416 research outputs found
Human Cytomegalovirus Encoded miR-US25-1-5p Attenuates CD147/EMMPRIN-Mediated Early Antiviral Response.
Cellular receptor-mediated signaling pathways play critical roles during the initial immune response to Human Cytomegalovirus (HCMV) infection. However, the involvement of type-I transmembrane glycoprotein CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) in the antiviral response to HCMV infection is still unknown. Here, we demonstrated the specific knockdown of CD147 significantly decreased HCMV-induced activation of NF-κB and Interferon-beta (IFN-β), which contribute to the cellular antiviral responses. Next, we confirmed that HCMV-encoded miR-US25-1-5p could target the 3 UTR (Untranslated Region) of CD147 mRNA, and thus facilitate HCMV lytic propagation at a low multiplicity of infection (MOI). The expression and secretion of Cyclophilin A (sCyPA), as a ligand for CD147 and a proinflammatory cytokine, were up-regulated in response to HCMV stimuli. Finally, we confirmed that CD147 mediated HCMV-triggered antiviral signaling via the sCyPA-CD147-ERK (extracellular regulated protein kinases)/NF-κB axis signaling pathway. These findings reveal an important HCMV mechanism for evading antiviral innate immunity through its encoded microRNA by targeting transmembrane glycoprotein CD147, and a potential cause of HCMV inflammatory disorders due to the secretion of proinflammatory cytokine CyPA
An integrated hardware/software design methodology for signal processing systems
This paper presents a new methodology for design and implementation of signal processing systems on system-on-chip (SoC) platforms. The methodology is centered on the use of lightweight application programming interfaces for applying principles of dataflow design at different layers of abstraction. The development processes integrated in our approach are software implementation, hardware implementation, hardware-software co-design, and optimized application mapping. The proposed methodology facilitates development and integration of signal processing hardware and software modules that involve heterogeneous programming languages and platforms. As a demonstration of the proposed design framework, we present a dataflow-based deep neural network (DNN) implementation for vehicle classification that is streamlined for real-time operation on embedded SoC devices. Using the proposed methodology, we apply and integrate a variety of dataflow graph optimizations that are important for efficient mapping of the DNN system into a resource constrained implementation that involves cooperating multicore CPUs and field-programmable gate array subsystems. Through experiments, we demonstrate the flexibility and effectiveness with which different design transformations can be applied and integrated across multiple scales of the targeted computing system
Construction of a prognostic signature associated with liver metastases for prognosis and immune response prediction in colorectal cancer
BackgroundAs the most common gastrointestinal malignancy worldwide, liver metastases occur in half colorectal cancer (CRC) patients. Early detection can help treat them early and reduce mortality in patients with colorectal cancer liver metastases (CRLM). Finding useful biomarkers for CRLM is thus essential.MethodsThe TCGA and GEO databases were used to download the expression profiles and clinical data of the patients. Differential analysis screened for genes associated with CRLM, and univariate Cox regression analysis identified genes associated with prognosis. The least absolute shrinkage and selection operator (LASSO) method further preferred genes to construct a prognostic signature. Kaplan-Meier survival curves were used to show patients’ overall survival (OS). Receiver operating characteristic (ROC) curves showed the accuracy of the model. Risk scores and clinical characteristics of patients were included in multivariate Cox regression analysis to identify independent risk factors, and a nomogram was constructed. The proportion of immune cells and infiltration were assessed using the ‘CIBERSORT’ package and the ‘ESTIMATE’ package.ResultsWe constructed a signature consisting of seven CRLM-associated genes, and signature-based risk scores have great potential in estimating the prognosis of CRC patients. Moreover, the poor response to immunotherapy in high-risk patients might contribute to the poor prognosis of individuals. Furthermore, we found that overexpression of Hepcidin antimicrobial peptide (HAMP), the only gene highly expressed in CRC and liver metastatic tissues, promoted CRC development and that it was associated with tumor mutation burden (TMB), DNA mismatch repair (MMR) genes, and microsatellite instability (MSI) in various tumors. Finally, we found that in CRC patients, low expression of HAMP also represented a better immunotherapeutic outcome, reflecting the critical role of HAMP in guiding immunotherapy.ConclusionWe identified a prognostic signature containing 7 CRLM-associated genes, and the signature was specified as an independent predictor and a nomogram containing the risk score was built accordingly. In addition, the derived gene HAMP could help guide the exploration of profitable immunotherapeutic strategies
CDK5RAP2 functions in centrosome to spindle pole attachment and DNA damage response
Two domains of centrosomal protein CDK5RAP2, CNN1 and CNN2, link centrosomes to mitotic spindle poles. CNN1 lacking centrosomes are unable to recruit pericentriolar matrix components that mediate attachment to spindle poles
Recessive <i>HYDIN</i> mutations cause primary ciliary dyskinesia without randomization of left-right body asymmetry
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous
recessive disorder characterized by defective cilia and flagella
motility. Chronic destructive-airway disease is caused by
abnormal respiratory-tract mucociliary clearance. Abnormal
propulsion of sperm flagella contributes to male infertility.
