Inhibiting IL11RA to mitigate hepatic metastasis in skin cutaneous melanoma: Comprehensive insights from in vitro and in vivo investigations.

OBJECTIVE: This study aimed to investigate the role of Interleukin-11 receptor alpha (IL11RA) in skin cutaneous melanoma (SKCM) metastasis to the liver. METHODS: Human SKCM cell lines (A375, A375-MA2, SK-MEL-28, RPMI-7951) and primary dermal fibroblasts (HDFa) were utilized to assess IL11RA expression. IL11RA siRNA was transfected into RPMI-7951 and A375-MA2 cells for Wound healing and Transwell invasion assays. Il11ra knockout (KO) mice and wild-type (WT) mice were injected with B16-F10 cells into the spleen to evaluate hepatic melanoma metastasis. Correlation between IL11RA and MMP family genes was explored using online databases, including LinkedOmics, TIMER (Tumor Immune Estimation Resource), and GEPIA (Gene Expression Profiling Interactive Analysis). RT-qPCR and Western blotting were performed for expression analysis of Mmp2 and Mmp9 in liver tissues of mice. The impact of IL11RA on the STAT3 pathway was investigated in vitro and in vivo. RESULTS: Elevated expression of IL11RA was observed in SKCM cell lines compared to normal cells. IL11RA downregulation significantly inhibited migratory and invasive capabilities of A375-MA2 and RPMI-7951 in vitro. Il11ra gene knockout in mice demonstrated a substantial reduction in hepatic melanoma metastasis. Correlation analyses revealed associations between IL11RA and MMP2/MMP8. Il11ra gene knockout significantly decreased Mmp2 expression while increasing Mmp8 in liver tissues. IL11RA correlated positively with STAT3, and its inhibition led to a suppressed STAT3 pathway in SKCM cells and mouse liver tissue. CONCLUSION: IL11RA plays a crucial role in SKCM metastasis, affecting migratory and invasive abilities. Targeting IL11RA may offer a promising avenue for therapeutic interventions in cutaneous melanoma progression.

Synthesis of 8-Fluoroneocryptolepine and Evaluation for Cytotoxic Activity against AGS Cancer Cells.

Neocryptolepine derivatives have attracted great interest because of their unique cytotoxic activity. 8-Fluoroneocryptolepine (8FNC) was synthesized, and its cytotoxicity was evaluated by MTT assay in AGS gastric cancer cells and gastric mucosa GES-1 cells. 8-Fluoroneocryptolepine showed greater selectivity and cytotoxicity to AGS cells than the cisplatin (CIS) and fluorouracil (5-Fu) commonly used in clinical treatment of gastric cancer. Most importantly, we significantly improved the cytotoxic effect of 8FNC against AGS cells by structural modification and reduced the cytotoxicity against GES-1 cells compared with neocryptolepine. We further evaluated the activity of 8FNC against AGS cells in vitro. Our results indicate that 8FNC arrests the AGS cell cycle in the G2/M phase, reduces the mitochondrial membrane potential of AGS cells, and drives the initiation of apoptotic body formation in 8FNC-induced apoptosis. Moreover, 8FNC exhibits strong inhibitory effects on AGS cell migration. Studies on the molecular mechanisms of the cytotoxic activities of 8FNC revealed that it may play a significant role in the inhibitory effect on AGS human gastric cancer cells through the PI3K/AKT signaling pathway. In conclusion, 8FNC may become a promising lead compound in the development of potential clinical drug candidates for the treatment of gastric cancer.

Compound heterozygous variations in IARS1 cause recurrent liver failure and growth retardation in a Chinese patient: a case report.

