question:You will be presented with a citation segment from the section of a research paper. Classify the intent behind this citation by choosing from one of the following categories:- Method: Cites the paper for its methodology or procedure.- Background: Cites the paper to provide background information.- Result: Cites the paper for its findings or results.Your answer should be a single word from the following list of options: ["Method", "Background", "Result"]. Do not include any other text in your response.Citation sentence:An alternate theory suggests the formation of free radicals by incident laser energy and light absorption by fungal pigment xanthomegnin, present in high concentration in Trichophyton rubrum [13].

question:You will be shown an excerpt from a computer science scientific research paper, followed by a question about the paper. Please answer the question. Do not include any text in your response other than the answer.Context: The role of this autoencoder is two-folds. Firstly, it helps to learn high-quality app embeddings from the co-occurrence relationship of apps. The weight matrix of the first hidden layer mathbf{W}^{(1)} acts as the shared app embedding matrix mathbf{W}^{a} for the whole network, i.e., we have(2)mathbf{W}^{a}=mathbf{W}^{(1)}inmathbb{R}^{Mtimes{d_{model}}}.To further alleviate the problem of sparsity, the shared app embedding matrix is carefully designed and tied with some other weight matrices. More details are provided in Section 4.3. Secondly, this autoencoder provides effective representations of user retention for the transformer part. The transformer encoder part needs to be fed with the retention for compressing long-term interests into user embeddings. However, retention is originally in the form of high-dimensional sparse features. This autoencoder encodes retention into the first hidden layer bm{x}^{(1)}inmathbb{R}^{d_{model}}. As a low-dimensional dense encoding, bm{x}^{(1)} plays an important role in the transformer encoder part.Question: What are the two roles of autoencoder in proposed model?

question:You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.Title: A network of epigenetic modifiers and DNA repair genes controls tissue-specific copy number alteration preference}Article:Abstract:Copy number alterations( CNAs) in cancer patients show a large variability in their number, length and position, but the sources of this variability are not known. CNA number and length are linked to patient survival, suggesting clinical relevance. We have identified genes that tend to be mutated in samples that have few or many CNAs, which we term CONIM genes( COpy Number Instability Modulators). CONIM proteins cluster into a densely connected subnetwork of physical interactions and many of them are epigenetic modifiers. Therefore, we investigated how the epigenome of the tissue-of-origin influences the position of CNA breakpoints and the properties of the resulting CNAs. We found that the presence of heterochromatin in the tissue-of-origin contributes to the recurrence and length of CNAs in the respective cancer type.Introduction:Genomic alterations in cancer show considerable heterogeneity across different tumor types and even across patients with the same type of cancer. For point mutations, we are beginning to understand the determinants of this variation: the epigenomic profile of the tissue-of-origin highly influences local mutation rates along the chromosome( Schuster-Böckler and Lehner, 2012; Polak et al., 2015; Supek and Lehner, 2015), different mutagens induce characteristic mutational signatures( Alexandrov et al., 2013), and tissue-specific exposure to environmental factors affects the selection of mutations during tumourigenesis( Schaefer and Serrano, 2016). The driving forces behind copy number alterations( CNAs), that is, amplifications or deletions of genomic regions, are much less understood than the causes of point mutations. Furthermore, we do not know why some cancer types are associated with many CNAs and other types with only a few. This is partly due to the fact that CNAs tend to affect several genes at the same time[in the dataset from The Cancer Genome Atlas( TCGA; http://cancergenome. nih. gov/) used in this analysis, 59 genes on average are affected by a single CNA]. Therefore, it is often difficult to tell whether, and on which of the genes in the amplified or deleted region, selection is acting. In addition, cancer samples usually carry a much lower number of CNAs( on average 46 CNAs in the patient samples considered in this study) than single nucleotide variants( SNVs; usually 10. 000s per cancer genome). The sparse number of CNAs hinders the detection of statistical associations between CNAs and genetic and epigenetic features, work that has previously been carried out for SNVs( Schuster-Böckler and Lehner, 2012; Polak et al., 2015; Supek and Lehner, 2015). Like other alterations, CNAs show a large variation in position, length and number across cancer types( Zack et al., 2013). Authors have reported that CNA breakpoints are preferentially located in close proximity to DNA-methylation-depleted G-quadruplex sequences( De and Michor, 2011). This suggests that DNA secondary structure contributes to the CNA distribution. In addition, CNAs that are close to telomeres are longer than those found in internal regions. This suggests that there are several different mechanisms of CNA generation( Zack et al., 2013). It has also been observed that DNA contact points in genome-wide chromosome conformation capture( HiC) proximity maps are more likely to become CNA breakpoints. Thus, the length distribution of CNAs reflects chromosomal interactions( Fudenberg et al., 2011). The observation that certain genes tend to be mutated in CNA-rich( TP53 and SPOP[Ciriello et al., 2013; Boysen et al., 2015]) or CNA-poor( CTCF and ARID1A[Ciriello et al., 2013]) cancers implies that, besides epigenetic factors, the genetic background of the cell influences CNA variation. Here, we make use of the wealth of cancer genomics data provided by TCGA, to understand how the genetic background influences the CNA count per sample. We identify mutations in genes that are statistically linked to the number of CNAs in cancer patients. We refer to the identified gene set as CONIM genes( COpy Number Instability Modulators; Figure 1A). The encoded proteins form a densely interacting network of epigenetic modifiers and DNA repair genes. To test whether this network is associated with the cancer-type-specific preference for CNAs in certain regions, we investigate how the chromatin organisation in the healthy tissue-of-origin relates to the occurrence of CNAs in cancer. 