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Alighieri, Dante (1265-1321)

  1. Opera Poetica, First Edition
  2. Parnaso D'Abruzzo Rassegna di Poeti in Italiano, Latino e Dialetto ()
  3. "Il buono amore è di bellezza disio"
  4. Massimo Lollini

Moreover, this entire section begins with an explicit mention to the debate about cosmic immortality vv. As the old peasants in Book 2, the induperator embodies another traditionally positive model of vir Romanus. In fact, he is a military commander full of devotion and religious zeal: before the sea storm, he immediately recurs to prayer. The phrase divom pacem votis adit v. Again, Lucretius highlights the ineffectiveness of a behavior based upon the mos maiorum v. Thus, the episode of the induperator and his army becomes a symbol of the end of Rome: the figurative meaning of these lines is stressed by the poet himself in the sublime epiphonema of the passage, depicting the most important icons of Roman power v.

Proinde licet quamvis caelum terramque reantur incorrupta fore aeternae mandata saluti; et tamen interdum praesens vis ipsa pericli subdit et hunc stimulum quadam de parte timoris, ne pedibus raptim tellus subtracta feratur in barathrum rerumque sequatur prodita summa funditus et fiat mundi confusa ruina. In Book 6, at the end of the section devoted to the explanation of seismic phenomena 6, , Lucretius sets another cosmic shipwreck.

The poet describes their reaction during an earthquake, which is destroying a city v. Thus, the passage ends with a destabilizing, sublime vision of the advent of chaos vv. Regarding the identity of these thinkers, Lucretius certainly alludes to the Greek philosophers who developed and defended the doctrine of cosmic immortality, that is, Aristotle, Theophrastus, and their heirs.

La letteratura italiana nel Settecento

However, it is likely that he also includes his Roman contemporaries, who inherited and proclaimed this doctrine. Here Lucretius, having refuted a Stoic doctrine about geocentrism — as demonstrated by Bakker , pp. Notwithstanding, some remarkable analogies with 6, make it possible that, in the lost lines, Lucretius imagined his philosophical enemies at the epicenter of the catastrophe cf.

Moreover, the cosmic catastrophe in Book 1 is introduced by the conjunction ne: like in 6, and , this conjunction could be preceded by a verbum timendi or an expression of fear. This formula is very similar to the one in vv. Why should Cicero be the target in only one of these passages? Moreover, in Book 5, just before his polemics against Cicero, Lucretius imagines the imminent end of the world as a cosmic earthquake vv. In this passage, Lucretius sheds light both on the contradictions in the argumentations of his enemies and on their deepest fears.

Facing the menace of death, even philosophers abandon their faith in cosmic immortality, showing that their credo was only a self- reassuring reaction against the irrational terror caused by the prospect of incoming chaos. Hence, seismic phenomena can be interpreted as a real apocalypse, an epiphany of the real nature of the world and of the darkest fears of human soul.

The natural catastrophe is a demystifying revelation which unveils the fallacy of the masks of ideology Lucr. Ciano , pp. Both passages are also characterized by great emphasis on the rapidity of the catastrophe 5, in parvo tempore; 6, raptim. Cosmic Shipwreck with Spectator: Lucretius and the End of Rome 29 —— They have a dramatic structure, with an emotional crescendo, culminating into an epiphonema. On the one hand, epic poets often represent heroes facing a natural catastrophe these moments become a sort of test for the hero, a turning point in which he could show his abilities and his courage, sometimes deserving the providential intervention of divinity.

Being scenes of limited length, these passages can also be connected with those particular similes in hexametric poetry where the poet depicts the reaction of humble characters e. On the other hand, Hellenistic philosophical tradition provides many rhetorical examples, focusing on the reaction of humble characters during natural catastrophes. For instance, the representation of innocent people during natural catastrophes such as earthquakes, volcanic eruptions, floods, and epidemics was included in the number of possible arguments against or in favor of the existence of divine providence and of the eternity of our world.

As for Epicurean use of this device especially by Philodemus , see Schroeder , pp. For example, in Hom. Santelia Nec vero ita refellendum est, ut, si segetibus aut vinetis cuiuspiam tempestas nocuerit aut si quid e vitae commodis casus abstulerit, eum, cui quid horum acciderit, aut invisum deo aut neglectum a deo iudicemus. Magna di curant, parva neglegunt. Quasi ego paulo ante de fundo Formiano P. Rutili sim questus, non de amissa salute. Hence, in his cosmic shipwrecks, Lucretius seems to blend two different literary traditions, coupling the poetic and emotional impact of epic-didactic similes with the argumentative force of examples in philosophical tradition.

As Alessandro Schiesaro , p. Therefore, extra Epicurum nulla salus. Iunius, eodem bello nonne tempestate classem amisit, cum auspiciis non paruisset. Omnia denique sancta deum delubra replerat corporibus mors exanimis onerataque passim cuncta cadaueribus caelestum templa manebant, hospitibus loca quae complerant aedituentes. Nec iam religio diuum nec numina magni pendebantur enim: praesens dolor exsuperabat. Of course, this episode displays a more complex and longer structure than the cases analyzed in the previous chapters. However, it is possible to identify also many similarities: the final position, the role of the demonstratio, the climax construction culminating into a final epiphonema.

The most impressive analogy between the Plague episode and other cosmic shipwrecks concerns the intent of these passages. Thus, in the most important shipwreck, Lucretius decides to stage an entire community,50 his community. The overlap between Athens and Rome becomes patent in the final epiphonema, closing the whole poem, where the tempore tali about Athens recalls the patriai tempore iniquo described in the general proem, clearly referred to Rome.

At the Spannung of the disaster, Lucretius shows that religio is forgotten and no one cares about Gods. Even the most sacred rule, giving burial to the dead mos sepulturae is abandoned. Schiesaro In fact, vv. Not only did Epicurus condemn poetry, but he also invited men not to anticipate future problems and sufferings, because this anticipation is itself a source of disquiet avocatio a cogitanda molestia, as synthetized by Cicero. Bettini Romano , pp. Nam neque vetustate minui mala nec fieri praemeditata leviora, stultamque etiam esse meditationem futuri mali aut fortasse ne futuri quidem: satis esse odiosum malum omne, cum venisset; qui autem semper cogitavisset accidere posse aliquid adversi, ei fieri illud sempiternum malum; si vero ne futurum quidem sit, frustra suscipi miseriam voluntariam; ita semper angi aut accipiendo aut cogitando malo.