BACKGROUND: Aminoacyl-tRNA synthetases (ARSs) are enzymes responsible for attaching amino acids to tRNA, which enables protein synthesis. Mutations in isoleucyl-tRNA synthetase (IARS1) have recently been reported to be a genetic cause for growth retardation, intellectual disability, muscular hypotonia, and infantile hepatopathy (GRIDHH). CASE PRESENTATION: In this study, we reported an additional case of compound heterozygous missense variations c.701 T > C (p.L234P) and c.1555C > T (p.R519C) in IARS1, which were identified using medical exome sequencing; c.701 T > C (p.L234P) was a novel variant, and c.1555C > T (p.R519C) was found in GnomAD. Unlike other reported patients, this individual presented prominently with recurrent liver failure, which led to her death at an early age of 19 months. She also had significant growth retardation, muscular hypotonia, chubby and flabby face, recurrent loose stools, and abnormal brain computed tomography (CT), while zinc deficiency and hearing loss were not present. Studies in zebrafish embryo modeling recapitulated some of the key phenotypic traits in embryo development, neurodevelopment, liver development, and myogenesis, demonstrating that these variations caused a loss of gene function in IARS1. CONCLUSIONS: We have found a novel mutation point c.701 T > C (p.L234P) in IARS1. Compound heterozygous mutations of c.701 T > C (p.L234P) and c.1555C > T (p.R519C) in IARS1 are pathogenic, which can cause GRIDHH in child.

[Application of Array-based Comparative Genomic Hybridization in the Prenatal Diagnosis of Fetal Chromosomal Aberration in Gravidas with Advanced Age].

OBJECTIVE: To evaluate the clinical application of array-based comparative genomic hybridization (a-CGH) in the prenatal diagnosis of fetal chromosomal aberrations in gravidas with advanced maternal age (AMA). METHODS: A total of 3 677 amniotic fluid samples from pregnant women who underwent amniocentesis for prenatal diagnosis solely due to AMA were selected. Array-CGH was performed on the Agilent CGX TM (8X60K) platform and the data were analyzed by the Genoglyphix software. RESULTS: The overall detection rate of chromosomal aberration was 2.04% (75/3677), with 53.33% (40/75) being aneuploidies, including 22 cases of trisomy-21, 5 cases of trisomy-18, 8 cases with XXY, 3 cases of XYY and 2 cases of mosaic monosomy X, 32.00% (24/75) being pathogenic copy number variations (pCNVs), including 19 cases of microdeletion and 5 cases of microduplication, with the fragment size ranging from 323 kb to 26 780 kb, and 14.67% (11/75) being likely pathogenic CNVs (lpCNVs), including 7 cases of microdeletion and 7 cases of microduplication, with the fragment size ranging from 358 kb to 16 873 kb. Besides, the detection rate of CNVs of unknown clinical significance (VUS) was 0.84% (31/3 677). The detection rate of aneuploidies increased significantly with increased maternal age ( P<0.05). However, there were no significant differences in the detection rate of p/lpCNVs among different maternal age groups ( P>0.05). CONCLUSION: Our findings suggest that, compared with traditional karyotype analysis, a-CGH not only detects aneuploidies, but also detect pathogenic CNVs, including microdeletion/microduplication syndromes. The detection rate of fetal aneuploidies was closely correlated to maternal age. However, no correlation was found between the detection rate of p/lpCNVs and maternal age.

[Application of Array-based Comparative Genomic Hybridization in Diagnostic Assessment of Abnormal Prenatal Serological Screening Results of Down's Syndrome].

