Although most researchers maintain that shame and guilt are distinct emotions, the debate on their differences is still open. We aim to show that some of the current distinctions between shame and guilt need to be redrawn, and their adaptive and social implications need to be revisited. We suggest the following distinguishing criteria: the kind of self-evaluation involved (inadequacy versus harmfulness); one’s focus on the perceived discrepancy between actual and ideal self versus one’s focus on the perceived responsibility for one’s fault; and consequently the different domains of self-esteem involved. Although these criteria have been in part suggested or alluded to in the relevant literature, we use and integrate them with each other in a novel way. This allows to better distinguish between shame and guilt, as well as to account for their possible coexistence or the shift from one emotion to the other. Shame and guilt have much in common: they are self-conscious emotions, implying self-reflection and self-evaluation e.g., ; they inBefore discussing the most common criteria used for distinguishing between shame and guilt, and then suggesting our own criteria, we need to explain why it is important to distinguish between these emotions. In so doing, we will also outline the core of our proposal.As widely acknowledged, emotions accomplish both an informative function about our relationship with the environment, by signaling the  failure or attainment of our goals e.g.,  and a molacking ; on the other hand, they may view themselves as wicked, unjust, sinful—that is, endowed with the power to violate norms and thwart others’ goals, and willing (or inclined) to do so.Both shame and guilt are “self-critical” emotions. However, self-criticism may take different self-evaluative forms: on the one hand, people may view themselves as ugly, stupid, handicapped, or morally defective—in a word, We suggest that it is adaptive to have differentiated emotional responses to different forms of self-criticism. As also pointed out by moral self-evaluation. Without attempting to give a definition of moral, we suggest that a necessary condition for regarding an evaluation as moral is that it should concern someone’s behavior, goals, beliefs or traits for which (s)he is regarded as responsible. The evaluation will be positive or negative depending on the beneficial or harmful quality ascribed to such behavior, goal, and so on. Guilt is indeed concerned with one’s responsibility for a harmful attitude or behavior.As we will argue, guilt implies a negative not his or her responsibility for the fault, but how this fault impacts on his or her ideal self.By contrast, shame implies a nonmoral negative self-evaluation. Note that “nonmoral” is not synonym to “immoral”. By “nonmoral” we mean that shame is not focused on responsibility issues. As we shall see, it is rather concerned with a perceived discrepancy between one’s actual and one’s ideal self. In fact, one may feel ashamed of one’s ugliness, disability, or any other flaw for which (s)he is not responsible. However, one may also feel ashamed (rather than guilty) of a responsible fault. We will suggest that even when a responsible fault is at stake, ashamed people do not focus on responsibility issues, but on the disappointing fact that such fault reveals their defectiveness with regard to their ideal self. To the extent that shame can make people care about the social order, it can be said to be a moral emotion e.g., . Howeverlack of power to meet the standards of one’s ideal self, whereas guilt implies perceived power and willingness to be harmful, that is, to violate the standards of one’s moral self. These differences have important motivational consequences, both positive and negative: whereas guilt is likely to motivate either reparative or self-punitive behavior, shame is likely to motivate either withdrawal or increased efforts in building one’s aspired-to identity. More generally, distinguishing between shame and guilt has significant implications for basic research on human emotions as well as for clinical treatment, by helping understand if and how these emotions relate to a variety of phenomena, such as empathic concerns, narcissism, self-destructive behavior, and moral compliance.Shame implies perceived As we will try to show, the distinguishing criteria suggested in the relevant literature do not satisfactorily account for the differences between shame and guilt, whereas our own criteria allow to better identify the respective features of the two emotions.We will group the most widespread distinguishing criteria into three categories: the kinds of failure or transgression that elicit these emotions; the action tendencies typically triggered by shame versus guilt; and the ascription of the fault to one’s self versus one’s behavior.In addition, we will consider a number of elements which are viewed as indicative of remarkable differences between shame and guilt in terms of their adaptive value: the cognitive states, as well as other feelings, that are associated with shame versus guilt; and the psychopathological symptoms related to shame-proneness versus guilt-proneness.public versus private experience of the fault; its proscriptive versus prescriptive nature; and the moral versus the both moral and nonmoral nature of the fault.Three possible kinds of fault have been identified: the According to this distinction, shame is elicited by public faults, and (one’s fear of) others’ negative evaluations, whereas guilt is a private feeling, elicited by one’s own negative self-evaluation e.g., .The public versus private criterion has already been questioned, both theoretically and empirically. For instance, can become public or imagining a judging audience. As often suggested, shame is more likely than guilt to imply a feeling of exposure to a judging audience  external sanctions, one might draw the inference that this emotion coincides with a mere fear of others’ disapproval, and that it can be experienced without evaluating oneself negatively—which is indeed stated by some authors e.g., .We question that shame coincides with being afraid of others’ disapproval. One can be afraid of other people’s negative evaluations while feeling no shame. For instance, a son who fails to live up to the standards set by his parents can be afraid to disappoint them or to be punished by them, and at the same time experience no shame.shame (as well as guilt) implies a negative self-evaluation against one’s own standards. Although personal standards result from the internalization of social ones, they are not necessarily absorbed in the same form as they are socially conveyed. Internalization involves developing a personalized interpretation of social standards . In fact, others’ evaluation and one’s self-evaluation may diverge, either because one may not share the evaluative standards of one’s “judges” or because, while sharing their standards, one may believe that their evaluations are mistaken in that no actual fault has been shown according to those standards.In our view, if a negative evaluation comes from outside, one has to discomfort at exposure (self-presentation (We suggest that in both the above cases the disapproved person will not experience shame (and certainly not guilt), but other possible feelings—fear of the consequences of the negative evaluation; disappointment and resentment for having received an “undeserved” evaluation; helplessness, elicited by the perceived inability to modify others’ judgment; or, most notably, embarrassment, which implies no necessary negative self-evaluation e.g., , but merexposure . Embarraentation , rather entation , p. 1260be certain that nobody will ever know about one’s own fault, and still experience shame. In the same vein, one does not need to imagine a judging audience. As claimed by typical of shame, it does not need to be constitutive of the emotion. Of course, one learns socially what is “shameful”, but one also learns socially what is threatening, or disappointing, or saddening—which does not imply the necessary involvement of an audience in the experience of fear, disappointment, or sadness.We also question that for feeling ashamed one should think that one’s fault can become public. One can even What we have said so far, however, by no means excludes that shame involves “to feel seen”. Even without any real or imagined audience, one can feel seen by one’s self in the role of self-evaluator, and experience shame. In According to However, a proscriptive violation  may elicit guilt, and a prescriptive violation (not reciprocating a favor) may elicit shame. As found by moral fault elicit shame rather than guilt?According to some authors e.g., , guilt iThus, in Guilt has been found to lead to repair action tendencies, such as apologizing, amending, and undoing, whereas shame appears to favor withdrawal and escape behaviors, as well as hostile and self-defensive reactions e.g., . On the However, the relationship between emotions and action tendencies is not so straightforward as one might expect. As shown by on condition that people consciously recognize their responsibility. Self-defensive maneuvers are not monopoly of shame. People also defend themselves from guilt  triggered by external sanctions , which in turn predict self-defensive avoidance. By distinguishing social-image concerns from self-image concerns, and the effects of felt rejection from those of felt shame, these findings suggest that shame proper is unrelated to self-defensive action tendencies.Therefore, based on the literature reviewed above, it seems unwarranted to conclude that shame is characterized by self-defensive action tendencies, and guilt by prosocial ones. Both emotions can elicit both prosocial and self-defensive behavior.am a bad, inadequate person”), the emotional response will be of shame. If one’s own negative evaluation is circumscribed to one’s behavior (“I did a bad thing”), it will give rise to guilt . According to the self-versus-behavior view, what matters is whether the fault is ascribed to the self or is circumscribed to one’s behavior: If it is ascribed to the self, which is supposed to imply a global negative self-evaluation  person. Even when starting from a specific wrongdoing, one may generalize one’s negative evaluation to the self: “Because I did something bad, I am bad”. It has been suggested that the behavior-to-self generalization implies a “fusion” between guilt and shame  relation to guilt feelings .Guilt has been found to be unrelated to anger, and negatively correlated with the externalization of blame e.g., . ActuallGuilt is also associated with perspective-taking and empathic concerns, that in turn favor prosocial behavior e.g., , whereasresponsibility for the fault. As long as guilt implies the conviction of having responsibly broken a norm (which is supposed to promote and defend the collective welfare) or having injured someone , the crucial aspect is that Turning to the psychopathological symptoms associated with shame-proneness versus guilt-proneness, there is a wide consensus on the dysfunctional consequences of shame-proneness , whereas there is less consensus on the psychopathological implications of guilt-proneness e.g., . Howeverglobal negative self-view, which may be associated with shame as well as guilt, when negative self-evaluations are generalized to the whole self.Therefore, it is unwarranted to conclude