Hutchisonmeyer3386
The requirement of promyelocytic leukaemia protein (PML) in interferon (IFN)-induced cell apoptosis is well-established. However, the exact mechanisms by which the multiple isoforms of PML protein participate in this process remain not well-understood. Danuglipron manufacturer We previously demonstrated that PML isoform II (PML-II) positively regulates induced gene expression during a type I IFN response and evaluate here how PML-II contributes to IFNα-induced cell death.
HeLa cells were transiently depleted of PML-II by siRNA treatment and the response of these cells to treatment with IFNα assessed by molecular assays of mRNA and proteins associated with IFN and apoptosis responses.
In HeLa cells, death during IFNα stimulation was reduced by prior PML-II depletion. PML-II removal also considerably decreased the induced expression of pro-apoptotic ISGs such as ISG54 (IFIT2), and substantially impaired or prevented expression of PUMA and TRAIL, proteins that are associated with the intrinsic and extrinsic apoptotic pathways respectively. Thirdly, PML-II depletion enhanced ERK and AKT pro-survival signaling activation suggesting that PML-II normally suppresses signaling via these pathways, and that lack of PML-II hence led to greater than normal activation of AKT signaling upon IFNα stimulation and consequently increased resistance to IFNα-induced apoptosis.
The positive contribution of PML-II to the expression of various IFNα-induced pro-apoptotic proteins and its inhibition of pro-survival signaling together provide a mechanistic explanation for reduced apoptosis under conditions of PML deficiency and may account for at least part of the role of PML as a tumor suppressor gene. Video Abstract.
The positive contribution of PML-II to the expression of various IFNα-induced pro-apoptotic proteins and its inhibition of pro-survival signaling together provide a mechanistic explanation for reduced apoptosis under conditions of PML deficiency and may account for at least part of the role of PML as a tumor suppressor gene. Video Abstract.
Recent genome wide analysis studies have identified a strong association between single nucleotide variations within the human ATP2B4 gene and susceptibility to severe malaria. The ATP2B4 gene encodes the plasma membrane calcium ATPase 4 (PMCA4), which is responsible for controlling the physiological level of intracellular calcium in many cell types, including red blood cells (RBCs). It is, therefore, postulated that genetic differences in the activity or expression level of PMCA4 alters intracellular Ca
levels and affects RBC hydration, modulating the invasion and growth of the Plasmodium parasite within its target host cell.
In this study the course of three different Plasmodium spp. infections were examined in mice with systemic knockout of Pmca4 expression.
Ablation of PMCA4 reduced the size of RBCs and their haemoglobin content but did not affect RBC maturation and reticulocyte count. Surprisingly, knockout of PMCA4 did not significantly alter peripheral parasite burdens or the dynamics of blood stage Plasmodium chabaudi infection or reticulocyte-restricted Plasmodium yoelii infection. Interestingly, although ablation of PMCA4 did not affect peripheral parasite levels during Plasmodium berghei infection, it did promote slight protection against experimental cerebral malaria, associated with a minor reduction in antigen-experienced T cell accumulation in the brain.
The finding suggests that PMCA4 may play a minor role in the development of severe malarial complications, but that this appears independent of direct effects on parasite invasion, growth or survival within RBCs.
The finding suggests that PMCA4 may play a minor role in the development of severe malarial complications, but that this appears independent of direct effects on parasite invasion, growth or survival within RBCs.
Episiotomy is a surgical incision of the perineum to hasten the delivery. There is a scarce of information related to episiotomy practice, and its associated factors, in developing countries, including Ethiopia. Thus, this study was aimed to determine the level of episiotomy practice and to identify its determinants at public health facilities of Metema district, northwest, Ethiopia.
Institutional-based cross sectional study was conducted among 410 delivered mothers from March 1 to April 30, 2020. We recruited study participants using systematic random sampling technique. Data were entered to Epi data version 3.1 and exported to STATA version 14 for statistical analysis. Stepwise backward elimination was applied for variable selection and model fitness was checked using Hosmer and Lemshows statistics test. Adjusted odds ratio with the corresponding 95% confidence interval was used to declare the significance of variables.
In this study, the magnitude of episiotomy practice was found 44.15% (95% CI 39.32han the recommended value of WHO. The WHO recommends an episiotomy rate of 10% for all normal deliveries. The result of this study showed that episiotomy practice is common among mothers whose age group are 18-24. In addition, mothers whose labor were assisted by instrumental vaginal delivery are more likely to have episiotomy as compared to those delivered by normal vaginal delivery. Laboring mothers who had used oxytocin were about three times more likely to be exposed for episiotomy than laboring mothers who did not use oxytocin drug. Moreover, episiotomy practice was nearly five times more likely among mothers who had birth spacing of 2 years and less as compared to mothers who had birth spacing of more than 2 years.