OBJECTIVE: To explore the application of array-based comparative genomic hybridization (a-CGH) technology in the prenatal diagnostic assessment of abnormal serological prenatal screening results of Down's syndrome (DS). METHODS: A total of 3 578 amniotic fluid samples from pregnant women who underwent amniocentesis for prenatal diagnosis solely due to abnormal serological prenatal screening results were selected. The samples were categorized into 3 groups, 2 624 in the high-risk group, 662 in the borderline-risk group, and 292 in the abnormal multiple of median (MoM) group. a-CGH was performed on the Agilent CGX ™ (8×60K) platform and the data were analyzed by the Genoglyphix ® software. RESULTS: The overall detection rate of chromosomal abnormalities was 3.38% (121/3 578). Among the chromosomal abnormalities, 49.59% (60/121) was aneuploidies, 42.15% (51/121) was pathogenic copy number variants (pCNVs), and 8.26% (10/121) was likely pathogenic CNVs (lpCNVs). The detection rate of copy number variant of uncertain significance (VUS) was 1.03% (37/3 578). In the high-risk, the borderline-risk and the abnormal MoM groups, the detection rate of chromosomal abnormalities was 3.54% (93/2 624), 2.87% (19/662) and 3.08% (9/292), respectively; the detection rate of p/lp CNVs was 1.64% (43/2 624), 1.81% (12/662) and 2.05% (6/292), respectively; the detection rate of trisomy 21 and trisomy 18 was 1.37% (36/2 624), 0.76% (5/662) and 0.34% (1/292) in the three groups, respectively. There were no significant differences in all the detection rate among these groups ( P>0.05). One sample with X(51)/XYY(49) confirmed by fluorescence in situ hybridization (FISH) was misdiagnosed by a-CGH. CONCLUSION: Prenatal diagnosis with a-CGH is of great significance for reducing birth defects in pregnancies with abnormal serological prenatal screening results of DS. It can also be used to detect CNVs of microdeletion/microduplication syndromes.

Castleman's disease. Large retroperitoneal masses and multiple calcifications detected by 18F-FDG PET/CT.

An 18 years old man was admitted to our hospital for intractable oral ulcer and abdominal discomfort. Bulky soft-tissue masses were found in pathology speciments in the retroperitoneum from the twelfth thoracic vertebra to the fifth lumbar vertebra during an abdominal computed tomography (CT) scan. Then he was referred for fluorine-18-fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) due to suspicion of paraneoplastic pemphigus. On the maximum intensity projection image, a large, elongated mass was displayed in the right abdomen near the spine with slightly increased 18F-FDG uptake; axial CT, corresponding PET images and PET/CT images showed multiple heterogeneous soft-tissue masses in the retroperitoneum. Some lesions were fused together with the SUVmax of 3.6, measuring 69mmx29mm, pushing the adjacent normal organs. Massive and large calcifications were observed in the center of the lesions, with coarse and arborizing patterns. The longest diameter of the calcified focus was 58mm. Finally, pathology confirmed the diagnosis of Castleman's disease (CD) with a hyaline-vascular variant after the operation. As a rare lymphoproliferative disorder, CD was first described by Dr Benjamin Castleman in 1954. Though lesions in the retroperitoneum are easier to calcify than in other locations, we have not seen a report with massive and so large calcifications (58mm of the longest diameter). Since prominent calcifications were the main feature of the lesions, we considered infections, tuberculosis, sarcoma, neurogenic tumor, teratoma and lymphoproliferative disorders in the differential diagnosis. We also considered the intractable oral ulcer and radiology sings. In addition, 18F-FDG uptake was revealed in most lesions of CD. Therefore, we thought of the diagnosis of CD, which was consistent with the final pathology.

Clonal Characteristics of Circulating B Lymphocyte Repertoire in Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by elevated serum anti-mitochondrial Ab and lymphocyte-mediated bile duct damage. This study was designed to reveal the clonal characteristics of B lymphocyte repertoire in patients with PBC to facilitate better understanding of its pathogenesis and better management of these patients. Using high-throughput sequencing of Ig genes, we analyzed the repertoire of circulating B lymphocytes in 43 patients with PBC, and 34 age- and gender-matched healthy controls. Compared with healthy controls, PBC patients showed 1) a gain of 14 new clones and a loss of 8 clones; 2) a significant clonal expansion and increased relative IgM abundance, which corresponded with the elevated serum IgM level; 3) a significant reduction of clonal diversity and somatic hypermutations in class-switched sequences, which suggested a general immunocompromised status; 4) the reduction of clonal diversity and enhancement of clonal expansion were more obvious at the cirrhotic stage; and 5) treatment with ursodeoxycholic acid could increase the clonal diversity and reduce clonal expansion of the IgM repertoire, with no obvious effect on the somatic hypermutation level. Our data suggest that PBC is a complex autoimmune disease process with evidence of B lymphocyte clonal gains and losses, Ag-dependent ogligoclonal expansion, and a generally compromised immune reserve. This new insight into the pathogenesis of PBC opens up the prospect of studying disease-relevant B cells to better diagnose and treat this devastating disease.