either that shame is an “ugly” and dysfunctional emotion or that guilt is constructive and adaptive. We suggest that many dysfunctional consequences that have been ascribed to shame depend on a is; on the other hand, we contend that shame is not necessarily focused on the self as a whole.As discussed so far, shame and guilt do not seem to be distinguishable from each other according to such criteria as the kinds of fault that elicit these emotions, their action tendencies, and their adaptive versus maladaptive implications. We have also questioned that the self-versus-behavior criterion adequately distinguishes shame from guilt. We do not see why guilt should be only felt about one’s own behavior, and will argue that it can also be felt about who the person kinds of negative self-evaluation implied by these emotions: Whereas shame implies a self-evaluation of inadequacy, guilt implies a self-evaluation of harmfulness. This is a new criterion. Although a sense of personal inadequacy or powerlessness has been typically associated with shame , as well as the implication that the ashamed person should necessarily perceive themself as non-responsible for the fault. (See “Is Perceived Non-Responsibility a Necessary Cognitive Component of Shame?”)One might endorse the attributional view, which relates shame to internal, stable, and uncontrollable attributions e.g., , and sugx in that the latter is viewed as a good or bad means for some (class of) goal(s). Evaluative beliefs can be either explicit  or implicit . The positivity or negativity of the evaluation is contingent on the specific goal for which x is viewed as a means. For instance, a sharp knife is “good” for a cook’s goal of slicing food, whereas it is “bad” for a child’s goal of putting butter on the bread.Evaluations can be defined as beliefs about “what is good/bad for what” . They imiii  with respect to some goal ; when appraised as harmful, x is regarded as possessing sufficient power to attain a negative goal, that is, to realize a world state not-p which is the opposite of someone’s goal p .ivNegative (self-)evaluations can be of two kinds—harmfulness versus inadequacyiii . A knifegoal or, at least, with the power to prevent such harm, (self-)evaluations of harmfulness are strictly linked to responsibility issues. In fact, to regard oneself as responsible for something, one should believe that: (a) one caused it ; and (b) one had the goal to cause it , or at least (c) one had the power to prevent it (avoidance responsibility), but omitted to do so  for feeling shame.Feeling guilty implies perceiving oneself as a wrongdoer, which entails a self-evaluation of stable, and uncontrollable attributions.So far, our distinguishing criteria seem to overlap with those suggested by attributional models of shame and guilt e.g., . Howeverinternal one. The self-attributed inadequacy is not necessarily perceived as stable and uncontrollable. It is sufficient that people focus on the discrepancy between a negative self-evaluation and the positive one they would like to have. Of course, a further attributional search can be performed: If one’s fault is traced back to uncontrollable and stable causes, shame will be associated with helplessness and hopelessness. Conversely, if one’s fault is attributed to unstable and controllable causes, guilty feelings can arise—which may account for the frequent coexistence of shame and guilt, or more plausibly, the shift from one emotion to the other. But all of those consequences are possible implications of a further attributional search.While endorsing the attributional model of guilt, we view shame as less cognitively sophisticated, and suggest that the only necessary and sufficient attribution is the not involved in shame even when it concerns moral faults.The issue of perceived responsibility, however, needs to be better specified. We have to establish if it is actually necessary as well as if it is sufficient for experiencing guilt. We also need to explain how perceived responsibility can involve the self, without necessarily implying a fusion between guilt and shame. Finally, we should clarify why perceived responsibility is Some authors consider responsibility unnecessary for feeling guilty e.g., . In variantecedent of guilt . Unsurprisingly, innocent rape victims often feel co-responsible for the rape because they think they provoked it through their appearance or behavior, or did not do everything possible to prevent the attack e.g., . Second,rm e.g., . Developrm e.g., . We suggty e.g., .undeserved, this condition seems insufficient to imply perceived responsibility for the inequity as long as they believe they neither did anything to cause it nor had the goal to cause it or the power to prevent it. However, they are now responsibly accepting an inequitable situation. They can feel responsible for not refusing the advantage, not trying to re-distribute what is undeserved, or not challenging the standards followed by the bestowers of rewards. Responsibility can regard not only acts of commission but also omissions.Let us now discuss a few cases of guilt “without responsibility”. People who are over-rewarded tend to feel guilty when their advantage causes another’s disadvantage e.g., . Even thfeel responsible. How can one feel responsible for not sharing others’ misfortunes?Another classical example of guilt without responsibility is survivor guilt e.g., . In manyTo start with, after an event people tend to overestimate their preexisting predictive capabilities—showing the well-known hindsight bias e.g., —as well happy that another died. The survivor can feel responsible for having experienced such a despicable feeling, which may be viewed as betraying a disposition to harm others as a means for pursuing one’s own interest. Or, even without self-ascribing the wretched feeling of schadenfreude, the survivor may feel guilty for being happy while others are grieving over their losses, and view one’s own happiness as a sign of self-centeredness and hard-heartedness  done something, and reaches the conclusion that being alive is a matter of luck. Luck is often  viewed in terms of a zero-sum game—to have good luck implies depriving another of it. Although the survivor is not responsible for this deprivation (the “responsible” one is Fate or God), (s)he is likely to feel happy that (s)he has escaped death, which somehow implies being ss e.g., .responsible for one’s own traits, rather than for specific wrongdoings? Isn’t character something one cannot choose and be responsible for  harm they engender – while omitting to do so. We acknowledge that guilt relates to the self as an agent, but this is different from assuming that guilt is exclusively concerned either with one’s behavior or with how one’s actual behavior reflects on the self. Guilt is rather concerned with one’s self as an actual or potential wrongdoer.Therefore, we suggest that one can feel guilty for one’s negative traits, provided one responsible harmfulness is a twofold assumption—a self-evaluation of harmfulness plus a self-ascription of responsibility. Responsibility is in itself a neutral notion. Responsibility judgments assess whether one caused something, good or bad as it may be, and intended to cause it or at least could prevent it from occurring. Assignment of responsibility and assignment of guilt should be kept distinct  harmfulness.One can acknowledge responsibility for a behavior, personal attitude or attribute As already pointed out, an evaluation of responsible harmfulness is a moral evaluation. Therefore guilt, being concerned with one’s self as an actual or potential wrongdoer, implies a blow to one’s moral self-image.image is insufficient for experiencing guilt. Although one’s moral standards are largely a sociocultural product, and “different moral orders favour different moralities... in their members“  worsened.According to involves the  self, and is not confined to one’s specific behavior. In a sense, we agree with In other words, the negative self-evaluation implied in guilt not responsible for one’s own faults. Many examples can be found of felt shame concerning a responsible wrongdoing. A child who consciously disobeys his parents, a student who neglects her homework, a soldier who cowardly tries to flee the battle may feel ashamed rather than guilty. But, how is it possible to experience shame in such instances, rather than a misnamed guilty feeling?Unlike guilt, shame can be experienced when one’s self-evaluation concerns a mere lack of power. But this doesn’t necessarily imply that one should view oneself as does not consider responsibility issues, and focuses on one’s own inadequacy with respect to one’s ideal self. That is, one compares one’s actual self with one’s ideal standard, and finds it is sub-standard.What makes the difference between shame and guilt is not the objective kind of fault, but how this fault is represented, and where one’s attention is focused. One can feel shame for a wrongdoing as long as one ideal self-discrepancy, independent of responsibility issues. However, he states that shame involves “feeling that one has been lowered in the esteem of others because one has disappointed their hopes and wishes for one” (p. 323). We view this condition as both insufficient for feeling ashamed  and unnecessary .share those expectations. So, in any case, the ashamed one has disappointed one’s own expectations for oneself.While acknowledging that the ideal self (as well as the ought self) is socially constructed e.g.,  and, devnonmoral one, even when a moral fault is at stake. No doubt, a soldier who cowardly tries to flee the battle can feel guilty for such a responsible misdeed, suffer a blow to her moral self-image, and blame herself for being “evil”. However it is also possible that she feels ashamed, if she remains focused on the discrepancy between her actual self and her ideal self-image of a “brave soldier”. Here, she suffers a blow to her nonmoral or “aesthetic” self-image  and of a responsible misdeed. In both cases, one compares one’s actual self with one’s ideal self, and is disappointed by the discrepancy between the two. Shame is a kind of This view of shame can also account for the frequent association of this emotion either with depressive reactions e.g.,  or with vi can as well be distinguished into “moral” and “nonmoral” or “aesthetic”  “ugly”, and dislike themselves.From sthetic” . The negsthetic” , p. 349:necessarily imply a global negative self-view. The latter, although often considered typical of shame, is not necessarily involved in it. For example, going back to our ashamed soldier, her ideal self may include not only the standard of a “brave soldier” but also those of a “considerate friend” or a “loving parent”, which may remain untouched  for a wrongdoing. In fact, although a self-evaluation of inadequacy may concern moral attributes – that is, harmful attributes for which one may view oneself as responsible – ashamed people are only considering the disappointing discrepancy between their ideal (good) self and their actual (not so good) self. Of course this discrepancy implies a “good/bad” dichotomy, but the meaning of “good/bad” is not necessarily moral. “Good/bad” may mean not only virtuous/wicked, but also competent/incompetent, beautiful/ugly, disappointing/satisfactory, and so on. Shame is a nonmoral emotion, meaning that it involves the nonmoral or “aesthetic” facet of one’s self-esteem, which