Levationem autem aegritudinis in duabus rebus ponit, avocatione a cogitanda molestia et revocatione ad contemplandas voluptates. As fo the role of avocatio in Lucretius and Philodemus, see Schroeder , pp. Cosmic Shipwreck with Spectator: Lucretius and the End of Rome 33 sed quibus ipse malis careas quia cernere suave est. Suave etiam belli certamina magna tueri per campos instructa tua sine parte pericli. Such an addressee needs a shock therapy that is where the cosmic shipwreck comes in.

Through this device, Lucretius stages hic et nunc the last day of the world59 una dies , using catastrophe as an instrument of demystification, which demonstrates the fallacy of the traditional world-view and the necessity of conversion. In fact, the poet often represents himself as a prophet, who is eager to persuade his suspicious readers with the power of poetry, communicating a revolutionary message with world-shattering words.

This literary choice is the result of the political and cultural context of the Late-Republican Age, a historical period of crisis and change. Schroeder , pp. In addition to this, even the other Epicurean philosophers known to us e. Philodemus or Diogenes of Oenoanda were not as concerned as Lucretius about cosmic eschatology. Thus, unlike the peasants, the induperator or the philosophers, the reader can draw lessons from the cataclysm. The essential message is that the motus exitiales that is, illness, senescence, and death will triumph and destroy men, cities and, eventually, the world.

There is no escape to this: as underlined by Petronius in a similar diatribic passage: si bene calculum ponas, ubique naufragium est Petr. As Gian Biagio Conte , pp. Bibliography Andreoni Fontecedro E. Andreoni Fontecedro E. I lettori moderni degli antichi, Roma, Kepos. Bakker F. Bessone L. Biologismo e storia romana, Padova, Cleup. Bettini M. Blumenberg H. Caliri E. On the Lucretian sublime see also Mazzoli , p. Ciano N. Su Cic. Clay D. Commager H. Conte G. De Rerum Natura 5, ed. Gale, Oxford, Oxbow. Galzerano M. Garani M. Garofalo L. Una riflessione sulle orme di Fritz Schulz, in Fondamenti e svolgimenti della scienza giuridica, a cura di Garofalo L.

Gigandet A. Graver M. Tusculan Disputations 3 and 4. Green W. Irshai O. Leonardis I. Longo Auricchio F. Luciani S. Mazzoli G. Trenta studi su Seneca tragico, Palermo, Palumbo. Moatti C. Lloyd, Cambridge, Cambridge University Press. Nardi C. Porter J. Potter D. Ramelli I. Romano E. La natura e la scienza, a cura di Beretta M. Russo F. Santangelo F. Santelia S. Gli argomenti analogici nel De rerum natura, Pisa, Giardini. Pollmann, H. Van Noorden edd. Schroeder F. Segal C.

Sordi M. Vesperini P. Von Stuckrad K. Secondo Fairweather , pp. Vedi infatti es. Vergilius , sicut Hesiodus ad Persen, Lucretius ad Memmium. Utili osservazioni si leggono anche in Toohey , pp. Sulle imitazioni ovidiane di Tibullo, vedi anche Von Albrecht Ovidio e il ludere didascalico 41 dicere praecipuae molior artis opus. Quisquis ubique, viri, dociles advertite mentes, pollicitisque favens, vulgus, adeste meis.

Particolare rile- vanza ha poi la testimonianza autobiografica di trist. Una discussione sintetica di queste tematiche con ulteriore bibliografia si legge in Gibson , pp. Nicandrum frustra secuti Macer atque Vergilius? Ovidio e il ludere didascalico 43 a Plinio il vecchio, il quale non esita a vedere in lui esule un infaticabile raccoglitore di mirabilia sui pesci durante il suo soggiorno forzato sulle rive del Ponto. Praeter haec insignia piscium tradit: channen ex se ipsam concipere, glau- cum aestate numquam apparere, pompilum, qui semper comitetur navium cursus, chromin, qui nidificet in aquis.

Helopem dicit esse nostris incognitum undis, ex quo apparet falli eos, qui eundem acipenserem existimaverint. Per i trattati greci sulla pesca Sider ; Magnelli in questo volume, p. Sintesi di esemplificazione in Gibson , pp. Immagini non dissimili sono peraltro presenti anche in poeti precedenti come Tibullo e Properzio. Non credo sia casuale che in conclusione del primo libro vv. Nec tellus eadem parit omnia; vitibus illa convenit, haec oleis; hac bene farra virent.

Pectoribus mores tot sunt, quot in ore figurae; qui sapit, innumeris moribus aptus erit, utque leves Proteus modo se tenuabit in undas, nunc leo, nunc arbor, nunc erit hirtus aper. Ovidio e il ludere didascalico 47 Non ego, Phoebe, datas a te mihi mentiar artes, nec nos aeriae voce monemur avis, nec mihi sunt visae Clio Cliusque sorores servanti pecudes vallibus, Ascra, tuis: usus opus movet hoc: vati parete perito; vera canam: coeptis, mater Amoris, ades! Sostiene La Penna , p. Arte citae veloque rates remoque moventur, arte leves currus: arte regendus amor.

Curribus Automedon lentisque erat aptus habenis, Tiphys in Haemonia puppe magister erat: me Venus artificem tenero praefecit Amori; Tiphys et Automedon dicar Amoris ego. Ille quidem ferus est et qui mihi saepe repugnet: sed puer est, aetas mollis et apta regi Phillyrides puerum cithara perfecit Achillem, atque animos placida contudit arte feros. Qui totiens socios, totiens exterruit hostes, creditur annosum pertimuisse senem. Quas Hector sensurus erat, poscente magistro verberibus iussas praebuit ille manus.

Aeacidae Chiron, ego sum praeceptor Amoris: saevus uterque puer, natus uterque dea. Il primo suggestivo riferimento letterario, appare raffinatamente dissimulato nel conte- sto iniziale del proemio. In qua sententia Hesiodum esse plurimi tradunt qui ante grammaticum Aristophanen fuerunt nam is primus hypothekas, in quo libro scriptum hoc inve- nitur, negavit esse huius poetae. Si veda Aristofane, fr. Una buona documentazione su questa tipologia di Eros, che ritorna in Apuleio, in Mattiacci , pp.

Properzio nella stessa elegia, pochi versi prima, pur rifacendosi alle narrazioni delle artes ai vv. Importante anche Prop. Ingenii est experientis amor. Inde Honoris et Virtutis templum est. Su Gallo in Ovidio, si veda da ultima Borgo , in particolare Si veda il commento di Cucchiarelli , pp. A, te ne frigora laedant! A, tibi ne teneras glacies secet aspera plantas!