Reduced phytotoxicity of propazine on wheat, maize and rapeseed by salicylic acid.

Propazine belongs to the triazine herbicide family and widely used in the farmland for crop production. Recent studies have shown that the residue of propazine in environment is accumulative. This inevitably results in accumulation of propazine in crops. Therefore, reduction of propazine toxicity and accumulation in crops is critically important. In this study, the growth of wheat, maize and rapeseed was significantly inhibited by 2, 8 and 0.4 mg kg-1 propazine in soils. The chlorophyll content of the three crops also showed significant decrease, while the electrolyte permeability, a biomarker of cellular damage, increased in the plant cells. However, when plants were sprayed with 5 mg L-1 of salicylic acid (SA), the propazine phytotoxicity of the crops was relieved, with increased chlorophyll content and reduced electrolyte permeability of all crops. Meanwhile, the activities of peroxidase (POD) and glutathione transferase (GST) remained lower. The propazine accumulation in the crops and the residues in the soil were determined by high performance liquid chromatography. The concentration of propazine in plants and soils treated by SA was less than that of the untreated control. Six propazine degraded products (derivatives) in rhizosphere of wheat were characterized using ultraperformance liquid chromatography with a quadrupole-time-of-flight tandem mass spectrometer. Our work indicates that the improved growth of crops was possibly due to the acceleration of propazine degradation by salicylic acid.

[Clinical Application Assessment of KaryoLite BoBs Combined with QF-PCR in the Detection of Products of Conception].

OBJECTIVE: To assess the accuracy and discuss the feasibility of KaryoLite bacterial artificial chromosome on beads (KL-BoBs) and quantitative fluorescent polymerase chain reaction (QF-PCR) in genetic testing of products of conception (POC) by comparing with the chromosomal microarray analysis (CMA) test results. METHODS: Eighty-one cases of abortion samples were collected in the prenatal diagnosis center of West China Second University Hospital in Sichuan University from May to August 2016,including 61 cases of placenta tissues,19 cases of fetal muscle tissues and 1 case of fetal liver tissue. KL-BoBs and QF-PCR were used to detect the samples. The results were compared with those of CMA test to evaluate the accuracy of KL-BoBs and QF-PCR. RESULTS: Of the 81 POC samples,the results of 70 samples tested by KL-BoBs was consistent with that of CMA. Among them,36 cases were normal karyotype and 34 cases were abnormal karyotypes (aneuploidy). Triploid could not been detected by KL-BoBs (the results were shown 2 cases were normal karyotype and 5 cases were aneuploidy),whereas CMA and QF-PCR could be detected. Copy number variation of small segments could not been detected by KL-Bobs. Four cases of copy number variationwere detected by CMA.Compared with CMA,the positive coincident rate of KL-BoBs combined with QF-PCR was 91.1% (41/45),the negative coincidence rate was 100% (36/36). The accuracy rate of KL-BoBs was 86.4% (70/81),the false positive was 0% and the false negative was 13.3% (6/45). Whereas both KL-BoBs and QF-PCR were simultaneously detected,the accuracy rate would be improved to 95.1% (77/81). CONCLUSION: The accuracy rate of KL-BoBs combined with QF-PCR was high for testing early pregnancy abortion tissue. It can be used as a first-tier test.

Fibroblast growth factor 2 protects against renal ischaemia/reperfusion injury by attenuating mitochondrial damage and proinflammatory signalling.