is concerned with the self’s adequacy with respect to its own wishes or aspirations.Shame is an unpleasant emotion implying a negative self-evaluation against one’s moral standards, that is, the standards concerning those behaviors, goals, beliefs or traits for which one regards oneself as responsible. The evaluation is negative in that such behaviors, goals, etc. are viewed as harmful. Therefore, guilt implies a self-evaluation of responsible harmfulness, that is, wrongfulness. The wrongdoing can be either actual or potential, that is, a possible consequence of personal traits and dispositions—provided the person views such traits as modifiable through effort (thereby feeling responsible for not trying to modify them). Therefore the self is involved in guilt, in that the fault can be ascribed not only to one’s behavior but also to the self. When one feels guilty, one’s self-image gets (more or less temporarily) worsened. However, in guilt it is the moral facet of one’s self-esteem – the facet concerned with the responsible harmfulness or beneficialness of the self’s behavior, attitudes, and dispositions – that suffers a blow.Guilt is an unpleasant emotion implying a In our view, the distinguishing criteria we have suggested allow to account for both the similarities and the differences between shame and guilt, as well as to clarify the most problematic cases. They explain how a moral fault can elicit shame rather than guilt; or, conversely, how a flaw of character can elicit guilt rather than shame. We have also questioned the widespread view of shame as an ugly and maladaptive emotion, versus guilt as a prosocial and adaptive one. Either emotion (and probably any emotion) can be adaptive or maladaptive depending on contextual factors and the regulation strategies used e.g., . Dysfunc


Microorganisms utilize complex enzymatic pathways to biosynthesize structurally complex and pharmacologically relevant molecules. These pathways are encoded by gene clusters and are found in a diverse set of organisms. The Minimum Information about a Biosynthetic Gene cluster repository facilitates standardized and centralized storage of experimental data on these gene clusters and their molecular products, by utilizing user-submitted data to translate scientific discoveries into a format that can be analyzed computationally. This accelerates the processes of connecting genes to chemical structures, understanding biosynthetic gene clusters in the context of environmental diversity, and performing computer-assisted design of synthetic gene clusters. Here, we present a Standard Operating Procedure, Excel templates, a tutorial video, and a collection of relevant review literature to support scientists in their efforts to submit data into MiBIG. Further, we provide tools to integrate gene cluster annotation projects into the classroom environment, including workflows and assessment materials.The online version of this article (10.1186/s40793-018-0318-y) contains supplementary material, which is available to authorized users. Biosynthetic gene clusters within microorganisms encode highly evolved molecular machines that catalyze the production of structurally complex specialized metabolites, many of which have been repurposed as pharmaceutical, agricultural, and manufacturing agents. Recent advances in genome sequencing have led to a flood of data about these BGCs, but how this information is reported, and where it is deposited, was inconsistent until recent efforts to create a standard systematic deposition procedure . The MinTo facilitate future depositions of BGC information into MIBiG, we herein present a detailed workflow, Excel templates that scaffold the annotation procedures, and a video tutorial in which the entire annotation process is presented for a sample BGC entry Fig. . We enviTo properly catalogue the information on a specific BGC, one must be informed of the scope of experiments that have been performed on the biosynthetic pathway in question. Using credible sources, namely trusted databases and published experimental results, a researcher who submits an MIBiG entry is tasked with accurately reporting this information in a Web form, which allows for the data to be stored in a format that facilitates future computational analysis. Relevant information includes publication identifiers associated with the BGC, parameters of the associated genomic loci, information about the chemical compounds(s) encoded, and experimentally verified gene functions. The curation of this information ultimately facilitates computational analyses to connect genes to chemical structures, understand cluster environmental diversity, and facilitate cluster engineering.To properly catalogue a BGC, all the available information about that cluster that is present in the literature must be gathered. However, for many attributes of the MIBiG annotation standard, there may be fields that require information about a cluster that is currently unknown. Therefore, one must first thoroughly search through the literature before submitting a MIBiG entry on a given BGC, to capture all that is known about it.Peer-reviewed scientific articles can be found using several platforms . First, search the name of the natural product, along with “biosynthetic gene cluster” or “biosynthesis.” After finding a paper that thoroughly reports on the BGC, it is helpful to generate – using a platform such as Google Scholar or Web of Science – a list of more recently published papers that have cited the original paper. This process can provide additional information on the BGC. Taking the time to search through the bibliography of the key authors of papers describing the gene cluster can also be helpful, as these scientists are likely to be experts on the biological pathway in question, yielding a source of additional publications and a potential point of contact. At the university level, Inter-Library Loan programs can be utilized to access journal articles for which a local university might not have the requisite credentials. Additionally, a compilation of review literature defining each of the major biosynthetic pathways that MIBiG focuses on, is referenced in the “MIBiG for Undergraduates” section as an additional resource for students to develop their background knowledge.To determine if the BGC has already been partially or fully annotated by another researcher, check the MIBiG Repository and sort by main product . It is nIf it appears that the gene cluster has not yet been assigned an MIBiG accession number after searching the MIBiG Repository for the compound and its corresponding BGC, an accession number should be requested on the MIBiG website . To requAspergillus[ORGN] or Penicillium[ORGN]),”). After finding the file with the desired sequence, be sure to verify the file contains all the genes that are believed to be included in the cluster and that the sequence is taken from the appropriate species.To find a GenBank entry for a pathway, check a paper that reports on the full BGC, which will likely provide the accession number of the relevant nucleotide sequence file. Additionally, GenBank can be used to search for nucleotide sequence files. For best results, GenBank searches should be concise and more detail should be added to narrow down the results of broad searches; however, adding too many terms can derail the search. Boolean logic  can be used to make search terms more specific  being reported. There is a field for comments for elaboration on instances where it was unclear how to proceed filling in a field or where the data provided needs further explanation.r Step 1 . The folFirst, provide the name of the contact for correspondence, academic institution or company name, and a contact email address that will be associated with the MIBiG entry.Record the MIBiG accession number assigned to the BGC.Report as to which biosynthetic class the BGC belongs. The MIBiG standard has focused on six major biosynthetic classes: non-ribosomal peptide, polyketide, ribosomally synthesized and post-translationally modified peptide, terpene, saccharide, and alkaloid. Note that natural products created by all other biosynthetic mechanisms fall under the category “other.” Select all the categories that apply to trigger the correct follow-up questions in the spreadsheet/form. For example, a glycosylated polyketide is classified as both a “polyketide” and a “saccharide.”Perform a literature search to develop a list of key publications associated with the gene cluster and molecule. This section should include every paper used to gather information as the entire MIBiG entry is prepared. The number of papers available will be subject to the ‘popularity’ of the cluster, i.e. how many publications have been devoted to it. List the papers by inputting their PubMed IDs , separated by commas . The PubMed Single Citation Matcher can be used to look up a PubMed ID [Determine if the BGC has been completely sequenced or if the provided sequence is incomplete. A completed sequence must contain every gene necessary to produce the final molecule. One way to verify if a sequence is complete is by searching the literature for statements such as: “the complete biosynthetic gene cluster was isolated and fully sequenced.”Specify the sequence of the BGC as deposited in a nucleotide sequence database, such as GenBank, ENA, or DDBJ , 7, 8. SAdd information about the major chemical compound (s) produced by the pathway. It is likely that the BGC will produce more than just the main bioactive compound (s), for which the pathway is of interest. While it is most important that the bioactive compound is included in the entry, compounds of lesser importance produced by the pathway should also be included. If a BGC creates multiple very similar but distinct compounds, it is best to consider the significance that minor modifications can have on the overall molecule and to air on the side of inclusion. For example, if three polymer-type compounds are produced and each differs solely by the first monomer, it is more feasible to list these as individual compounds compared to a scenario where 25 highly similar polymer-type compounds are produced. If the scenario is such that it remains unclear how to proceed, contact an MIBiG expert (by emailing mibig@secondarymetabolites.org) for help or be sure to elaborate on the confusion in the appropriate “comments” section of the entry. The Excel spreadsheet can support 12 distinct compounds, but the final Web form will allow an unlimited number to be entered. For more information on the Excel template capacity, review Step 1 under genomic loci.For each of these compounds, first enter its name.Use the chemical databases (listed next) to find all available synonyms of the compound. In this field, only include “common name” synonyms and avoid using International Union of Pure and Applied Chemistry names or database IDs. Separate these synonyms by commas, without using spaces.To link the MIBiG entry to the information about the compound available in popular databases, search for records of the compound on PubChem, Chemical Entities of Biological Interest, chEMBL, and ChemSpider –15.If available in PubChem, insert the PubChem ID . Insert If available in chEBI, insert the chEBI ID . Insert If available in chEMBL, insert the chEMBL ID . Insert If available in ChemSpider, insert the ChemSpider ID . Insert Use the chemical databases (listed above) to find information