Il non… vadam ovidiano mi pare modulato, per opposizione, su un passaggio della stessa ecloga, la ripresa di ibo del v. Riferimenti bibliografici Armstrong R. Barchiesi A. Bonadeo A. Borgo A. Casali S. Churchill L. Seguo qui la sempre valida analisi di Conte , pp. Ovidio e il ludere didascalico 55 Ciccarelli I. Citroni M. Forme della comunicazione letteraria, Roma- Bari, Laterza.

Colakis M. Davis P. Qualche nota su tra- dizione romana e cultura letteraria in Ov. De Martino F. Dimundo R. Fairweather J. Fraenkel E. Gagliardi P. Gazich R. Geymonat M. Gibson R. Green C. Hollis A. Hommel H. I, Hildesheim-New York, Olms, pp. Holzberg N. Keith A. Kennedy D. Kleve K. Korzeniewski D. Kurke L. Labate M. La Penna A. Nota a Ovidio Ars am. Leach E. Lenz F. Lowrie M. Lyne R. MacLachlan B. Mader G. Malaspina E. Maltby R. Mattiacci S. Werk und Wirkung. Geburstag, I, hrsg. Studien zur klassischen Philologie , Frankfurt am Main, Lang, pp.

Ovidio e il ludere didascalico 57 Miller J. Miller J. Montana F. Moretti G. Atti del secondo incontro internazionale di studio del Lexicon Iconographicum Numismaticae Genova, novembre , Roma, Giorgio Bretschneider, pp. Myerowitz M. Narcy M. Obbink D. Peirano I. Frame, Texts, Readers, ed. Pellacani D. Studi sulla poesia latina in frammenti, ed. Pieri B.

Pianezzola E. Richmond J. Rosati G. Schniebs A. Schulman J. Schwartz J. Sharrock A. Sommariva G. Steudel M. Tosi R. Von Albrecht M. Watson L. Wheeler A. Wildberger J. Ziogas I. Any precept, to be successfully expressed and received, requires, first of all, the presence of a teacher doctor, as Servius makes clear and of an addressee discipuli persona , to whom the content of the teachings may be addressed.

The multiple strategies of dismissal will be examined primarily from a stylistic perspective, an angle mostly overlooked by scholarship. At a first glance, and especially if we compare it with his main didactic and philosophical anti- model Lucretius,2 Manilius appears less concerned with dismissing rival theories throughout the five books of the Astronomica. A plausible reason for this difference may be his different philosophical background, and the absence of a strong polemical tradition in it, as well as a lack of rivals in the field. Most recently, Volk has stressed the relevance of four different elements: a explicit didactic intent; b teacher-student constellation; c poetic self-consciousness; d poetic simultaneity.

We know of his criticism of Epicurus, whom, according to Cicero, he mocked as desipiens for believing that there were no gods,10 and of his attack on Chrysippus both for his theory on the cause of excessive impulse and his definition of distress;11 Plutarch tells us that Posidonius published a lecture against the rhetorician Hermagoras, while Proclus reports that he wrote an entire book against Zeno of Sidon.

As Alesse , p. For a detailed analysis of the passage see Alesse , pp. Another criticism of Epicurus can be found in fr. His first dismissal is introduced when, after claiming the supremacy of his subject 1, and its celestial origins 1, , he tackles the origin of the universe 1, , the necessary premise to his survey of the sky. A few different theories are referred to anonymously,14 presented as alternatives to one other siue… seu, 1, Very few philosophers are named without qualms in the De rerum natura.

If we accept the latter hypothesis, Manilius makes mention of rival views without bias: none could be said to be right or wrong, as they are investigating hidden phenomena. Conversely, the Stoic creed bases its belief upon the visible, and Manilius would be stressing that it therefore stands as unchallengeable. The same sceptical approach is adopted when Manilius attempts to explain the origin of the Milky Way 1, his effort does not go much further than listing various theories about its origin. The reference is developed with an account of notable Greek personalities , Homeric heroes, legislators, war leaders, and Roman politicians , until the apotheosis of Augustus, who is celebrated as a living god descended from Venus Moreover, he might be suggesting the idea that a divine force ruling the components of the cosmos exists regardless the formation of the cosmos itself, and it could not be challenged by any scientific explanations.

His poem, in view of its different content, had to be endorsed by empirical evidence and could not allow the poet to adopt the same attitude. Consequently, any combative tone is replaced with a more conversational one, avoiding the risk of counter-arguments. The conclusion of Book 3 presents a hasty treatment of a few other rival theories. Probably for the sake of completeness, Manilius chooses to report three different theories on the tropic degree: two anonymous quidam 3,, sunt quibus 3, , and, quite unexpectedly, the auctoritas: nec defuit auctor 3, The identity of auctor here remains disputed: Housman does not discuss the line, while Goold , pp.

However, one point remains ambiguous. Why would Manilius employ the perfect tense defuit if referring to himself, especially when the imperfect subjunctive in the following relative clause suggests an aoristic sense? The interpretation of the line is doubtful. The litotes seems to suggest a strong assertion of presence being equivalent to certe adfuit , stressing the authority of this auctor and the validity of his theory. The tone is noticeably ironic, and allows him to have his cake and eat it too: he acknowledges a previous authority, thereby setting himself within an established astrological background, but, in simultaneously obscuring the auctor, leaves himself as the only one with a say in the matter.

Manilius warns the reader against the vulgata ratio, thereby expressing his negative judgment about the common method. After explaining how it works, he introduces its flaws sed, , which contrasts factual reality to the popular theory. He is merely aligning himself with the evidence, and his stance is not the result of applying any specific methodology, but rather of unarguable mathematical calculations.

Lucretius is also echoed by moenia mundi 1, , seminibus 1, and principia 1, Only then is its groundlessness pointed out, through a sequence of rhetorical questions on Epicurean physics,27 propounding a fixed law governing the regularity of natural phenomena. He simply presents them and here specifically the Epicurean one , pointing out their flaws, being sure that, faced with natural evidence, nobody would deny the presence of a divine power and the everlasting nature of the firmament: idem semper erit quoniam semper fuit idem.

Deus est, qui non mutatur in aevo 1, At first glance, the reason may lie in the different topic he treats. Manilius in fact did not have any actual proof to back up his dismissal of the origins of the universe or of the Milky Way. What is also surprising is the absence of any previous Stoic authority as a term of comparison for the theories presented.

