresected group-B (5%) patients. Oral formulation of receptor tyrosine kinase inhibitors (RTKI) was effective in non-responders. Conclusion: Stratification of patient population based on chemotherapy prescriptions could be a useful method to find chemotherapy response in retrospective analysis. Patients with pre-chemotherapy leukocytosis should be closely monitored prior to selection of chemotherapy dose and formulation.

Ovate Family Proteins (OFPs) are a class of plant-specific, negative nuclear transcriptional regulators characterized by conserved C-terminal OVATE domain. This study on comparative functional characterization of two head-to-head arranged OFPs - AtOFP2 (Ovate-OFP with full ovate domain) and AtOFP17 (Ovate-Like OFP with partial ovate domain) provides critical insight into how structural variations in ovate domain leads to functional divergence. Detailed phenotypic analysis of 28 physical and physiological traits of loss- and gain-of-function mutants revealed that both genes act as broad, pleotropic repressors of plant growth and development. Removal of repression in knock-down mutants of both genes exhibited reduced duration of seed dormancy, faster rate of germination and growth, bigger plants and significantly higher seed yield. In contrast, constitutive over-expression showed a generalized repressive nature of both genes, with nuanced differences for fine tuning of specific traits. For example, both genes showed antagonistic behaviours on root hair architecture. AtOFP2 act as a strong repressor of root hair development whereas AtOFP17 is a stronger repressor of hypocotyl and root cell architecture. AtOFP17 owing to partial ovate domain exerts a mild level of repression throughout life span as indicated by smaller plants and lesser yield in knock-down AtOFP17 mutants. On the contrary, AtOFP2 exerted a much stronger repressor effect in which > 90% over-expression mutants died at the juvenile stage ; the survival of remaining 10% is probably owing to activation of dosage-dependent feedback loop mechanism as indicated by normal growth of mature plants, and is also evident by transcriptome data. Transcriptome analysis of roots of 7-day old seedling of knock-down and over-expression mutants of AtOFP2 showed downregulation of OFP2 in over-expressed mutants. However, severely stunted phenotype indicated presence of stable OFP2 protein to exert effects. Analysis of DEGs in OFP2 mutants revealed that it acts as an important regulator working at intersection of hormonal signalling affecting critical genes required for auxin, cytokinin, GA, BR and ABA functioning. Perturbations across hormonal signalling pathways affects cell wall remodelling factors such as EXPANSINS, Xyloglucan hydrolases (XTHs) and cellulose synthases (CSLs) causing overall stunted growth; and epidermal patterning genes such as WER, GL1, EGL3, TTG1 leading to severely reduced root length and root hairs. Significantly, functional analysis of this master regulator highlighted a significant economic potential. Knockdown of both these genes relieves their natural repression on reproductive traits, leading to longer siliques, bigger and heavier seeds, and substantially increased overall seed yield, positioning AtOFP2 and AtOFP17 as highly valuable targets for agricultural crop improvement.

It has been previously shown that chronic social defeat stress caused by paired agonistic interactions between male mice is accompanied by the development of depression-like state and immune deficiency. The aim of this study was to investigate changes in the expression of C1qtnf superfamily genes (encoding the complement component related with tumor necrosis factor) in the hypothalamus, thymus and lungs against the background of the Lewis lung adenocarcinoma growth. In the experiments, on the 5th day of social stress, male mice were injected with tumor cells into the tail vein. Chronic social stress continued for the next two weeks. The transcriptomes of the hypothalamus, thymus and lungs of mice were sequenced at the Genoanalytica Collective Center (http://genoanalytica.ru/, Moscow). Changes in the expression of the C1qtnf genes in the tissues of stressed mice were studied compared with the control and mice that were additionally injected with tumor cells. Overall, significant correlations were found between expression of most genes in each tissue of the experimental groups. In the hypothalamus of stressed animals, when tumor cells were introduced, an increase in the expression of the genes C1qtnf1, C1qtnf2, C1qtnf3, C1qtnf6 and C1qtnf7 was observed compared to controls. In the thymus of these animals, tumor cell injection increased expression of the C1qtnf1, C1qtnf5, and C1qtnf6 genes. In the lung of tumor-injected stressed mice, expression of the C1qtnf1, C1qtnf2, C1qtnf7, and C1qtnf9 genes was decreased relative to controls and non-tumor-injected depressed mice, reaching near-zero levels in some mice. Analysis of C1qtnf superfamily gene expression in the all tissues revealed negative correlations between the expression of the C1qtnf1, C1qtnf2, and C1qtnf7 genes in the hypothalamus and lungs indicating synchronization of processes against the background of social stress and Levis lung adenocarcinoma.