on the available structure of the compound. This field is mandatory for all structurally characterized compounds, except for large ones, such as most RiPPs and polysaccharides. Chemical structure should be entered as a Simplified Molecular-Input Line-Entry System string, preferentially isomeric type, in order to include information on stereochemistry . If thisUse the chemical databases (listed above) to find an available molecular formula for the compound. If this data is not available on a database, the information can be easily acquired using software, such as ChemDraw or the PubChem Sketcher .Use the chemical databases (listed above) to find the molecular mass of the compound. If this data is not available on a database, the information can be easily acquired using software, such as ChemDraw or the PubChem Sketcher .m/z of the molecule for the respective ion type. Use a period as a decimal point, not a comma. If the exact mass was reported in the form of a convoluted ion type , select this from the provided options.If the mass was obtained from unprocessed mass spectrometry data, provide the monoisotopic Report nuclear magnetic resonance spectroscopy (NMR), mass spectrometry, X-ray diffraction, chemical derivatization, total synthesis, and/or other experimental results used to verify the structure of the natural product. To find sources, search the name of the molecule using a literature database platform . Also, the Dictionary of Natural Products as well as the open-access compound databases listed above can be useful resources for finding experimental data. The compound name can be searched along with each verification method . Any additional papers found should be included in the “key publications” section above.Select only experimentally-proven activities from the available options, and choose multiple if appropriate, from the provided list to best describe what is known about the compound. This information is likely to be found in the introduction or discussion sections of papers reporting on the cluster. The Excel spreadsheet can support up to five molecular activities per compound, but the final Web form will allow all potential options to be selected. For more information on the Excel template capacity, review Step 1 under genomic loci.Enter proteins, RNAs or other (macro) molecules targeted by this compound, as text separated by commas. Enter only experimentally proven targets. Use the common name of the specific target molecule if possible and avoid IUPAC or database identification number terminology. This information is often found in the introduction or discussion sections of papers about the gene cluster.Unusual moieties are components of a natural product that are synthesized by means not covered by the NRP/polyketide/RiPP/terpene/saccharide/alkaloid biosynthetic mechanisms. Precursors synthesized by a separate, small, stand-alone synthase, such as 6-methylsalicylic acid, should also be indicated.(GEN) This (GEN) notation refers to the MIBiG standard for reporting the identifier of a gene(s)  that can be found for each gene in the GenBank, ENA, or DDBJ file [When entering this information into the Excel spreadsheet, first enter the number of moieties to be reported. The Excel spreadsheet can support up to five moieties, but the final Web form will allow an unlimited number to be entered. For more information on the Excel template capacity, review Step 1 under genomic loci. For each moiety, use the “chemical moiety” field to select from the prepared options. If the moiety is not on this list, select “other” and indicate the type of moiety in the field labeled “specify moiety.” Next, cite the nucleotide sequence of the subcluster responsible for producing this moiety.DBJ file , 7, 8 an(GEN) Additionally, provide the type of experimental evidence used to determine that these genes are clustered in an operon. The Excel spreadsheet can support up to six operons, but the final Web form will allow an unlimited number to be entered. For more information on the Excel template capacity, review Step 1 under genomic loci.Include information about operons only if there are experiments reporting that an operon exists within the cluster. If there is no mention of operons, then this section is not applicable. If there is an operon to report, cite the sequences of the genes that are present in the operon. This section is only applicable if the cluster is part of the NRP biosynthetic class. Select the most appropriate NRP subclass from the provided options. In many cases, the option “other” should be used for compounds that do not belong to one of the listed subclasses. For more information on how to determine which subclass is applicable, view the “Table of Parent Molecules for Biosynthetic Subclasses” provided in the Supplemental Information section To determine if the thioesterase in the nonribosomal peptide synthase gene cluster is type I, type II, or both, look at the relation of the TE to the rest of the assembly line. Type II TEs exist as separate and distinct proteins from the pathway, whereas type I TEs are an integral part of the assembly line and constitute a domain within the larger protein complex. If the TE is type I or of unknown type, identify the TE-encoding genes. Review the types of release/cyclization from the provided options and select based on the characterization of the pathway from the literature . MacrolaThis section is only applicable if the cluster is part of the polyketide biosynthetic class. Select the most appropriate polyketide subclass from the provided options. In many cases, the option “other” should be used for compounds that do not belong to one of the listed subclasses. For more information on how to determine which subclass is applicable, view the “Table of Parent Molecules for Biosynthetic Subclasses” provided in the Supplemental Information section A modular type I PKS is a large protein complex consisting of sequential modules, each of which completes a successive chain lengthening step and intermediate modification. The various enzymes associated with the PKS are organized into modules, each of which contributes one additional building block to the nascent polyketide. A module is composed of domains, each of which have a defined function and are separated from one another by short spacer sequences. For this synthase subclass, provide the starter unit used, the TE type , and the release/cyclization type. If the TE is type II, both, or other, report the TE encoding genes. (GEN) and the number of chain synthesis iterations performed by the iterative PKS module. Additionally, identify the iterative PKS subtype based on reducing capability from the provided options. This reduction is traditionally performed by ketoredutase, dehydratase, and enoyl reductase domains. A non-reducing subtype produces each chain extending unit as a carbonyl, whereas a fully reducing subtype will fully reduce each extending unit. A partially reducing subtype works in between these extremes. Next, provide the iterative PKS cyclization type, TE type, and release/cyclization type. If the TE is type II, both, or other, report the TE encoding genes. (GEN)An iterative type I PKS is a large protein complex consisting of a set of domains, used in a repetitive cycle of chain elongation. For this synthase subclass, provide the starter unit used, the genes in the cluster encoding nonmodular PKS/ketosynthases, (GEN) TE type , and release/cyclization type. If the TE is type II, both, or other, report the TE encoding genes. (GEN)A trans-acyltransferase type I PKS is a large protein complex capable of producing a polyketide but depends on a separate protein to function as an AT. For this synthase subclass, provide the starter unit used, the genes in the cluster encoding trans-acyltransferases, (GEN)An enediyne type I PKS produces a polyketide that is an enediyne. For this synthase subclass, provide the starter unit used, the genes in the cluster encoding nonmodular PKSs/KSs, TE type , and release/cyclization type. If the TE is type II, both, or other, report the TE encoding genes. (GEN) polyketide length, genes in the cluster involved in folding and cyclization of the aromatic polyketide, (GEN) and TE encoding genes. (GEN)A type II PKS is an aggregation of small monofunctional proteins that are analogous to the domains of a type I PKS. For this synthase subclass, provide the starter unit used, the genes that encode nonmodular PKSs/KSs, (GEN) polyketide length, and TE encoding genes. (GEN)A type III PKS is most recognizable by its lack of acyl-carrier protein domains. For this synthase subclass, provide the starter unit used, the genes in the cluster encoding nonmodular PKSs/KSs, (GEN) the nonreductive scaffold-modifying domain in this synthase from the provided options (if applicable), TE type, and release/cyclization type. If the TE is type II, both, or other, report the TE encoding genes. (GEN)A polyunsaturated fatty acid synthase or related PKS produces PUFAs or related polyketides. For this synthase subclass, provide the starter unit used, the genes in the cluster encoding nonmodular PKSs/KSs, (GEN)For other PKS, provide the starter unit used and the genes in the cluster encoding nonmodular PKSs/KSs. This section is only applicable if the cluster is part of the RiPP biosynthetic class. Select the most appropriate RiPP subclass from the provided options. In many cases, the option “other” should be used for compounds that do not belong to one of the listed subclasses. For more information on how to determine which subclass is applicable, view the “Table of Parent Molecules for Biosynthetic Subclasses” provided in the Supplemental Information section  Next, RiPP core peptide amino acid sequence (s) are provided by inputting the sequence as single-AA abbreviations . If there are multiple sequences, separate them by commas. Then, record the length in amino acids, including N-terminal signal if present, of the leader peptide. Following this, provide the amino acid sequence (s) of cleavage recognition site (s), if known. If there are multiple, separate them by commas. Next, provide the recognition motif in the leader peptide for the modification peptide . Record the peptidase (s) involved in precursor cleavage. (GEN) Finally, provide information about each crosslink with the final peptide, specifically the first and second amino acids involved in the crosslink and the type of crosslink.When recording information about RiPP precursor peptides, the gene ID of the RiPP precursor should be provided. This section is only applicable if the cluster is part of the terpene biosynthetic class. Select the most appropriate terpene subclass from the provided options. In many cases, the option “other” should be used for compounds that do not belong to one of the listed subclasses. For more information on how to determine which subclass is applicable, view the “Table of Parent Molecules for Biosynthetic Subclasses” provided in the Supplemental Information section  Finally, provide the genes in the cluster encoding prenyltransferases.(GEN)Also, select the terpene subclass by number of carbon units: hemiterpene (C5), monoterpene (C10), homoterpene (C11 or C16), sesquiterpene (C15), diterpene (C20), sesterterpene (C25), triterpene (C30), sesquarterpene (C35), tetraterpene (C40), polyterpene (>C40), norisoprenoid (C13), and other. Select the final isoprenoid precursor. Then, provide the genes in the cluster encoding terpene synthases/cyclases .