Huntingtin (Htt) protein is the product of the gene mutated in Huntington's disease (HD), a fatal, autosomal dominant, neurodegenerative disorder. Normal Htt is essential for early embryogenesis and the development of the central nervous system. link2 However, the role of Htt in adult tissues is less defined. Following the recent promising clinical trial in which both normal and mutant Htt mRNA were knocked down in HD patients, there is an urgent need to fully understand the molecular consequences of knocking out/down Htt in adult tissues. Htt has been identified as an important transcriptional regulator. Unbiased investigations of transcriptome changes with RNA-sequencing (RNA-Seq) have been done in multiple cell types in HD, further confirming that transcriptional dysregulation is a central pathogenic mechanism in HD. However, there is lack of direct understanding of the transcriptional regulation by normal Htt.
To investigate the transcriptional role of normal Htt, we first knocked out Htt in the human neuro directly caused by the loss of Htt-mediated transcriptional regulation or due to the secondary consequences of disruption in the gene regulatory network. Our study therefore provides valuable information about key genes associated with Htt-mediated transcription and improves our understanding of the molecular mechanisms underlying the cellular functions of normal and mutant Htt.
The widespread transcriptome changes in Htt-null cells could be directly caused by the loss of Htt-mediated transcriptional regulation or due to the secondary consequences of disruption in the gene regulatory network. Our study therefore provides valuable information about key genes associated with Htt-mediated transcription and improves our understanding of the molecular mechanisms underlying the cellular functions of normal and mutant Htt.
Maternal and newborn mortality is high immediately after childbirth and up to 42 days postnatally despite the availability of interventions. Postnatal care is crucial in preventing mortality and improving the health of women and newborns. This prospective cohort study investigated the initiation and utilization of postnatal care at health facilities and explored users' and providers' perspectives on utilization of postnatal care services.
A sequential explanatory mixed method was used involving women who were followed from the 3rd trimester of pregnancy to 3-4 months postnatally in Northwest, Tanzania. From January to December 2018, a door-to-door survey was conducted 3-4 months postnatally among 1385 of these women. A convenience sample of women and community health workers participated in focus group discussions, and traditional birth attendants and nurses participated in key informant interviews to complement quantitative data. link3 Data analyses were conducted using STATA version 13 and NVIVO version 12.
h demand and supply sides factors need to be addressed.
Utilization of postnatal care services remains low in this setting as a result of a number of disparate and complex factors that influence women's choices. Provision of effective postnatal care is hindered by lack of supplies, staffing, and inadequate infrastructure. To ensure accessibility and availability of quality services in this setting, both demand and supply sides factors need to be addressed.
Gastric cancer (GC) is one of the most common cancer worldwide. It is essential to identify non-invasive diagnostic and prognostic biomarkers of GC. The aim of the present study was to screen candidate biomarkers associated with the pathogenesis and prognosis of GC by a novel strategy.
The expression level of gene higher in cancer than in adjacent non-cancer tissue was defined as "positive", and the top 5% genes with "positive rate" were filtered out as candidate diagnostic biomarkers in three Gene Expression Omnibus (GEO) datasets. Further, a prognostic risk model was constructed by multivariate Cox regression analysis in GEO dataset and validated in The Cancer Genome Atlas (TCGA). The expression level of candidate biomarkers was determined in serum and serum-derived exosomes of GC patients. Moreover, the effect of biomarkers in exosomes on migration of GC cells was analyzed by transwell assay.
Ten candidate biomarkers (AGT, SERPINH1, WNT2, LIPG, PLAU, COL1A1, MMP7, MXRA5, CXCL1 and COL11A1) were ident findings provided a novel strategy to identify diagnostic biomarkers based on public datasets, and suggested that the three-gene signature was a candidate diagnostic and prognostic biomarker for patients with GC.
Osteosarcoma (OS) is a common type of bone malignancy that often occurs in children and adolescents. Chemoresistance is a huge barrier to cancer therapy. This study aimed to investigate the role and potential mechanism of circ_0001721 in doxorubicin (DXR) resistance and OS development.
The levels of circ_0001721, miR-758 and transcription factor 4 (TCF4) were detected by quantitative real-time polymerase chain reaction or western blot assay. Cell Counting Kit-8 (CCK-8) assay was used to calculate the half inhibition concentration (IC
) of DXR and assess cell viability. Cell migration and invasion were evaluated by transwell assay. Cell apoptosis was monitored by flow cytometry. The levels of multidrug resistance-related and Wnt/β-catenin pathway-related proteins were measured by western blot assay. The interaction among circ_0001721, miR-758 and TCF4 were confirmed by dual-luciferase reporter assay, RNA immunoprecipitation assay or RNA pull-down assay. The xenograft model was established to analyze tumor growth in vivo.
Circ_0001721 and TCF4 were upregulated, whereas miR-758 was down-regulated in DXR-resistant OS tissues and cells. Circ_0001721 silence reduced DXR resistance of KHOS/DXR and MG63/DXR cells. Circ_0001721 regulated DXR resistance via sponging miR-758. Moreover, miR-758 modulated DXR resistance by targeting TCF4. Besides, circ_0001721 knockdown inhibited tumor growth in vivo.
Circ_0001721 potentiated DXR resistance and facilitated the progression of OS by regulating miR-758/TCF4 axis, which provides promising therapeutic targets for OS treatment.
Circ_0001721 potentiated DXR resistance and facilitated the progression of OS by regulating miR-758/TCF4 axis, which provides promising therapeutic targets for OS treatment.