BackgroundReactive Oxygen Species (ROS) are the small, unstable and highly reactive species, having DNA oxidizing ability. Oxidation of the DNAs purine and pyrimidine bases can lead to single or double strands in this macromolecule. In this situation, the ATM molecule, a serine-threonine kinase, targets several proteins for phosphorylation, which causes the cell cycle to stop and the DNA damage repair begins. It has previously been proven that natural polyphenols have the cancer inhibiting properties due to their high efficacy and low side effects. Silibinin is the main herbal and medical ingredient in Milk Thistle (Silybum marianum) is a polyphenol flavonolignan, which has been widely considered as an antioxidant and anticancer agent. The purpose of the present study was to investigate the ATM gene expression and measurement of reactive oxygen species (ROS) in SKBR3 cell line, treated with Silibinin. Materials and MethodsAt first, the SKBR3 cell line was cultured in RPMI1640 culture medium and MTT assay was carried out to evaluate the Silibinin cytotoxicity. Flow Cytometry was carried out for cell cycle analysis, apoptotic induction, and ROS detection. While, Real Time PCR was used to evaluate the ATM gene expression in the Silibinin-treated and un-treated SKBR3 cells. ResultsPresent results have shown that 150 {micro}M Silibinin had the most significant cytotoxicity and apoptotic induction influence after the treatment period of 48 h. Flow cytometry data have shown that Silibinin induced considerable amount of apoptosis and caused cell cycle arrest at G1/S phase and induced production of ROS. Real-time PCR results have revealed that Silibinin increased the ATM expression in SKBR3 cell line. ConclusionSilibinin causes increased ATM gene expression by inducing ROS production, which initiates cell cycle arrest and apoptotic induction in SKBR3 cells line.

Background with objective: Detecting EGFR mutations is critical for treating lung adenocarcinoma with highly effective targeted therapies. However, standard genetic testing is expensive, complex, and often unavailable in resource-limited settings like Bangladesh. Because elevated serum CEA has been linked to these genetic alterations, it could serve as an accessible screening tool. This study aims to evaluate the association between serum CEA levels and EGFR mutation status to determine if routine CEA testing can reliably predict these mutations and guide treatment. Methodology: In this cross-sectional analytical study, we recruited 58 patients with histologically confirmed treatment naive lung adenocarcinoma. The presence of EGFR mutations in the ctDNA was determined via ARMS (Amplification Refractory Mutation System) PCR. Patient data was statistically analyzed to assess the diagnostic correlation between serum CEA levels and the presence of EGFR mutations. Result: The overall EGFR mutation rate was 43.1% with exon 19 deletion (48%) and exon 21 mutations (44%) were the predominant types. Median serum CEA levels were significantly higher in patients with EGFR mutations compared to wild-type cases (14.6 ng/ml vs 2.8 ng/ml, p<0.001). A multivariate analysis revealed a 14% increased likelihood of an EGFR mutation for 1 ng/ml rise in serum CEA. Furthermore, serum CEA showed strong diagnostic accuracy for ctDNA samples at a 6.39 ng/ml cut-off (AUC 0.82, sensitivity 68.0%, specificity 84.8%). Conclusion: Serum CEA is a valuable, cost-effective, and non-invasive biomarker demonstrating significantly higher levels and strong diagnostic accuracy in EGFR-mutated lung adenocarcinoma compared to wild-type cases.