(GEN) FiThis section is only applicable if the cluster is part of the saccharide biosynthetic class. Select the most appropriate saccharide subclass from the provided options on the MIBiG site. In many cases, the option “other” should be used for compounds that do not belong to one of the listed subclasses. For more information on how to determine which subclass is applicable, view the “Table of Parent Molecules for Biosynthetic Subclasses” provided in the Supplemental Information section  Report as to whether the glycosyltransferase has a specificity as pertains to the sugar molecule it interacts with, if known. (GEN) Also, provide evidence for this claimed specificity, select the strongest evidence of the available choices. Additionally, provide the sequence of the gene subcluster responsible for the biosynthesis of that specific sugar, if the gene(s) is encoded within the gene cluster of this entry. (GEN) Note that a subcluster may consist of genes dispersed throughout the BGC. A subcluster only needs to be declared once, in case there are multiple glycosyltransferases with the same substrate specificity.Then, provide a reference to the sequence of the gene for each glycosyltransferase (s), enzymes that establish natural glycosidic linkages. This section is only applicable if the cluster is part of the alkaloid biosynthetic class. Select the most appropriate alkaloid subclass from the provided options. For more information on how to determine which subclass is applicable, view the “Table of Parent Molecules for Biosynthetic Subclasses” provided in the Supplemental Information section . Each bolded section below corresponds to each column on the Excel spreadsheet and each field on the MIBiG Web form that is applicable to each gene being reported. In the spreadsheet, as well as in the Web form, each row corresponds to an individual gene. There is a field for comments at the end of each row for elaboration on instances where it was unclear how to proceed filling in a field or where the data provided needs further explanation.If you have no tailoring reactions, experimentally verified gene functions, knock-out phenotypes or custom gene names to declare for your cluster, click “skip this step” to move onward to Step 3.The following information will be entered for each gene in the cluster if available. Annotate each gene that is necessary to make the molecule, as specified in the literature. Note that using the nucleotide sequence file alone to select genes for this step could be problematic, as this file could potentially contain more genes than are necessary to create the desired product. In many of the following categories, the field should be left blank , when the requested information is either not applicable or not available.First, visit the Web form for Step 2 . When a The genome or contig accession number refers to the database (often GenBank) accession number for the nucleotide sequence file. If the gene cluster is split up over multiple GenBank files, then provide the GenBank accession number for each gene that will refer to a file containing that gene’s sequence.While looking at the GenBank nucleotide sequence file, under the section “features,” every gene should have a feature next to it called “CDS.” If this feature is present, click yes or TRUE in Excel. Untick this box, or select FALSE in the Excel document, if the gene was not included in the original annotation in the GenBank sequence file and therefore would also not have a CDS feature .In the GenBank file, each gene is presented as, for example, 1...2364 /gene = “calY”. This notation indicates that for the gene “calY,” the start coordinate is 1.If there is not pre-filled sequenced-based data for a given gene but the gene is annotated in GenBank with a protein ID, then the start and end coordinates for that gene do not have to be provided. In contrast, if a gene is not annotated in GenBank with a protein ID, then start and end coordinates for that gene are mandatory.In the GenBank file, each gene is presented: for example, 1...2364 /gene = “calY”. This notation indicates that for the gene “calY,” the end coordinate is 2364.This refers to the GenBank accession number for the protein produced by the gene. For each gene with CDS features in the GenBank file, each CDS feature should provide the gene name as “/gene = “calY”” and the protein ID as “/protein_id = “BAP05573.1”.” If this is the case for your entry, enter the protein ID accordingly.This refers to the name of the gene. In the GenBank file, each gene feature should provide the gene name as “/gene = “calY”.” “calY” is the Gene ID. If there is no Gene ID type “No gene ID.”This refers to a short description of the gene’s function, often referencing the name of the protein it produces. For each gene with CDS features in the GenBank file, each CDS feature should provide the gene name as “/gene = “calY”” and the gene function annotation as “/product = “CalY”.” If this is the case for your entry, enter the gene function annotation as “CalY”.This field should only be filled in if the function of the gene has been experimentally verified (not just inferred based on homology). The link to the publication that characterizes the gene function should be included in the “publications on this gene” field.This field is only applicable if “gene function category” has been entered as a tailoring reaction. Select the appropriate option from the provided options.This field is only applicable if “gene function category” has been filled out. Please select the strongest or most decisive type of evidence. In the Excel document, only one choice may be selected. If multiple types are needed, in the Web form use the exact same wording as in the provided options for each descriptor, but separate them by commas: e.g., “Knock-out, Other in vivo study”.If a knockout study was performed on this gene, a short description of the phenotype should be included. The publication that contains the experiment where this knockout study was performed should be included in the “publications on this gene” field.Include publications that provide additional information about this specific gene entry. PubMed ID or DOI of a publication that specifically addresses the function of this gene or the protein it encodes, if any, should be included. If multiple, separate the PMIDs/DOIs by commas.Provide any additional information that may be necessary for MIBiG staff to know when processing your MIBiG annotation.This section should be completed in tandem with the Excel spreadsheet “Offline MIBiG Steps 2 and 3 Form,” in the sheet called “Step 3” . Each bolded section below corresponds to a column in the Excel spreadsheet and each row refers to a different module being reported. After entering information into the spreadsheet, data can be transferred to the appropriate fields in the MIBiG Web form for PKS and NRPS module information. There is a field for comments at the end of each row for elaboration on instances where it was unclear how to proceed filling in a field or where the data provided needs further explanation.If your gene cluster does not contain PKS/NRPS modules, click ‘Skip this step’.First, visit the Web form for Step 3 , enter tCounting starts from 1 at the start of the assembly line, and includes loading modules (which are numbered ‘0’). If a module is split across two genes, re-indicate the same module number for both of the genes, but only include the domains present in that gene. Every module with at least a substrate-selecting domain (adenylation/acyltransferase/Co-A ligase) is included in the count.For PKS/NRPS hybrids, both PKS and NRPS modules are included in the counting. If this PKS/NRPS module is not part of a main assembly-line for producing this compound or if the PKS/NRPS complex is noncanonical and cannot be described in a linear fashion, please enter ‘x’ as the module number. The same applies for monomodular precursor synthases such as 6-methylsalicylic acid synthase, which may be encoded within larger multi-modular NRPS/PKS-encoding gene clusters.If there are multiple independent assembly-lines involved in synthesis of the main product, these can be indicated as ‘A1, A2, A3, etc.’ and ‘B1, B2, B3’. Similarly, if the assembly-line branches at a later stage to make multiple products, the shared part can be called e.g. ‘1, 2, 3’ and the split part ‘A4, A5’ and ‘B4, B5’. Up to four parallel assembly-lines are supported (with letters A-D).The protein ID corresponding to the different modules should be included with the pre-filled information.Provide whether this module is a PKS or NRPS module.Indicate if the module is skipped or iterated. Either of these characterizations would be specified in the literature defining the cluster. If the module is not designated as either skipped or iterated, then it is assumed to be neither.If the module is not skipped or iterated, leave as “N/A”. If applicable, provide evidence of skipping or iteration by choosing from the pre-filled selection.Please use standard abbreviations, separated by commas, to include the core domains included in each module: AT, KR, DH, ER, KS, T, CAL, C, A, E. Notably, ACP and PCP domains can both be designated as thiolation domains. Do not include custom modifying domains, but select these in the next column. This information is likely part of the pre-filled information but should be checked for its accuracy and adjusted accordingly with the literature and experimentally verified results.Enter additional modifying domains present in the module that are not included in the list of core domains in the previous step. In the Excel document, only one choice may be selected. If multiple types are needed, in the Web form use the exact same wording as in the provided options for each descriptor, but separate them by commas .Report as to whether the AT or CAL domain has a specificity for a particular monomer, if known. In other words, does it selectively interact with one type of monomer.Enter ‘None’ if no AT-domain is present  or the AT containing module is skipped. Enter ‘Unknown’ if the substrate specificity is not known. In the Excel document, only one choice may be selected. If the specificity is promiscuous (multiple substrates accepted), in the Web form please enter all specificities on the Web form separated by a forward slash (“ / ”) .Report as to whether the adenylation domain has a specificity for a particular monomer, if known.Glycine/Valine”).Enter ‘None’ if no A-domain present or module is skipped. Enter ‘Unknown’ if specificity not known. In the Excel document, only one choice may be selected. If the specificity is promiscuous (multiple), in the Web form please enter all specificities separated by a forward slash (“ / ”)  can be used to organize and store data as it is gathered prior to entry submissions. Additionally, the “Table of Parent Molecules for Biosynthetic Subclasses” is provided to simplify the classification of a cluster/compound into the appropriate biosynthetic subclass. To provide for assistance with overcoming any logistical challenges while completing an entry, we have created a tutorial video that overviews a step-by-step process of gathering the requisite data for one cluster, althiomycin  Additional file 1:Supporting documents for MIBiG entries. (ZIP 1328 kb)