Ischaemia-reperfusion injury (I/RI) is a common cause of acute kidney injury (AKI). The molecular basis underlying I/RI-induced renal pathogenesis and measures to prevent or reverse this pathologic process remains to be resolved. Basic fibroblast growth factor (FGF2) is reported to have protective roles of myocardial infarction as well as in several other I/R related disorders. Herein we present evidence that FGF2 exhibits robust protective effect against renal histological and functional damages in a rat I/RI model. FGF2 treatment greatly alleviated I/R-induced acute renal dysfunction and largely blunted I/R-induced elevation in serum creatinine and blood urea nitrogen, and also the number of TUNEL-positive tubular cells in the kidney. Mechanistically, FGF2 substantially ameliorated renal I/RI by mitigating several mitochondria damaging parameters including pro-apoptotic alteration of Bcl2/Bax expression, caspase-3 activation, loss of mitochondrial membrane potential and KATP channel integrity. Of note, the protective effect of FGF2 was significantly compromised by the KATP channel blocker 5-HD. Interestingly, I/RI alone resulted in mild activation of FGFR, whereas FGF2 treatment led to more robust receptor activation. More significantly, post-I/RI administration of FGF2 also exhibited robust protection against I/RI by reducing cell apoptosis, inhibiting the release of damage-associated molecular pattern molecule HMBG1 and activation of its downstream inflammatory cytokines such as IL-1α, IL-6 and TNF α. Taken together, our data suggest that FGF2 offers effective protection against I/RI and improves animal survival by attenuating mitochondrial damage and HMGB1-mediated inflammatory response. Therefore, FGF2 has the potential to be used for the prevention and treatment of I/RI-induced AKI.

Circumventing intratumoral heterogeneity to identify potential therapeutic targets in hepatocellular carcinoma.

BACKGROUND & AIMS: Identifying target genetic mutations in hepatocellular carcinoma (HCC) for therapy is made challenging by intratumoral heterogeneity. Circulating cell-free DNAs (cfDNA) may contain a more complete mutational spectrum compared to a single tumor sample. This study aimed to identify the most efficient strategy to identify all the mutations within heterogeneous HCCs. METHODS: Whole exome sequencing (WES) and targeted deep sequencing (TDS) were carried out in 32 multi-regional tumor samples from five patients. Matched preoperative cfDNAs were sequenced accordingly. Intratumoral heterogeneity was measured using the average percentage of non-ubiquitous mutations (present in parts of tumor regions). Profiling efficiencies of single tumor specimen and cfDNA were compared. The strategy with the highest performance was used to screen for actionable mutations. RESULTS: Variable levels of heterogeneity with branched and parallel evolution patterns were observed. The heterogeneity decreased at higher sequencing depth of TDS compared to measurements by WES (28.1% vs. 34.9%, p<0.01) but remained unchanged when additional samples were analyzed. TDS of single tumor specimen identified an average of 70% of the total mutations from multi-regional tissues. Although genome profiling efficiency of cfDNA increased with sequencing depth, an average of 47.2% total mutations were identified using TDS, suggesting that tissue samples outperformed it. TDS of single tumor specimen in 66 patients and cfDNAs in four unresectable HCCs showed that 38.6% (26/66 and 1/4) of patients carried mutations that were potential therapeutic targets. CONCLUSIONS: TDS of single tumor specimen could identify actionable mutations targets for therapy in HCC. cfDNA may serve as secondary alternative in profiling HCC genome. LAY SUMMARY: Targeted deep sequencing of single tumor specimen is a more efficient method to identify mutations in hepatocellular carcinoma made from mixed subtypes compared to circulating cell-free DNA in blood. cfDNA may serve as secondary alternative in profiling HCC genome. Identifying mutations may help clinicians choose targeted therapy for better individual treatments.

Exploring the Mechanisms of Electroacupuncture-Induced Analgesia through RNA Sequencing of the Periaqueductal Gray.