10. 7554/eLife. 16519. 003Figure 1. Mechanisms of CNA number modulation and clinical importance.( A) Schematic showing how CONIM gene mutations can result in a higher or lower CNA number.( B) We performed Kaplan-Meier statistics on data from lower grade glioma( LGG) patients with deviating CNA numbers and lengths. LGG patients with fewer CNAs have a significantly better survival prognosis as compared to patients with many CNAs.( C) LGG patients with shorter CNAs have a significantly better survival prognosis when compared to patients with longer CNAs. DOI: http://dx. doi. org/10. 7554/eLife. 16519. 003Discussion:Here, we describe a new class of cancer-related genes: the CONIM genes. They are characterised by being associated with the amount of chromosomal gain or loss in a cancer cell, but only about 24% of these genes have previously been associated with cancer. Our study highlights their possible role as copy number instability modulators and suggests a mechanism for how they contribute to cancer development. Mutations in all but one of the CONIM genes are associated with a smaller number of CNAs. One explanation for this observation could be that mutations in CONIM genes tend to occur late during cancer development. This is supported by the low VAFs of CONIM genes that we observe in two cancer types. When many alterations have already been accumulated, high proliferation rates increase the risk of further damage which – at this point – would be detrimental to the cancer. The exception is TP53, which is associated with a higher number of CNAs when mutated. Inactivation of TP53 decreases sensitivity to apoptosis, and therefore more DNA damage( including CNAs) is tolerated. Previously, an inverse relation between the number of CNAs and the number of point mutations has been described( Ciriello et al., 2013), subdividing tumors into two groups: one CNA-rich and one mutation-rich. The CNA-rich group has been associated with recurrent mutations in TP53 and the mutation-rich( and CNA-depleted) group with mutations in ARID1A and CTCF. These three genes are also in our CONIM gene list. Several other studies investigated relations between point mutations and CNA numbers in single cancer types: a higher number of CNAs has been reported in SPOP-mutated prostate cancer( Boysen et al., 2015). Lower CNA numbers have been detected in CASP8-mutated oral squamous cell carcinoma( Pickering et al., 2013) and in CTNNB1-mutated endometrial cancer( Kandoth et al., 2013). Unlike CASP8 and CTNNB1, which are part of our CONIM list, SPOP did not pass our pan-cancer CNA enrichment filter criteria because the effect of SPOP on CNAs is highly cancer-type-specific. However, SPOP was recovered by our cancer-type-specific alternative detection pipeline( see Materials and methods). Our study goes beyond these previous studies by also considering the influence on CNA occurrence of the epigenome in the tissue from which the cancer originated. As the inverse relation between CNA and point mutations might affect the detection of CONIM genes, we apply different strategies to correct for this potential confounder( regressing out mutation rates, removing highly mutated samples and applying a mutation-number-matched permutation test). We found that the greater amount of CONIM genes associated with lower CNA number, the enrichment of epigenetic modifiers and the high connectivity can be reproduced with different CONIM gene detection pipelines. We also tested whether a gene that is associated with an elevated point mutation rate would automatically end up in our CONIM gene list due to the inverse relation between CNA and mutation counts. POLE has been described in the literature to cause a hypermutation phenotype when somatically mutated( Roberts and Gordenin, 2014; Briggs and Tomlinson, 2013). We can confirm that samples with POLE mutations have higher point mutation counts as compared to randomly selected samples( carrying mutations in genes with similar mutation frequencies as POLE). However, we do not find a reduced number of CNAs in POLE mutated samples. The most strongly enriched pathway among CONIM genes is ATM-dependent DNA repair. ATM is required for the repair of DNA double-strand breaks in heterochromatic regions, a process which is characterised by slow repair kinetics( Goodarzi et al., 2010). ATM-mediated phosphorylation of KAP1( KRAB-associated protein 1) triggers local decondensation of heterochromatin and thereby facilitates efficient repair. This suggests that it is not only the amount of cellular heterochromatin but also the cell’s ability to decondense it that is important. Other studies have begun to investigate the causes of variation in the frequency of CNAs throughout the genome by comparing distributions of CNAs to those of genomic and epigenomic features( De and Michor, 2011; Fudenberg et al., 2011; Zack et al., 2013). These analyses have suggested, among other features, the involvement of chromatin formation in determining the distribution of CNAs. However, none of the previous studies have systematically compared tissue-of-origin