Background and Objectives: Nepal has witnessed several periods of organized violence since its beginnings as a sovereign nation. Most recently, during the decade-long Maoist Conflict (1996–2006), armed forces used excessive violence, including torture, resulting in deaths and disappearances. Moreover, there is widespread gender-, ethnic- and caste-based discrimination, and grossly unequal distribution of wealth in the country. While the immediate mental health effects of the conflict are well studied, less is known about the long-term effects of the conflict. This article sets out to explain how Nepalese survivors of violence perceive their wellbeing and mental health, search for help and construct their health care pathways and therapeutic itineraries. The aim is to provide a better understanding of local explanatory models and healthcare behaviors.Methods: Semi-structured interviews were carried out with 25 people  aged 30 to 65 in Dang district in 2013. To elicit illness narratives, a translated and culturally adapted version of the McGill Illness Narrative Interview (MINI) was used. Additionally, participants were interviewed about their war experiences and present-day economic and social situations. The transcripts were coded using deductive and inductive approaches and analyzed through thematic analysis.Results: The study provides insight into temporal narratives of illness experience and explanatory modules. Symptoms were found to be widespread and varied, and were not solely attributed to violent experiences and memories, but also to everyday stressors related to survivors’ economic, social, and familial situations. In terms of help- and health-seeking behavior it was found that participants resorted to various coping strategies such as social activities, avoidance, withdrawal, and substance use. Many participants had received biomedical treatment for their psychosocial problems from doctors and specialists working in public and private sector clinics and hospitals as well as different forms of traditional healing.Conclusions: These results shed light on the long-term impact of the Nepalese conflict on survivors of extreme violence, highlighting local explanatory models and help- and health-seeking behaviors. These findings inspire recommendations for the development of context specific and holistic psychosocial interventions focusing on well-being, social determinants of health, and human rights. Nepal, although never colonized by any other country, has witnessed structural and organized violence since its unification as a sovereign nation in the mid-eighteenth century including, most recently, during the decade-long Maoist Conflict 1996–2006)  experience and reflect on their mental health and wellbeing, help- and health-seeking, as well as received treatment seven years after the end of the conflict. We begin by reviewing the epidemiological, public health and anthropological literature in order to establish mental health outcomes during and right after the conflict. This is followed by findings of our own investigation into temporal narratives of illness experience; salient prototypes regarding current health problems; and causal attributions and treatment expectations. In addition, help- and health-seeking behavior and pathways to care will be explored as they unfold in the present. The findings inspire recommendations for the development of holistic as well as culture- and context-specific, and long-term psychological and social interventions focusing on well-being, social determinants of health, and human rights.The Nepalese Civil War, also known as the Maoist Conflict or Maoist Revolution, was a decade-long armed conflict between the Communist Party (Maoists) and the government of Nepal that ended with a comprehensive peace agreement in 2006. Between 1996 and 2006, armed forces on both sides of the conflict are alleged to have used excessive violence resulting in deaths and enforced disappearances. The conflict has resulted in between 13,000 to 16,500 deaths, with thousands more missing. More than 150,000 people were internally displaced and more than 100,000 incidents of torture have been reported –19. DespWhile there have been rapid social, cultural, political, and economic changes in recent years, inequalities in wealth distribution and according to gender, caste, and ethnicity prevail. Theoretically, Nepal abolished caste-based discrimination in 1963; however, caste-based exclusion is still widespread and affects every aspect of life, particularly among Dalits (“untouchables”) in rural areas of Nepal , 23. MorMass violence during the Maoist Conflict as well as protracted and organized political violence and injustice have been shown to negatively affect the mental health of exposed populations , 30. Higman (heart–mind); dimāg (brain–mind); jiu ; sāto (spirit); and ijjat . The man and dimāg are particularly relevant for mental health: too much activity in the man is associated with psychosocial complaints while dimāg dysfunction is associated with being crazy, mad, or psychotic. Other studies have identified local idioms of distress and found that jham-jham (numbness and tingling) and gyastrik (dyspepsia) are common complaints that can be associated with depression (dukha lāgyo (sadness), dar laagyo (fear), jharko lāgyo (irritation), jiu sukera gayo (drying of the body) and kat kat khancha (tingling and burning sensation). Kohrt and Hruschka , chinta , dar , or ris  are commonly used to refer to related emotional states. Other studies have drawn attention to high rates of somatization among survivors of violence  and biomedicine , 46, 47.Despite the apparent limitations of biomedical and specialized mental health care, it has been noted that the western biomedical model of psychiatric care is being increasingly recognized and practiced, especially in hospitals and private clinics in major cities and by non-governmental organizations , 52–54. This research builds on previously conducted epidemiological research identifying prevalence rates of mental health problems, factors associated with poor mental health and protective and risk factors in post-conflict Nepal . Based ohttps://nepalmap.org/profiles/district-60-dang/).This qualitative study took place in Nepal’s Dang district from mid-February until April 2013. Dang district is located approximately 280 km west of Kathmandu. The district’s population is estimated to be 552,583 people belonging to multiple linguistic and ethnic groups including Tharu (30%), Chhetri (25%), Magar (14%), Brahman-Hill (10%), Kami (6%), and other (16%). Dang was badly affected during the Maoist armed conflict. Civilians were subjected to extreme violence including killing, abduction, disability and injury due to landmines, torture and sexual abuse. The region continues to be affected by poverty, deprivation and discrimination . A recently conducted epidemiological study that involved randomly selected participants from three districts identified that living in Dang was a risk factor for psychosocial and mental health problems  aged between 30 and 65. All of them were civilians with three former Maoist fighters  among them. Most lived in villages while five participates lived in towns. Most of the participants were farmers and very few held additional occupations such as health volunteer (n = 1), teacher (n = 1), VDC leader (n = 2), and restaurant owner (n = 1). The majority had some reading and writing skills, with three participants being illiterate. Most participants considered their economic situation “simple” but sufficient to make a living and support their families. Thirty-two percent of the interviewees described themselves as poor and experienced difficulty providing for their families, particularly their children, in terms of food, clothing and school supplies See Table 1.https://www.mcgill.ca/tcpsych/files/tcpsych/mini-nepali-revised_v.3.1_0.pdf)  . The MINInterviews were conducted with individual participants except in two instances where couples were interviewed together based on their specific request for such an arrangement. Interviews were carried out by both authors. They were conducted in Nepali by the second author and involved, when the first author was interviewing, the help of a Nepali translator. The interviews lasted between 40 min and 1 h and were, with the consent of study participants tape-recorded and later transcribed verbatim and translated into English. Both authors read the transcripts carefully before coding them by combining deductive and inductive approaches , 58. TheEthical approval for this study was received from the Research Ethics Board of the Douglas Mental Health University Institute in Montreal, Canada and from the ad-hoc ethical committee at the Department of Psychiatry and Mental Health at Tribhuvan University Teaching Hospital in Kathmandu, Nepal. We obtained written informed consent for the publication of the data from the participants.To develop an in-depth understanding of how survivors of the armed conflict in Nepal perceive their distress and related health problems seven years after the conflict, we elicited basic temporal narratives of symptoms and illness experiences. We asked the following questions: (i) From what kind of emotional or physical health problems do you suffer? And, since when do you suffer from these health problems? (ii) When you have these health problems, what kinds of symptoms do you experience? (iii) What else happens when you experience these (symptoms)? These questions were designed to act as a prompt for further discussion concerning the frequency, intensity and location of symptoms.Respondents listed many and a wide range of symptoms of emotional, physical, and psychosomatic nature. The following excerpt of an interview with an older couple who had been tortured, beaten, and almost drowned to death by Maoist fighters is exemplary:Maobadi (Maoists). I see the same unfortunate event in my dreams.Husband: In my dreams I see people dying and (I feel) dizzy and shaking, I see those same Q: Does this happen to you (wife) too? Seeing something like that in your dreams?Wife: Yes, the same thing happens to me too. Sometimes (I dream) that I’m walking along the river, and sometimes that they’ve thrown me into the river. (…) When I’m about to wake up and my heart is racing, I remember that event and I feel that maybe it is still happening? Maybe they’ll come back and try to kill my husband again? Maybe they’ll kill me?Q: When those kinds of things come to your mind, do you experience any emotional or physical symptoms? If so, what kind of symptoms do you experience?man ātinchha), sometimes my chest hurts, my heart hurts (mutu dukhchha); during this time, it feels like my ribs hurt, my finger doesn’t function well because my nerve is swollen so I cannot even knead dough, I can’t cut grass, you know I can’t even serve dinner well.Wife: In my body unusual things happen, my stomach hurts, my mind is restless , worries (n = 11), headache (n = 8), pain (n = 7), eating problems (n = 6), goosebumps (n = 6), anger (n = 5), fear (n = 5), emotional pain (n = 4), listlessness (n = 4), restlessness (n = 4), nightmares (n = 4), and mental tension (n = 4). Less frequently mentioned yet shared were back pain, weakness, stomach pain, thinking too much, heat in their bodies, and flashbacks. Other symptoms included heart pain, heart racing, chest pain, forgetting, stress, sweating, speaking problems, avoidance, hurting eyes, dizziness, constriction of the throat, high blood pressure, and vision problems. Finally, a number of symptoms