Moreover, the Stoic doctrine, which Manilius covertly presents in Book 1, about the cyclical nature of the universe, seems to clash with the search for its physical causes. Just as it was born, so too will the universe perish, and from its death a new birth will follow: this pattern will continue forever, with no beginning or end, most resembling the status of the gods 1, Moreover, a didactic reason can be sought in this different approach. Evidence exists, from a fragment of Posidonius, of a stark difference between the tasks of astronomer and philosopher, the former mainly looking at the aspect of the sky, the latter mainly concerned with its causes.

He presents himself more as a vates than a teacher, concerned with the avoidance of contradictions or opposing arguments, sometimes even at the expense of consistency. There are also significant overlaps between the domains of influence of specific cardines, temples and athla, allowing for conflicts that Manilius does not discuss Housman , p. We must first bear in mind that the Stoics held myth in high regard for its inner truths. Physical allegories of myth were apparently a common feature in the Stoic school.

Myth possesses a unique explanatory power,33 able to express the ultimate truth about nature and the divine, making clearer a number of phenomena that are themselves difficult to rationalise. Since Cicero widely attests to the employment of the physical allegory of myth a Graeciae sapientissimis et a maioribus nostris nat. What instead deserves attention is why, though claiming to reject mythological poetry, Manilius grants myth a conspicuous role within the Astronomica.

In the proem to Book 2, which Effe reads as an open polemic against Alexandrianism,34 Manilius sets himself within the didactic tradition,35 referencing other poetic models in a long recusatio. Homer was the trailblazer of epic poetry, which he composed without emulating any model. Similarly, Manilius went through integra prata composing an astronomical poem.

Garrod , p. He becomes more critical in the development of the recusatio, as if he wishes to stress a process of decline caused by all successors of the two great bards, against whom he contrasts the novelty of his own attempt 2, It is broadly held that Manilius is thinking of Aratus,45 although his poem lacks of catasterisms. Although he claims to reject mythological fabulae, anticipating the leitmotif of the proem to Book 3, he will not always keep this promise, since his scientific arguments are often interrupted by mythological digressions and catasterisms.

The consequence of such an attitude was that the constellations and the sky were not observed as physical entities but rather as the result of catasterisms. Manilius sets his own song against this tradition, which he introduces in the poem as his possession: nostra loquar, nulli vatum debebimus orsa 2, He therefore claims the originality of his subject matter and method of treating astronomical topics, which he does not owe to any other vates.

I instead agree with Perutelli , p. Manilius here avers that he is the sole truthful poet, and accuses the others of falsity. The main criticism that Manilius levels against them is their detachment from the rural world that they wish to portray and teach about. However, why assume that the targets are all Greek here, apart from Grattius? Equally, the reference to Hesiod 2,22 may carry a covert hint at Virgil himself. This reference, alongside the other Roman poets that Manilius might have in mind in the passages previously discussed, may reflect his concern to make clear his originality and unfamiliarity with what was a common practice in his age.

More important is what Manilius opposes to the furtum: he speaks of the opus nec furtum sed opus veniet Does the poet establish a link between his work and the operation of divine reason? He certainly does, and this is what grants his poem authority compared to typical astronomical poetry. Manilius is stressing the active force that guides him: calling his poem opus is a strong declaration of the role that it will play in reproducing the universe, the same as the divine reason that Manilius celebrates.

The target of this third proem can be identified in epic poetry, which only seems to have copied, and thereby degraded, the original Homeric model. He is seeking assistance from the Muses, as he wishes to widen their domains. He employs here one of the most common literary topoi — the invocation to the Muses — which he freely adapts to his needs: though acknowledging the divine inspiration necessary to compose poetry, he knows that the Muses will not be able to inspire him as they did with the maximus vates, since he will direct his attention to a goal removed from their traditional field of influence.

His divine inspiration will come directly from the cosmos, and this is what will make his poetry unique. Manilius refers indiscriminately to mythical, historical and epic traditions, which are targeted for their topics. He highlights the inferiority of the epic and tragic genres when compared with astronomical science and, instead of avoiding those fields because of his lack of skill, he stresses the service that his poetic choice will render to the audience …tibi praecipuos usus monstrata ministret 3,44 and the obscurity of astronomical doctrine …per numeros ignotaque nomina rerum 3, This attitude helps him define his role, one proudly distinct from the other traditions.

No negative implication is carried by fama in these contexts: the ancient tales — and in both cases the poet stresses their antiquity, as if this confers more authority upon them — are reported among the possible origins of the phenomenon considered. The poet does not express his stance, nor does he engage in any critical discussion.

Gale , p. This long digression is therefore not isolated from the broader context of the poem, but it conversely originates from it: at this stage of the concluded learning process, the pupil is in a position to understand a kind of demythologised myth, following the poet in the process of extracting from it more general ideas on which the lesson has been built. However, did Manilius really believe in the truth of myths?

Or did he rather know that myth does not apply to the real world, but, finding it particularly suited to the subject matter of his poem, chose to include it in his lesson without questioning it lest it should spoil the illusion?


Opera Poetica, First Edition

If Manilius were really committed to the falsity of myth, his decision to list these aetiological legends indiscriminately together with other scientific explanations would make little sense. At 1,, the poet claims his devotion to bina altaria, carminis et rerum, referring to his decision to write about stars in poetry: myth is integral to the expressions of heaven, explaining content that is otherwise difficult to understand. Therefore, Manilius was most likely viewing mythical stories as part of the multiple explanations for those phenomena of unknown origins: myth might contain some degree of truth, but the poet is not committed to survey it.

The reader knows that, regardless of the causes that might be given, there will always be an incontrovertible principle that is the first cause of everything, i. Myth could be a vehicle to aid human understanding in those fields removed from our comprehension, or, at least, from our perceptions. Manilius appears deeply conscious of the role he is playing in the path of a long-lasting tradition and in respect of a peculiar content as that of the Astronomica, to which he consequently adjusts himself.

He is an astronomer more than a philosopher, but at the same time a convinced trailblazer of the Stoic belief of a divine force enlivening the universe, of which he proclaims himself the vates: this is the main task he foresees for him, and the main reason behind his way of approaching any rival doctrines.

Opposing to them would be a fruitless effort: conversely, drawing any explanation back to the outward appearance of the cosmos and to the undeniable divine principle that governs it all is the safest attitude to assume. On the other hand, when it comes to dismissing poetic rivals, Manilius appears more methodical. He builds a recusatio ad excludendum, in which, stressing the decline of poetry, especially after the unsurpassed example of the maximus vates Homer, he attempts to find his own space.

