Bothrops venoms targeting hemostasis are responsible for a broad range of clinical and biological syndromes including local and systemic bleeding, incoagulability, thrombotic microangiopathy and macrothrombosis. Beyond hemostais disorders, toxins are also involved in the pathogenesis of edema and in most complications such as hypovolemia, cardiovascular collapse, acute kidney injury, myonecrosis, compartmental syndrome and superinfection. These toxins can be classified as enzymatic proteins  and non-enzymatic proteins (desintegrins and C-type lectin proteins). Bleeding is due to a multifocal toxicity targeting vessels, platelets and coagulation factors. Vessel damage due to the degradation of basement membrane and the subsequent disruption of endothelial cell integrity under hydrostatic pressure and tangential shear stress is primarily responsible for bleeding. Hemorrhage is promoted by thrombocytopenia, platelet hypoaggregation, consumption coagulopathy and fibrin(ogen)olysis. Onset of thrombotic microangiopathy is probably due to the switch of endothelium to a prothrombotic phenotype with overexpression of tissue factor and other pro-aggregating biomarkers in association with activation of platelets and coagulation. Thrombosis involving large-caliber vessels in B. lanceolatus envenomation remains a unique entity, which exact pathophysiology remains poorly understood.Toxins from  Bothrops snakes, also called lanceheads, are the main genus of medical importance in the Neotropical Americas. They are involved in most cases of envenomation in studies performed in Brazil [Bothrops genus comprises nearly 50 species, widely distributed in South and Central America (from southern Mexico to Argentina) and in the Caribbean. Lanceheads usually occupy terrestrial, arboreal and semiarboreal biotopes, but may be occasionally found in disturbed habitats around human settlements and urban areas [B. atrox in the Amazon region, B. asper from southern Mexico to western Ecuador and Colombia, and B. jararaca in South East Brazil, Argentina and Paraguay, with a large body of medical literature for these three taxons [B. atrox and B. asper are phylogenetically close and belong to the B. atrox group [B. jararaca to a new genus, Bothropoides [Bothrops [n Brazil ,2,3,4,5,n Brazil , French n Brazil , Colombin Brazil , Argentin Brazil , Costa Rn Brazil  and Panan Brazil . Belongian areas ,13. The e taxons ,15,16. Box group ,17. Fenwropoides , subsequBothrops .Bothrops venom exhibit a great diversity and are predominately represented by snake venom metalloproteinases (SVMP), snake venom serine proteinases (SVSP), phospholipases A2 (PLA2), C-type lectin-like toxins (CTL), desintegrins, cysteine-rich secretory proteins (CRISP), L-amino acid oxidases (LAAO), natriuretic peptides including vasoactive peptides, bradykinin potentiating and inhibitory peptides [Bothrops venoms have various targets against hemostasis. This process aims to stop or limit bleeding after vascular injury. The three distinct phases, primary hemostasis (mainly involving platelets), coagulation (related to fibrin formation) and fibrinolysis, are closely linked [2-antiplasmin, α2-AP) [Snake venoms contain a highly potent mixture of bioactive molecules, known as toxins. Toxins from peptides . Bothropy linked . The vony linked . Initiaty linked . During y linked . Thrombiy linked . Fibrinoy linked . Plasmin, α2-AP) . Bothrops envenomation are pain, edema, bruising, bleeding from fang punctures, sometimes blistering or dermonecrosis [Local features of necrosis ,16,27. Hnecrosis ,28,29, wnecrosis . B. lanceolatus and B. caribbaeus, found only in Martinique and Saint Lucia, respectively, also belong to the B. atrox group [B. atrox or B. asper including local hemorrhage and ecchymosis, envenomations due to these Caribbean species are unusually associated with systemic bleeding and incoagulabiblity, but may by contrast be complicated by multiple systemic infarctions within 48 h after the bite [ox group ,17. Despthe bite . Bothrops venoms are responsible, directly or indirectly, for a large number of clinical impairments, sources of marked morbidities and potential fatality. Understanding the underlying mechanisms is therefore challenging as prerequisite to optimize current management strategies and develop new approaches.Thus, hemostasis disorders induced by A discrete trickle of blood from the fang punctures starts minutes after the bite with venom injection, even in the absence of systemic signs and blood incoagulability ,29,32,33Mucosal hemorrhages are the earliest manifestations of systemic bleeding. Gingival bleeding and hematuria are the most frequent but other mucous membranes may occur with epistaxis, conjunctival bleeding, otorrhagia and metrorrhagia ,29,32,33Bothrops envenoming, it was found that 2.6% of the victims developed a cerebrovascular event, of which about 60% died and 40% remained with sequelae [Visceral hemorrhages are less frequent but more severe and may include hemarthrosis  , hepaticsequelae ,38,41. Ssequelae  and ampusequelae .B. atrox et B. jararaca envenomation [Thrombocytopenia and unclottable blood on admission are independently associated with systemic bleeding during hospitalization for nomation ,43,44.B. jararaca evidenced that systemic bleeding is more frequent in patients with thrombocytopenia than in patients with blood incoagulability [B. atrox [B. atrox, suggesting peripheral platelet destruction, which tends to increase the mean platelet volume [Clinical studies in patients bitten by lability ,46. By cB. atrox ,43. A net volume . Thrombot volume . The hemorrhagic syndrome is exacerbated by incoagulability ,29. UnclEnvenomed patients present increased prothrombin time (PT) and activated partial thromboplastin time (aPTT), with low level of fibrinogen. Factors II, V, VII, X, XIII also decrease ,47,48. FB. jararaca venom upregulates hepatic mRNA synthesis of fibrinogen chains, which may explain the fast recovery of clotting tests and fibrinogen level, even without antivenom [PT and aPTT take respectively 3 and 1 day(s) to normalize without antivenom. Fibrinogen level reaches 100 mg/dL in 24 h . In micentivenom .Owing to its low cost, simplicity and good correlation with plasma fibrinogen concentration, the 20 min whole blood clotting test (20WBCT) is an effective and reliable method for evaluation of hemostatic status in the primary care centers without laboratory . IncreasB. atrox in Manaus, especially those with systemic bleedings, high levels of D-dimers and fibrin/fibrinogen degradation products (FDP) and low levels of plasminogen and α2-AP [Secondary hyperfibrinolysis was observed in patients envenomed by nd α2-AP ,43. ThisB. jararaca evolving with systemic bleeding with or without incoagulable blood, suggesting that the fibrinolysis is also due to vascular endothelial damage [High levels of PAI-1 and tPA as well as increase in vWF and thrombomodulin were recorded in patients bitten by l damage ,52.B. jararaca [B. venezuelensis [B. erythromelas [B. venezuelensis bite, hyperfibrinogenemia began at day 2 and persisted over 2 weeks despite the administration of antivenom 4.5 h after the bite [Thrombotic microangiopathy (TMA) was recently described in envenomation cases by jararaca ,54, B. vuelensis  and B. ehromelas . These pthe bite . When asB. jararacussu bite, autopsy reported evidence of multiple fibrin and platelet microthrombi in the subcutaneous and muscular tissue around the bite site, and in the heart and lung microcirculations [In a fatal case due to massive pulmonary hemorrhage occurring 1 h after ulations . BleedinB. lanceolatus is responsible for 20–30 snakebite cases in Martinique each year [B. lanceolatus envenomations are associated with systemic multifocal thrombotic complications, usually occurring within 5 h to a week after the bite, even after a moderate envenomation limited to local signs [B. lanceolatus have thrombocytopenia while rare patients develop disseminated intravascular coagulation. Thrombocytopenia, minimally reduced prothrombin, normal activated partial thromboplastin time, and elevated fibrinogen concentration are typical features in B. lanceolatus-envenomed patients who will further develop thromboses [ach year . Approxial signs ,58,59. Tromboses ,59. B. lanceolatus envenomation with diffuse thrombotic microangiopathy causing multiple cerebral, myocardial and mesenteric infarctions at autopsy was reported. Laboratory features associated hemolytic anemia with increased LDH and biblirubin levels, thrombocytopenia and hyperfibrinogenemia with minimally reduced prothrombin ratio and normal activated partial thromboplastin time [A fatal case of tin time .B. caribbaeus in Saint-Lucia, who developed multiple cerebral infarctions [A similar clinical presentation was reported in a patient bitten by arctions . Beyond the hemorrhagic consequences, microcirculation impairment around the bite site may partly explain the edematogenic process due to vascular permeability increase ,63. AddiBothrops venom [Bothrops envenomation-related AKI development [Presence of thrombi in arterioles and arteries associated to local microcirculation impairment may contribute to limit vascularization of distal muscle tissues leading to poor regeneration of muscles and local myonecrosis followed by secondary infection . AKI is ps venom . Glomeruelopment ,68. Finaelopment .2 or Fab-fragment therapies to be administered intravenously [Antivenom is the first-line treatment of snakebite envenomation and its related hemostasis disorders. It consists of polyclonal antibodies generated by immunizing animals with small amounts of snake venom. The resulting antibodies are purified from serum or plasma and formulated into intact IgG or F(ab’)venously . B. atrox [B. asper [The majority of patients showed rapid restoration of blood coagulability and cessation of bleeding ,71,72,73B. atrox ,74 and BB. asper ,71 bitesB. asper . In someB. asper . Blood cB. asper ,48,71,72B. asper ,47,49.