Long-term predictions of current confirmed and dead cases of COVID-19 in China by the non-autonomous delayed epidemic models

In this paper, we make long-term predictions based on numbers of current confirmed cases, accumulative dead cases of COVID-19 in different regions in China by modeling approach. Firstly, we use the SIRD epidemic model (S-Susceptible, I-Infected, R-Recovered, D-Dead) which is a non-autonomous dynamic system with incubation time delay to study the evolution of the COVID-19 in Wuhan City, Hubei Province and China Mainland. According to the data in the early stage issued by the National Health Commission of China, we can accurately estimate the parameters of the model, and then accurately predict the evolution of the COVID-19 there. From the analysis of the issued data, we find that the cure rates in Wuhan City, Hubei Province and China Mainland are the approximately linear increasing functions of time t and their death rates are the piecewisely decreasing functions. These can be estimated by finite difference method. Secondly, we use the delayed SIRD epidemic model to study the evolution of the COVID-19 in the Hubei Province outside Wuhan City. We find that its cure rate is an approximately linear increasing function and its death rate is nearly a constant. Thirdly, we use the delayed SIR epidemic model (S-Susceptible, I-Infected, R-Removed) to predict those of Beijing, Shanghai, Zhejiang and Anhui Provinces. We find that their cure rates are the approximately linear increasing functions and their death rates are the small constants. The results indicate that it is possible to make accurate long-term predictions for numbers of current confirmed, accumulative dead cases of COVID-19 by modeling. In this paper the results indicate we can accurately obtain and predict the turning points, the end time and the maximum numbers of the current infected and dead cases of the COVID-19 in China. In spite of our simple method and small data, it is rather effective in the long-term prediction of the COVID-19.     

Biocontrol of Pests of Apples and Pears in Northern and Central Europe: 2. Parasitoids

The parasitoids of arthropod pests of apple and pear in northern and central Europe and their use as biological control agents are reviewed. The review demonstrates that apple and pear pests are host to a large and varied parasitoid fauna. All important pests are known to be host of parasitoids, but many parasitoids play only a minor part in regulating populations of their host. However, many parasitoid species are important natural enemies and some effectively regulate pest populations in unsprayed and/or commercial (insecticide sprayed) apple or pear orchards either individually or as part of parasitoid guilds. Exploitation/fostering of existing populations of parasitoids has been demonstrated to be an effective or partially effective approach for natural control of several important pest species. Important examples include natural regulation of the apple sawfly by Lathrolestes ensator and Aptesis nigrocincta, of the summer fruit tortrix moth by Colpoclypeus florus and Teleutaea striata, of leaf midges by Platygaster demades, of woolly aphid by Aphelinus mali and of leaf mining moths by guilds of parasitoid species. Introduction of parasitoids is an alternative approach to the exploitation of parasitoids already present in the orchard. This approach has been little explored and its success rate has been low, mainly confined to the control of non-indigenous pests by introducing parasitoids from their native region. Mass production methods for parasitoids are difficult and costly and are likely to be economic only where long-term populations can be established. Even where low cost mass culture techniques are developed, the degree of control may not be high enough to prevent economic pest damage as demonstrated by negative results with mass release of Trichogramma egg parasites for control of tortricids in orchards. Suitability of the orchard habitat is recognized as crucial to the success of individual parasitoids. Key requirements are adequate populations of the pest(s) and/or alternative hosts, suitable shelter, overwintering sites or food sources and avoidance of harmful effects of pesticides. Many species are highly sensitive to broad-spectrum insecticides, especially in the adult life-stage. Avoiding the harmful affects of insecticides is crucial to successful exploitation. The use of insecticides needs to be avoided, either altogether or at crucial times in the parasitoids' life cycle, or less harmful alternatives need to be used. Numerous parasitoids could potentially be exploited as biological control agents but hitherto have received little attention because little is known about them and/or because they are sensitive to broad-spectrum pesticides and are thus virtually absent from commercial orchards. The aim of future studies should be to develop effective strategies for establishing equilibria between important pests and their parasitoids, with pest damage rarely exceeding the economic threshold.     