He rejects the hackneyed topics of myth, epic, tragedy and history. His opus will be an expression of the active reason that rules the cosmos. Myth is not rejected as false or deceptive in the Astronomica, but the poet shows an attitude of indifference towards it, sometimes even of respect when he stresses how it is an old fama. He has no worries, apparently, that myth can undermine the truthfulness of his Stoic beliefs. What he dismisses is rather the tradition of mythological poetry, as distinct from any moral aims, thus blurring the boundaries between Stoic philosophy and metapoetics.

This never results in a less clear definition of his role as a teacher and of the didactic aims of his poem: on the contrary, finding himself a well-defined space, and making his position explicit in respect to pre-conceived traditions that his audience was most likely familiar with is the necessary condition to establish his authority more persuasively. Bibliography Abry J. Abry J. Poignault ed. Piganiol, pp. Alesse F. Baldini Moscadi L. Feraboli S. Flores, R. Gillespie, P. Hardie eds. The case of Manilius, in Green S. Garrod H. Gee E. Oakley eds. Goold G. Green S. Habinek T. Housman A.

Landolfi L. Lehoux D. Montarese F. Musso S. Salemme C. Sedley D. Uden J. The Perseus and Andromeda epyllion, in Green S. Van Wageningen J. Manilii Astronomica, Amsterdam, [s. Warren J. Whitman J. Un particolare ringraziamento devo a Paolo Mastandrea e Luca Mondin per le loro preziose osservazioni nella fase di revisione del lavoro. De medicamentis, appendice, Niedermann Quod natum Phoebus docuit, quod Chiro Achillem, quod didicere olim Podalirius atque Machaon a genitore suo, qui quondam versus in anguem templa Palatinae subiit sublimia Romae, quo Cous docuit senior quodque Abdera suasit, 5 quod logos aut methodos simplexque empirica pangit: hoc liber iste tenet diverso e dogmate sumptum.

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Parnaso D'Abruzzo Rassegna di Poeti in Italiano, Latino e Dialetto ()

Sane agriculturae huius praecepta non ad omnes pertinent terras, se ad solum situm Italiae, et praecipue Venetiae, teste ipso Vergilio, qui ait [georg. Servio, nella famosa praefatio al commento alle Georgiche, definisce un poema di- dascalico sulla base della funzione comunicativa necesse est, ut ad aliquem scribantur : devono esserci un maestro e un allievo praeceptum et doctoris et discipuli personam requirit e in linea di massima un oggetto specifico non astratto e generale di trattazione. Una definizione di carmen didascalicum si rintraccia infatti entro uno scambio epistolare tra Simmaco e Ausonio in cui il primo sta replicando a una perduta lettera del secondo, dove questi si lamentava per la circolazione non autorizzata di un suo componimento, originariamente inviato in via privata a un amico.

Callu Certe aliquod didascalicum seu protrepticum nostro quoque nomini carmen adiudica. Mondin Illud quod paene praeterii, qua adfectatione addidisti, ut ad te didascalicum aliquod opuscu- lum aut sermonem protrepticum mitterem? Ego te docebo docendus adhuc, si essem id aetatis, ut discerem? Nel suo contributo Mondin ivi, p. Tuque, potens artis, reduces qui tradere vitas nosti et in caelum manes revocare sepultos, qui colis Aegeas, qui Pergama quique Epidaurum 5 qui quondam placida tectus sub pelle draconis tarpeias arces atque inclita templa petisti depellens taetros praesenti numine morbos: huc ades et quicquid cupido mihi saepe locutus firmasti, cunctum teneris expone papyris.

Dopo il proemio comincia, al v. Cignolo Sic nostrum senium quoque, quia iam dicere grandia maturum ingenium negat nec spirant animas fibrae, angustam studii viam 55 et callem tenuem terit, tantum ne male desidi suescant ora silentio. Quid sit littera, quid duae, iunctae, quid sibi syllabae, 60 dumos inter et aspera, scruposis sequimur vadis. Fronte exile negotium et dignum pueris putes, adgressis labor arduus 65 nec tractabile pondus est. Instat callida cautio, ne sermo ambiguum sonet, ne priscum nimis aut leve, 75 vocum ne series hiet, neu compago fragosa sit, vel sit quod male luceat.

Dum certo gradimur pede, ipsi ne[u] trepident pedes. I testi ausoniani qui proposti, dunque, varranno non tanto o non solo come casi di studio riguardo al genere didascalico, quanto piuttosto come assaggi di una dispensa superstite in grado di fornirci un possibile squarcio su uno degli ambiti entro cui la poesia didascalica, o almeno una certa parte di essa oggi perduta, poteva muoversi sulla fine del IV secolo. Un approfondimento in questa direzione porterebbe certo risultati assai degni di nota. Si segnala inoltre il recente volume dedicato ad Ausonio da Wolff Di Giovine 30 Misi ad te Technopaegnion, inertis otii mei inutile opusculum.

In questa praefatio Ausonio parla della sua opera e dei suoi intenti: descrive il testo e gli conferisce un titolo Technopaegnion , grecismo e neologismo per indicare lo scherzo artificiale proposto. Ecco dunque un esempio tratto dal gioco ausoniano: Auson.

Di Giovine Saepe in coniugiis fit noxia, si nimia est, dos. Green , pp. Sicut enim sacerdos a sacrificando, ita et rex a regendo. Non autem regit, qui non corrigit. Recte igitur faciendo regis nomen tenetur, peccando amittiut. Sivan , pp. Una letteratura didascalica per gli amici dotti, per i litterati. Ludus, III: Ludius ed. Riguardo in particolare alla dedica, cfr. Cazzuffi , pp. Vedi anche Green , pp. Multi hoc Laconis esse Chilonis putant.

Multi hoc Solonem dixe Croeso existimant.

"Il buono amore è di bellezza disio"

Sed imperitos scite quos dixit malos. Dixi; recedam. Legifer venit Solon. Si tratta di un tema ben noto, che transita e riemerge in vari momenti e ambiti della tradizio- ne.

  • Editors: Jonathan Druker and L. Scott Lerner.
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  • The Falls: May Flowers (The Falls small town mystery series Book 8);

Dunque una poesia forse impoetica, ma effettivamente, e a buon diritto, didascalica. Quin etiam nebula saeptus pervenit in urbem, abreptos socios undis cum classe recepit hospitioque usus Didus per cuncta benignae excidium Troiae iussus narrare parabat. V-VI d. Come si diceva, gli Argumenta sono tramandati sia in codici virgiliani sia in codici miscellanei. Non certo dunque, come ha sottolineato ancora Gioseffi,50 prove scolastiche di studenti alle prime armi.