®, Instituto Bioclon, Ciudad de México, Mexico) is currently used to treat snakebites including B. atrox envenomations. A retrospective study shown that compared to patients receiving no antivenom, the 3-vials dosage initially used had no benefit in correction of snakebite-related coagulopathy [In French Guiana, a non-local antivenom , prevents thrombosis if it is early given, up to 6 h following the bite [® [A monovalent antivenom against the bite . Since ithe bite . However bite [® . In thes bite [® . Anticoa bite [® ,58.Bothrops venoms and involved in hemostasis disorders are classified into different families.Snake venoms are complex mixtures of proteins with toxic activities, with many distinct isoforms, affecting different physiological targets, including enzymes and non-enzymatic proteins. Toxins isolated from Viperinae and Crotalinae venoms, especially in Bothrops venoms [SVMP are zinc-dependent endopeptidases belonging to the metzincin family . They res venoms . They dis venoms . Based os venoms .The mature protein forms of P-I SVMP (20–30 kDa) contain a catalytic domain characterized by a zinc-binding sequence (HEXXHXXGXXH) followed by a conserved “Methionine-turn” motif. The P-I SVMP are divided into two subgroups, i.e., P-IA which induce hemorrhage and P-IB with weak (or no) hemorrhagic effects . StructuIIBβ3  inhibiting platelet aggregation [Class P-II includes enzymes containing the metalloproteinase domain described above and a disintegrin domain (30–60 kDa). Disintegrins have most often an RGD motif which is the primary recognition site for the integrin αregation . This caregation . B. jararaca [P-III SVMP (60–100 kDa) contain a metalloproteinase catalytic domain and disintegrin-like and cysteine-rich domains in a single polypeptide chain, many of them being glycosylated. Proteolytic cleavage, repeated domain loss and presence of other ancillary domains are responsible for structural diversities of P-II and P-III SVMP. The former P-IV class characterized by the addition of a lectin-like domain is now considered as a P-III class (P-IIId) due to a post-translational modification . Jararhajararaca . Becausejararaca .2-AP. SVSP isolated from Bothrops venoms are most often TLE or fibrin(ogen)olytic [SVSP have a typical trypsin fold with a highly reactive serine residue in their active site and catalyze the cleavage of specific covalent bonds in peptides and proteins . These en)olytic ,88.2 are small proteins with the molecular mass of 13–15 kDa. PLA2 hydrolyze the ester linkages in glycerophospholipids at the sn-2 positions to produce equimolar amounts of lysophospholipids and free fatty acids. It requires calcium for their catalytic actions. Their structure has three major α-helices and two antiparallel β-sheets cross-linked by disulfides bonds. Snake venom PLA2 are classified into two groups, I and II, according to the location of disulfide bonds [2 from Bothrops venoms belong to group II. Asp49 and Lys49 are the most well studied PLA2 of group II. These PLA2 are classified according to the amino acid located at position 49 [PLAde bonds ,90. PLA2ition 49 . They display a wide range of biological effects such as neurotoxicity, cardiotoxicity, local or systemic myotoxicity, hemolysis, and anticoagulating, antiplatelet and edema-forming activities.LAAO are homodimeric flavoenzymes that catalyze the stereospecific oxidative deamination of L-amino acid to α-keto acid and produce hydrogen peroxide. These enzymes have a molecular mass of 110–159 kDa and three major domains: substrate-binding domain, FAD-binding domain and helical domain.LAAO can inhibit or induce platelet aggregation, depending on the isoform. In addition, LAAO may be responsible for edema, inflammation, apoptosis, hemolysis and hemorrhage .Disintegrins are small polypeptides (40–100 amino-acid) derived by proteolytic processing from P-II SVMP or from genes solely encoding disintegrins  . They arMost of their toxic effects are due to their interaction with cell surface ligands: inhibition of platelet aggregation, apoptosis, cytotoxicity. Moreover, they interfere with the functions of integrins by altering different cellular processes such as migration, adhesion or proliferation . Snake venom CTL bind to mono- and oligo-saccharides in a calcium-dependent manner. They are distinguished between classical CTL possessing a carbohydrate recognition domain that binds to sugars, and non-sugar-binding C-type lectin-related proteins, also called snaclecs. Snaclecs are more widely present in snake venoms than classical CTL. While CTL are disulfide-linked homodimers or homo-oligomers, snaclecs are disulfide-bonded heterodimers or oligomeric complexes of heterodimers including two highly homologous subunits tightly associated by loop-swapping, with a concave surface between the two subunits. The concave surface is probably the main ligand binding site . Most classical CTL isolated in snake venoms bind to galactose and induce platelet aggregation. Snaclecs could be agonists or antagonists of platelet aggregation, or anticoagulant  ,96.B. lanceolatus and B. caribbaeus, rather associated with the occurrence of thrombosis, mainly contain SVMP, PLA2, SVSP, LAAO [B. jararaca and B. lanceolatus, the difference being in the distribution of SVMP subgroups. B. lanceolatus has relatively more P-I SVMP identified than B. jararaca venom while B. jararaca venom has a higher amount of hemorrhagic P-III SVMP [B. lanceolatus and B. caribbaeus venoms [Venoms of SP, LAAO  and do nIII SVMP . On the s venoms .These contradictory results could be explained by an important intraspecific variability linked to different factors such as sex, geographical distribution, ontogeny and captivity.B. atrox venom was observed even in siblings. Male venom showed higher LAAO, PLA2 and hemorrhagic activities, while female venoms showed higher coagulant activity [B. jararacussu males is more procoagulant than those of females [Sex-based variation of activity . Venom f females .B. asper lineages from North-Western South America, especially in the four major toxin families: SVMP (mainly PI- and PII-SVMP), PLA2, SVSP and CTL [Bothrops venezuelensis venoms, from five localities in the North-Central Venezuelan regions, showed differences in minimal hemorrhagic dose and fibrinolytic activity [A geographic and altitudinal venom variability was observed in  and CTL . In the activity . B. atrox, B. asper [B. jararacussu [B. asper, whereas venoms of neonates have a predominance of P-III SVMP [B. jararacussu venom, P-III-class SVMP with pro-coagulant and hemorrhagic functions were the most abundant components in venom of smaller snakes, while the basic myotoxic PLA2 were the major components in larger snakes venoms [B. atrox snakes cause more severe local inflammatory effects, whereas venom-induced coagulopathy is more frequent in envenomings caused by juvenile specimens [A linear relation between ontogenetic variability and snake size has been described in the venom composition of B. asper  and B. jaracussu . ConcentIII SVMP . In B. js venoms . Higher s venoms . These ppecimens . Similarpecimens .B. atrox showed a weak variability restricted to the less abundant components in the majority of snakes. However, in some individuals, SVMPs were drastically affected showing the plasticity of the venom phenotype during the lifespan of snakes held in captivity for more than one year [Few studies reported modifications of the venom in snakes kept in captivity. The venom from one year .Intraspecies variation in snake venom has consequences on antivenom treatment because snakes of different sex, age or localities may be result in envenomation needing higher doses to achieve total neutralization of lethality or other toxic activities, in particular hemostatic ones ,116,117.Bothrops venoms are endowed with multiple biological activities targeted against hemostasis  and not per diapedesis (through widened intercellular junctions) [B. asper venom induced endothelial cell degeneration in 1 min. On electron microscopy, the morphological pattern of vascular damage associated a reduction in the thickness of endothelial cells with blebs and cytoplasmic projections protruding to the vascular lumen, a decrease in the number of pinocytotic vesicles and a detachment of some endothelial cells from their surrounding basal lamina, leading to gaps in the continuity of endothelial cells then extravasation. No alterations in the intercellular junctions were observed in damaged capillaries [Hemorrhage happened nctions) . In miceillaries . Bothrops venoms including B. lanceolatus and B. caribbaeus ones have hemorrhagic activity  and BaH-1 (P-III SVMP) from B. asper venom, suggesting that SVMP have an important role in bleeding [2EDTA were administered at various time intervals after experimental envenoming in mice at the same site of B. asper venom injection, both compounds effectively neutralized local hemorrhage [Serum SVMP levels are significantly higher in patients with systemic bleeding compared to those without bleeding in nomation . In expebleeding ,125. Whemorrhage . This hiThe ability of SVMP able to induce hemorrhage, named hemorrhagins, is not related to a direct cytotoxic effect on capillary endothelium and the rapid degenerative changes of endothelial cells observed in vivo are the result of the proteolytic degradation of basement membrane (BM) components of microvessels ,127. SVMB. leucurus venom), a striking difference was noticed regarding the hydrolysis of type IV collagen [The proteomic analysis of exudates collected in the vicinity of damaged gastrocnemius muscle of mice showed the early presence of BM components and other extracellular matrix proteins reflecting the rapid microvascular damage induced by SVMP. Presence of fragments of type IV collagen and perlecan one hour after envenoming suggests that hydrolysis of these BM components plays a key role in the genesis of hemorrhage . When cocollagen , suggestcollagen .P-II and P-III SVMP bind more specifically to capillary BM than P-I SVMP, owing to the presence of exosites in the disintegrin, disintegrin-like and cysteine-rich domains of these SVMP, thus explaining their generally higher hemorrhagic activity ,136. ColB. atrox venom, has a high hydrolytic activity towards extracellular matrix proteins, including laminin and collagen IV and is able to cause a fast disruption of capillary vessels allowing the induction of hemorrhage similar to those induced by Batroxrhagin, a P-III SVMP isolated from the venom of the same species [However, the presence of non-catalytic domains in the SVMP is not essential for hemorrhagic activity. Atroxlysin-Ia, a P-I SVMP from  species . 