Purpose: To identify transcript-level variants in crystallin genes in paediatric patients with unilateral cataracts. Methods: Anterior capsulorhexis (n=12) from patients underwent surgical management of congenital unilateral cataracts was collected. Total RNA was isolated from lens epithelial cells, and complementary DNA (cDNA) was synthesized. Full-length RNA transcripts of 10 lens-specific crystallin genes were PCR-amplified and analysed via Sanger sequencing. Identified transcript variants were further validated using genomic DNA (gDNA) through Sanger sequencing. In addition, the full-length (~7,535 bp) CRYBA1 genomic region was sequenced using Oxford Nanopore Technology. Results: Aberrant low molecular weight (LMW) amplicons (~370 bp) of the CRYBA1 transcript were identified in three patients presented with unilateral cataract. Of 3 patients, 2 had persistent fetal vasculature (PFV) and 1 had pre-existing posterior capsular defect (PPCD). Sanger sequencing revealed a precise loss of exons 2 to 4 in the CRYBA1 RNA transcript. No coding, splice-site, or large deletion variants were detected in the genomic DNA of the patients or their parents. In silico analysis predicted two possible truncated proteins arising from these alternatively spliced transcripts: one comprising the first 11 amino acids of the N-terminal region with a loss of all Greek key motifs, and another comprising 90 amino acids encoded by exons 5 and 6, initiated from an alternative start codon in exon 5, and loss of Greek key motifs 1 & 2. Conclusion: The precise skipping of exons 2 to 4, consistent with canonical splicing signals (5-prime-GU...AG-3-prime), in the absence of genomic alterations, suggests the presence of alternatively spliced (AS) CRYBA1 transcripts in human lenses. This is the first report documenting AS-CRYBA1 transcripts in association with childhood cataracts with PFV and PPCD.

Currently, the genetic architecture of Middle Eastern populations is underrepresented in global genomic databases. This gap increases the rate of Variants of Uncertain Significance (VUSs) and clinical misinterpretations of genomic data especially in Middle Eastern populations. Whole exome sequencing was conducted on 90 healthy individuals from Jordan and the data were analysed using Principal Component Analysis (PCA) and multi-computational filtering. PCA revealed a double ancestry (EUR-AFR) admixture rather than a triple admixture (EUR-AFR-AMR). More than 3,500 populations-specific variants (PSVs) were identified, of which 72% were singletons. Additionally, 19 variants were significantly enriched compared to the maximum allele frequencies in public global databases (Fisher's exact test with Benjamini-Hochberg false discovery rate correction, p-value < 0.05). Consequently, the results suggest the reclassification of variants of Uncertain Significance (VUS) which reside in the ECE2 gene to likely benign and the variants of Conflicting Classification of Pathogenicity in the genes IL1RN and THPO to benign based on the significant allele frequency (AF=0.0389, p-value < 0.05). Furthermore, a pathogenic ClinVar variant was identified in a healthy individual, warranting careful interpretation. The findings underscore the importance of identifying PSVs in order to minimize or even prevent clinical misdiagnosis and highlight the unique genetic signature in Jordan. The study serves as a foundational resource for precision medicine in the region.

BackgroundHeterochromatic long arm of mouse Y chromosome harbors the multicopy species-specific sequences Ssty, Sly, Asty and Orly that are transcribed in testis and have known functions in male fertility. Of these Ssty and Sly encode proteins - yet all the transcripts are not translated. To investigate the roles of these Y-heterochromatic transcripts further, we analyzed them. MethodsMice with 2/3rd deletion of the Y-chromosome (XYRIIIqdel) and its wild type (XYRIII) were used in this study. Bioinformatic approaches, small RNA northern blots, Electrophoretic Mobility Shift Assays, Luciferase reporter assays, dPCR analysis, RT-qPCR assays and western blotting techniques were used to identify piRNAs that regulate autosomal genes. ResultsWe demonstrate that the multicopy gene families from mouse Y-long arm generate piRNAs predominantly in testis. We observed sequences homologous to these piRNAs in the UTRs of a few autosomal genes, which are differentially expressed in the sperms of XYRIIIqdel mice. Furthermore, the Endogenous Retrovirus Element (ERV) LTR, found in the Orly1 transcript identified piRNAs in the database, showed homology to UTRs and associated genomic regions of a few autosomal genes. Orly1 showed a reduction in genomic copy number by digital PCR in XYRIIIqdel mice. One of the four autosomal genes containing the ERV segment in their UTRs, showed a differential testicular protein expression in the mutant mice. ConclusionsThus, we further elucidate that different classes of repeats from Y-chromosome regulate autosomal gene expression via piRNAs. Besides, this study also identified novel roles for a Y-derived ERV in autosomal gene regulation in testis.