chromatin conformation to cancer-type-specific recurrence of CNAs( in a similar manner as it has been done for epigenetic marks and point mutations[Polak et al., 2015]). Our study complements these previous efforts by showing that not just the distribution of SNVs but also the CNA breakpoint distribution seem to be influenced by local chromatin structure. Here, we establish a link between heterochromatin enrichment and the variation in CNA number, length, and position across cancer types. In accordance with other studies, density of chromatin( for example, differences in mechanical forces or exposure to mutagens resulting from the localisation of dense chromatin at the nuclear periphery[Misteli, 2007]) determines where CNAs occur or persist( the high degree of condensation might hinder the detection and repair of DNA damage[Peterson and Côté, 2004]). These factors are governed by the properties of the tissue-of-origin( which contribute to the variability in the number, length and distribution of CNAs over cancer types) and could be influenced by abnormal activity of epigenetic modifiers through mutation or differential expression( contributing to the variation on the patient-level). With respect to possible mechanisms of heterochromatin formation interruption, it is worth mentioning that CONIM genes encode rather more H3K9me3 ‘readers’ than ‘writers’. Interestingly, we found that the local epigenome not only impacts where a DNA breakpoint occurs but also the length of the resulting CNAs. CNAs originating from H3K9me3-enriched regions tend to be longer than those without neighboring H3K9me3 marks. This increased average length is probably due to the fact that a greater degree of packaging of the interphase genome into heterochromatin facilitates long-range contacts between distant parts of the DNA, which then serve as end points for CNAs. This interpretation is in agreement with the observation that the chromatin shapes the length distribution of CNAs( Fudenberg et al., 2011). It has previously been reported that CNAs originating from telomeres are longer than chromosome-internal CNAs( Zack et al., 2013). We found that breakpoints in H3K9me3-enriched regions are associated with longer CNAs than other breakpoints, independent of their positions with respect to the chromosome ends. As telomeres in fact form heterochromatin( Blasco, 2007), our findings might explain the previously observed position-dependent length differences. Regarding the link between cancer-type-specific CNA numbers or lengths and heterochromatin proportions in the corresponding tissue-of-origin, ovarian cancer may not follow the same trend as other cancer types due to very high mutation fractions in TP53( 94%[Lawrence et al., 2014]). In accordance with previous studies( Ciriello et al., 2013), we show that TP53 deficiency is strongly associated with high CNA numbers. More research needs to be done on the mechanistic details of CNA breakpoint generation by chromatin disorganisation. To this end, our study highlights several interesting candidate genes that could be valuable drug targets as our analyses suggest that CNA number and size are clinically relevant. In summary, our observations suggest that the epigenome impacts CNA occurrence in a tissue- and patient-specific manner. CNA breakpoints are overrepresented in heterochromatic regions, so the epigenome of the tissue from which a cancer originates has a large impact on where CNAs arise during carcinogenesis. In addition, we identified genes in which mutations are associated with differential CNA number and length. Interestingly, this gene set is enriched in chromatin-modifying genes, which could suggest that these genes influence CNA properties through chromatin modifications.

question:You are presented with multiple paper abstracts, alongside the associated literature review and chapter titles. Given the provided information, you are going to do a literature review. Please generate a coherent literature review that synthesizes the content, draws connections between different works, highlights major findings, and identifies any gaps in the existing research.Literature Review Title: Monitoring Beach Topography and Nearshore Bathymetry Using Spaceborne Remote Sensing: A Review Chapter Title: Interferometric SAR (InSAR) 1. Abstract of Cited Paper (BIB001): Synthetic aperture radar interferometry is an imaging technique for measuring the topography of a surface, its changes over time, and other changes in the detailed characteristic of the surface. By exploiting the phase of the coherent radar signal, interferometry has transformed radar remote sensing from a largely interpretive science to a quantitative tool, with applications in cartography, geodesy, land cover characterization, and natural hazards. This paper reviews the techniques of interferometry, systems and limitations, and applications in a rapidly growing area of science and engineering. 2. Abstract of Cited Paper (BIB002): Synthetic aperture radar interferometry (InSAR) from Earth-orbiting spacecraft provides a new tool to map global topography and deformation of the Earth's surface. Radar images taken from slightly different viewing directions allow the construction of digital elevation models of meter-scale accuracy. These data sets aid in the analysis and interpretation of tectonic and volcanic landscapes. If the Earth's surface deformed between two radar image acquisitions, a map of the surface dis- placement with tens-of-meters resolution and subcentimeter accuracy can be con- structed. This review gives a basic overview of InSAR for Earth scientists and presents a selection of geologic applications that demonstrate the unique capabilities of InSAR for mapping the topography and deformation of the Earth. 