Electroacupuncture (EA) can relieve various pains. However, its mechanism in terms of the transcriptome is still not well-known. To explore the full profile of EA-induced molecular modification in the central nerve system, three twins of goats were selected for a match-paired experiment: EA stimulation (60 Hz, 30 min) and none-EA (control). Goats in the EA group showed an increased (p < 0.05) nociceptive threshold compared with the control goats. Experimental goats were sacrificed at 4 h of the experiment, and the periaqueductal grays were harvested for RNA sequencing. As a result, 2651 differentially expressed genes (1803 up-regulated and 848 down-regulated genes) were found and enriched in 30 Kyoto Encyclopedia of Genes and Genomes pathways and 149 gene ontology terms. EA-regulated five neuropeptide genes (proenkephalin, proopiomelanocortin, preprodynorphin, diazepam-binding inhibitor and proprotein convertase 1 inhibitor) were validated with quantitative PCR. Furthermore, up-regulated glutamate receptors, glutamate transporters, γ-aminobutyric acid (GABA) receptors, GABA transporters, synaptotagmins or mitogen-activated protein kinase (MAPK) genes might contribute to EA-induced analgesia through regulating the glutamatergic synapse, GABAergic synapse, MAPKs, ribosome or ubiquitin-proteasome pathways. Our findings reveal a full profile of molecular modification in response to EA and provide a solid experimental framework for exploring the mechanisms underlying EA-induced analgesia.

[Application of Chromosomal Microarray Analysis for Chromosomal Abnormalities of Spontaneously Aborted Fetuses].

OBJECTIVE: To evaluate the clinical significance of chromosomal microarry analysis (CMA) for detection of chromosomal abnormalities in spontaneously aborted fetuses. METHODS: Chorionic villi samples from 431 spontaneously aborted fetuses were detected on the chromosomal abnormalities by CMA in our department form September 2014 to April 2016. RESULTS: The overall success rate of CMA was 100%,and 283 cases were detected with abnormalities (65.67%). Of these 283 cases with abnormal results,126 were common aneuploidies (trisomy 13,16,18,21,22 as well as X and Y aneuploidies) (44.52%),72 were uncommon aneuploidies (25.44%),10 were composited aneuploidies (3.53%),9 were partial aneuploidies (3.18%),29 were polyploidy (10.25%),4 were mosaicism (1.41%),31 were with multiple duplications and deletions (10.96%),and 2 were microduplication/microdeletion syndromes. CONCLUSION: CMA has great advantage for the detection of chromosomal abnormalities in spontaneously aborted fetuses comparing with fluorescence in situ hybridization (FISH). It is of great clinical significance for etiological diagnosis of spontaneous abortion and guidance on reproduction.

4-[(5-Chloro-2-hy-droxy-benzyl-idene)amino]-3-ethyl-1H-1,2,4-triazole-5(4H)-thione.

The title compound, C11H11ClN4OS, crystallizes with two mol-ecules, A and B, in the asymmetric unit in which the dihedral angles between the triazole and benzene rings are 54.6 (3) and 56.0 (3)°. Both mol-ecules feature an intra-molecular O-H⋯N hydrogen bond, which generates an S(6) ring. In the crystal, A-B dimers are linked by pairs of weak C-H⋯S hydrogen bonds along with π-π stacking inter-actions between the triazole rings [centroid-centroid separations = 3.631 (3) and 3.981 (4)Å]. N-H⋯S hydrogen bonds link the dimers into [100] chains, which feature R 2 (2)(8) loops.

[The influence of fibronectin on the formation of multi-cellular spheroid of ovarian cancer].

OBJECTIVE: To investigate the role of Fibronectin in the formation of multi-cellular spheroid of ovarian cancer and the integrin receptor involved in the process. METHODS: In vitro model of multi-cellular spheroid of SKOV3 was constructed by liguid overlay technique. The influence of fibronectin on the formation of the spheroid was observed. The gene expressions of potential integrin receptors were examined from the levels of mRNA and protein using real time reverse transcription PCR and Western-blot. RESULTS: Fibronctin stimulated the formation of multi-cellular spheroid of ovarian cancer larger than 250 microm. fibronectin suppressed the expression of subtype of integrin receptor ITGA5. CONCLUSION: Fibronectin can enhance the formation of multi-cellular spheroid of ovarian cancer. The subtype of integrin receptor ITGA5 is probably involved in the process.

Clinical significance of downregulated NISCH expression in skin cutaneous melanoma: Modulation of tumor cell invasion, migration, and EMT via PAK1 inhibition.