The production of reactive oxygen species (ROS) in response to cadmium (Cd) has been extensively studied, demonstrating that they play a key role in the plants response to this heavy metal. While the role of enzymes like RBOHs has been thoroughly studied, the function of other ROS-producing enzymes, such as peroxisomal glycolate oxidase (GOX), remains largely overlooked. Peroxisomal GOX is a core metabolic enzyme of the photorespiratory pathway occurring in chloroplasts, mitochondria and peroxisomes. Using Arabidopsis (Arabidopsis thaliana) mutants lacking the main peroxisomal GOX genes, GOX1 (gox1-1) and GOX2 (gox2-1) we explored their function in plant response to Cd. Although photosynthetic capacity appears to be affected to the same extent in both mutants under control and Cd stress conditions, GOX2 seems to play a greater role in ROS production in response to the metal. Transcriptomic analyses on WT and gox2-1 pointed to the mitochondrial electron transport chain (mETC) as a target of Cd stress. We further investigated the individual GOX1 and GOX2 functions in mETC regulation and redox state. Although oxidative ratio of mitochondria was higher in both mutants, it was more pronounced in the absence of GOX1. Furthermore, the mETC is affected in both mutants but the regulation of its components differs in each mutant. These results point out the different functions of the two photorespiratory GOX isoforms in Arabidopsis, leading to a better understanding of the photorespiratory pathway.

Biological sequences are known to be not random. Thus, the comparison of in silico restriction fragment distributions of random and biological sequences may be an indicator of this non-randomness. Our analyses show that for most of the tested combinations of restriction enzyme and genome sequence the fragments per Megabase of the biological sequence deviate at least more then 10% from the corresponding random sequence. This deviation goes into both directions, i.e. clearly increased values are as common as clearly decreased values. Although there is no species- or restriction-enzyme-specific effect, a clear impact of the GC content both of the restriction site and of the genome sequence can be seen. In contrast to the random sequences, the genome sequences show distinct peaks in their fragment length distributions, hinting to repetitive elements such as transposons.

BackgroundThe MDM2-p53 signaling pathway plays a central role in tumor suppression, and genetic variants that disrupt this pathway may influence breast cancer (BC) susceptibility. However, data from South Asian populations, particularly Bangladesh, remain limited. MethodsA case-control study was conducted in Bangladeshi women, including BC patients and healthy controls (HCs). Genotyping of MDM2 polymorphisms was performed using PCR-based methods. Circulating MDM2 and p53 protein levels were measured using enzyme-linked immunosorbent assays (ELISA). Associations between genotype, protein levels, BC status, and clinicopathological features were evaluated using appropriate statistical models. ResultsA strong and genotype-specific association was observed for MDM2 rs2279744. Women carrying the heterozygous TG genotype had a markedly increased risk of BC across additive, dominant, and over-dominant models, whereas the GG genotype showed a protective effect under the recessive model. In contrast, rs937282 did not show a significant association with BC risk. Circulating MDM2 levels were significantly elevated in patients compared with controls and varied by rs2279744 genotype, while circulating p53 levels showed an opposite trend. A strong inverse correlation was observed between serum MDM2 and p53 levels, supporting dysregulation of the MDM2-p53 feedback loop. Elevated MDM2 levels were also noted in HER2-positive and triple-positive BC subtypes. ConclusionTogether, these findings indicate that the MDM2 rs2279744 polymorphism contributes to BC susceptibility in a genotype-specific manner, likely through disruption of the MDM2-p53 regulatory balance. However, the absence of functional validation limits direct causal inference.

Background: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. It is associated with limited targeted treatment options, early relapse, and a high propensity for visceral metastasis. Data describing metastatic patterns and treatment characteristics of TNBC in Nigeria remain limited. Methods: This retrospective descriptive cohort study included 869 patients with TNBC managed at the Medserve-LUTH Cancer Center, Lagos University Teaching Hospital, Nigeria between June 2019 and June 2024. Demographic, clinicopathologic, metastatic, and treatment-related data were extracted from electronic medical records. Descriptive statistics were used to summarize patient characteristics, metastatic patterns, and treatment profiles. Associations between metastatic disease and selected clinicopathologic and treatment variables were explored using Pearsons chi-square test. Complete-case analysis was applied throughout. Results: The mean age at presentation was 52.09 {+/-} 12.26 years. Most patients were married (79.1%), postmenopausal (64.3%), and of Yoruba ethnicity (56.8%). Advanced disease predominated, with Stage III and Stage IV disease accounting for 42.9% and 35.6% of cases, respectively. Invasive ductal carcinoma was the most common histologic subtype (77.0%), while Grade II tumours constituted 51.3% of graded cases. Surgery was performed in 73.1% of patients, predominantly mastectomy (70.9% of surgical procedures). Chemotherapy was administered to 83.2% of patients, most commonly anthracycline-based regimens (41.8%), while radiotherapy was delivered to 63.5% of patients, with hypofractionated schedules of 42-43 Gy in 15-16 fractions accounting for 47.2% of radiotherapy courses. Metastatic disease was documented in 32.9% of evaluable patients. Lung metastasis was the most frequent site (62.5%), followed by bone (46.3%), regional lymph node invasion (38.5%), liver (23.0%), and brain (22.6%). Tumour grade and histologic subtype were not significantly associated with metastatic disease, whereas radiotherapy exposure demonstrated a significant association with metastatic status ({chi}{superscript 2} = 10.35, p = 0.001). Conclusion: TNBC in this Nigerian cohort was characterized by advanced-stage presentation, invasive ductal predominance, extensive use of multimodality treatment, and substantial visceral metastatic burden. Lung metastasis was the most common metastatic site. These findings provide contemporary real-world data on TNBC in Nigeria and highlight the continuing need for earlier diagnosis, timely referral, and sustained investment in comprehensive cancer care services.