3. Abstract of Cited Paper (BIB003): Satellite-based interferometric synthetic aperture radar (InSAR) provides a synoptic high spatial resolution perspective of Earth’s deforming surface, permitting one to view large areas quickly and efficiently. We review basic InSAR theory for geodetic applications and attempt to provide an overview of what processing and analysis schemes are currently used and a glimpse of what the future may hold. As part of this discussion, we present a biased view of what constitutes best practices for use of InSAR observations in geodetic modeling. Finally, we provide a basic primer on the ties between different mission design parameters and their relationship to the character of the resulting observations. 4. Abstract of Cited Paper (BIB004): Synthetic Aperture Radar (SAR) has been widely used for Earth remote sensing for more than 30 years. It provides high-resolution, day-and-night and weather-independent images for a multitude of applications ranging from geoscience and climate change research, environmental and Earth system monitoring, 2-D and 3-D mapping, change detection, 4-D mapping (space and time), security-related applications up to planetary exploration. With the advances in radar technology and geo/bio-physical parameter inversion modeling in the 90s, using data from several airborne and spaceborne systems, a paradigm shift occurred from the development driven by the technology push to the user demand pull. Today, more than 15 spaceborne SAR systems are being operated for innumerous applications. This paper provides first a tutorial about the SAR principles and theory, followed by an overview of established techniques like polarimetry, interferometry and differential interferometry as well as of emerging techniques (e.g., polarimetric SAR interferometry, tomography and holographic tomography). Several application examples including the associated parameter inversion modeling are provided for each case. The paper also describes innovative technologies and concepts like digital beamforming, Multiple-Input Multiple-Output (MIMO) and bi- and multi-static configurations which are suitable means to fulfill the increasing user requirements. The paper concludes with a vision for SAR remote sensing.Literature Review:

question:You will be shown a paragraph from a biomedical research paper, followed by a question about the paper. Please extract text from the paragraph to answer the question. Do not include any text in your repsonse other than the answer.Paragraph: As an RNA-binding protein that engages the hairpin termini of the genomic segments with high affinity [49, 50] , it limits the access of the RNA to host nucleases and helps to render viral replication a closed process within the cytoplasm. It also acts as a peripheral membrane protein, as does the L protein [51] , an activity that could play a role in its presumed, but not yet demonstrated function as matrix [52] . Until recently, it had not been appreciated that N has a wide variety of other activities, some of which can be linked, not only to fundamental requirements of replication, but also to the interference with an array of the intracellular processes of the normal cell. Thus, an interaction between the amino terminus of the hantavirus N protein and the cellular protein Daxx has been proposed, with the suggestion of potential pro-apoptotic consequences [51] . N is also reported to interact with actin microfilaments, and the SUMO-1 protein [53, 54] . Using reporter-gene based assays, Connie Schmaljohn and her colleagues have reported that Hantaan virus' nucleocapsid protein has an inhibitory role in inflammatory responses mediated by NF kappa B (NF-B). The effects on NF-B expression appeared to be confined to prevention of its nuclear translocation after its attempted activation with lipopolysaccharide, LPS [55] . In the cytoplasm of infected cells, N protein can be found in cellular P bodies where it sequesters and protects 5' caps. It may locate the caps through its interaction with DCP1, a key constituent of P bodies. During hantavirus infection, the viral RNAs become concentrated in P bodies, through their interaction with N and DCP1. The N protein demonstrates preferential protection of mRNAs engineered to prematurely terminate their encoded protein in comparison to native mRNAs [56] . N protein has been increasingly linked to viral replication and translation, sometimes in previously unanticipated ways. It is among a growing family of diverse viral proteins that can serve as a nonspecific -RNA chaperone‖, an activity that should facilitate the L polymerase's access to vRNA for transcription and replication, in that it can transiently dissociate misfolded RNA structures [57] . Some of N protein's effects on translation might not immediately be recognized to be adaptive in nature. It can replace the entire EIF4F translational initiation complex, simultaneously presenting the ribosome with a replacement for the cap-binding activity of eIF 4E, binding to the 43S pre-initiation complex as does eIF 4G, while replacing the helicase activity of eIF 4A, which is presumed to be needed to dissociate higher-order RNA structure [56, 58] . These three factors normally work together to achieve translational initiation. In P bodies, N protein's ability to bind at high affinity to capped native cellular oligoribonucleotides, along with its activity in protecting capped RNAs from degradation likely facilitates the access of capped oligonucleotides for use in transcriptional initiation by L polymerase (-cap snatching‖). Trafficking of N for viral assembly: Classically, N protein in infected cells appears to be clustered or particulate in nature, with a heavy concentration at a single perinuclear location, widely considered to be the Golgi [27] . The N proteins of hantaviruses are found in association with particulate fractions, and confocal microscopy and biochemical-inhibitor studies have shown that N tracks along microtubules but not