OBJECTIVE: This study aimed to investigate the expression and functional role of NISCH in skin cutaneous melanoma (SKCM), exploring its association with clinical characteristics and its potential impact on human skin melanoma cell behavior. METHODS: The research assessed differential NISCH expression in SKCM tissues using the GEPIA (Gene Expression Profiling Interactive Analysis) database and validated these findings through immunohistochemical staining of 45 clinical samples. To affirm NISCH expression at the cellular level, three human skin melanoma cell lines (RPMI-7951, A375, MEL-5), and the human normal skin cell line HEMa underwent quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting. Transwell experiments evaluated the migration and invasion capabilities of RPMI-7951 and A375 cells post-transduction with NISCH or PAK1 lentiviral activation particles. Additionally, qRT-PCR analysis of epithelial-mesenchymal transition (EMT)-related gene expression (Vimentin, E-cadherin, N-cadherin) was conducted in A375 and RPMI-7951 cells. RESULTS: SKCM tissues exhibited significantly reduced NISCH expression compared to normal tissues. Immunohistochemical analysis revealed predominant nuclear localization of NISCH in melanoma cells, with reduced expression significantly correlating with sex, advanced stage, and lymph node metastasis. Melanoma cell lines displayed lower NISCH expression levels compared to normal skin cells. Functional experiments showcased that NISCH overexpression suppressed p-PAK1/PAK1, while PAK1 upregulation notably increased melanoma cell migration, invasion, and induced EMT. Remarkably, NISCH overexpression counteracted PAK1-induced effects on EMT, migration, and invasion in melanoma cells. CONCLUSION: NISCH may significantly influence the aggressive behavior of SKCM cells via the PAK1 pathway, making it a potential therapeutic target for managing melanoma metastasis.

Association of early-term birth and breastfeeding practices with nutritional outcomes in singleton term infants: a multicenter cross-sectional study.

BACKGROUND: Limited research has explored the associations of gestational age (GA) and breastfeeding practices with growth and nutrition in term infants. METHODS: This multicenter cross-sectional study recruited 7299 singleton term infants from well-child visits in Shandong, China, between March 2021 and November 2022. Data on GA, gender, ethnicity, birth weight, parental heights, gestational diabetes and hypertension, age at visit, breastfeeding practices (point-in-time data at visit for infants < 6 months and retrospective data at 6 months for infants ≥ 6 months), complementary foods introduction, infant length and weight, were collected. 7270 infants were included in the analysis after excluding outliers with Z-scores of length (LAZ), weight or weight for length (WLZ) <-4 or > 4. Linear regression models adjused for covariates explored the impact of GA and breastfeeding practices on LAZ and WLZ, while logistic regression models evaluated their effect on the likelihood of moderate and severe stunting (MSS, LAZ<-2), moderate and severe acute malnutrition (MSAM, WLZ<-2) and overweight/obesity (WLZ > 2). Sensitivity analysis was conducted on normal birth weight infants (2.5-4.0 kg). RESULTS: Infants born early-term and exclusively breastfed accounted for 31.1% and 66.4% of the sample, respectively. Early-term birth related to higher WLZ (< 6 months: ß = 0.23, 95% confidence interval (CI): 0.16, 0.29; ≥6 months: ß = 0.12, 95% CI: 0.04, 0.20) and an increased risk of overweight/obesity throughout infancy (< 6 months: OR: 1.41, 95% CI 1.08, 1.84; ≥6 months: OR: 1.35, 95% CI 1.03, 1.79). Before 6 months, early-term birth correlated with lower LAZ (ß=-0.16, 95% CI: -0.21, -0.11) and an increased risk of MSS (OR: 1.01, 95%CI 1.00, 1.02); Compared to exclusive breastfeeding, exclusive formula-feeding and mixed feeding linked to lower WLZ (ß=-0.15, 95%CI -0.30, 0.00 and ß=-0.12, 95%CI -0.19, -0.05, respectively) and increased risks of MSAM (OR: 5.57, 95%CI 1.95, 15.88 and OR: 3.19, 95%CI 1.64, 6.19, respectively). Sensitivity analyses confirmed these findings. CONCLUSIONS: The findings emphasize the health risks of early-term birth and the protective effect of exclusive breastfeeding in singleton term infants, underscoring the avoidance of nonmedically indicated delivery before 39 weeks and promoting exclusive breastfeeding before 6 months.