The function of the endocytic scaffold protein Pan1p depends on multiple domains

Pan1p is an essential protein of the yeast Saccharomyces cerevisiae that is required for the internalization step of endocytosis and organization of the actin cytoskeleton. Pan1p, which binds several other endocytic proteins, is composed of multiple protein-protein interaction domains including two Eps15 Homology (EH) domains, a coiled-coil domain, an acidic Arp2/3-activating region, and a proline-rich domain. In this study, we have induced high-level expression of various domains of Pan1p in wild-type cells to assess the dominant consequences on viability, endocytosis, and actin organization. We found that the most severe phenotypes, with blocked endocytosis and aggregated actin, required expression of nearly full length Pan1p, and also required the endocytic regulatory protein kinase Prk1p. The central coiled-coil domain was the smallest fragment whose overexpression caused any dominant effects; these effects were more pronounced by inclusion of the second EH domain. Co-overexpressing nonoverlapping amino- and carboxy-terminal fragments did not mimic the effects of the intact protein, whereas fragments that overlapped within the coiled-coil region could. Yeast two-hybrid and in vivo coimmunoprecipitation analyses suggest that Pan1 may form dimers or higher order oligomers. Collectively, our data support a view of Pan1p as a dimeric/oligomeric scaffold whose functions require both the amino- and carboxy-termini, linked by the central region.     

Identification and Functional Characterization of a Ku-binding Motif in Aprataxin Polynucleotide Kinase/Phosphatase-like Factor (APLF)

Aprataxin polynucleotide kinase/phosphatase-like factor (APLF) facilitates nonhomologous end joining (NHEJ) and associates with the core NHEJ components XRCC4-DNA ligase IV and Ku. The APLF forkhead-associated (FHA) domain directs interactions with XRCC4, but the APLF-Ku interaction has not been well characterized. Here we describe an evolutionarily conserved amino acid motif within APLF that is required for mediating the physical interaction between APLF and Ku. This APLF Ku-binding motif possesses a similarity to regions identified in other NHEJ factors, WRN and XLF, which also direct interactions with Ku. Indeed, peptides derived from the Ku-binding region of APLF, WRN, or XLF were sufficient to reconstitute the interaction with Ku in vitro. Although APLF is localized predominantly to the nucleus, it does not possess a nuclear localization signal (NLS). Interestingly, the disruption of the APLF-Ku interaction by substituting key residues in the APLF Ku-binding motif was associated with increased relocalization of APLF to the cytoplasm and reduced association with XRCC4, which was rescued by the introduction of an NLS onto APLF. When human cells stably depleted of APLF were reconstituted with APLF Ku-binding mutants, or with an APLF FHA mutant that is known to disrupt interactions with XRCC4, APLF-dependent NHEJ and the retention of APLF at sites of laser-generated DNA damage were impaired. These data suggest functional requirements for Ku and XRCC4 in APLF-dependent NHEJ and a unique role for Ku as a factor required to facilitate the nuclear retention of APLF.     

HMGB1 Protein Does Not Mediate the Inflammatory Response in Spontaneous Spinal Cord Regeneration: A HINT FOR CNS REGENERATION*

Uncontrolled, excessive inflammation contributes to the secondary tissue damage of traumatic spinal cord, and HMGB1 is highlighted for initiation of a vicious self-propagating inflammatory circle by release from necrotic cells or immune cells. Several regenerative-competent vertebrates have evolved to circumvent the second damages during the spontaneous spinal cord regeneration with an unknown HMGB1 regulatory mechanism. By genomic surveys, we have revealed that two paralogs of HMGB1 are broadly retained from fish in the phylogeny. However, their spatial-temporal expression and effects, as shown in lowest amniote gecko, were tightly controlled in order that limited inflammation was produced in spontaneous regeneration. Two paralogs from gecko HMGB1 (gHMGB1) yielded distinct injury and infectious responses, with gHMGB1b significantly up-regulated in the injured cord. The intracellular gHMGB1b induced less release of inflammatory cytokines than gHMGB1a in macrophages, and the effects could be shifted by exchanging one amino acid in the inflammatory domain. Both intracellular proteins were able to mediate neuronal programmed apoptosis, which has been indicated to produce negligible inflammatory responses. In vivo studies demonstrated that the extracellular proteins could not trigger a cascade of the inflammatory cytokines in the injured spinal cord. Signal transduction analysis found that gHMGB1 proteins could not bind with cell surface receptors TLR2 and TLR4 to activate inflammatory signaling pathway. However, they were able to interact with the receptor for advanced glycation end products to potentiate oligodendrocyte migration by activation of both NFκB and Rac1/Cdc42 signaling. Our results reveal that HMGB1 does not mediate the inflammatory response in spontaneous spinal cord regeneration, but it promotes CNS regeneration.     