2 may participate in bleeding, by increasing the activity of SVMP. For example, a PLA2 from B. alternatus venom exhibits no toxicity towards endothelial cells in culture but was found to significantly enhance the detaching activity of balteragin, a hemorrhagic P-III SVMP from the same venom, on endothelial cells [PLAal cells .Bothrops envenoming-related endotheliopathy [In vitro BM proteins hydrolysis occurred at relatively late time intervals, whereas in vivo hemorrhage developed within minutes of injection . This diliopathy .Bothrops venoms induce endothelial injury which may participate to bleeding. Important increase in plasma soluble thrombomodulin level was reported indicating severe endothelial injury after the intravenous injection of B. jararaca venom in rabbits [B. jararaca venom is not due to the direct toxicity of SVMP but to thrombin activated by venom [Despite the absence of direct toxicity,  rabbits . High le rabbits . Elevatiby venom .B. jararaca venom, cleaves in vivo endothelial glycocalyx proteoglycans such as biglycan, decorin, glypican-1, lumican and syndecan-1, participating to the disruption of microvasculature integrity and contributing to hemorrhage [Hemorrhagic Factor 3 (HF3), a hemorrhagic P-III class SVMP from morrhage .B. asper venom [B. jararaca venom directly aggregated washed human and mouse platelets in vitro and stimulated secretion of adenosine triphosphate (ATP), platelet factor 4 (PF4) and β-hexosaminidase, which are present in dense granules, alpha granules and lysosomes of platelets, respectively [In mice, a dose-dependent drop in the number of platelets was observed after the intravenous injection of er venom . B. jaraectively . Bothrops venoms. Clinical studies establishing an inverse correlation between platelet count and hemorrhagin level suggested a link between thrombocytopenia and SVMP activity [Bothrops envenomation [B. moojeni venom, induced direct and thrombin-mediated platelet aggregation [Thrombocytopenia may be due to different groups of toxins from activity . Hemorrhnomation . Reductinomation . Moojenaregation . Howeverregation . B. atrox and B. jararaca respectively, induce platelet aggregation and granule secretion without clotting fibrinogen. Both enzymes induced calcium mobilization in platelets, and cleaved the protease-activated receptor (PAR)1-receptor [B. jararaca venom activate platelets by interacting with GPIb which is a thrombin receptor [Thrombocytin and Platelet-aggregating proteinase (PA-BJ), SVSP isolated from the venom of receptor . Bothromreceptor .B. jararaca venom and Aspercetin from B. asper venom induced platelet aggregation in the presence of vWF, promoting its interaction with platelet receptor GPIb and leading to thrombocytopenia and prolonging the bleeding time in mice [Mild thrombocytopenia was observed in patients with either incoagulable or coagulable blood, suggesting an independent mechanism from procoagulant toxins . Bothroc in mice ,151. The in mice . Bothrops PLA2 are able to induce platelet aggregation such as bothropstoxin-II, an Asp49 PLA2 isolated from B. jararacussu venom [2 to induce platelet activation is related to the capacity to hydrolyse phophatidylcholine and the liberation of arachidonic acid [B. moojeni venom induces platelet aggregation although the exact underlying mechanisms are not well understood [su venom . The abinic acid . BmooLAAderstood .Bothrops venom may induce qualitative thrombopathy. In a work studying platelet function during human envenomations by B. jararaca, most of patients who presented systemic bleeding showed hypoaggregation to ADP, ristocetin and collagen [Besides thrombocytopenia, collagen . B. asper venom and jararacussin-I, a TLE SVSP from B. jararacussu venom, induced hypoaggregation to ADP in a mouse model. It was suggested that the hypoaggregating effect depends on defibrin(ogen)ation, because fibrinogen is needed for interaction with integrin αIIbβ3 or because the fibrin(ogen) degradation products generated interact and block this integrin receptor [B. jararaca venom, NPP-BJ, is a homodimeric glycoprotein inhibiting platelet aggregation induced by ADP, by hydrolysis of adenylated nucleotides secreted from platelet dense bodies during platelet activation. Polyclonal antibodies raised against this phosphodiesterase could not abolish the lethal activity of B. jararaca venom, suggesting a minor contribution to the lethality [Basparin A, a prothrombin activator P-III SVMP from receptor . A phospethality .B. jararaca venom in vitro shown a marked degradation of vWF with loss of high and intermediate molecular weight bands and an increase in low molecular weight fragments, but these results were much less obvious in patients envenomed by this species [The inhibition of ristocetin-induced aggregation has been observed with jararhagin and was attributed to a direct effect on vWF rather than to its action on the GP Ib-IX-V receptor. Jararhagin degrades vWF, in particular the portion of the molecule, which contains the ligand site for the GPIb receptor, the A1 domain . Mutimer species .2-subunit I domain of the platelet surface α2β1 integrin (collagen receptor) [1 subunit of the same integrin [2β1, because this effect is not related to P-I SVMP which lack such sequences [In contrast, collagen-induced platelet aggregation is inhibited by jararhagin following its binding to the αeceptor) . Jararhaintegrin . This inequences . Baspariequences . In miceequences ,159.2 inhibit platelet aggregation such as BJ- PLA2 from B. jararaca [2 from B. jararacussu [2 [B. moojeni and BE-I- PLA2 from B. erythromelas [2 is due to the cleavage of the by-products of arachidonic acid [Some PLAjararaca , BthA-I-aracussu , BmooTX-aracussu  and Bmoocussu [2  from B. hromelas . The inhnic acid .B. leucurus venom dose-dependently inhibited platelet aggregation of both human platelet-rich plasma (PRP) and washed platelets [Bl-LAAO from latelets .Bothrops venoms by thromboelastographic method in human plasma showed a predominantly procoagulant activity with an increase in coagulation speed and of clot growth velocity [Crude venoms exhibit strong procoagulant effects in dose-dependent manner in vitro ,166,167.velocity . This pavelocity ,158. B. jararaca venom) and P-III SVMP (like basparin A) activate prothrombin to α-thrombin by producing meizothrombin without requiring additional cofactors such as calcium or phospholipids, which ranks them in the group A of snake venom prothrombin activators [Bothrops spp. are distinguishable from group B , group C (SVSP similar to factor Xa-factor/Va complex) and group D (SVSP similar to factor Xa). Group B prothrombin activators convert prothrombin to meizothrombin while groups C and D prothrombin activators convert prothrombin to mature thrombin [B. atrox venom produce two other cleavages, i.e., one near the N-terminal end of the heavy chain of factor X, generating factor Xmu and a second located at one extremity of the heavy chain of factor Xa alpha, generating factor Xav [SVMP are able to clot citrated plasma by activating prothrombin and/or factor X. P-I SVMP ation if intravenously or intramuscularly administered, with reduction in plasma fibrinogen concentration. When injected with SVMP BaP1, BjussuSP-I induced a slightly larger hemorrhagic lesion in the skin of mice, suggesting local hemorrhagic activity exacerbation induced by hemorrhagic SVMP [Bothrops venom, whereas the TLE play a minor role, probably due to the low content of the latter enzyme in these venoms [BjussuSP-I, from gic SVMP . Experime venoms ,147,180.B. jararaca venom, inhibits α-thrombin by the non-covalent binding to exosites 1 and 2, decreases the binding of α-thrombin to fibrinogen and thrombomodulin and reduces protein C and prothrombin activation [Bothrojaracin I, a CTL purified from tivation ,182.B. jararaca venom is able to inhibit factors IX and X and protein S in a calcium-dependent fashion [An anticoagulant C-type lectin isolated in  fashion .B. atrox venom, is a P-I SVMP degrading preferentially the Aα- and Bβ-chains, but also inducing a partial degradation of the γ-chain [Non-coagulant proteinases having fibrin(ogen)olytic activity may contribute to fibrinogen consumption without conversion to fibrin. P-I SVMP have direct fibrin(ogen)olytic activity. Their main biological substrate is fibrin(ogen), whose Aα-chain is degraded rapidly and independently of activation of plasminogen. They are termed as α-fibrinogenases, but the other chains of fibrinogen can be substantially degraded during time . For exa γ-chain . Hemorrhagic P-III SVMP may take part to the consumption of clotting factors. Jararaghin cleaves fibrinogen in the C-terminal part of the Aα chains, resulting in the removal of a 23 kDa fragment while β and γ chains remain unaffected. The remaining purified fibrinogen molecule is still fully functional in both platelet aggregation responses to ADP and in its ability to clot plasma by activating thrombin. The only consequence of the α-fibrinogenase activity of jararhagin was abnormal fibrin polymerization by thrombin . In vitrB. jararaca venom cleave the Aα- and Bβ-chains of fibrinogen without forming fibrin clots [B. jararacussu venom, has a primary fibrinolytic activity [SVSP can exhibit fibrin(ogen)olytic without thrombine-like activity. For example, BjSP from in clots . BjussuSactivity .Hyperfibrinolysis can also contribute to fibrinogen and fibrin consumption . In mice2-AP [B. jararaca venom, inactivates two fibrinolysis inhibitors, PAI-1 and α2-AP, and thus induces fibrinolysis pathway [In guinea-pig, plasma, purified jararhagin increases tPA activity by causing dissociation of the tPA/PAI-1 complex and promotes fibrinolysis by the inactivation of α2-AP . Reptila pathway .B. asper venom on the mouse cremaster muscle showed the formation of thrombi and emboli in veinules, not in arterioles, before the onset of bleedings [B. jararaca venom [B. asper venom in mice, numerous capillaries were damaged with platelet aggregates and fibrin deposition in their lumen [B. jararacussu and B. insularis venoms induced vascular occlusive thrombosis besides hemorrhage, suggesting that ischemia contributed to muscle necrosis [B. jararaca venom combined with stasis of inferior vena cava resulted in venous thrombosis [As stated previously, toxins responsible for platelet aggregation and coagulation activation lead to platelet and coagulation factor consumption, thus promoting bleeding. However, this initial thrombogenic state may cause microthrombi. An in vivo study of local tissue damage after the topical administration of leedings . Similarca venom . After tir lumen . The intnecrosis ,191. In rombosis ,193 whilrombosis . Based oB. jararaca venom in rats increased the activity and expression of TF at the site of venom injection as well as in plasma and lungs [B. erythromelas venom, was demonstrated in vitro to render endothelial cells highly thrombogenic, with releasing of vWF and expression of TF, ICAM-1 and E-selectin [Bothrops venom-related AKI [B. moojeni venom, induces a procoagulant behavior in peripheral blood mononuclear cells by increasing TF in vitro [The intravenous or subcutaneous injection of nd lungs . Berythrselectin ,196. Endated AKI . Moojenain vitro ,198.Bothrocetin has been found to induce platelet aggregates and microthrombi in the lung and spleen . SimilarB. atrox venom, to promote fibrin accretion was found 18-fold greater than that of thrombin, that may promote microvascular thrombosis and fibrin deposition [Once bound to fibrin the capacity of batroxobin, a TLE from position ,201.B. jararaca envenomation, TMA was reported with thrombocytopenia, hemolytic anemia, schizocytes and microcytes [In a rat model