In this task, you're given a paragraph from the research paper and your task is to generate a suitable title for the research paper based on the given paper. Under 100 words is a good title length.
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Question: Ebola virus (EBOV) disease can result in a range of symptoms anywhere from virtually asymptomatic to severe hemorrhagic fever during acute infection. Additionally, spans of asymptomatic persistence in recovering survivors is possible, during which transmission of the virus may occur. In acute infection, substantial cytokine storm and bystander lymphocyte apoptosis take place, resulting in uncontrolled, systemic inflammation in affected individuals. Recently, studies have demonstrated the presence of EBOV proteins VP40, glycoprotein (GP), and nucleoprotein (NP) packaged into extracellular vesicles (EVs) during infection. EVs containing EBOV proteins have been shown to induce apoptosis in recipient immune cells, as well as contain pro-inflammatory cytokines. In this manuscript, we review the current field of knowledge on EBOV EVs including the mechanisms of their biogenesis, their cargo and their effects in recipient cells. Furthermore, we discuss some of the effects that may be induced by EBOV EVs that have not yet been characterized and highlight the remaining questions and future directions. It is estimated that only approximately 20%-25% of GP products are the membrane-anchored GP 1,2 form, while the remaining 75%-80% are of the secreted type, with~70% sGP and~5% ssGP [7] [8] [9] [10] . During early infection, EBOV targets mainly monocytes/macrophages and dendritic cells (DCs). It is thought that these migrating cells aid in systemic dissemination of the virus throughout the host, especially into secondary lymphoid organs and the liver. Intense replication of the virus then takes place in other host cell types, including endothelial cells, epithelial cells, fibroblasts and hepatocytes [11] [12] [13] [14] . Fatal filovirus infections often involve severely dysregulated innate and adaptive immune responses, defective coagulation, and are typified by systemic cytokine storm and multi-organ failure. Immune system damage includes type-I and type-II interferon (IFN) antagonism by VP35 and VP24, respectively, NK and T-cell depletion known as bystander lymphocyte apoptosis, and impaired DC maturation [15] . Severe presentations of disease are accompanied by viral replication within and necrosis of the spleen, liver, kidneys, gonads, gastrointestinal tract and endocardium [13, 16] . In those who are fortunate enough to survive acute Ebola virus disease (EVD), the virus becomes undetectable in the blood, depicting a typical phenotype of viral clearance. However, either entire virus or viral components may remain detectable in patients relatively long after recovery, particularly in immune-privileged sites [17] [18] [19] [20] [21] [22] [23] [24] . Notably, recent studies have shown that over 1 in 4 male survivors from the 2016 outbreak contained virus within their semen up to 7-9 months past the disappearance of EVD symptoms. Furthermore, virus has still been detectable up to 16-18 months later [17] . This type of "clinical latency" or persistent infection has significance for public health in the following ways: (1) viral reservoirs within immune privileged sites have implications for reemergence and persistence of the virus within the infected individual, potentially allowing for resurgence of infection, morbidity, and mortality [25]; (2) these reservoirs may allow for the transmission of the virus to additional individuals long after initial infection, hindering efforts to control the spread of outbreaks by public health infrastructures [25]; and (3) significant political, socio-economic, and social stigma considerations must be taken into account for policies to support the normal life and travel of EVD survivors [26] [27] [28] [29] . Spread of the virus by this route is of particular concern, as several cases of sexual transmission from male to female have already been documented. One of the first such cases involved transmission from a man 6 months past his recovery to a woman in Liberia [30, 31] . To date, three additional "flare-ups" of EBOV by sexual contact have been determined, together accounting for approximately half of the eight mini-outbreaks caused by persistently infected survivors documented since 2016 [32] [33] [34] [35] . The most concerning of these cases occurred over 480 days (nearly 17 months) past the initial recovery of the patient [35] . To further complicate the matter, there have been multiple reports addressing potential asymptomatic or undiagnosed portions of the population. Previous studies have put the number of seropositive but undiagnosed/asymptomatic individuals anywhere between 0%-47% [36] [37] [38] [39] [40] [41] [42] [43] [44] . This of course implies that such individuals may represent an invisible source of viral transmission and future outbreaks. Exemplifying this is a case involving an asymptomatic mother who likely transmitted EBOV to her 9-month-old infant (as determined by sequencing and phylogenetic analysis) through breast milk, ultimately resulting in the fatality of the child [19] . Interestingly, the asymptomatic father's semen was also EBOV-positive, but was distantly related to the strains found in the mother and child. Currently, the mechanism of this viral persistence is not well characterized, although new studies have hinted as several possibilities, which will be discussed later. Extracellular vesicles (EVs) are small, membrane-bound vesicles that are released from numerous cell types and are involved in cell-to-cell communication. The intercellular communication is mediated by EV cargo, consisting of nucleic acids and proteins, which can be transferred between cells to elicit a phenotypic change in the recipient cell [45] [46] [47] . EVs are heterogeneous; as such, the current literature separates EVs into several different categories based mainly on differences in size and cellular origin, including subtypes such as exosomes and microvesicles [48] . Microvesicles bud directly from the plasma membrane and are generally larger than exosomes with diameters ranging from Viruses 2019, 11, 410 3 of 25

Answer: viruses Extracellular Vesicles and Ebola Virus: A New Mechanism of Immune Evasion

Question: Viruses use a limited set of host pathways for infection. These pathways represent bona fide antiviral targets with low likelihood of viral resistance. We identified the salicylanilide niclosamide as a broad range antiviral agent targeting acidified endosomes. Niclosamide is approved for human use against helminthic infections, and has anti-neoplastic and antiviral effects. Its mode of action is unknown. Here, we show that niclosamide, which is a weak lipophilic acid inhibited infection with pH-dependent human rhinoviruses (HRV) and influenza virus. Structure-activity studies showed that antiviral efficacy and endolysosomal pH neutralization co-tracked, and acidification of the extracellular medium bypassed the virus entry block. Niclosamide did not affect the vacuolar H + -ATPase, but neutralized coated vesicles or synthetic liposomes, indicating a proton carrier mode-of-action independent of any protein target. This report demonstrates that physico-chemical interference with host pathways has broad range antiviral effects, and provides a proof of concept for the development of host-directed antivirals.