with actin filaments [52] . The ultimate destination for N, for its assembly into viral particles is the Golgi, and it traffics there via the endoplasmic reticulum-Golgi intermediate complex (ERGIC), also known as vesicular-tubular cluster [52] . A dominant negative inhibitor, dynamitin, associated with dynein-mediated transport, reduced N's accumulation in the Golgi. Later studies suggested that the specific dependence on microtubular transport is specific to Old World hantaviruses such as HTNV, but that the New World hantavirus ANDV is instead associated with actin filaments [59] . However, recent data indicates that microtubular transport is indeed utilized for the New World hantavirus SNV [60] . Hantavirus diseases of man have long been suspected of having an immunopathogenic basis in part because of their relatively long incubation period of 2-3 weeks and the observed temporal association between immunologic derangements and the first appearance of signs and symptoms of hantavirus illness. HFRS and HCPS share many clinical features, leading many investigators to consider them to be, in essence, different manifestations of a similar pathogenic process, differing mainly in the primary target organs of disease expression ( Table 2 ). The pathogenesis of hantavirus infections is the topic of a continuously-updated review in the series UpToDate [61] . By the time symptoms appear in HCPS, both strong antiviral responses, and, for the more virulent viral genotypes, viral RNA can be detected in blood plasma or nucleated blood cells respectively [63, 64] . At least three studies have correlated plasma viral RNA with disease severity for HCPS and HFRS, suggesting that the replication of the virus plays an ongoing and real-time role in viral pathogenesis [65] [66] [67] . Several hallmark pathologic changes have been identified that occur in both HFRS and HCPS. A critical feature of both is a transient (~ 1-5 days) capillary leak involving the kidney and retroperitoneal space in HFRS and the lungs in HCPS. The resulting leakage is exudative in character, with chemical composition high in protein and resembling plasma. The continued experience indicating the strong tissue tropism for endothelial cells, specifically, is among the several factors that make β3 integrin an especially attractive candidate as an important in vivo receptor for hantaviruses. It is likely that hantaviruses arrive at their target tissues through uptake by regional lymph nodes, perhaps with or within an escorting lung histiocyte. The virus seeds local endothelium, where the first few infected cells give rise, ultimately, to a primary viremia, a process that appears to take a long time for hantavirus infections [62, 63] . By the time that secondary viremia emerges, the agents of the more severe forms of HFRS and HCPS have begun to achieve sufficient mass as to induce, through PAMP-PRR interactions and other means, the expression of proinflammatory cytokines [64] . For HCPS, that expression favors the pulmonary bed and lymphoid organs, yet, for unknown reasons, spares the retroperitoneum and, in general, the kidney. In HFRS the situation is reversed, and yet it is often not appreciated that the expected preferential tissue tropism of HFRS-associated viruses and their HCPS-associated counterparts for the renal and pulmonary beds, respectively, is not as one would predict through the manifestations of the two diseases. Local elaboration of inflammatory and chemotactic mediators is considered to be a requirement for the development of systemic disease symptoms, with those abnormalities sometimes culminating in shock and death. Yet it is not hypoxemia, due to the prominent pulmonary edema, that leads to death in most fatal cases of HCPS, but rather intoxication of the heart by as-yet-undefined mediators that leads to the low cardiac output state and the associated shock syndrome [64, 65] . It is tempting to speculate that mediators produced in the lung in connection with the inflammatory infiltrate can percolate through the coronary circulation with minimal dilution in HCPS, a disadvantageous consequence of the close anatomic juxtaposition of the two organs. Thus, at least three classes of potential mechanisms, some overlapping and all certainly nonexclusive of the others, could be presumed to underlie the pathogenesis of HCPS. These include:(1) Innate immune mechanisms. The nature of interactions between hantavirus pathogen-associated molecular patterns (PAMP) with the pattern recognition receptors (PRR) of susceptible endothelial cells are beginning to be clarified. The prototypical HTNV appears to be recognized by TLR-3 [43] . Such an infection has consequences such as increased expression of HLA-DR in dendritic cells [66] and differentiation of monocytes toward dendritic cells [67] . (2) Direct viral effects. The observed correlation between viral load and disease severity leaves the possibility open that hantavirus particles or RNA can themselves have toxic effects on cells or on signaling. Some investigators have favored direct viral toxicity, acting through the inhibition of endothelial cell barrier function, as an explanation for much of the capillary leak, although there is widespread agreement that multiple mechanisms that mediate pathogenesis likely operate simultaneously in the affected patient [68] . A potentially important clue toward the mechanism by which hantavirus infections deplete blood platelets and, in some cases cause hemorrhagic manifestations, was advanced by the recent discovery that pathogenic hantaviruses are able to recruit platelets to adhere to endothelial cell surfaces, with β3 integrin used as a critical binding element [69] . (3) Pathogenic effects caused by the activities of specific viral macromolecules. We have reviewed some of the activities associated with the Gn, Gc and N, virally-encoded polypeptides in