Riferimenti bibliografici Bergamin M. Bisanti A. Bowersock G. Brown P. Bruggisser Ph. Recherches sur le premier livre de la correspondance, Fribourg, Editions Universitaires Fribourg Suisse. Cartassa G. Cazzuffi E. Cignolo C. Homenaje a M. Consolino F. Cutino M. De Meyier K. Di Giovine C. Farmhouse Alberto P. Friedriech A. De Gruyter. Gioseffi M.

Paniagua, Nordhausen, Traugott Bauz, pp. Green R. Herzog R. Munich, Beck. Jouanna-Bouchet J. Kaster R. Leary T. The Aenigmata, London, Bloomsbury. Leotta R. Luceri A. Osservazioni sui carmina minora 4, 42 e app. Maini P. Manca M. Marpicati P. McGill S. Mondin L. Epistole, Venezia, Il Cardo. Onorato M. Pelttari A. Perutelli A. Fedeli, A. De Gruyter, pp. Polara G. Boccone del Povero. Rosellini M. Ruffato C. Salanitro G. Salvadore I. Segoloni M. Scivoletto, Prefazioni, prologhi, proemi di opere tecnico-scientifiche latine, Roma, Herder, I, pp.

Sivan H. Genesis of a Gallic aristocracy, London, Routledge, pp. Stok F. Wolff E. Ziolkowski J. Ziolkowski, III, pp. This lacuna is not a consequence of fate, nor does it suggest less of a focus on Lucretius compared with other classics on the part of Italian humanists. This is why, when in the s the first verse translations of the classics started to appear, Lucretius enjoyed not one but two verse translations. So their translations disappeared, leaving no discernible impact.

My warmest thanks to colleagues and friends at both institutions for organizing two extremely engaging conferences and to all those whose questions and suggestions helped me improve hopefully the following pages. Collective volumes include: Gillespie and Hardie , Beretta and. Citti , Lestringant and Naya The manuscript of the sixth book was still extant in the 18th cent. Magnoni , p. On this humanist, cfr. Riccioni Gordon is not aware of this translation. Favorite bits and pieces of the De rerum natura thus crop up within works of vernacular poetry, in the form of extended, almost literal quotes; whereas in prose works, humanists linger with gusto on their translated Lucretian passages.

Renaissance authors everywhere showed through their work an urge to pay homage to a text of which not even extreme ideological aversion could hide the charm. A tacit but universally shared imperative to limit access to the De rerum natura ruled its circulation in all realms of Italian culture.

The obtained sequencing reads were mapped to reference sequences and analyzed by the Amplicon Variant Analyzer software Roche to establish the mutant allele frequency. For each probe, at least interphase cells with well-delineated fluorescent spots were examined. Irrelevant isotype-matched antibodies Becton—Dickinson were used to determine background fluorescence.

Massimo Lollini

FACS data of all samples are listed in Supplementary file 2. As shown in Figure 1—figure supplement 1A , MCF represents the fraction of cancer cells containing particular alterations. To infer MCF of different types of lesions, we applied the following strategy:. MCF of a copy number abnormality i.

However, MAF of some mutations might exceed 0. Here, MCF could be simply defined as a Piecewise function:. To smooth this function, a Hill function was introduced, assuming. A grid-search method was applied to exhaust potential values of K and n. Additionally, by comparing FACS measurement of tumor purity, this Hill function form of MCF is more robust than either MAF without adjustment or simplistic piecewise function in assessing the fraction of cancer nuclei Figure 1—figure supplement 1E.

We assume four different cell types: wild type upper left , heterozygous deletion upper right , mutation lower left , and both mutation and deletion lower right. To define the transition probability, we focused on two simple models of four mutations x 1 , x 2 , x 3 , x 4. In the linear evolution model, we assumed that all mutations were mutated in a linear order shown in the left panel of Figure 2A.

All possibilities of mutation status are. According to Nordling's multi-mutation model Nordling, , the transition probability was defined as. The transition probability is shown in Figure 2B. The longitudinal data were then generated for each patient following the above model. To simplify the model, we fixed the number of time points three and the length of interval between time points ten.

We asked whether or not TEDG framework can reconstruct the order of mutations and how many patients are required. For each combination, we randomly simulated the cancer patients and applied TEDG framework to reconstruct the order for 10 times. The frequency of reconstructing the exact order was defined as the accuracy of TEDG. Edge weights of ISN present the number of simulated patients with one mutation happening before another. The techniques of deconvolution and minimal spanning tree reconstruct the real structure by removing indirect interactions.

Different from linear model, the branching model assumes that x 3 and x 4 are independently following the mutation of x 2. Figure 2G summarized the correlation between number of patients and optimal accuracy of TEDG in branching model. To construct the sequential network of alterations for each tumor, we monitored the presence or absence of each genetic lesion in each sample. If event A predates event B, we added a directed link between A and B. The ISN was constructed by pooling all sequential networks from different patients.

To simplify ISN, we removed self-loops by subtracting the weight of weaker direction. With this method, nodes were placed in hierarchically arranged layers and the nodes within each layer are ordered in such a way that minimizes the number of edge crossings Smoot et al. To test the statistical association of lesions in TEDG, we counted the number of samples carrying each pair of lesions and then calculated the p-value based on hypergeometric distribution to test whether the two genetic lesions are independent or not.

To consider the effect of multi-hypothesizes, we corrected p-values with Bonferroni method and made a cut-off of 0. If two lesions were significantly co-mutated, a red link was added, while if they were significantly mutually exclusive, a blue edge was added. The resulting matrix of deconvolution formula indicates the score of an edge to be a direct interaction edge weights in the middle panel of Figure 2D,F. We then introduced a minimal spanning tree-based method to determine the final TEDG, in which we transformed the deconvoluted weights with a negative exponential function, and then calculated the minimal spanning tree with Prim's algorithm.

We developed Fit the Evolutionary Model FEM to properly fit the evolutionary model by systematically identifying clonal replacement in all sample pairs. For i th mutation in j th patient at the k th time point t k. Similarly, for the i th copy number change in the j th patient at the k th time point t k.

The change of genetic lesion frequency is a synergic effect of treatment, tumor progression, and experimental noises, such as sequencing error or change of tumor purity. Based on this, we could calculate p-values of each genetic lesion in all sample pairs. To assess whether there was a significantly increased or decreased subclone in a given sample pair, we use Fisher's combinational test to combine p-values of all increased or decreased genetic lesions. All the others were compatible with the gradual linear model.

To investigate the fitness of genetic lesions, we defined growth rate and the maximal mutation frequency slope MMFS. Overall survival OS was measured from date of initial presentation to date of death from any cause event or last follow-up censoring. The cumulative probability of Richter syndrome transformation was measured from date of initial presentation to date of the biopsy documenting Richter syndrome transformation event , death or last follow-up censoring. Survival analysis was performed by the Kaplan—Meier method. The crude association between time-fixed exposure variables at diagnosis and survival was estimated by Cox proportional hazard regression.