The cytoplasmic domain of TGFβR3 through its interaction with the scaffolding protein, GIPC, directs epicardial cell behavior

The epicardium is a major contributor of the cells that are required for the formation of coronary vessels. Mice lacking both copies of the gene encoding the Type III Transforming Growth Factor β Receptor (TGFβR3) fail to form the coronary vasculature, but the molecular mechanism by which TGFβR3 signals coronary vessel formation is unknown. We used intact embryos and epicardial cells from E11.5 mouse embryos to reveal the mechanisms by which TGFβR3 signals and regulates epicardial cell behavior. Analysis of E13.5 embryos reveals a lower rate of epicardial cell proliferation and decreased epicardially derived cell invasion in Tgfbr3^−/− hearts. Tgfbr3^−/− epicardial cells in vitro show decreased proliferation and decreased invasion in response to TGFβ1 and TGFβ2. Unexpectedly, loss of TGFβR3 also decreases responsiveness to two other important regulators of epicardial cell behavior, FGF2 and HMW-HA. Restoring full length TGFβR3 in Tgfbr3^−/− cells rescued deficits in invasion in vitro in response TGFβ1 and TGFβ2 as well as FGF2 and HMW-HA. Expression of TGFβR3 missing the 3 C-terminal amino acids that are required to interact with the scaffolding protein GIPC1 did not rescue any of the deficits. Overexpression of GIPC1 alone in Tgfbr3^−/− cells did not rescue invasion whereas knockdown of GIPC1 in Tgfbr3^+/+ cells decreased invasion in response to TGFβ2, FGF2, and HMW-HA. We conclude that TGFβR3 interaction with GIPC1 is critical for regulating invasion and growth factor responsiveness in epicardial cells and that dysregulation of epicardial cell proliferation and invasion contributes to failed coronary vessel development in Tgfbr3^−/− mice.     

Solution structure of the soluble receptor for advanced glycation end products (sRAGE)

The receptor for advanced glycation end products (RAGE) is a multiligand cell surface receptor involved in various human diseases, as it binds to numerous molecules and proteins that modulate the activity of other proteins. Elucidating the three-dimensional structure of this receptor is therefore most important for understanding its function during activation and cellular signaling. The major alternative splice product of RAGE comprises its extracellular region that occurs as a soluble protein (sRAGE). Although the structures of sRAGE domains were available, their assembly into the functional full-length protein remained unknown. We observed that the protein has concentration-dependent oligomerization behavior, and this is also mediated by the presence of Ca(2+) ions. Moreover, using synchrotron small angle x-ray scattering, the solution structure of human sRAGE was determined in the monomeric and dimeric forms. The model for the monomer displays a J-like shape, whereas the dimer is formed through the association of the two N-terminal domains and has an elongated structure. These results provide insights into the assembly of the RAGE homodimer, which is essential for signal transduction, and the sRAGE:RAGE heterodimer that leads to blockage of the receptor signaling, paving the way for the design of therapeutic strategies for a large number of different pathologies.     

Ethanol-induced death in yeast exhibits features of apoptosis mediated by mitochondrial fission pathway

Cell death in yeast (Saccharomyces cerevisiae) involves several apoptotic processes. Here, we report the first evidence of the following processes, which are also characteristic of apoptosis, in ethanol-induced cell death in yeast: chromatin condensation and fragmentation, DNA cleavage, and a requirement for de novo protein synthesis. Mitochondrial fission protein, Fis1, appears to mediate ethanol-induced apoptosis and ethanol-induced mitochondrial fragmentation. However, mitochondrial fragmentation in response to elevated ethanol levels was not correlated with cell death. Further, in the presence of ethanol, generation of reactive oxygen species was elevated in mutant fis1Delta cells. Our characterization of ethanol-induced cell death in yeast as being Fis1-mediated apoptosis is likely to pave the way to overcoming limitations in large-scale fermentation processes, such as those employed in the production of alcoholic beverages and ethanol-based biofuels.