of crocytes . The onsThe intravenous injection of moojenactivase induced intravascular hemolysis and red blood cell fragmentation, and microthrombi in small vessels in lungs then hemorrhage in rats. The local ischemia at the injection site seemed due to abundant thrombi formation since this SVMP did not provoke vessel disruption and local hemorrhage . At low To date, determinants leading to a hemorrhagic or thrombotic phenotype during envenomation remain unknown. Interestingly, patients with TMA did not experience systemic bleeding. Likewise, P-III SVMP such as berythractivase, moojenactivase or basparin A, able of inducing systemic thrombi, are devoid of hemorrhagic activity ,158,198,B. lanceolatus and B. caribbaeus remains unknown. There is not successful animal model describing the thrombotic manifestation with one of these two species [The exact mechanism of macrothrombosis in human envenomation by  species ,202, sugB. caribbaeus venom and isolated snaclec from these venoms induce platelet aggregation and agglutination in human PRP. The snaclec binds directly to glycoprotein Ib (GPIb) without platelet activation and induces agglutination in washed fixed platelets without requiring vWF, contrary to botrocetin or aspercetin [B. lanceolatus venom had no direct effect on platelet aggregation in human PRP [Both crude percetin . Despiteuman PRP ,123. B. atrox, B. asper and B. jararaca, B. lanceolatus and B. caribbaeus venoms were not coagulant when tested on human citrated plasma . The main TMA-related diseases are thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) . TTP is In typical HUS, endothelial activation is induced by a microbial toxin called Shiga toxin, causing a cytotoxic, proapoptotic and prothrombotic phenotype of the endothelial cell, with increased TF expression, vWF release and platelet activation. By contrast, typical HUS is caused by the complement system activation leading to terminal complement complex formation .B. lanceolatus and B. caribbaeus have vascular toxicity. Their intravenous administration induced lung hemorrhage in mice, suggesting the involvement of hemorrhagic SVMP [B. lanceolatus venom [B. caribbaeus venom [Venoms of gic SVMP ,123,202.gic SVMP ,123. A hus venom  while a B. caribbaeus venom injection in mice [B. lanceolatus venom showed low gelatinolysis activity and probably lacking activity on critical extracellular matrix proteins, which degradation is associated with hemorrhage [B. lanceolatus venom showed particularly low toxicity in endothelial cells (EAhy926) compared to B. jararaca venom. After 24 h of exposure, B. lanceolatus venom appeared about 10 times less toxic than B. jararaca venom, while longer times of incubation enhanced B. lanceolatus venom cytotoxicity. B. lanceolatus venom did not induce adhesion molecules expression such as ICAM-1, VCAM-1 or E-selectin, neither TF expression on vascular endothelial cell membranes [However, the absence of increments in plasma sE-selectin levels suggested the lack of endothelial cell damage after the intravenous  in mice . Similarmorrhage . B. lancembranes .B. lanceolatus venom seems to exhibit poor direct endothelial cell toxicity, suggesting the involvement of an intermediate system able to activate endothelium in vivo. The complement system may induce thrombosis by activating endothelial cells, with the production of C5a and terminal complement complex triggering TF expression [B. lanceolatus venom can activate all three complement-pathways. In an ex vivo human blood assay, this venom strongly induced the generation of anaphylatoxins, such as C3a, C4a, C5a and the soluble terminal complement complex [Bothrops are able to activate the complement system by one or several activation pathways, generating high quantities of anaphylatoxins by directly cleaving C3 and C5 or by inactivating the regulator C1-INH. These events involved both metalloproteases and serine proteases [Thus, based on these experimental findings, pression ,210. B.  complex ,212. Venroteases . Bothrops venoms are endowed with multiple activities on hemostasis, responsible for different clinical manifestations, ranging from local bleeding to thrombosis and/or systemic bleeding. It has been clearly established that bleeding is not due to disseminated intravascular coagulopathy but to the direct multifocal toxicity involving the vessels, platelets and coagulation. Compared to bleeding, microthrombosis is rarely reported in Bothrops envenomation. Fibrin deposition induced by venom-related hemostasis disorders seems at least initially not to result in clinical impact. However, the high incidence of further complications such as AKI suggests a larger involvement of hemostasis disorders than initially believed. In some situations, thrombi may lead to TMA. Case reports and experimental studies suggest that thrombosis involvement is more important when hemorrhage is absent and coagulopathy rapidly corrected. This paradoxical observation requires vigilance even in mild-to-moderate envenomation presentations.B. lanceolatus envenomation are not fully understood. Endothelial damage seems the most likely involved basis. Due to weak venom activity on vessels, the suggested involvement of the complement system based on in vitro studies merits further investigation in vivo. Mechanisms responsible for thrombosis during Bothrops venoms suggests that bleeding and thrombosis should not be considered as two different pathologies but rather two sides of the same pathophysiological continuum. Factors predisposing to envenomation with rather hemorrhagic versus thrombotic phenotype are unknown. Their identification would allow better understanding hemostasis disorders induced by venoms from a dynamic perspective and thus anticipating their onset when managing a bitten patient.The relatively similar composition of the different


Plants, unlike animals, do not have defender cells or an adaptive immune system. Instead, plants rely on each cell’s innate immunity and systemic signals emitted from infection sites. On the other hand, not all plants, even within the same species, are genetically identical, and their genetic backgrounds determine how well they respond to stress factors. Through evolution, plants have acquired various defense mechanisms that play important roles in the never-ending fight between plants and pathogens. Genetic variation in relation to plant disease resistance can thus be contextualized to provide new insights into these defense mechanisms and evolutionary processes that lead to resistance to pathogens. By focusing on genetic variations and mutational events linked with plant–pathogen interactions, the paper explores how genome compartments facilitate plant and pathogen evolutionary processes.Phytopathologists are actively researching the molecular basis of plant–pathogen interactions. The mechanisms of responses to pathogens have been studied extensively in model crop plant species and natural populations. Today, with the rapid expansion of genomic technologies such as DNA sequencing, transcriptomics, proteomics, and metabolomics, as well as the development of new methods and protocols, data analysis, and bioinformatics, it is now possible to assess the role of genetic variation in plant–microbe interactions and to understand the underlying molecular mechanisms of plant defense and microbe pathogenicity with ever-greater resolution and accuracy. Genetic variation is an important force in evolution that enables organisms to survive in stressful environments. Moreover, understanding the role of genetic variation and mutational events is essential for crop breeders to produce improved cultivars. This review focuses on genetic variations and mutational events associated with plant–pathogen interactions and discusses how these genome compartments enhance plants’ and pathogens’ evolutionary processes. Eucalyptus marginata) dieback disease caused by Phytophthora cinnamomi in Western Australia [Plant diseases caused by bacteria, fungi, viruses, nematodes, and protists have occurred throughout the history of plant colonization on Earth. As a result of plants’ continued interactions with pathogens, plant genomes have been shaped through coevolution processes, with pathogen-imposed selection pressures leading to selection signatures in the genome ,2. Nonetustralia . Plant pustralia ,5. TheseMelampsora lini [Avr) genes [Avr genes encode small, secreted proteins called AVR proteins or effectors that are recognized by cytoplasmic R proteins inside the host cell. Avr genes are pathogen genes that only encode a conditionally recognized protein by plants with the corresponding R gene. However, even if the plant contains an R gene, the pathogen may still cause disease, even though the pathogen possesses the avirulence gene. Rapid breakthroughs in ‘omics’ technologies have accelerated the identification of Avr genes in plant pathogenic fungus. To date, many Avrs have been cloned from the filamentous fungi that infect a wide range of agriculturally important crops [Leptosphaeria maculans and Brassica napus has been widely investigated. In total, 23 resistance genes and 14 avirulence genes have been identified, of which three R genes and eight Avr genes have been cloned. Recently, Neik et al. [AvrLmS and AvrLep2 and found that these Avr genes, which were previously described as different avirulence genes, to be perceived by different resistance genes; RlmS and LepR2, were found to be the same. Additionally, Rlm4 and Rlm7, which confer resistance to L. maculans, were found to be alleles of the Rlm9 wall-associated kinase-like resistance locus [Plant disease control has historically relied on traditional breeding for disease resistance. It was not until the 1940s that Harold Henry Flor published his important study on the interaction between flax and its obligatory rust pathogen, ora lini , resultir) genes ,8. Avr gce locus . This gene-for-gene plant disease resistance is linked to another response called hypersensitive response (HR) . HR geneAvr genes—to control host cellular processes and form parasitic relationships [R) genes and activate a more robust and faster defense response, known as effector-triggered immunity (ETI) [According to the zigzag model of plant–pathogen interactions, induced defense consists of two layers. The first layer is called microbe- or pathogen-associated molecular-pattern (MAMP or PAMP)-triggered immunity (PTI) ,18. Pathionships ,20. Thesty (ETI)   ,23. Arabidopsis [Two recent studies investigated the relationship and interactions between PTI and ETI using complementary approaches in bidopsis ,25. Thesbidopsis . Arabidopsis plants were inoculated with Pseudomonas syringae, salicylic acid (SA) accumulation rapidly increased, and signaling pathway transcripts with boosted