Genetic defects in most individuals affected by PCD cause
randomization of left-right body asymmetry; approximately half
show situs inversus or situs ambiguous. Almost 70 years after
the hy3 mouse possessing Hydin mutations was described as a
recessive hydrocephalus model, we report HYDIN mutations in PCD-
affected persons without hydrocephalus. By homozygosity mapping,
we identified a PCD-associated locus, chromosomal region 16q21-
q23, which contains HYDIN. However, a nearly identical 360 kb
paralogous segment (HYDIN2) in chromosomal region 1q21.1
complicated mutational analysis. In three affected German
siblings linked to HYDIN, we identified homozygous c.3985G>T
mutations that affect an evolutionary conserved splice acceptor
site and that subsequently cause aberrantly spliced transcripts
predicting premature protein termination in respiratory cells.
Parallel whole-exome sequencing identified a homozygous nonsense
HYDIN mutation, c.922A>T (p.Lys307( *)), in six individuals from
three Faroe Island PCD-affected families that all carried an 8.8
Mb shared haplotype across HYDIN, indicating an ancestral
founder mutation in this isolated population. We demonstrate by
electron microscopy tomography that, consistent with the effects
of loss-of-function mutations, HYDIN mutant respiratory cilia
lack the C2b projection of the central pair (CP) apparatus;
similar findings were reported in Hydin-deficient Chlamydomonas
and mice. High-speed videomicroscopy demonstrated markedly
reduced beating amplitudes of respiratory cilia and stiff sperm
flagella. Like the hy3 mouse model, all nine PCD-affected
persons had normal body composition because nodal cilia function
is apparently not dependent on the function of the CP
apparatus
Association Study with 77 SNPs Confirms the Robust Role for the rs10830963/G of MTNR1B Variant and Identifies Two Novel Associations in Gestational Diabetes Mellitus Development
CONTEXT: Genetic variation in human maternal DNA contributes to the susceptibility for development of gestational diabetes mellitus (GDM). OBJECTIVE: We assessed 77 maternal single nucleotide gene polymorphisms (SNPs) for associations with GDM or plasma glucose levels at OGTT in pregnancy. METHODS: 960 pregnant women (after dropouts 820: case/control: m99'WHO: 303/517, IADPSG: 287/533) were enrolled in two countries into this case-control study. After genomic DNA isolation the 820 samples were collected in a GDM biobank and assessed using KASP (LGC Genomics) genotyping assay. Logistic regression risk models were used to calculate ORs according to IADPSG/m'99WHO criteria based on standard OGTT values. RESULTS: The most important risk alleles associated with GDM were rs10830963/G of MTNR1B (OR = 1.84/1.64 [IADPSG/m'99WHO], p = 0.0007/0.006), rs7754840/C (OR = 1.51/NS, p = 0.016) of CDKAL1 and rs1799884/T (OR = 1.4/1.56, p = 0.04/0.006) of GCK. The rs13266634/T (SLC30A8, OR = 0.74/0.71, p = 0.05/0.02) and rs7578326/G (LOC646736/IRS1, OR = 0.62/0.60, p = 0.001/0.006) variants were associated with lower risk to develop GDM. Carrying a minor allele of rs10830963 (MTNR1B); rs7903146 (TCF7L2); rs1799884 (GCK) SNPs were associated with increased plasma glucose levels at routine OGTT. CONCLUSIONS: We confirmed the robust association of MTNR1B rs10830963/G variant with GDM binary and glycemic traits in this Caucasian case-control study. As novel associations we report the minor, G allele of the rs7578326 SNP in the LOC646736/IRS1 region as a significant and the rs13266634/T SNP (SLC30A8) as a suggestive protective variant against GDM development. Genetic susceptibility appears to be more preponderant in individuals who meet both the modified 99'WHO and the IADPSG GDM diagnostic criteria
Casein kinase I delta controls centrosome positioning during T cell activation
CK1delta binds and phosphorylates the microtubule plus-end–binding protein