Answer: Niclosamide Is a Proton Carrier and Targets Acidic Endosomes with Broad Antiviral Effects

Question: Translational control of memory processes is a tightly regulated process where the coordinated interaction and 47 modulation of translation factors provides a permissive environment for protein synthesis during memory 48 formation. Existing methods used to block translation lack the spatiotemporal precision to investigate cell-49 specific contributions to consolidation of long-term memories. Here, we have developed a novel chemogenetic 50 mouse resource for cell type-specific and drug-inducible protein synthesis inhibition (ciPSI) that utilizes an 51 engineered version of the catalytic kinase domain of dsRNA-activated protein (PKR). ciPSI allows rapid and 52 reversible phosphorylation of eIF2 causing a block on general translation by 50% in vivo. Using this resource, 53 we discovered that temporally structured pan-neuronal protein synthesis is required for consolidation of long-54 term auditory threat memory. Targeted protein synthesis inhibition in CamK2 expressing glutamatergic 55 neurons in lateral amygdala (LA) impaired long-term memory, which was recovered with artificial chemogenetic 56 reactivation at the cost of stimulus generalization. Conversely, genetically reducing phosphorylation of eIF2 in 57 CamK2 positive neurons in LA enhanced memory strength, but was accompanied with reduced memory 58 fidelity and behavior inflexibility. Our findings provide evidence for a finely tuned translation program during 59 consolidation of long-term threat memories. Memory is the capacity of an organism to encode, store, and retrieve information, and often guides the 83 action of the organism towards a better survival outcome. Aversive life-threatening events often lead to long-84 term associative memories between the environment in which those events were experienced in and the 85 threat, such that a salient cue from the event when presented again can elicit species-specific defensive 86 behaviors. Pavlovian cued threat conditioning is a useful experimental paradigm for understanding the 87 biological substrates of an associative threat memory, in which a neutral cue (e.g. light or tone) co-presented 88 with an innately aversive stimulus (e.g. air puff or footshock) elicits a defensive response such as freezing by a 89 repeat presentation by itself 1 . Cued threat conditioning is particularly amenable to studying memory 90 consolidation process because one-trial training is sufficient to form a persistent long-term memory and a 91 unimodal cue can be used for memory retrieval. Long-term aversive memories are thought to recruit a 92 distributed network of neurons across the brain, including subnuclei within amygdala, hippocampus, thalamus, 93 as well as the neocortex, depending on the brain state, cue complexity, and the sensory pathways engaged 2, 3 . Lateral amygdala is the central sensory gateway for the amygdaloid complex and is crucially engaged both in 95 the processing and storage of the associative aversive memories 4, 5, 6 . Decades of studies have reported that consolidation of long-term memories requires one or more 98 waves of new protein synthesis after the memory is first encoded 7, 8, 9, 10 ; however, the use of pharmacological 99 protein synthesis inhibitors (PSI) in these studies is burdened with limitations. For instance, an extensively 100 used PSI, anisomycin, causes unwanted side effects that include superinduction of immediate early genes, 101 activation of stress signaling pathways, and catecholamine release 11, 12 . Pharmacological PSIs also do not 102 discriminate between molecularly heterogeneous cell populations and thus, do not allow manipulation of cell 103 autonomous protein synthesis. Genetic approaches to alter the translation machinery at the initiation step 104 provide less ambiguous evidence for the role of protein synthesis in memory processes 13, 14 . However 105 constitutive deletion of genes encoding translational control molecules lacks the temporal control needed to 106 convincingly interrogate the role of protein synthesis in memory consolidation. Past attempts at making 107 chemogenetic tools for blocking protein synthesis have had limited success 15 . A key regulatory step in mammalian protein synthesis is the assembly of active eIF2.GTP and initiator-110 methionyl tRNA into a ternary complex that binds the 40S ribosome. Various types of cellular stress engage 111 pathway-specific protein kinases that phosphorylate the subunit of eIF2 on serine 51, which converts eIF2 112 from a substrate to a competitive inhibitor of eIF2B, a guanine exchange factor that promotes the conversion of 113 inactive eIF2.GDP to active eIF2.GTP. Thus, phosphorylation of eIF2 stops the recycling of the ternary 114 complex and inhibits general translation 16 . However, phosphorylation of eIF2 also leads to a paradoxical 115 increase in gene-specific translation of transcripts harboring upstream open reading frames (uORFs) by 116 overcoming the inhibitory effects of uORFs on reinitiation at the putative start codon as ternary complexes 117 decline 17 . Dephosphorylation of eIF2 occurs during L-LTP as well as during consolidation and reconsolidation

Answer:
Chemogenetic evidence that rapid neuronal de novo protein synthesis is 3 required for consolidation of long-term memory Introduction 82