previous sections. Testing models of pathogenesis can be done more effectively when there is an animal model that mimics key aspects of the disease. There is no such model that closely mimics HFRS, but animal models exist for both the asymptomatic carriage of PUUV and SNV by their native carrier rodents, the bank vole Myodes glareolus and the deer mouse P. maniculatus; as well as a Syrian hamster model using ANDV or the related Maporal virus from Venezuela, for which an HCPS-mimetic disease is observed [70] [71] [72] [73] . The ANDV-Syrian hamster model has a number of features in common with the human disease, as well as some differences. Unlike the neurologic diseases that have been possible to elicit with HTNV, the hamster model for HCPS appears to be caused by capillary leak that results in pulmonary edema and the production of a pleural effusion with exudative characteristics. Typically the hamsters die between 11 and 14-d post-inoculation, reflecting a slightly accelerated incubation period in comparison to human infections. As with human HCPS, the microscopic examination of the lung reveals abundant fibrin deposition, thickened alveolar septa, and viral antigen expressed abundantly in the microvascular endothelium. ANDV-infected hamsters fitted with physiologic monitoring devices exhibited diminished pulse pressures, tachycardia, and hypotension that appear to closely mimic the shock that is believed to be the proximate cause of demise in patients who succumb to HCPS [65, 74] . Compared to the human disease, ANDV-infected hamsters exhibit exceptionally high titers of live ANDV in their tissues, with much of the viral replication occurring in hepatocytes, which are spared in the human disease. Titers of live ANDV in some cases exceed 10 8 /g, whereas hantavirus isolates from human tissues have been notoriously difficult to obtain. Despite the universal occurrence of mildly-elevated hepatic enzymes in patients with HCPS, hepatic enzymes do not appear to be present at elevated levels in the blood of diseased hamsters even immediately before death [75] . The protracted incubation period associated with hantavirus disease gives the host considerable time to mount a mature immune response against the virus. Thus, in contradistinction to infections of comparable severity and related symptomatology associated with arenaviruses and filoviruses, hantavirus infections of humans are associated with antibody responses of significant titer by the time symptoms commence. Despite this observation, it appears to be possible that natural variation in individual neutralizing antibody responses among patients with SNV infections can be linked to disease severity, suggesting that administration of antiviral antibodies could prove effective therapeutically [76] . In the case of ANDV infection, new evidence has emerged indicating that the apparent clearance of the virus from the blood does not result in the complete removal of antigenic stimulus by the virus, suggesting that the virus may persist, perhaps in some as-yet undetermined immunologically privileged site [77] . A role for T cell-mediated pathological responses in HFRS and HCPS has been the source of speculation for a variety of reasons. The severity of SNV-associated HCPS may have made it more apparent that the onset of pulmonary edema, tachycardia and hypertension seemed to be all but universally temporally associated with the appearance of a spectrum of highly-activated cells of the lymphoid lineage in the peripheral blood. Cells with a close morphologic similarity to these -immunoblasts‖ were detected in the congested, heavy lungs of patients who came to autopsy, as well as in lymphoid organs and in the portal triads [63, [78] [79] [80] . These observations led to speculation that some component of hantavirus pathogenesis could be linked to the appearance of antiviral T cells that could stimulate or contribute to the appearance of a -storm‖ of mediators and the associated capillary leak phenotype. Subsequent studies have borne out the expectation that a significant fraction of the immunoblast population in patients with HCPS are T cells with specificity for specific class I HLA-presented epitopes of viral antigens, including Gn, Gc and N [77, [81] [82] [83] . Presumably, the antiviral activities of such cells, manifested in part through their elaboration of mediators in the affected interstitium, can contribute to the endothelial/capillary leak that lies at the heart of hantavirus pathogenesis. Because early cases of HCPS often came to autopsy, it became possible to examine necropsied tissues for expression of cytokines. The study by Mori et al. (1999) revealed high relative expression of proinflammatory cytokines including TNF, IL-1, IL-6, providing evidence in favor of a -cytokine storm‖ model for pathogenesis [64] . The authors believed, based on the morphology of cytokine-secreting cells, that both monocytes and lymphocytes were contributing to the production of cytokines. That proinflammatory mediators are found in elevated levels in the plasma as well as the renal interstitium of patients with acute hantaviral illness has been recognized for some time as well [84, 85] . While diagnosis of HCPS as well as HFRS is best accomplished with IgM serology, in the acute stage of SNV infection, RT-PCR can also be used if blood cells or blood clot are used instead of plasma or serum, where sensitivity even using nested PCR primers drops to about 70% [86] [87] [88] . In a facility at which many cases of HCPS are treated, the University of New Mexico medical center in Albuquerque, a diagnostic service has long been offered in which the patient's hematologic findings are analyzed to establish the probability that a patient has HCPS.Question: As an RNA-binding protein that engages the hairpin termini of the genomic segments, what does the N-protein of hantavirus do?