Sequences for all annotated exons and flanking splice sites were retrieved from the UCSC Human Genome database using the corresponding mRNA accession number as a reference. All PCR primers and conditions are listed in Supplementary file 1. Candidate variants were confirmed from both strands on independent PCR products. Synonymous variants, previously reported germline polymorphisms and changes present in the matched normal DNA were removed from the analysis.

An edited version of the letter sent to the authors after peer review is shown, indicating the substantive concerns or comments; minor concerns are not usually shown. Reviewers have the opportunity to discuss the decision before the letter is sent see review process. Similarly, the author response typically shows only responses to the major concerns raised by the reviewers.

Your article has been favorably evaluated by Chris Ponting Senior editor , a Reviewing editor, and 2 reviewers. The Reviewing editor has assembled the following comments to help you prepare a revised submission. Overall, the reviewers found the work interesting but raised a number of concerns that need to be addressed regarding the analysis of the data as well as clarifications on the design and presentation of the work. Really, the only true method for inferring temporal ordering is through reconstruction of phylogenetic trees; this can be difficult from bulk sequencing data, but there are methods emerging to do this.

Also, how are double hits in a given gene dealt with in the graph method? The initiating lesion, by definition, will be present in all the tumor cells, and therefore cannot increase at the same magnitude as later mutations. Given that it is a prerequisite for entry into the study that the patient be diagnosed with CLL, one would imagine that, at that diagnostic time point, all the earliest mutations might already be clonal, and therefore will not change over time. The only way to know is if there were a set of samples from which there was frequent sampling, and if there were within clinical defined groups.

Robustness of the network is dependent on how good the data is going in. While they do mention that they selected 70 samples for TEDG for which there were at least two sequential samples, in all likelihood, 2 samples are inadequate for defining the hierarchical relationships. There needs to be some table that provides information on the distribution of sequential samples per patient, and what types of time intervals between sequential samples. While a figure about the samples is provided as Figure 3—figure supplement 1 , this is very hard to digest. This is a very very heterogeneous dataset, with 10 of 70 proceeding to Richters, more than half with treatment.

A question is whether or not there are enough samples, by the time that one breaks down the patients into discrete clinical groups, to understand the hierarchical relationships. Related to this, the numbers of samples are very confusing. This is what the reviewer understood: it seems that they start out with patients, but only 70 had known highly recurrent drivers. By the time we get to Figure 4 , there are 32 samples, but there is no discussion how this number came about.

In general, in what percentage of sample was a polyclonal tumor population or a subclonal driver identified at the time of diagnosis? Your revised article has been favorably evaluated by Chris Ponting Senior editor , a member of the Board of Reviewing Editors, and the original two reviewers. The manuscript has been improved but there are two remaining major issues that will need to be addressed before acceptance, as outlined below.

We have copied the exact wording of the reviewer to facilitate the response. This was done to address the concern of adjusting for local copy number changes that could affect estimation of the clone size with a gene alteration. Unfortunately, the approach taken by the authors to calculate MCF seems not well defined. This reviewer is concerned that sampling error in VAF values might fluctuate above or below 0.

No convincing data is presented by the authors to justify their novel and elaborate seeming approach. Several approaches for correcting mutation VAF values for tumor purity and somatic copy number changes have been described e. Carter et al. Could the authors simply use one of these established and principled approaches? This would leverage their exome data more fully. This is not accurate, as it is not possible to correct for purity when using FISH data. We found the comments extremely helpful, and according to the suggestions we have made several major revisions summarized as follows:.

A We introduce the concept of mutation cell frequency MCF to adjust mutation allele fractions using copy-number information. After the adjustment, all our main results are consistent as shown in the following. B To address the major comment 1, we introduce a phylogenetic tree method to infer timing order of mutations. Our analysis shows that the phylogenetic tree method and TEDGs differ in capturing the effect of competition between different subclones. However, the main results inferred from both methods are consistent, indicating the robustness of the overall analysis see detailed response below.

In the new analysis this conclusion remains. D To clarify the confusion of the sample size in our study, we generate a new figure with a clear statement of how we select patients, and how many samples of each patient. To show how many patients are necessary to reveal the ground truth, we simulate the evolutionary and sampling process by an artificial example. The results indicate 30 patients will be enough to reconstruct a simple evolutionary graph.

Note: comment 2 is addressed first because other comments will depend on the adjustment of mutation data. The black lines within the circles represent DNA copies, and the crosses represent mutations. This is a good suggestion. As shown in Author response image 1 , MCF represents the fraction of cells containing alterations. To infer MCF of different types of alterations, we apply the following strategy:. However, MAF of some mutations may exceed 0.

MCF could be defined in a simple Piecewise function:. To smooth this function, a Hill function strategy is introduced. Assume where K and n are parameters of the Hill function. A grid search method is applied to exhaust potential values of K and n. We assume four different genotypes: wild type upper left , heterozygous deletion upper right , mutation lower left , and both mutation and deletion lower right. Black lines within the circles represent copies of DNA, and crosses on the lines indicates point mutations.

The above methods have been applied to adjust the data reported in this study before the TEDG analysis. This adjustment not only reduces the potential bias caused by copy number alterations, but also addresses another concern mentioned in Minor comment 4 about the integration of FISH data and NGS data. A We have updated all relevant data in this manuscript, updated the description of TEDG framework in Figure 1A , and added the following sentence to the legend of the Figure 1 :. To unify both types of data, and to adjust the MAF of mutations in genes with CNA, we introduce mutation cell frequency MCF for quantification of genetic lesions Materials and methods, Figure 1—figure supplement 1.

C We have put Author response images 1—4 in Figure 1—figure supplement 1 , and added expanded the Materials and methods accordingly. Each column represents one patient with at least two time points. For one patient, if the present of alteration A is earlier than B, we claim A predates B. In our work, the relative timing of mutations is inferred by longitudinal data with multiple time points. Twenty-one out of all CLL patients contain the change of mutation status during disease progression.

The phylogenetic trees are constructed based on mutation status of the driver genes. Green balls are normal cells, while all the others are cancer cells with particular alterations. First, if a given genetic lesion is observed to be temporally earlier than another lesion, we connected them with a directed edge to represent their sequential order of development Figure 1A. We agree that the construction of phylogenetic trees is a good option to infer temporal orders of gene mutations by assuming common ancestors are early events, but limited to the fact that only very few genes have been considered in this study, it is difficult to reconstruct an accurate phylogenetic tree of patients.