Kalanchoe pinnata is a perennial plant that grows wild in tropical regions and is traditionally used as a medicinal plant. Plants of the Kalanchoe genus have been shown to possess several effects, including antibacterial and antihypertensive properties. However, effects such as the induction of apoptosis in cancer cells have not been reported for any substance other than leaf extracts of this plant and remain unexplained. Therefore, in this study, we investigated the effects of extracts from various parts of K. pinnata (flowers, leaves, and roots) on human colon cancer cell death. We conducted the study using three colorectal cancer cell lines (HT-29, SW620, and DLD-1) and three types of extracts derived from the flowers, leaves, and roots of this plant. Each K. pinnata extract significantly reduced cell viability in a dose-dependent manner in all colon cancer cells. In particular, the root extract induced cancer cell death and inhibited proliferation at lower concentrations than the other extracts. For the colon cancer cells examined, caspase-dependent apoptosis was suggested as the primary mechanism, although cell death was observed in some cells without detectable caspase activation. K. pinnata extracts induced both apoptosis and necrosis in colorectal cancer cells. In addition, K. pinnata extracts increased protein level of cleaved caspase-9, caspase-3, and PARP in SW620 and DLD-1 cells. The decrease in mitochondrial membrane potential was confirmed for all extracts, however caspase-mediated apoptosis was not observed in all cell lines, indicating the need for further investigation. Taken together, our results indicate the potential of the plant K. pinnata and the bioactive compounds it contains as new candidates for adjuvant therapy in colorectal cancer. In the future, it will be necessary to examine the relationship with genetic mutations in each cell line and to investigate the details of the cell death mechanism.

BACKGROUND: Anemia is a negative factor in cancer, influencing the prognosis, quality of life and financial situation of cancer patients. Recent studies have shown that anemia in cancer is provoked by augmented erythrocyte removal. OBJECTIVE: In this study we sought to investigate the molecular bases for erythrocyte removal in cancer patients with anemia. In particular, we explored the levels of erythrocyte CD47, lactadherin, calreticulin and MCP1. METHODS: Thirty five anemic cancer patients (25 women, aged 66.4 +/-11.35 years old) and twelve healthy non-anemic controls (8 men, aged 61.1+/-9.98 years old) participated in our study. Red blood cells were isolated throug multiple centrifugations, and were lysed with the use of Triton-X 100. The levels of CD47, lactadherin, calreticulin and monocyte chemoattrractant protein 1 were determined by ELISA. RESULTS: Erythrocytes of anemic cancer patients display reduced CD47 (p<0.001), MCP1 (p=0.05), CD47 to lactadherin ratio (p<0.05), and increased lactadherin levels (p<0.01) in comparison to the healthy controls. DISCUSSION: Reduced CD47 along with increased lactadherin possibly drive erythrocyte removal in anemic cancer patients. Conclusions: The role of CD47 and increased lactadherin should be examined in the future as potential therapeutic targets and biomarkers for anemia diagnosis and iron dymsetabolism.