Phthalates Induce Neurotoxicity by Disrupting the Mfn2-PERK Axis-Mediated Endoplasmic Reticulum-Mitochondria Interaction.

Di-(2-ethylhexyl) phthalate (DEHP), as the most common phthalate, has been extensively used as a plasticizer to improve the plasticity of agricultural products, which pose severe harm to human health. Mitochondrial dynamics and endoplasmic reticulum (ER) homeostasis are indispensable for maintaining mitochondria-associated ER membrane (MAM) integrity. In this study, we aimed to explore the effect of DEHP on the nervous system and its association with the ER-mitochondria interaction. Here, we showed that DEHP caused morphological changes, motor deficits, cognitive impairments, and blood-brain barrier disruption in the brain. DEHP triggered ER stress, which is mainly mediated by protein kinase R-like endoplasmic reticulum kinase (PERK) signaling. Moreover, DEHP-induced mitofusin-2 (Mfn2) downregulation results in imbalance of the mitochondrial dynamics. Interestingly, DEHP exposure impaired MAMs by inhibiting the Mfn2-PERK interaction. Above all, this study elucidates the disruption of the Mfn2-PERK axis-mediated ER-mitochondria interaction as a phthalate-induced neurotoxicity that could be potentially developed as a novel therapy for neurological diseases.

AQP1 Deficiency Drives Phthalate-Induced Epithelial Barrier Disruption through Intestinal Inflammation.

Di-2-ethylhexyl phthalate (DEHP) is frequently used as a plasticizer to enhance the plasticity and durability of agricultural products, which pose adverse effects to human health and the environment. Aquaporin 1 (AQP1) is a main water transport channel protein and is involved in the maintenance of intestinal integrity. However, the impact of DEHP exposure on gut health and its potential mechanisms remain elusive. Here, we determined that DEHP exposure induced a compromised duodenum structure, which was concomitant with mitochondrial structural injury of epithelial cells. Importantly, DEHP exposure caused duodenum inflammatory epithelial cell damage and strong inflammatory response accompanied by activating the TLR4/MyD88/NF-κB signaling pathway. Mechanistically, DEHP exposure directly inhibits the expression of AQP1 and thus leads to an inflammatory response, ultimately disrupting duodenum integrity and barrier function. Collectively, our findings uncover the role of AQP1 in phthalate-induced intestinal disorders, and AQP1 could be a promising therapeutic approach for treating patients with intestinal disorders or inflammatory diseases.

Deciphering neo-sex and B chromosome evolution by the draft genome of Drosophila albomicans.

BACKGROUND: Drosophila albomicans is a unique model organism for studying both sex chromosome and B chromosome evolution. A pair of its autosomes comprising roughly 40% of the whole genome has fused to the ancient X and Y chromosomes only about 0.12 million years ago, thereby creating the youngest and most gene-rich neo-sex system reported to date. This species also possesses recently derived B chromosomes that show non-Mendelian inheritance and significantly influence fertility. METHODS: We sequenced male flies with B chromosomes at 124.5-fold genome coverage using next-generation sequencing. To characterize neo-Y specific changes and B chromosome sequences, we also sequenced inbred female flies derived from the same strain but without B's at 28.5-fold. RESULTS: We assembled a female genome and placed 53% of the sequence and 85% of the annotated proteins into specific chromosomes, by comparison with the 12 Drosophila genomes. Despite its very recent origin, the non-recombining neo-Y chromosome shows various signs of degeneration, including a significant enrichment of non-functional genes compared to the neo-X, and an excess of tandem duplications relative to other chromosomes. We also characterized a B-chromosome linked scaffold that contains an actively transcribed unit and shows sequence similarity to the subcentromeric regions of both the ancient X and the neo-X chromosome. CONCLUSIONS: Our results provide novel insights into the very early stages of sex chromosome evolution and B chromosome origination, and suggest an unprecedented connection between the births of these two systems in D. albomicans.