disease resistance were observed in the plants’ next generation, suggesting that plants can pass on resistance to subsequent generations [Arabidopsis thaliana, which is dependent on jasmonic acid (JA) and ethylene signaling [Other immunological responses in plants include the systemic acquired response (SAR) ,28. SAR erations ,32. Induerations . Unlike erations . For exaerations . PGPRs perations ,36 and verations . MAMPs aerations ,39. Theserations ,39. Addierations ,39. Amonerations ,41. PGPRignaling . The comignaling .Avr gene products are very small and colocalized with R gene products, reinforcing this ligand-receptor hypothesis. (2) In the guard model, AVR and R proteins indirectly interact. The R protein recognizes changes in the host target protein of an effector, known as a “guardee” [A. thaliana bacterial R-Avr systems [Resistance proteins recognize AVR through four different coexisting models . (1) In guardee” . The mos systems . The gua systems . (4) In  systems .Genomic variation describes the differences between individuals’ genomes. More precisely, genomic variation is a DNA segment that differs in length, orientation, copy number, or chromosomal location between different individuals . GenomicThere are several causes of genetic variation such as mutation and genetic recombination . GenomicL. maculans ‘brassicae’ and Zymoseptoria tritici, TE-rich genome sections are exemplified by epigenetic alterations that are further associated with diverse patterns of transcription and accumulation of mutations [Verticillium dahliae and Z. tritic, accessory genome sections originate through structural changes and unfaithful DNA repair across repeated sequences [Transposable element (TE) insertions and deletions, originally considered selfish DNA or ‘genome parasites’ , are mobutations . These cutations . For exaequences . PathogeUstilago maydis, Sporisorium scitamineum, and S. reilianum have low TE content, the TEs are remarkably linked to virulence gene clusters [Magnaporthe oryzae and Fusarium oxysporum [M. oryzae, TEs are frequently found near pathogenicity factors [Mycosphaerella fijiensis, which causes black Sigatoka in bananas [M. graminicola, which causes Z. tritici blotch in wheat [The activity of transposable elements plays a significant role in effector gene evolution ,62. For clusters . The assxysporum ,65. As d factors . The TE- bananas  and M. gin wheat . TE inseNeurospora crassa [Aspergillus fumigatus [Aspergillus nidulans [F. oxysporum [Magnaporthe grisea [L. maculans [AvrLm1-AvrLm6 regions), as well as the low GC content in corresponding retrotransposon-rich isochores. Furthermore, in L. maculans ‘brassicae’, the RIP mutation can play a crucial role in transposable element silencing and effector evolution [M. grisea during the sexual phase [The repeat-induced point (RIP) mutation is a genome defense mechanism specifically found in fungi that protects against the harmful effects of repetitive genomic regions and TEs by mutating cytosine to thymine in repetitive sequences . The RIPa crassa . RIP-likumigatus , Asperginidulans , F. oxysxysporum , and Mage grisea . RIPs armaculans , as showvolution . Furtheral phase . The deval phase . The widal phase .L. maculans genome was the first fungal genome published with a considerable proportion of AT-rich regions (~33% of the assembly) [Passalora fulva [Blastomyces dermatitidis [Epichloë spp. [Z. tritici [L. maculans genes AvrLm6, AvrLm4-7, and AvrLm1, have increased interest in AT-rich regions [L. maculans, it was reported that like all other AvrLm genes, AvrLmS-AvrLep2 exist in an AT-rich genome environment; encode for small, secreted proteins rich in cysteines; and are extremely overexpressed in the initial cotyledon infections [Venturia inaequalis, the region comprising AvrVg is located in isochores with significantly different GC content [M. fijiensis and Passalora fulvum, which have effector-encoding genes in repeat-rich regions [Lupinus angustifolius L., 22 genes were linked with AT-rich regions. While none were expected to be effector candidates, four continued the Pfam-related domain [Pyrenochaetalycopersici ER1211 and L. maculans genomes in another work. AT-rich regions made up about one-third of the L. maculans genome and ~10% of the P. lycopersici ER1211 genome [The AT-rich isochore is a region with high content of thymine and adenine residues. AT-rich isochores usually concur with deactivated repetitive elements . AT-richssembly) . Since tra fulva , Blastomatitidis , multiplloë spp. , and Z.  tritici . Studies regions . In L. mfections . In Vent content . This or regions . In a std domain . AT-rich1 genome . It was 1 genome . B. napus were shown to reduce seed glucosinolate content [B. napus. In addition, Song et al. [A chromosomal rearrangement encompasses different events, including duplications, inversions, and translocations of pieces of chromosomes between the sub-genomes. Sequence exchanges between homeologous chromosomes in polyploid plants result in immediate gene deletions and amplification or homeologous exchanges (HEs) ,89. HEs  content . The str content . These r content . In euka content ,96. Supe content . The hom content  as an al content  and the  content  in B. nag et al.  discoverg et al. . Severalg et al. ,103.RPM1 gene in Arabidopsis [Verticillium longisporum resistance such that both short- and long-range PAV assist with V. longisporum resistance in canola [B. napus population. In addition, Bakker et al. [V. longisporum resistance. In L. maculans, V. dahliae, Phytophthora infestans, Z. tritici, and M. oryzae, many effector genes show within-species PAV and remarkable connections with transposable-element-rich regions of chromosomes [Insertions/deletions (InDels) are small fragments of DNA (a few nucleotides up to 50 bp) that are present or absent compared to a reference genome. InDels are prevalent in many species and cause frame shifts by deleting or altering genes . In contbidopsis , many PAbidopsis ,107,108.n canola . Gabur en canola  also star et al.  showed tomosomes ,110,111.omosomes . One reaomosomes , suggestomosomes . AdditioRhg1 confers resistance to soybean cyst nematodes and seems to act via the multiplication of the locus [Avr1a and Avr3a from P.sojae and showed how the copy number variation and transcriptional differences of these Avr genes represent mechanisms for the evasion of Rps-mediated immunity. It was reported that R genes present higher CNVs than the rest of the genome [R genes) and rice (508 R genes) [Copy number variations (CNVs) are chromosome insertions, deletions, and/or duplications, and are generally described as a DNA fragment with a different copy number than the reference genome . CNVs imhe locus . In a prhe locus  identifie genome . For exaR genes) . Erysiphe necator) can be controlled by sterol demethylase inhibitor (DMI) fungicides. A point mutation in the target gene EnCYP51A is a known mode of resistance to DMIs; however, resequencing DMI-resistant E. necator isolates showed frequent increases in the copy number of the mutant allele [EnCYP51 copy number and enhanced gene expression.CNVs were found in various plant pathogens, especially fungi, with some promising instances in an express link between CNVs and pathogenicity. For instance, grape powdery mildew  locus, a positive regulator of arbuscular mycorrhizal (AM) fungal colonization in M. truncatula roots infected by Phytophthora palmivora [The replacement of a single nucleotide at a specific position in the genome is called a single nucleotide polymorphism (SNP). SNPs can occur within coding regions in amino acid substitutions, mis-splicing, or premature stop codons. SNPs have a broad distribution and can be detected in any region of a gene, mRNA, or intergenic region . SNPs ca sativum , Aphanomuncatula , resistai in pea , verticii in pea , and resB. napus . Using eB. napus  mapped bB. napus  developealmivora . Single Brassica species [Saccharomyces cerevisiae [Magnapothe grisea and F. oxysporum, many families of TEs were discovered and linked as key factors affecting karyotypic instability [Chromosomal polysomy occurs when an individual has at least one more chromosome than normal. Thus, instead of the expected two copies, there may be three or more copies of a chromosome. Core or dispensable chromosomes can become duplicated. Chromosomal polysomy occurs in various species, including plants, fungi, insects, and mammals . Polysom species . In plan species . In fungrevisiae . In addirevisiae . In fungrevisiae . In Magntability . Alternaria species [Fusarium solani [F. oxysporum [Colletotrichum gloeosporioides [Colletotrichum higginsianum has critical effects on the fungus’ pathogenicity. Additionally, Ayukawa et al. [F. oxysporum f. sp. conglutinans (Focn) has multiple CDCs. The authors identified specific CDCs required for virulence on Arabidopsis, cabbage, and both. They also described a pair of effectors encoded on one of the CDCs required to suppress Arabidopsis-specific phytoalexin-based immunity. It was proposed genes playing a role in coding for host-specific toxins (HSTs), including AF-toxin from the strawberry pathotype [Unlike core chromosomes, conditionally dispensable (CDCs), or accessory chromosomes, are not essential for an organism. CDCs often differ from the core chromosomes in their size , gene content, and sequence characteristics . Additio species , Fusarium solani , and F. xysporum . Dispensxysporum , includiorioides . Plaumanorioides  showed ta et al.  indicateathotype , AK-toxiathotype  and ACT-athotype , are posathotype .BSC4 gene in Saccharomyces cerevisiae is an example of de novo gene birth [Arabidopsis lyrata, almost half of the orphan genes in A. thaliana appear to have originated de novo [A. thaliana showed an altered phenotype when stressed, conferring either protection against, or serving as suppressors of, different abiotic stressors, notably oxidative and osmotic stresses [Fusarium graminearum genome [De novo genes are species-specific (orphan) genes that derive from DNA sequences that previously lacked coding potential . De novone birth . The orine birth ,165,166. de novo . Plant r de novo . For exastresses . A groupm genome . The rolEpigenetic modifications  are heritable alterations in gene expression patterns that occur without affecting the underlying DNA sequence and impacting the outcome of a locus or chromosome . Epigene3) group to DNA and is an epigenetic mechanism that controls gene expression. As part of the plant’s defensive system, DNA methylation due to pathogen infection was reported in many plant species such as Oryza sativa, A. thaliana, Nicotiana tabacum, Brassica rapa, Glycine max, Citrullus lanatus, and Aegilops tauschii [Arabidopsis, infection with P. syringae pv. tomato DC3000 led to DNA