were only mentioned by individual respondents (see footnote).Since study participants were allowed to freely list their symptoms, a wide range were mentioned which is in line with previous studies see , 19, 35.Most participants stated that their symptoms had been initially caused by the violence and insecurity they had to endure and witness during the decade-long armed conflict. They reported that their symptoms increased or tended to reappear when they recalled the armed conflict and related violence, were confronted with persons who had inflicted violence on them or their family members, or visited places that reminded them of particular gruesome events.barta) for the gods and goddesses is useless. I don’t believe in any gods now.”Many of the participants listed a number of violent experiences including the loss of family members (n = 9), living through and surviving torture (n = 9), experiencing and witnessing kidnappings (n = 3), imprisonment (n = 2), and long-term displacement (n = 2). The loss of family members was experienced as extremely painful, affecting a person’s entire being emotionally, physically, and socially. A man told us about the shock he had felt when his son was shot in their family garden and how this experience haunts him until this very day. He said, “even now, my mind doesn’t work. If I think something, I forget about it immediately.” He continued to feel depressed, felt as though there was no one he could rely on, and had lost his faith in the gods: “I feel that the fasting . I withstood a lot of [emotional] pain. (…) It was difficult for me to even feed and dress myself. I didn’t get pennies from anywhere, I had difficulties to educate my children.She went on to explain that remembering her daughter presently led to her feeling emotionally low which became particularly strong when she saw young girls passing by who were her daughter’s age as they made her wonder who her daughter would have become had her life not been cut short.Mostly male participants reported that their suffering and emotional pain was caused by experiences of torture during the conflict. They reported gruesome mistreatment at the hands of government forces and Maoists including severe beatings with rifles, stones, and boots; breaking of bones; cutting; attempts at drowning; blind folding; and shackling with ropes and sticks. A village teacher provided the following testimony:It was around 10 o’clock in the evening when they came … there were 10-15 of them. Some had covered their face (…). They surrounded my house (…). When I went outside, they captured me all of a sudden and blindfolded me. Then they took me to a small river. They accused me of being CID [a spy]. They took me to the bank of the river and started beating me. They pointed the guns at me and acted as if they were going to kill me. They beat me very badly. I told them that I was a teacher at the village, not a spy, but they did not accept what I said (…). I told them that I teach students in the village. After that, they beat me a lot and in the end they broke my leg. They broke my leg into three pieces and left me (…). Two of them carried me and threw me on the front lawn of my house.jieu thar thar garne), felt weak, had nightmares, anticipated his attackers’ return as he lay half awake, and suffered from fear and heart ache—”It (the heart) doesn’t ache , it’s not in my body”, he explained, “but it is in my man (heart–mind) and in my dimāg (brain–mind)”. Similarly, a farmer told us that he had suffered from fear and the anticipation of violence at nightfall since the time he was severely beaten until his aggressors thought he was unconscious.He went on to explain that it was since then that he felt his body trembling  feel sleepy at night, and before I (know) it, it is light outside. I think about how I would raise my children. When they were little, there weren’t too many expenses for them, but the older they get, the more expenses they require. Look, my children are growing up, and they yell at me when I can’t fulfil their financial demands (…). My children also ask me what I am so worried about. My children tell me not worry, that we must find something or the other (a source of income). But, sometimes it’s like we can’t even eat dinner. Of course, I worry, why wouldn’t I worry.man). Despite people’s overall negative perception of their economic situation, there were a few study participants (n = 4) who felt that their particular situation had improved due to the fact that their children were employed (n = 2) or that they received regular monetary support from family members who worked abroad (n = 2). With the extra help from family members, they were able build a new house, purchase some land for agricultural production, and support their basic needs.Others complained that their dire economic situation did not allow them to pay for specialist doctors’ visits or medication. A middle-aged farmer who suffered from health problems related to the torture he had endured at the hands of government forces during the Maoist Conflict laid his situation out for us, explaining, “I don’t have any land of my own, I have to go plough others’ land. Fertilizer is expensive. If we don’t put fertilizer then there is no production, and when there is no production then I get worried about where I’m going to find the money for  treatment”. Indeed, economic problems themselves were considered to cause or aggravate health problems and to impact on general wellbeing due to worries, sleeplessness, and problems with the heart-mind  led to exclusionary practices. This was illustrated by a widow who stated that others looked down upon her, related to her with disgust, and excluded her from social gathering and even family events. In frustration she exclaimed, “After our husbands die, we can’t die with them. And even though it is difficult, we have to carry on caring for our children.” Similarly, others complained that they might as well have died with their husbands instead of living a life at the margins of society, that others blamed them for the death of their husbands, and that they felt disabled without male support. “Well, without a husband around I feel limbless, I don’t have much support” a woman began. She continued, “When I walk around without a husband, I receive unfair treatment from others and (…) other people and my sons blame me.” Such statements were echoed by other widows who lacked support, had difficulty finding work with a decent income, and could not support their children financially while also protecting them from others’ prejudices.The comparison between losing one’s husband and losing a limb was an apt one as men who suffered from torture-related physical disabilities also complained about the societal exclusion they experienced, disrespectful treatment and discriminatory practices which hindered them in finding employment. A middle-aged man whose leg had been broken and crushed by government forces felt that his disability had brought a part of his life to an end. He said, “Well, what can you do in life. If I were able to use my foot well, then I could go to someone else’s house and work. I would be able to live (from these earnings).” However, it was not just the missing limb, the disability, that kept men like him homebound. It was also the prejudice and lack of respect that people harbored towards the disabled. “I’m without a limb and they feel that whatever I do or say comes from a lowly level” someone said. Instead of being able to care for themselves, they perceived themselves as a burden for other family members who had to struggle to meet their and others’ needs. A former Maoist fighter, who was blinded as part of the torture that government prison guards had exposed him to, stated with resignation in his voice, “I must be fed, I must be cooked for, and going to the bathroom is whole other story…” His wife, a former Maoist fighter like her husband, struggled with “mental tension”, stomach pain, sleeping and eating problems, thinking too much and fatigue due to her memories of the violence she had been forced to endure and challenges connected to keeping the family farm running on her own. She was responsible for raising a small son, caring for her husband, keeping the house in order, and dealing with the cattle and agricultural production.Strained family relations were an additional source of stress. While most participants considered their families supportive and generous, some women complained about being exploited and ill-treated by their in-laws. A widow shared with us that she had been used as a maidservant since her husband’s death while her in-laws remained idle and expected to be served. Consequently, she decided to leave their compound and live on her own despite struggling to secure an income and provide for her children. Two men, on the other hand, complained that their dreams and aspirations were cut short by their families who discouraged them from progressing in their education and careers. This, they stated, was an important source of frustration and stress. We were told, “They [my family] lack basic education, they don’t know anything (…) and can’t give advice. That’s why I don’t receive support from my family. I console my soul myself.” Others were distraught that their family members lived far away or even abroad and were, thus, unable to provide emotional support. The female Maoist fighter introduced above lamented, for instance, “Our family doesn’t live close by and I feel that if they did, then we could have talked and exchanged about the good and bad times we are experiencing.” Consequently, she often felt alone with her gruesome memories, emotional and physical pain, and pressure to provide for her husband and son.One of the long-term effects of the Maoist Conflict was the intersection of traumatic memories with daily stressors. In their coming together, they were relentless and constant, affecting people’s social position through disability and widowhood; impacting on their ability to earn an income or perform daily tasks due to emotional and physical pain; and, as will become apparent in the following sections, affecting community cohesion, regional economy, and infrastructure.In order to ease the physical and emotional pain induced by traumatic memories and daily stressors, study participants resorted to various coping strategies including social activities, avoidance strategies and withdrawal, and substance use. Several explained that it helped them to find meaning in their illness through analogy, that is, by comparing their experiences to others  I tell myself some people have lost their husbands, some people have lost their wives, some have lost their daughters too, I am not the only one who has lost someone. I tell myself that everyone has pain and problems and that is how I console myself.Although trauma and suffering were experienced at the level of the individual, the notion of shared grief and pain created a sense of companionship and solidarity which seemed to say ‘we are in this together’. Other times, companionship through social interaction was sought more actively as a form of distraction from one’s grief and worries and a means to escape loneliness and troubling thoughts. The same woman introduced above mentioned that since the death of her daughter, she could not stand being alone and consequently sought company by walking into the village to chat with her friends and visit