Natural systems are often complex and dynamic (i.e. nonlinear), making them difficult to understand using linear statistical approaches. Linear approaches are fundamentally based on correlation. Thus, they are illposed for dynamical systems, where correlation can occur without causation, and causation may also occur in the absence of correlation. ''Mirage correlation'' (i.e., the sign and magnitude of the correlation change with time) is a hallmark of nonlinear systems that results from state dependency. State dependency means that the relationships among interacting variables change with different states of the system. In recent decades, nonlinear methods that acknowledge state dependence have been developed. These nonlinear statistical methods are rooted in state space reconstruction, i.e. lagged coordinate embedding of time series data. These methods do not assume any set of equations governing the system but recover the dynamics from time series data, thus called empirical dynamic modeling (EDM). EDM bears a variety of utilities to investigating dynamical systems. Here, we provide a step-by-step tutorial for EDM applications with rEDM, a free software package written in the R language. Using model examples, we aim to guide users through several basic applications of EDM, including (1) determining the complexity (dimensionality) of a system, (2) distinguishing nonlinear dynamical systems from linear stochastic systems, and quantifying the nonlinearity (i.e. state dependence), (3) determining causal variables, (4) forecasting, (5) tracking the strength and sign of interaction, and (6) exploring the scenario of external perturbation. These methods and applications can be used to provide a mechanistic understanding of dynamical systems.
In the past 5 years, there has been a substantial increase in the use of Y-short tandem repeat loci (Y-STRs) in forensic laboratories, especially in cases where typing autosomal STRs has met with limited success. The AmpFlSTR Yfiler PCR amplification kit simultaneously amplifies 17 Y-STR loci including the loci in the "European minimal haplotype" (DYS19, DYS385a/b, DYS389I, DYS389II, DYS390, DYS391, DYS392, and DYS393), the Scientific Working Group on DNA Analysis Methods (SWGDAM) recommended Y-STR loci (DYS438 and DYS439), and the highly polymorphic loci DYS437, DYS448, DYS456, DYS458, Y GATA H4, and DYS635 (formerly known as Y GATA C4). The Yfiler kit was validated according to the FBI/National Standards and SWGDAM guidelines. Our results showed that full profiles are attainable with low levels of male DNA (below 125 pg) and that under optimized conditions, no detectable cross-reactive products were obtained on human female DNA, bacteria, and commonly encountered animal species. Additionally, we demonstrated the ability to detect male specific profiles in admixed male and female blood samples at a ratio of 1:1000.
DNA typing of degraded DNA samples can be a challenging task when using the current commercially available multiplex short tandem repeat (STR) analysis kits. However, the ability to type degraded DNA specimens improves by redesigning current STR marker amplicons such that smaller sized polymerase chain reaction (PCR) products are generated. In an effort to increase the amount of information derived from these types of DNA samples, the AmpF'STR Ò MiniFiler TM PCR Amplification Kit has been developed. The kit contains reagents for the amplification of eight miniSTRs which are the largest sized loci in the AmpF'STR Ò Identifiler Ò PCR Amplification Kit (D7S820, D13S317, D16S539, D21S11, D2S1338, D18S51, CSF1PO, and FGA). Five of these STR loci (D16S539, D21S11, D2S1338, D18S51, and FGA) also are some of the largest loci in the AmpF'STR Ò SGM Plus Ò kit. This informative nine-locus multiplex, which includes the gender-identification locus Amelogenin, has been validated according to the FBI ⁄ National Standards and SWGDAM guidelines. Our results demonstrate significant performance improvements in models of DNA degradation, PCR inhibition, and nonprobative samples when compared to the AmpF'STR Ò Identifiler Ò and SGM Plus Ò kits. These data support that the MiniFiler TM kit will increase the likelihood of obtaining additional STR information from forensic samples in situations in which standard STR chemistries fail to produce complete profiles.
Enterovirus 71 (EV71) has emerged as an important virulent neurotropic enterovirus in young children. DTriP-22 (4{4-[(2-bromo-phenyl)-(3-methyl-thiophen-2-yl)-methyl]-piperazin-1-yl}-1-pheny-1H-pyrazolo[3,4-d]pyrimidine)was found to be a novel and potent inhibitor of EV71. The molecular target of this compound was identified by analyzing DTriP-22-resistant viruses. A substitution of lysine for Arg163 in EV71 3D polymerase rendered the virus drug resistant. DTriP-22 exhibited the ability to inhibit viral replication by reducing viral RNA accumulation. The compound suppressed the accumulated levels of both positive-and negative-stranded viral RNA during virus infection. An in vitro polymerase assay indicated that DTriP-22 inhibited the poly(U) elongation activity, but not the VPg uridylylation activity, of EV71 polymerase. These findings demonstrate that the nonnucleoside analogue DTriP-22 acts as a novel inhibitor of EV71 polymerase. DTriP-22 also exhibited a broad spectrum of antiviral activity against other picornaviruses, which highlights its potential in the development of antiviral agents.Enterovirus 71 (EV71), a positive-stranded RNA virus, belongs to the genus Enterovirus in the family Picornaviridae. EV71 infection typically causes hand, foot, and mouth disease or herpangina, followed by severe central nervous system complications, including aseptic meningitis, encephalitis, poliomyelitis-like paralysis, neurogenic cardiopulmonary failure, and even death in some young children. Infants, following infection by EV71 with central nervous system complications, reportedly suffer from neurologic sequelae and delayed neurodevelopment (6). In 1998, a large outbreak of EV71 infection occurred in Taiwan, resulting in almost 80 fatalities and 405 severe cases (7, 21). Subsequently, many outbreaks of EV71 infection in Taiwan have been reported, with a total of 51 verified fatal cases in 2000 and 2001 (29). Severe EV71 infections continued to occur for several years thereafter. EV71 infection also has been reported to occur in many countries, such as Malaysia, Singapore, Australia, Japan, the United States, Germany, and mainland China (1-3, 5, 13, 22, 33, 34).The development of anti-EV71 agents is important because EV71 is regarded as the most important neurotropic enterovirus, after poliovirus control (34). A novel series of pyridyl imidazolidinones targeting VP1 protein, based on the skeletons of WIN compounds, has been developed using computerassisted drug design (37). The new EV71 3C protease inhibitors, based on rhinovirus 3C protease inhibitor AG7088, exhibit inhibitory activities in both enzymatic and cell-based assays (25). A pharmacologically active drug library has been employed to identify anti-EV71 compounds (4). Ribavirin used in combination with interferon to treat patients with hepatitis C virus infection reduces the mortality rate of EV71-infected mice by reducing viral replication (26).We previously discovered piperazine-containing pyrazolo [3,4-d]pyrimidine derivatives as a novel class of anti-EV71 c...