question:You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.Title: The LSH/DDM1 Homolog MUS-30 Is Required for Genome Stability, but Not for DNA Methylation in Neurospora crassa}Article:Abstract:LSH/DDM1 enzymes are required for DNA methylation in higher eukaryotes and have poorly defined roles in genome maintenance in yeast, plants, and animals. The filamentous fungus Neurospora crassa is a tractable system that encodes a single LSH/DDM1 homolog( NCU06306). We report that the Neurospora LSH/DDM1 enzyme is encoded by mutagen sensitive-30( mus-30), a locus identified in a genetic screen over 25 years ago. We show that MUS-30-deficient cells have normal DNA methylation, but are hypersensitive to DNA damaging agents. MUS-30 is a nuclear protein, consistent with its predicted role as a chromatin remodeling enzyme, and levels of MUS-30 are increased following DNA damage. MUS-30 co-purifies with Neurospora WDR76, a homolog of yeast Changed Mutation Rate-1 and mammalian WD40 repeat domain 76. Deletion of wdr76 rescued DNA damage-hypersensitivity of Δmus-30 strains, demonstrating that the MUS-30-WDR76 interaction is functionally important. DNA damage-sensitivity of Δmus-30 is partially suppressed by deletion of methyl adenine glycosylase-1, a component of the base excision repair machinery( BER); however, the rate of BER is not affected in Δmus-30 strains. We found that MUS-30-deficient cells are not defective for DSB repair, and we observed a negative genetic interaction between Δmus-30 and Δmei-3, the Neurospora RAD51 homolog required for homologous recombination. Together, our findings suggest that MUS-30, an LSH/DDM1 homolog, is required to prevent DNA damage arising from toxic base excision repair intermediates. Overall, our study provides important new information about the functions of the LSH/DDM1 family of enzymes.Introduction:Many chromatin-based processes require the activity of ATP-dependent chromatin remodeling enzymes, which can alter local chromatin structure by repositioning, removing, or restructuring nucleosomes[1–3]. Mammalian LSH( Lymphoid-specific helicase; also known as HELLS, PASG, and SMARCA6) and Arabidopsis DDM1( Decreased DNA methylation 1) are the founding members of the LSH/DDM1 subfamily of ATP-dependent chromatin remodelers–one of 24 subfamilies that comprise the larger SNF2 enzyme family[4, 5]. In vitro, DDM1 is able to hydrolyze ATP and reposition nucleosomes on a short DNA template, demonstrating that the LSH/DDM1 subfamily includes bona fide chromatin remodeling enzymes[6]. Moreover, molecular and genetic studies have implicated LSH and DDM1 in a number of important cellular processes. Lsh was originally identified as lymphocyte-specific; however, the gene is ubiquitously expressed in mammals[7–9]. In particular, high levels of Lsh are found in proliferating cells, suggesting that the protein might function during DNA synthesis or cell division. Subsequent studies revealed that Lsh is essential for development. Mice bearing homozygous deletions of Lsh die within 24 hours of birth, reportedly due to a host of developmental defects[8, 10]. Additional studies in chimeric mice or with tissue explants revealed that LSH is essential for both male and female meiosis[11, 12], as well as for proliferation of T-lymphocytes[13]. Thus, LSH is essential for gametogenesis and for proper development of the immune system. Notably, LSH has also been implicated in cancer[7, 14–18]. An in-frame Lsh deletion in the putative catalytic domain is frequently identified in human leukemias[7], and transplantation of hematopoietic precursors from Lsh-/- mice produced abnormal hematopoiesis and elevated rates of erythroleukemia in recipients[14]. Despite its role in these important processes, the molecular functions of LSH are not well understood. Lsh mutant mice exhibit significantly reduced DNA methylation( 5mC) at many sites in the genome[19–26]. Similarly, Arabidopsis thaliana ddm1 mutants display reduced DNA methylation and developmental defects, suggesting that at least some LSH/DDM1 functions are conserved across eukaryotic kingdoms[27–33]. Recently, studies in both plants and animals have uncovered a role for LSH/DDM1 in maintenance of genome stability. Arabidopsis DDM1-deficient mutants are hypersensitive to a variety of DNA damaging agents, including MMS( methyl methanesulfonate)[34, 35]. Similarly, mammalian Lsh-/- cells are hypersensitive to DNA damage and are unable to mount a robust DNA damage response[36]. There is some controversy regarding the relationship between the DNA methylation and DNA damage phenotypes of LSH/DDM1-deficient cells. The DNA damage-sensitivity phenotype of ddm1 plants was proposed to be an indirect effect of DNA hypomethylation[35], whereas in animals, stable knockdown of Lsh in immortalized lung fibroblasts led to hypersensitivity to DNA damage before a reduction in DNA methylation levels was observed[36]. Notably, an LSH homolog was also implicated in genome maintenance in Saccharomyces cerevisiae, an organism that lacks DNA methylation. The yeast gene, named IRC5( Increased repair centers-5), was uncovered in a high throughput screen for deletion strains that accumulate spontaneous DNA repair foci[37]. Thus, LSH-family enzymes are important for genome stability in fungi, plants, and animals, but precisely how LSH/DDM1 homologs control DNA methylation or genome stability is not clear. LSH-family members are absent from several model systems including Drosophila melanogaster, Caenorhabditis elegans, and Schizosaccharomyces pombe[5], but the model fungus Neurospora crassa encodes a single LSH/DDM1 homolog( NCU06306; also called Chromatin Remodeling Factor 5)[5, 38]. N. crassa is a particularly attractive model for studies of chromatin structure and function because its complement of chromatin modifications and chromatin-associated proteins is similar to higher eukaryotes. For example, hallmarks of heterochromatin such as histone H3 lysine-9 