hypomethylation in several genomic regions, such as peri/centromeric repeats and Athila retrotransposon [Arabidopsis ago4  mutants feature reduced DNA methylation rates at different genomic locations and showed increased susceptibility to virulent P. syringae pv. tomato DC3000 [Arabidopsis ros1  mutant presented greater susceptibility to P. syringae pv. tomato DC3000, which corresponded with substantially elevated cytosine methylation in a TE (AtREP11) present in the promoter of an R gene (RMG1 or At4g11170) and consequently decreased gene expression [DNA methylation refers to adding a methyl  is carried out via HISTONE MONOUBIQUITINATION (HUB1) and HUB2 [SNC1 and RPP4 expression following P. syringae pv. tomato DC3000 attack [The transfer of ubiquitin to histone core proteins is known as histone ubiquitination. Histone ubiquitination, whether monoubiquitination or polyubiquitination, controls a series of cellular processes in plants. In and HUB2 , which c0 attack . Agrobacterium-mediated transformation is the best example of HGT. After transferring a segment of Agrobacterium DNA into the host’s genome, Agrobacterium induces neoplastic growth or unregulated cell division, leading to crown galls or growing roots [Magnaporthiopsis incrustans. The authors discovered two instances of exclusive sharing of HGT-derived gene markers between Magnaporthales and another lineage of plant–pathogenic fungi in the genus Colletotrichum. Yin et al. [Valsa mali, most of which were HGTs from bacteria, along with several others from eukaryotes. The non-sexual transfer of genetic material, either a single gene or whole chromosomes between unicellular and/or multicellular organisms and acceptor organisms without a parent–offspring relationship is known as horizontal gene transfer (HGT). ng roots . HGT plang roots . Studiesng roots ,199. Theng roots . In a prng roots  analyzedn et al.  identifiC. gloeosporioides [A. alternata [F.oxysporum f.sp. lycopersici to nonpathogenic F. oxysporum strains confers the pathogenicity of these strains towards tomato [HCT between two vegetative incompatible biotypes of orioides  and the lternata  are exams tomato .Brassica species. For example, chromosome B4 from Brassica nigra was introgressed into the rapeseed variety “Darmor” as a source of resistance against L. maculans  and led to high resistance [B. carinata to B. napus indicating high resistance against L. maculans [The process of interbreeding individuals of different varieties or species to produce a hybrid is called hybridization. Breeding programs have yielded extensive hybridization between individuals of the same or different plant species. The introgression of genes for disease resistance between species has been widely studied in sistance . Similarmaculans .B. carinata (donor) and B. oleracea to enhance resistance against Erysiphe polygoni (which can cause powdery mildew disease) [B. carinata to B. oleracea [Alternaria brassicae) from B. hirta to B. juncea [B. carinata to B. oleracea through embryo rescue followed by backcrossing to B. oleracea [Phytophthora clade 8b pathogenicity. Other cases of resistance transfer through hybridization include hybridization between disease) , the traoleracea , the tra. juncea , and theoleracea . From tholeracea  showed tR genes reflects altered pathogen resistance [P. infestans and Tecia solanivora in 4x potato was, moreover, observed using QTL analysis [V. inaequalis compared to diploid cultivars [Plectranthus esculentus) were more resistant to root-knot nematodes than diploids [P. infestans, which caused the Great Irish Potato Famine [Bremia lactucae by Fletcher et al. [B. lactucae. Heterokaryosis has phenotypic consequences on fitness that may include an increased sporulation rate and qualitative differences in virulence. Polyploidization, or whole-genome duplication, refers to the acquisition of extra sets of chromosomes in a cell or organism and frequently occurs in vascular plants. Polyploidization is an essential aspect of plant evolution and can significantly modify a plant’s genetic make-up, physiology, morphology, and ecology within one or more generations . Polyplosistance . For exasistance . Quantitanalysis . In a prultivars . Anotherdiploids . Pathogeo Famine . From tho Famine , which mr et al.  who repoR/pathogenicity genes to genetically improve crop species that are resistant to pathogens. In addition, genome editing, which is one of the most important biotechnological tools, has increased our biological knowledge and lead to rapid progress in agriculture and crop breeding. Furthermore, combined with pangenomics, genome editing facilitates functional and comparative analyses. Finally, we expect genomic variation to create a paradigm shift in resistance breeding and to help crop breeding achieve accelerated crop improvements to contribute to a food-secure world. In this context, efficient crop breeding programs and recent advances in genotyping and phenotyping will accelerate crop breeding and pave the way toward developing the next generation of disease resilient and high-performance crop varieties.As selective agents, pathogens play a crucial role in plant evolution. However, this role depends on the extent of genetic variation among resistance traits and their relationship with host robustness. Deciphering plant and pathogen genome content alongside the evolutionary relationships of ancestral species and their descendants can be beneficial in developing resistant varieties. Although our understanding of plant–pathogen interactions has advanced considerably in recent decades, there are still many questions regarding the role of genetic variation and mutational events in evolution and plant–pathogen interactions; for example, what are the key factors that influence genetic variation? How do genetic variation and mutational events lead to disease resistance? What form of genetic variation promotes disease resistance, and how does genetic variation add to breeding resistance and the development of pathogen-resistant crops for human food sustainability? To address these questions and to further advance our knowledge of plant–pathogen interactions and disease management, biomolecular and genomic research tools such as next-generation sequencing technology and functional genomics, various ‘omics’ technologies, and databases for metabolic modeling are essential . Omics t


Tiliqua (blue tongue skinks) as well as known predator species within the genera Varanus (monitor lizards). In addition to identifying significant variation in the natural responses of the coagulation cascade between species from the genera Tiliqua and Varanus relative to each other, as well as other vertebrate lineages, notable differences in venom activity were also observed. Within the genus Tiliqua, both T. rugosa and T. scincoides plasma displayed significant resistance to the procoagulant activity of Pseudechis porphyriacus venom, despite being susceptible to all other procoagulant elapid venoms. These results indicate that T. rugosa and T. scincoides have evolved resistance within their plasma to the coagulotoxic venom activity of the sympatric species P. porphyriacus. Other venoms were able to activate Tiliqua prothrombin, which suggests that the lessened activity of P. porphyriacus venom is not due to modifications of the prothrombin and may instead be due to a serum factor that specifically binds to P. porphyriacus toxins, as has been previously seen for squirrels resistant to rattlesnake venom. In contrast, none of the predatory lizards studied  demonstrated resistance to the venom. This suggests that the mechanical protection afforded by thick osteodermic scales, and prey handling behaviour, removes a selection pressure for the evolution of resistance in these large predatory lizards. These results therefore reveal differential interactions between venoms of snakes with sympatric lizards that are on opposite sides of the predator–prey arms race.Some Australian elapids possess potently procoagulant coagulotoxic venoms which activate the zymogen prothrombin into the functional enzyme thrombin. Although the activity of Australian elapid prothrombin-activators has been heavily investigated with respect to the mammalian, and in particular, human clotting cascades, very few studies have investigated the activity of their venom upon reptile plasmas. This is despite lizards representing both the primary diet of most Australian elapids and also representing natural predators. This study investigated the procoagulant actions of a diverse range of Australian elapid species upon plasma from known prey species within the genera  Boiga irregularis concluded it was non-venomous due to the lack of effects when tested on rodents [Denisonia genus identified that the known amphibian specialist D. devisi showed significant anticoagulant activity only upon amphibian plasma [Venom is a key evolutionary innovation underpinning the explosive radiation of advanced snakes. Previous research has indicated that venom specificity and potency is closely associated with a species’ dietary composition ,2. Venom rodents . However rodents ,5,6. Simn plasma .Bothrops jararaca has also been revealed to convey resistance towards thrombin-like enzymes [Venoms are evolutionarily selected to be prey-selective; there is a corresponding selection pressure for the evolution of resistance in prey and predators of venomous snakes. Such resistance may be accomplished in a myriad of ways. For example, two mechanisms of resistance to α-neurotoxins (steric hinderance and electrostatic repulsion) have been discovered, with both mechanisms involving modifications of the othosteric site of the nicotinic acetylcholine receptor α-subunit ,9,10,11. enzymes ,14. Conv enzymes .Austrelaps, Cacophis, Cryptophis, Demansia, Drysdalia, Furina, Hemiaspis, Pseudechis, Suta and Vermicella are all known to either primarily or exclusively feed upon reptiles [Australia is well known for its extraordinary diversity of reptilian fauna, which includes over 200 species of snakes from six families and over 800 species of lizards across seven families . In partreptiles ,18,19,20Oxyuranus/Pseudonaja clade when FVa was recruited as another venom component [Australian elapid snakes are unique relative to African, American, and Asian elapids in being potently procoagulant. This is due to the blood-clotting enzyme Factor Xa being recruited for use as a toxin at the base of the Australian snake radiation . FXa hasomponent . The difomponent ,23,24,25omponent .Ctenotus and Egernia skinks surviving high venom doses of Notechis, Pseudonaja and Acanthophis venom [Notechis scutatus and Tropidechis carinatus FXa venoms did not induce coagulation in Notechis scutatus or Pseudonaja textilis plasma, although were effective