Existing individual size distribution (ISD) theories assume that the trophic level (TL) of an organism varies as a linear function of its log-transformed body size. This assumption predicts a power-law distribution of the ISD, i.e., a linear relationship between size and abundance in log space. However, the secondary structure of ISD (nonlinear dome shape structures deviating from a power-law distribution) is often observed. We propose a model that extends the metabolic theory to link the secondary structure of ISD to the nonlinear size-TL relationship. This model is tested with empirical data collected from a subtropical reservoir. The empirical ISD and size-TL relationships were constructed by FlowCAM imaging analysis and stable isotope analyses, respectively. Our results demonstrate that the secondary structure of ISD can be predicted from the nonlinear function of size-TL relationship and vice versa. Moreover, these secondary structures arise due to (1) zooplankton omnivory and (2) the trophic interactions within microbial food webs.
Vincristine is one of the core chemotherapy agents used in the treatment of pediatric acute lymphoblastic leukemia (ALL). However, one of the major toxicities resulting from vincristine exposure is vincristine‐induced peripheral neuropathy (VIPN). When VIPN results in significant morbidity, the vincristine dose may need to be reduced, thus potentially decreasing the effectiveness of treatment. To date, there are no robust biomarkers used clinically to determine which patients will be at risk for worse neuropathy. The current study included genomewide association study (GWAS) in two independent cohorts: Pediatric Oncology Group (POG) ALL trials and a multicenter study based at Indiana University in children with ALL. A meta‐analysis of the cohorts identified two single‐nucleotide polymorphisms (SNPs), rs1045644 and rs7963521, as being significantly (P value threshold 0.05/4749 = 1.05E‐05) associated with neuropathy. Subsequently these SNPs may be effective biomarkers of VIPN in children with ALL.
The NS1 protein encoded by influenza A virus antagonizes the interferon response through various mechanisms, including blocking cellular mRNA maturation by binding the cellular CPSF30 3= end processing factor and/or suppressing the activation of interferon regulatory factor 3 (IRF3). In the present study, we identified two truncated NS1 proteins that are translated from internal AUGs at positions 235 and 241 of the NS1 open reading frame. We analyzed the cellular localization and function of the N-truncated NS1 proteins encoded by two influenza A virus strains, Udorn/72/H3N2 (Ud) and Puerto Rico/8/34/H1N1 (PR8). The NS1 protein of PR8, but not Ud, inhibits the activation of IRF3, whereas the NS1 protein of Ud, but not PR8, binds CPSF30. The truncated PR8 NS1 proteins are localized in the cytoplasm, whereas the full-length PR8 NS1 protein is localized in the nucleus. The infection of cells with a PR8 virus expressing an NS1 protein containing mutations of the two in-frame AUGs results in both the absence of truncated NS1 proteins and the reduced inhibition of activation of IRF3 and beta interferon (IFN-) transcription. The expression of the truncated PR8 NS1 protein by itself enhances the inhibition of the activation of IRF3 and IFN- transcription in Ud virus-infected cells. These results demonstrate that truncated PR8 NS1 proteins contribute to the inhibition of activation of this innate immune response. In contrast, the N-truncated NS1 proteins of the Ud strain, like the full-length NS1 protein, are localized in the nucleus, and mutation of the two in-frame AUGs has no effect on the activation of IRF3 and IFN- transcription. IMPORTANCEInfluenza A virus causes pandemics and annual epidemics in the human population. The viral NS1 protein plays a critical role in suppressing type I interferon expression. In the present study, we identified two novel truncated NS1 proteins that are translated from the second and third in-frame AUG codons in the NS1 open reading frame. The N-terminally truncated NS1 encoded by the H1N1 PR8 strain of influenza virus that suppresses IRF3 activation is localized primarily in the cytoplasm. We demonstrate that this truncated NS1 protein by itself enhances this suppression, demonstrating that some strains of influenza A virus express truncated forms of the NS1 protein that function in the inhibition of cytoplasmic antiviral events.
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