acquaintances. Similarly, another woman told us, “During daytime, I talk to people while walking around and I don’t feel any pain. But when I am alone in the evening and start thinking, I experience such problems.” These examples make apparent that both illness and coping are social experiences which are shaped by historical and contemporary social change.While illness and coping may be social, this does not mean that social relations are always sought after or that such relations are necessarily positive. We found that it was mostly men who tried to control their feelings by explicitly avoiding social company. They wandered around by themselves, visited temples or quiet places on their own, or worked harder than usual. For instance, a middle-aged man stated, “When I have the problem, then I keep working all the time. I feel pain, yet I keep working. But if I feel restless, and if it hinders my work, then I take medication. This is how I am living.” A few participants tried to relax or numb their feelings with alcohol or cigarettes. While alcohol was seen as a form of escapism, cigarettes were experienced as taking the tension away and were, accordingly, viewed as a form of relaxation by some. A woman who had lost both her son and daughter along with their friends had the urge to forget her sorrow. She exclaimed, “I couldn’t forget them and so I started drinking alcohol. I was so much hurt and I wanted to learn to smoke cigarettes. If I hadn’t learned smoking cigarettes, my headache would be severe. I was suffering badly so I learned how to smoke.” Alcohol-induced forgetting and pain relief for headaches through smoking felt like justified approaches, even skills (“I learned how to smoke”), to this woman in light of her suffering.mit lāune: a tradition of friendship established through ritual) with a person suffering from similar health problems as their relationship provided him with a sense of solidarity and mutual understanding while, at the same time, it “freshened his mind” when he was feeling nervous or worried.Help-seeking was mainly interrelational in that respondents requested and drew on family, community, and institutional supports. Most stated that it was their immediate family and friends who provided them with support. Family members provided material support in the form of money or financing the building or rebuilding of homes as well as social and emotional support and care. Similarly, friends and neighbors were perceived to be supportive in that they encouraged participants to socialize, listened to them, calmed them in times of distress, and/or tried to provide some comfort when in pain. A man with disability highlighted the importance of having forged a special type of bond  I came to learn this.”Most study participants had also received support from non-governmental organizations and governmental institutions in the immediate years following the conflict. The aid had been short-term and predominantly consisted of monetary and in-kind donations  as well as psychosocial activities including self-help groups and trainings . While the aid was welcomed, it was often considered too short-term and insufficient. A widow highlighted that the government had provided her generously with 5 lakh  as seed capital but, from then on, only provided 150 rupee per month for her children– pocket money which she considered “not even enough to buy vegetables or a samosa.”The major complaint was directed at the unfair distribution of aid which favored influential families, people with “connections” or those with ties to particular political parties. The resulting inequalities were experienced as stressful and as negatively impacting on people’s sense of wellbeing. A widow reflected on the unfair distribution of aid stating angrily, “Whoever has endured a painful conflict, that person will not receive any help. Whoever hasn’t endured conflict has received help from institutions. Even people who haven’t endured any conflict are making fake petitions and receive funding.” Similarly, others explained that there were those who wrote “fake claims” to receive funds based on their non-existent disability or veteran status or false description of their economic situation. We were also told about the distribution of funds based on political partisanship and nepotism as well as about politicians who attempted to increase their popularity and party membership by promising people access to welfare or in-kind donations. A man said, for instance, “ parties started to be biased saying ‘this victim is the one I know’ and started to provide (them with) much more relief and support (compared to) others.” Trying to verify these complaints, we interviewed a village leader who indeed acknowledged the study participants’ grievances as accurate, but, relativized their complaints by adding that many villagers were actually unaware of the eligibility criteria for welfare and aid, whom to approach to receive support, and what documentation to provide in order to file a claim. Nevertheless, he admitted that those working in administrative positions tend to ignore the situation and, thus, fail to engage in advocacy and knowledge transmission to improve access to welfare and other forms of support. Thus, aid was experienced as both a welcomed relief and a source of stress and communal conflict due to the way it was distributed, its scarcity and the lack of sustainability in a context where poverty and unemployment are widespread.Almost all study participants had received some form of biomedical treatment for their health problems as they visited a combination of doctors working in public and private sector clinics (n = 9); hospitals (n = 5) in Kathmandu, Palpa district, and India; mental health specialists (n = 2) including a neurologist and a psychiatrist; and professionals working for non-governmental organizations (n = 2) such as the ICRC or the Centre for Victims of Torture (CVICT). Although many received medication, most could not actually recall what kind, while some referred specifically to sleeping pills (n = 2), analgesics (n = 4), and medication for high blood pressure (n = 1). Medication was variously combined with other types of treatment and advice including scans , psychiatric medication, counselling, advice from both doctors and family members not to worry or be preoccupied, exercise, and various forms of traditional healing.Many felt that their health problems had improved over the years partly due to “time” and partly due to medical treatment, counselling and traditional healing. However, several participants felt that medication was not particularly effective as it was not perceived to lead to a cure. It was highlighted that medication had to be taken continuously while health problems kept re-surfacing at regular intervals despite the treatment. One man stated, “When I am alone, I think too much—if people are with me, then I think less. If I don’t take medicine then I can’t sleep at all. I can only sleep once I take the medicine that my son has sent me from India.” Another man explained that he had visited various doctors who had prescribed “four to five different medicines” which he considered ineffective. Finally, at a clinic in Gangalal he was prescribed medication he considered helpful and was willing to continue taking. Only one woman perceived the medication she had been prescribed to be completely unhelpful. She complained:The pain from the death of my daughter caused so many types of illnesses. I spent about 12 lakhs (1.2 million) for my healthcare – the money that my eldest son had sent me was used to go to Kathmandu, Palpa and Lukhnow (India) where the doctors still couldn’t figure out what my problem was. (…) Even when I take the medicine that the hospital gave me, it hurts just as much as if I were not to take the medicine.guruba  healer and as neuroinflammation by a biomedical practitioner. When asked how he made sense of these different illness explanations, he responded:Interestingly only four participants said that they visited traditional healers for their health problems. We believe, however that this reflects under-reporting rather than actual health-seeking practice considering that well known healers lived in the area and existing literature highlights the widespread use of traditional healing for trauma-related as well as physical health problems. Those who reported seeking traditional healing visited both healers and temples to find inner peace and pain relief. For instance, we were told by one of our male participants that his illness had been variously interpreted as witchcraft by a A: (smiling) Who is correct? Both couldn’t do anything for me. Although the traditional healer couldn’t do anything, he did something. (…) I might consult others .Q: So you think that you have been bewitched?A: Yes, something like that.guruba do to make you feel better?Q: What did the jhaar phuuk) would be correct.A: He told me that using the traditional way through rituals , nor did there appear to be any social interventions in the region that could directly address social and economic determinants of health and thus indirectly affect conflict-related memories and associated emotional pain.This study has several limitations. First, the study was cross-sectional rather than longitudinal and based entirely on retrospective self-reporting of war-exposure and related illness symptoms. Although respondents indicated that their mental health problems originated from traumatic experiences endured during the Maoist Conflict, the actual time of onset of symptoms is impossible to determine. In fact, we suspect that most people experienced a number of triggers including conflict-related violence and structural violence as well as daily stressors experienced in the aftermath. Second, the study was based on a small sample and sampling was conducted in only one out of 77 districts in Nepal. Therefore, the results may not be representative of conflict-affected populations in other geographical areas or across all linguistic, caste, ethnic, and socioeconomic groups. Third, we failed to systematically collect information about ethnicity and participants’ socioeconomic status before the conflict. Consequently, it is impossible for us to more objectively determine whether or not respondents’ socioeconomic situation had changed due to or since the conflict. Despite these limitations, the data offer crucial insights into the long-term consequences of war and the ways in which people perceive war exposure and daily stressors to affect their mental health and wellbeing.Our findings provide insight into the ways long-term consequences of war intersect with daily stressors and, in combination, affect people’s mental health and wellbeing. The findings further highlight the importance of designing interventions and support mechanisms that address not only immediate humanitarian, health and mental health needs, but also the social determinants of health  which affect the context in which people are born, grow, live, work, and age see . Respondkarma and fate  and hence stigmatization. Therefore, people preferred not to share their traumatic experiences ; developing capability, partnerships and research in the Middle and Near East (MENA) ES/P010962/1. The funder contributed to the analysis, writing and dissemination of our work. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The handling editor declared a past co-authorship with the author HK.