To approximate the phylogenetic trees, we define the pairwise distances between samples by considering both the number of common mutations and the number of different mutations, and make use of the complete linkage distance method to construct the phylogenetic trees of wild type cell, tumor cell at diagnosis, and tumor cell at different stages of relapse Author response image 6.

Other methods, such as neighbor-joining and parsimony, produce similar results, as expected from the small number of branches and informative sites driver mutations that vary within a tumor and, as described below, branching assessment using bootstrap is generically non-significant. There are four samples for patient 1. Mutation frequencies of different alterations change according to the progression of the disease.

In most of cases, phylogenetic tree method indicates the same order of mutations as our longitudinal method used in TEDG. However, the order of gene mutations inferred by longitudinal method and phylogenetic tree method are not totally identical. For example, the phylogenetic tree of patient 1 Author response images 6 and 7 indicates del13q and delRB1 are early events, and then two branches are independently developed with one harbors SF3B1 KE and del11q, and the other harbors SF3B1 KE.

The temporal order of delBIRC3 and mutation SF3B1 KE may not occur in the same subclone, but it indicates the competition between two subclones, suggesting subclone with delBIRC3 may have stronger fitness in this particular patient. Therefore, different from the phylogenetic tree method, the longitudinal analysis of TEDG presents the temporal orders of mutations, not only the results of the disease progression within a subclone but also consequences of competition among different clones. Furthermore, we rank all events based on fold change between indegree and outdegree by phylogenetic tree method and TEDG separately.

Strikingly, the rank of all events based on those two methods is significantly related with Pearson correlation more than 0. In the TEDG network analysis, the backbone of CLL evolution is slightly changed, but two main branches are the same, indicating two major types of CLL patients suffering T12 and del13q independently Author response image 8.

It is interesting to observe that the differences are in the order of del17p and TP53 mutations and the indirect association of SF3B1. The two methods are compared in terms of the order of mutations and the TEDG networks. We would like also to emphasize that phylogenetic methods usually require higher number of alterations than the ones considered in our manuscript.

eLife digest

Standard statistical techniques to assess the branching for each tree rely on bootstrapping segregating sites. The statistical power of these techniques using longitudinal data from cancer patients in few selected driver genes is extremely limited. In summary, we introduce a phylogenetic tree method to compare with our longitudinal method, and show that although the two methods are slightly different in capturing the effect of competition of different subclones, the main results inferred from both methods are almost the same, indicating the robustness of our overall analysis.

Given that it is a prerequisite for entry into the study that the patient be diagnosed with CLL, one would imagine that at that diagnostic time point, all the earliest mutations might already be clonal, and therefore will not change over time. To address this concern, we only consider the growth rate of subclonal mutations.

This is a very heterogeneous dataset, with 10 of 70 proceeding to Richters, more than half with treatment. We do not know the ground truth, and this is the main purpose of our and other methods to infer the order of alterations from longitudinal data. However, we have performed simulations where we start with the ground truth, a model of how mutations accumulate and a sampling strategy.

In particular, we tested the TEDG method in an artificial example by separately simulating linear evolution and branching evolution of cancer as one-step Markov process. Simulations allow estimating the power of our data and method to assess the order of alterations and the different evolutionary trajectories. A The 70 patients are selected from a big cohort of 1, CLL patients with no-bias screening. B 70 patients are ranked according to their minimal cell frequency at diagnosis.

Patient with minimal cell frequency less than 20 are in red, the others are in green. Regarding the number of samples considered in each analysis, we are sorry for the confusion of the presentation of sample size in Figure 3—figure supplement 1 and Figure 4. To clarify the samples used in our study, we present our data in Author response image No biases are present in the case series we have utilized in the manuscript. Indeed, we have collected 14,03 newly diagnosed CLL patients between the year of and the year of , during which patients contain samples of multiple time pints.

We systematically genotyped all the sequential samples collected at each progression for progressive cases and at the last follow-up for non- progressive cases from consecutive cases recruited in our database. Our study is mainly focusing on those 70 patients. The mutation information, as well as the number of sequential samples of each patient is shown in Author response image 5.

In total, we have 50 patients with two time points, 16 with three time points, and 4 with four time points. In Figure 4 , we did not say there are 32 samples. We used 70 CLL patients to analyze evolution network of 32 alterations one gene can have more alterations by considering mutation sites. Based on dilution experiments, we calibrated for systematic biases that lead to sequencing errors and derived the depth distribution of sequencing errors to be negative binomial. A detailed account of calibration of estimates using ultra-deep sequencing has been described in a related publication Figure S3 of Rossi et al.

The two assumptions may limit the application of this approach in cn-LOH regions or low-purity samples. Unfortunately, we do not have whole-exome or SNP array data for most of our longitudinal cases. However, whole-exome sequencing data are available for 10 out of 70 patients, including a four patients with paired tumor and normal control published recently in Messina et al.

To check whether the driver genes i. In a recent study, Pfeifer et al. We compare all our diver genes with their results, and find none of our genes in their list. In summary, based on limited cases with heterozygosity information in the list of driver genes selected in these studies and in published results by an independent group in an extended cohort, we reason that cn-LOH is not a major effect in the targeted genes of our current study.

Irrelevant isotype-matched antibodies Becton-Dickinson were used to determine background fluorescence. One blue dot represents one sample, and contours indicate the density of dots. A suitable calculation of maximal driver mutation fraction will approximate but not exceed the fraction of cancer nuclei. Apparently, tumor purities of 55 samples are properly assessed by the Hill function MCF, which is better than both MAF without adjustment 10 samples and simple piecewise MCF 27 samples. More recently, cloneHD Fischer et al.

All these approaches have been proved to be robust in the analysis of cancer genome, but all methods require genome-wide information, such as SNP array, whole-exome or whole-genome sequencing, which are only available for a few samples in our analysis. We want to emphasize that compared to the other approaches this manuscript presents the analysis of a few targeted alterations in large number of longitudinal samples 70 longitudinal patients.

To compare our method to genome-wide methods, we have analyzed previously published whole-exome sequencing WES and SNP array data of four of our patients: 57, 4, 37, and 59 Fabbri et al. SNP array data for the other six patients are not available. By comparing MCF with the confidence interval of CCF, for mutations of 3 out of 4 cases, the results are consistent Author response image To address this concern, we have included FACS analysis.

Accordingly, Figure1—figure supplement 2 , Figure 3A were updated edges in the network plot, indegree, outdegree, etc.