methylation( H3K9me3), Heterochromatin protein-1 and DNA methylation are shared between Neurospora and higher eukaryotes, but are all absent from S. cerevisiae[39–42]. To gain insights into the functions of the LSH/DDM1 subfamily, we performed molecular, genetic and genomic analyses to investigate N. crassa NCU06306/CRF5. We found that this LSH/DDM1 homolog is not required for DNA methylation, but is essential for survival from DNA damage. ncu06306/crf5-1 is allelic to the previously described mutagen sensitive-30( mus-30). The encoded protein is localized to the nucleus and interacts with WDR76, a conserved WD40 domain-containing protein. Based on genetic interactions with known DNA repair components, we propose that the Neurospora LSH/DDM1 homolog functions to limit genome instability resulting from toxic base excision repair intermediates.Discussion:Chromatin remodelers can impact genome maintenance by regulating specific types of DNA repair, facilitating DNA replication, and enhancing propagation of DNA damage signals[3]. LSH/DDM1 homologs have been implicated in genome maintenance from yeast to humans, but how these proteins contribute to genome maintenance is not understood. Plant ddm1 mutants are hypersensitive γ-radiation, UV-light, and MMS[34, 35]. Similarly, Lsh-/- cells are hypersensitive to a number of DNA damaging agents and display muted induction of γH2A. X as well as diminished recruitment of γH2A. X-binding proteins following DNA damage. Based on these observations, it was concluded that LSH promotes efficient DSB repair.[36]. Our study provides additional evidence that LSH/DDM1 proteins are key regulators of genome stability and provides new insights into the role of an LSH/DDM1 family member in genome maintenance. We propose that N. crassa MUS-30 plays an important role in preventing genome instability when replication forks encounter toxic base excision repair intermediates. This idea is supported by our findings that: 1) deletion of mag-1 can partially rescue the MMS-sensitivity of Δmus-30 strains, 2) Δmus-30 and Δmei-3 interact genetically, 3) MUS-30 is not required for normal BER or DSB repair, and 4) MUS-30 interacts with WDR76. It is not known if other LSH/DDM1 enzymes in other systems act to maintain genome stability independently of DSB repair, but data from yeast and animals are compatible with the idea. A high throughput study in yeast found that irc5Δ strains accumulate spontaneous Rad52-GFP foci in the absence of exogenous DNA damage and exhibit elevated recombination rates with non-sister chromatids[37]. In animals, Lsh expression is highest in proliferating tissues and was correlated with the onset of S-phase[7–9, 13]. Moreover, Burrage and colleagues showed that DNA damage in LSH-deficient cells triggers normal cell cycle arrest, followed by rapid cell death once S-phase resumes[36]. Thus, it is possible that mammalian LSH and yeast Irc5 function during S-phase to prevent collapsed replication forks at specific types of DNA lesions. Our protein interaction studies provide additional evidence supporting a conserved role for LSH/DDM1 in different systems. We found that N. crassa MUS-30 interacts with a well conserved protein, WDR76. Not only is the WDR76 protein conserved in fungi and animals, its interaction with LSH/DDM1 family members appears to be conserved across species. Proteomic analysis of Cmr1, the yeast WDR76 homolog, identified Irc5p as a putative Cmr1-interacting protein[77]. In addition, while this manuscript was in preparation, it was reported that mammalian LSH co-purifies with WDR76[76]. Our observation that mus-30 and wdr76 interact genetically provides compelling evidence that physical interaction of MUS-30 and WDR76 is functionally important. Although the specific functions of WDR76 and its homologs are unknown, it was recently reported that both Cmr1 and mammalian WDR76 form DNA damage-dependent foci that are distinct from DSB repair centers[75, 76]. Thus, the interaction between WDR76 and MUS-30 provides additional evidence that MUS-30 is not directly involved in DSB repair. Interestingly, in the presence of the replication inhibitor HU, cmr1Δ exhibits positive genetic interactions with gene deletions of replication fork protection components[76]. We found a similar positive genetic interaction between mus-30 and wdr76 in the presence of MMS. These data could indicate that WDR76 somehow acts to destabilize stalled replication forks. Yeast Cmr1 localizes to a unique sub-nuclear compartment that was hypothesized to promote protein degradation, consistent with this possibility[76]. Alternatively, it was proposed that yeast Cmr1 negatively regulates the DNA damage response[76]. WDR76 may target MUS-30 and other components of the DNA damage response for degradation. Increased activity of other DNA repair components in the Δwdr76 strain could explain why the Δmus-30 phenotype is rescued by the wdr76 deletion. In plants and animals, LSH and DDM1 proteins have been extensively investigated for their role in regulating DNA methylation. It was suggested that changes in 5mC may lead to differential expression of DNA repair genes in A. thaliana ddm1 mutants[35]. In contrast, it was proposed that mammalian LSH controls DNA repair and DNA methylation through distinct mechanisms[36]. Indeed, knock down of Lsh-knockdown caused hypersensitivity to DNA damage prior to methylation loss, demonstrating that loss of DNA methylation is not indirectly responsible for the hypersensitivity to DNA damage. Here, we found normal DNA methylation levels in mus-30 strains by comprehensive MethylC-seq, clearly demonstrating that loss of 5mC does not drive DNA damage-sensitivity in Δmus-30 strains. It remains possible, however, that loss of DNA methylation in LSH/DDM1-deficient cells results in part from defective DNA repair functions. Future work is needed to fully understand how LSH/DDM1 family members function to regulate DNA methylation and contribute to genome stability.