The TETRATRICOPEPTIDE THIOREDOXIN-LIKE (TTL) proteins are a plant-specific family proposed to function as peripheral membrane proteins that contribute to abiotic stress tolerance in Arabidopsis, likely by maintaining cell wall integrity through brassinosteroid signaling. Previously, we identified a TTL gene that was differentially regulated at the translational level in nitrogen-fixing soybean plants under water deficit (WD) conditions. This finding prompted the characterization of the soybean TTL gene family. Using the Glycine max v4.0 proteome, we identified ten TTL homologs (GmTTL1-GmTTL10), which are unevenly distributed across five chromosomes. Phylogenetic and structural analyses grouped these genes into three clades and revealed a highly conserved exon-intron organization. Likewise, GmTTL proteins display a conserved number and arrangement of TPR and TRXL motifs. To gain insights into their potential biological functions, we integrated co-expression and differential expression analyses. This approach identified a co-expression module enriched for translationally downregulated genes related to the Gene Ontology terms "cellular anatomical entity", "membrane", "cell periphery", "cell wall modification", "nitrate assimilation", and "cell wall organization or biogenesis". Protein-protein interaction network analysis of this specific subset of genes uncovered a novel GmTTL connection with two nitrate reductase enzymes in nitrogen-fixing plants subjected to WD, potentially linking the TTL gene family to new functions or roles. This study provides a framework for future functional studies of GmTTL proteins and their contribution to abiotic stress adaptation in soybean. Key MessageThis work presents the first functional characterization of TTLs proteins in legume species and highlights key processes that may link the TTL gene family to new functions or roles.

Magnaporthe oryzae, the rice blast fungus, plays a role as a model organism for molecular plant-microbe interaction research. Studies on the pathogenic mechanism of this fungus revealed many genes involved in signaling pathways. As multi-omics data are being available, genomic-level researches have been conducted to uncover the underlying biological processes during the pathogenesis of M. oryzae. Identifying the genome-wide protein-protein interaction (PPI) network is one of the omics-level approaches, which helps to understand signaling and regulatory pathways. However, existing biological network resources of M. oryzae are not sufficient to decipher pathogenesis mechanisms due to the abundance of false positives/negatives. In this study, a reliable PPI network database of M. oryzae, MagNet, was constructed with three methods, including homology-based Interolog search, co-expression network construction, and domain-domain interaction (DDI)-based prediction. With three approaches altogether, the pan-network with 5,600,976 interactions was generated, including 217,531 highly confident interactions supported by all three methods. Experimental data on M. oryzae PPIs supported that our PPI network can predict PPIs with higher accuracy compared to the previously constructed databases. MagNet would provide integrated biological network data, which can help to understand the molecular mechanisms of the rice blast fungus. The PPI data can be accessed via https:/magnet.scnu.ac.kr.

Background and AimsPaspalum notatum reproduces through either sexuality or apomixis, two pathways that may coexist within the same individual and are regulated by interconnected molecular networks responsive to environmental cues. Here, we characterized the transcript structure and expression of BUD SITE SELECTION PROTEIN 13 (BUD13), a component of the RES spliceosomal complex previously reported as differentially expressed in florets of sexual and apomictic plants, as a first step toward testing its involvement in the molecular regulation of the apomixis-sexuality switch. MethodsPreviously generated floral and leaf transcriptomes from sexual and apomictic Paspalum notatum plants, including Oxford Nanopore long-read data, were mined to characterize BUD13 transcript structure and expression. Phylogenetic analyses and in silico mapping were conducted to infer evolutionary relationships and determine the origin of the transcripts. Differential expression was validated by RT-qPCR, while in situ hybridization was used to reveal cell-specific ovule expression patterns. Key resultsBUD13 is expressed in Paspalum notatum florets as a truncated isoform (SHORT) encoding a small protein lacking part of the herpes simplex virus regulatory protein (ICP4) domain. Two SHORT transcripts, SHORT1 and SHORT2, with different 5' untranslated region (UTR) regions, were identified in flowers. SHORT1 was consistently upregulated in apomictic ovules from premeiosis to anthesis. Both transcripts originated from a single genomic locus located in the subtelomeric region of the short arm of chromosome 6. SHORT isoforms with variable structures were detected in other monocots. In situ hybridization showed that, whereas BUD13 was expressed throughout sexual ovules, expression was absent from the female germline of apomictic ovules. A consistent expression was observed in somatic proembryos of aposporous embryo sacs. ConclusionsOur findings reveal structural, spatial and temporal divergence in BUD13 expression between sexual and apomictic reproductive programs, providing new insights into the molecular regulation of asexual seed formation.