at clotting the plasmas of the outgroup species  and reticulated python ) [P. textilis was not clotted by N. scutatus or T. carinatus venoms, whereas P. textilis was able to clot its own plasma, thus demonstrating that auto-resistance is not always present [Only one study has been undertaken investigating the in vivo lethality of a range of Australian snake venoms upon prey classes which yielded intriguing results, such as species of is venom . Anotherulatus)) . The pla present .Pseudechis ssp) and brown snakes (Pseudonaja ssp) . Monitor lizards are anecdotally said to be resistant to snake venom effects, although no studies have investigated the effect of coagulotoxins upon monitor lizards; recent research has also shown that the Australian Varanus spp. lack any modifications in their nicotinic acetylcholine receptor orthosteric site, which would confer resistance to α-neurotoxins [V. giganteus and V. varius is due to the protection afforded by the thick scales which contain protective pieces of bone (osteoderms), as well as efficient prey handling which allows them to successfully predate upon elapids.Monitor lizards are generalist predators which have been routinely observed feeding upon snakes, including highly venomous species such as black snakes (rotoxins . This prTiliqua genus) or predators (monitor lizards in the Varanus genus). The results also shed light in differences in fundamental clotting parameters between the different lizard species included in this study.This study aimed to fill the knowledge gap concerning the actions of procoagulant Australian elapid snake venoms against sympatric prey and also against sympatric predators. We investigated the in vitro coagulotoxic activity of specific Australian elapid species by determining the effects of their venom upon the clotting ability of plasma from sympatric species which may represent either prey  formed clots at similar speeds but were over twice as strong. It is important to note that although D. psammophis is a skink specialist and sympatric to T. scincoides, even juvenile T. scincoides would likely be too large to predate upon, and potentially the coagulation factors present in T. scincoides plasma are significantly divergent to the smaller skink species D. psammophis favours, leading to the variation in clot strength.a plasma A. Althoutextilis ,31. Demar venoms . This waTiliqua species was the weak action of P. porphyriacus venom (P. porphyriacus was much weaker upon Tiliqua plasma (V. varius plasma (D. psammophis (p < 0.0001), C. nigrescens (p < 0.0001) and P. textilis (p < 0.0001) in comparison to P. porphyriacus venom. Analysis also confirmed the statistically significant difference that the procoagulant activity of P. porphyriacus was significantly weaker upon T. rugosa plasma compared to P. affinis (p < 0.0001) and P. textilis (p < 0.0001). These results are highly suggestive of venom resistance in Tiliqua plasma towards the procoagulant toxins present in the venom of P. porphyriacus. In contrast, both Tiliqua species were much more strongly affected by small sympatric species  that share the FXa venom phenotype, or venoms which were of the FXa:FVa venom phenotype (Pseudonaja venoms)  . The venPseudechis porphyriacus are sympatric to T. scincoides, as well as other Tiliqua spp., across a large extent of their distribution [T. scincoides being a slow-moving, vulnerable prey-item, they are recorded as infrequent prey of P. porphyriacus [T. scincoides against P. porphyriacus venom. Tiliqua rugosa was also less affected by P. porphyriacus venom than other procoagulant venoms, perhaps indicating that a recent common ancestor developed resistance which has been retained to a greater extent by T. scincoides. Evidence which further supports that the slower action of P. porphyriacus is not a general limitation of this venom against lizards, but resistance exerted by Tiliqua species, is the rapid procoagulant effect P. porphyriacus venom exerted upon V. varius plasma  and P. porphyriacus (p = 0.1735) produced strong clots in the plasma of V. giganteus and V. varius, respectively, whereas the clot induced by C. nigrescens (p < 0.0001) was significantly weaker on V. varius plasma (P. ingrami (p < 0.0001) and P. mengdeni (p < 0.0001) produced very weak clots in V. giganteus plasma, as did P. textilis (p < 0.0001) for V. varius  to induce a strong clot was observed across both ematicus . Thus, tP. ingrami and P. textilis, which were pooled samples sourced from Venom Supplies, South Australia. Tested were the FXa venoms Cryptophis nigrescens , Demansia psammophis , and Pseudechis porphyriacus . Additionally, tested were the FXa:FVa venoms Pseudonaja affinis , Pseudonaja aspidorhyncha , Pseudonaja ingrami , Pseudonaja mengdeni , and Pseudonaja textilis . Original venom extractions were flash-frozen, lyophilized, and stored at −80 °C. Using a NanoDrop2000 UV-Vis Spectrophotometer  to determine venom concentrations, venom working stock solutions were made at a concentration of 1 mg/mL in 50% glycerol and 50% double-deionised water (DDH2O) and stored at −20 °C until required to preserve enzymatic activity. Calcium chloride , kaolin , phospholipid  and Owren-Koller buffer  were supplied by Stago .All venom work was conducted under University of Queensland Biosafety Committee Approval # IBC/134B/SBS/2015 and venoms were individually sourced from the long-term cryogenic research collection of the Venom Evolution Lab, except for Tiliqua rugosa plasma was collected from seven individuals, T. scincoides plasma was collected from nineteen individuals, V. mertensi plasma was available only from a single individual, V. giganteus plasma was from two individuals, and V. varius plasma from three individuals. Gallus gallus plasma was pooled from nine individuals and collected at the University of Queensland Gatton Campus. Rhinella marina plasma was a pooled sample from thirty-five wild-caught individuals. Rattus norvegicus plasma was supplied by Animal Resources Centre Western Australia, and was a pooled sample from twenty-five individuals. Pooled human plasma was supplied by the Australian Red Cross Blood Service and stored at −80 °C.All plasma work was conducted under University of Queensland Biosafety Committee Approval # IBC/149B/SBS/2016 and Animal Ethics Committee Approval #2020/AE000324. All reptile plasma was collected from captive, healthy adult individuals during routine veterinary health checks. Plasma was collected from the caudal vein and pooled from multiple individuals when possible. 2O in the replacement of venom. Where possible, only sympatric species of venom were tested upon plasma, although D. psammophis venom was used upon the plasma of V. giganteus because venom was not available from any species of Demansia sympatric to V. giganteus.Thromboelastography was utilised to test the in vitro viscoelastic clotting properties of plasma in the absence and presence of venom. Thromboelastography assays were adapted and utilised from previously published protocols ,37,38. FAll investigations were conducted in triplicate. All data in this study were analysed using Prism 9.0 software . One-way ANOVAs with multiple comparisons were conducted to assess statistical significance throughout the study. Potent procoagulant activity was considered in this study as venom activity which caused clotting to occur in less than 50 s. All raw data is available in


Shewanella algae is widely distributed in marine and freshwater habitats, and has been proved to be an emerging marine zoonotic and human pathogen. However, the genomic characteristics and pathogenicity of Shewanella algae are unclear. Here, the whole-genome features of 55 S. algae strains isolated from different sources were described. Pan-genome analysis yielded 2863 (19.4 %) genes shared among all strains. Functional annotation of the core genome showed that the main functions are focused on basic lifestyle such as metabolism and energy production. Meanwhile, the phylogenetic tree of the single nucleotide polymorphisms (SNPs) of core genome divided the 55 strains into three clades, with the majority of strains from China falling into the first two clades. As for the accessory genome, 167 genomic islands (GIs) and 65 phage-related elements were detected. The CRISPR-Cas system with a high degree of confidence was predicted in 23 strains. The GIs carried a suite of virulence genes and mobile genetic elements, while prophages contained several transposases and integrases. Horizontal genes transfer based on homology analysis indicated that these GIs and prophages were parts of major drivers for the evolution and the environmental adaptation of S. algae. In addition, a rich putative virulence-associated gene pool was found. Eight classes of antibiotic-associated resistance genes were detected, and the carriage rate of β-lactam resistance genes was 100 %. In conclusion, S. algae exhibits a high intra-species diversity in the aspects of population structure, virulence-associated genes and potential drug resistance, which is helpful for its evolution in pathogenesis and environmental adaptability. The sources and genomic sequences used throughout this study have been deposited in the National Centre for Biotechnology Information (NCBI), under the assembly accession numbers provided in Tables S1 and S2 (available in the online version of this article).S. algae have become dominant species associated with human and aquatic livestock disease in the genus of Shewanella. Cases of bacteremia, sepsis, and infective endocarditis have also been reported. However, the evolution, biodiversity and pathogenic potential of S. algae are poorly understood. Through a comparative pan-genomic analysis of S. algae strains, we identified new pathogenic genomic islands, prophages, and virulence factors, suggesting that independent acquisition of these mobile genetic elements could play an important role in the evolution and virulence of S. algae. This study provides important insights into intra-species divergence and environmental adaptability underlying genomic sequences. The relationship between genome features and environmental adaptation strategies is an essential part for understanding the ecological functions of S. algae in the marine environments. The investigation of bacterial resistance shows that S. algae plays an important role as a reservoir of antibiotic resistance genes in the nature, which provides a scientific basis for surveillance and control of infectious diseases caused by S. algae.Shewanella spp. are Gram-negative, oxidase-positive, H2S-producing, facultative anaerobe bacteria that are ubiquitously distributed in seafood, marine and freshwater environments, even in deep-sea and polar regions [Shewanella spp. are characterized by prominent