EB1 and promotes centrosome translocation to the immunological synapse in T
cells
Systematic Review of Potential Health Risks Posed by Pharmaceutical, Occupational and Consumer Exposures to Metallic and Nanoscale Aluminum, Aluminum Oxides, Aluminum Hydroxide and Its Soluble Salts
Aluminum (Al) is a ubiquitous substance encountered both naturally (as the third most abundant element) and intentionally (used in water, foods, pharmaceuticals, and vaccines); it is also present in ambient and occupational airborne particulates. Existing data underscore the importance of Al physical and chemical forms in relation to its uptake, accumulation, and systemic bioavailability. The present review represents a systematic examination of the peer-reviewed literature on the adverse health effects of Al materials published since a previous critical evaluation compiled by Krewski et al. (2007).
Challenges encountered in carrying out the present review reflected the experimental use of different physical and chemical Al forms, different routes of administration, and different target organs in relation to the magnitude, frequency, and duration of exposure. Wide variations in diet can result in Al intakes that are often higher than the World Health Organization provisional tolerable weekly intake (PTWI), which is based on studies with Al citrate. Comparing daily dietary Al exposures on the basis of “total Al”assumes that gastrointestinal bioavailability for all dietary Al forms is equivalent to that for Al citrate, an approach that requires validation. Current occupational exposure limits (OELs) for identical Al substances vary as much as 15-fold.
The toxicity of different Al forms depends in large measure on their physical behavior and relative solubility in water. The toxicity of soluble Al forms depends upon the delivered dose of Al+ 3 to target tissues. Trivalent Al reacts with water to produce bidentate superoxide coordination spheres [Al(O2)(H2O4)+ 2 and Al(H2O)6 + 3] that after complexation with O2•−, generate Al superoxides [Al(O2•)](H2O5)]+ 2. Semireduced AlO2• radicals deplete mitochondrial Fe and promote generation of H2O2, O2 • − and OH•. Thus, it is the Al+ 3-induced formation of oxygen radicals that accounts for the oxidative damage that leads to intrinsic apoptosis. In contrast, the toxicity of the insoluble Al oxides depends primarily on their behavior as particulates.
Aluminum has been held responsible for human morbidity and mortality, but there is no consistent and convincing evidence to associate the Al found in food and drinking water at the doses and chemical forms presently consumed by people living in North America and Western Europe with increased risk for Alzheimer\u27s disease (AD). Neither is there clear evidence to show use of Al-containing underarm antiperspirants or cosmetics increases the risk of AD or breast cancer. Metallic Al, its oxides, and common Al salts have not been shown to be either genotoxic or carcinogenic. Aluminum exposures during neonatal and pediatric parenteral nutrition (PN) can impair bone mineralization and delay neurological development. Adverse effects to vaccines with Al adjuvants have occurred; however, recent controlled trials found that the immunologic response to certain vaccines with Al adjuvants was no greater, and in some cases less than, that after identical vaccination without Al adjuvants.
The scientific literature on the adverse health effects of Al is extensive. Health risk assessments for Al must take into account individual co-factors (e.g., age, renal function, diet, gastric pH). Conclusions from the current review point to the need for refinement of the PTWI, reduction of Al contamination in PN solutions, justification for routine addition of Al to vaccines, and harmonization of OELs for Al substances
- …