Adults with Down syndrome (DS) are two times more likely to be diagnosed with chronic heart failure post-anthracycline chemotherapy compared to age and sex-matched adults without DS. They have an elevated lifetime risk of cardiovascular diseases, increasing their likelihood of anthracycline-induced chronic cardiovascular toxicity. We investigated the chronic effects of daunorubicin on the cardiovascular system of the adult Ts65Dn mouse model of DS compared to wild type euploid mice (WT). WT and Ts65Dn mice received two doses of 2mg/kg or 4mg/kg of daunorubicin or saline and were monitored for up to 117 days. Cardiac and vascular function were evaluated using left ventricular catheterization, histology, pulse wave velocity, and cardiac troponin tests. Survival significantly decreased in the Ts65Dn 4mg/kg group compared to saline controls (p<0.001). Further experiments were carried out with the saline and 2mg/kg groups, which exhibited lower mortality, more consistent with chronic toxicity. Body weight (p=0.001), end-diastolic pressure (p=0.016), and left ventricular mass (p=0.021) decreased in treated mice. The effect of treatment differed significantly between strains for ejection fraction (p=0.029). Pulse wave velocity increased over time (p<0.001). A significant interaction between treatment and strain was observed for collagen in both the left ventricles and thoracic aorta (p=0.002 and p<0.001, respectively). There was a strain difference for cardiac troponin I, indicating an increase in Ts65Dn mice (p=0.020). Daunorubicin treatment results in a distinct cardiovascular remodeling phenotype in Ts65Dn mice. More mechanistic studies are warranted to outline the pathophysiology of anthracycline cardiovascular toxicity in DS.

Objective To develop and validate a risk model for predicting postoperative bleeding in patients with thyroid cancer. Methods A total of 2800 consecutive patients diagnosed with thyroid cancer in the Department of Thyroid and Breast Surgery of the Affiliated Hospital of Xuzhou Medical University between January 2020 and December 2023 were retrospectively analyzed. Patients were categorized into two groups based on postoperative bleeding occurrence: bleeding and non-bleeding groups. Univariate and multivariate logistic regression analyses were utilized to screen independent risk factors. Meanwhile, risk prediction models were developed and nomogram . Subgroup analysis was performed to identify independent risk factors. The predictive effects of the models were assessed using the Hosmer-Lemeshow test and receiver operating characteristic (ROC) curves. Results Of the 2800 recruited patients, 50 had postoperative bleeding, with an incidence rate of 1.7%. Multivariate logistic regression analysis showed that age, hypertension, total thyroidectomy, tumor size [&ge;]4 cm, and operation time [&ge;]90 min were the risk factors for postoperative bleeding in thyroid cancer patients (P<0.05). A risk prediction model was established based on the above factors, and the area under the ROC curve was 0.881, with a sensitivity of 94.0%, a specificity of 67.3%, and an accuracy of 74.0%. Decision curve analysis revealed that the model had good predictive ability. Conclusions The constructed risk prediction model has good predictive power and can provide a reference for healthcare professionals to predict the risk of bleeding in patients after thyroid cancer surgery.

The ultimate cause of blindness in glaucoma is the death of retinal ganglion cells, and understanding the mechanism behind retinal ganglion cell loss during glaucoma could lead to the development of novel treatments for glaucoma. Endothelin-1 has been shown to mediate retinal ganglion cell death during glaucoma through impairment of mitochondrial function. Retinal ganglion cells are highly metabolically active, and susceptible to oxidative damage and decreased respiratory capacity. Mitophagy is the process whereby damaged mitochondria are degraded to prevent further propagation of oxidative damage. The current study evaluates the effect of endothelin-1 on mitophagy in retinal ganglion cells. Electron microscopy revealed endothelin-1 administration lead to a decrease in healthy mitochondria in the optic nerve. The MitoQC mouse was used to evalute mitophagy in response to endothelin-1, along with immunohistochemical analysis of mitophagy proteins. Mitophagy follows different trends in the optic nerve and retinal ganglion cell bodies following endothelin-1 administration, mitophagy was increased in the optic nerve but decreased in the retina following endothelin administration. With elevation of intraocular pressure, mitophagy was increased in the retina but decreased in the optic nerve. In retinal ganglion cells, parkin expression and activation was unchanged 24 hours after endothelin-1 administration, but was decreased 72 hours following endothelin-1 administration. Taken together, these results suggest that endothelin-1 impacts mitophagy through parkin-independent mechanisms in retinal ganglion cell bodies, and the ganglion cell bodies and optic nerve appear to have different responses to endothelin-1.