biodiversity, and they have evolved to develop complex lifestyles. The most outstanding ecological functions are bioremediation and application in the microbial fuel cells production [Shewanella [http://www.bacterio.net/shewanella.html). regions . Shewaoduction . Variousanella . At the Shewanella algae and Shewanella putrefaciens have been identified as opportunistic pathogens [Shewanella spp. have raised the concern of microbiologists. Reported illnesses included skin and soft tissue infections, otitis media and bacteremia. By 2012, over 50 case reports of human infection caused by the genus Shewanella had been found in PubMed database [Shewanella infections in literature has already exceeded 300. Recent advances in the taxonomy and phylogenetic relatedness of Shewanella spp. supported the concept that most human infections were caused by S. algae [Despite the beneficial roles, some species like athogens . The pro algae .Shewanella [et al. discovered multidrug-resistant (MDR) plasmid in S. xiamenensis [Shewanella spp. were resistant to different antibiotic classes, including β-lactams, quinolones and aminoglycosides. However, the genetic characterization of antimicrobial resistance in Shewanella spp. remains limited.Currently, multidrug resistance has been increasingly reported in the genus anella . Severalnensis . ShewaShewanella are sequenced, there are more studies focused on the whole genus rather than specific species. Fang et al. have constructed multilocus sequence analysis (MLSA) methods to accurately identify Shewanella strains at the species level [et al. used the whole-genome sequencing to redefine Shewanella taxonomy [Shewanella, S. algae is still largely unknown for its genomic characteristics, virulence factors and antimicrobial resistance. Therefore, in this study, we sequenced the genomes of 12 new S. algae strains and combined the genome sequences of 43 S. algae strains from public databases, to illustrate the intra-species hereditary and present a comprehensive analysis of S. algae.In recent years, the rapid development of high-throughput sequencing technology has brought opportunities for the genetic research of pathogens . The impes level . Thorelltaxonomy . As a prS. algae strains were used in this study, including 43 strains from public database (genomes with less than 200 contigs were selected) and 12 newly sequenced strains isolated from different sources in China . These strains were isolated from China , Tanzania , Korea , Peru , France , Japan , USA , Argentina , and unknown regions , respectively. Also, according to the sources of isolation, there were 32 clinical strains and 23 environmental strains. It is worth noting that the S. haliotis strain JCM 14758 from GenBank was included, because S. haliotis has been recently identified as a synonym of S. algae by the previous research [A total of 55 http://www.bioinformatics.babraham.ac.uk/projects/fastqc/) was used to evaluate the quality of the reads [de novo (version 2.04) was used to assemble the clean data of each strain [The genomic DNA was extracted by Wizard Genomic DNA Extraction Kit  following the manufacturer’s instructions. The HiSeq sequencer  was used to perform 250 bp paired-end whole-genome sequencing with 150× coverage. FastQC  [*.gff output files for each sample. Roary pan-genome pipeline [The genomes of 55 on 1.12)  was usedpipeline  with an http://github.com/sanger-pathogens/gubbins) was used as a recombination-removal tool to reorganize the core genome. PhyML (version 3.1) [https://github.com/gtonkinhill/fastbaps) by a fast hierarchical Bayesian analysis [Coding sequences prediction was carried out using Prodigal (version 2.6.3) . Then a ion 3.1)  was usedanalysis .http://www.pathogenomics.sfu.ca/islandviewer/) is a widely-used webserver for the prediction and interactive visualization of GIs . It integrates with IslandPath-DIMOB, SIGI-HMM and IslandPick to make accurate and complementary GI predictions [http://phaster.ca) was used for rapid identification and annotation of prophage sequences in bacterial genomes and plasmids. An online search was performed against a custom prophage/phage database containing protein sequences from NCBI phage database developed by Srividhya et al. [http://www.genomicepidemiology.org/). CRISPRCasFinder (https://crisprcas.i2bc.paris-saclay.fr/CrisprCasFinder) was used for the detection of CRISPRs  and Cas (CRISPR-associated proteins) genes in the submitted sequence data. A blast comparison was performed against NCBI-NR database using the protein sequences of strain-unique genes with default parameters. The R package of plotrix was used to form the flower plot of unique genes.Accessory genes were analysed using three online databases with default parameters. IslandViewer   was usedhttp://arpcard.mcmaster.ca). The parameters of BLAST+ were an E-value of 1e-5, the percentage of sequence identity ≥80 % and the percentage of length coverage ≥80 %.Potential antimicrobial resistance genes were predicted by Comprehensive Antibiotic Research Database (CARD) , intermediate (I), and drug resistance (R) were interpreted according to the Enterobacteriaceae standards of the American Committee for Clinical Laboratory Standardization (CLSI) [Escherichia coli ATCC 25922 was used as a control for chloramphenicol, tetracyclines, sulfonamides, and trimethoprim-sulfamethoxazole.The Antimicrobial Susceptibility Testing (AST) panel for aerobic Gram-negative bacilli  was used to perform the antimicrobial susceptibility testing by the micro-broth dilution method. Each antibiotic has a concentration gradient on the drug sensitive plate. The bacteria suspension was added to the plate, and then after an incubation period of 18 to 20 h, the results were interpreted. The minimal inhibitory concentration (MIC) values were obtained. There is no CLSI breakpoints for n (CLSI) . EscheT/ATCC 51192/CECT 5071; JFC3/RC/YTH).The genome sizes of the 55 strains ranged from 4.60 Mb (strain CLS3) to 5.20 Mb (strain KC-Na-R1), and the G+C content ranged from 52.5 mol% to 53.1 mol%. The general information of the 55 genomes was summarized in Table S2. Based on the matrix of ANI values, the dendrograms were drawn . The ANIS. algae strains, were found, with the CDSs ranging from 4105 (strain CLS3) to 5694 (strain C6G3)  . Among tin C6G3) .S. algae strains (n=22), followed by clade 2 (n=18) and clade 3 (n=15). Among the 38 strains isolated from China, 31 strains were clustered in clade 1 and clade 2. Most strains derived from clinical patients appeared to be clustered in clade 2. The distribution of pairwise SNP distances  showed that most isolates in clade 2 had a closer pairwise evolutionary relationship than those in clade 1 and clade 3.A robust core genome sequences based ML-tree was inferred to investigate the phylogenetic relationship of the 55  strains . Three cS. algae JCM 21037T and three strains of other Shewanella spp. with the closed genetic relationships  was performed, according to the report of Thorell et al. [S. algae JCM 21037T, S. carassii 08MAS2251T, S. chilikensis KCTC 22540T and S. indica KCTC 23171T strains shared 2478 core genes  were detected. The detected genes were related to virulence, metabolism, resistance, structure, fitness factors, modification-restriction systems, transport and toxins. GIs related to mobile element protein, integrase, transposase, acetyltransferase and transcriptional regulator were found in all six strains. Multidrug resistance transporter and heat shock protein were found in both RQs-106 and VGH117.One hundred and sixty-seven GIs from six complete genomes of S. algae strains (Table S4). The detection of the presence of fitness factors encoded inside these sequences showed that 19 sequences carried transposase-like elements and 15 sequences contained integrase-like elements linked to horizontal gene transfer.Sixty-five different prophage-related elements were detected, in which four genomes  had intact prophages. Specifically, 40 (61.5 %) prophage-related sequences with the length between 4.4 and 42 kb were unique in 24 strains (Table S3), while five prophage-related sequences were shared by Plasmids were found in six strains, in which four strains were isolated from clinical specimens and the remaining two were sourced from environment. Three types of plasmid replicons were predicted. The information about the antimicrobial resistance genes and the functions of products encoded by the virulence-associated genes were described. The strains 18064-CSB-B-B and CCU101 appeared to carry resistance-transfer factors (RTFs). For complete genomes (18064-CSB-B-B and CCU101), the plasmid lengths were defined, otherwise the plasmid replicons were just localized. The detailed information was shown in Table S5.S. algae genomes. Two Cas types were detected, namely Cas-TypeIE for strains NCTC 10738, JFC2, JFL, SYT2 and CHL, and Cas-TypeIF for the others. The number of spacer sequences contained in CRISPR varied greatly among different strains. Specifically, strain C6G3 only harboured CRISPR sequences but not Cas clusters. The detailed information was shown in Table S6.Credible CRISPR-Cas system (evidence level=4) was predicted in the entire S. algae strains ranged from one to 813 (P>0.05).A large number of CDSs were annotated as hypothetical proteins. The number of unique genes in the 55 e to 813 . The stre to 813 , and 106e to 813  . The prophage-related element, playing the role of transposase, was detected in strain 18064-CSB-B-B isolated from poultry stool. Interestingly, this prophage-related element was found to be very similar to those in E. coli AR435 and Salmonella SL131 by blast homology comparison , aminoglycosides -Ib, aph(6)-Id, ant(2'')-Ia, aadA2), quinolones (qnrA), phenicols , macrolides (erm), sulfonamides , tetracyclines (tet), lincosamides (vga) were detected by BLAST+ against the database. The blaOXA gene was located in all strains with the major genotype of blaOXA-SHE (81.8%). Thirty-six strains carried qnr with the most common genotype of qnrA3. The environmental strain KC-Na-R1 carried the highest number of antimicrobial resistance genes, which indicated a capacity to resist multiple antibiotics. The genetic environments of identified resistance genes had been analysed. Twenty-two strains had mobile genetic elements (MGEs) in the upstream and downstream 10 kb sequences of resistance genes. The resistance genes possessed by strain KC-Na-R1 had the most abundant MGEs in its genetic environment. The detailed information was shown in the Table S8.We found genes associated with the resistance to eight antibiotics in the  genomes . The genThe antimicrobial susceptibility of 12 clinical strains was shown in Table S9. All strains were resistant to cefazolin, but sensitive to minocycline, amikacin, cefepime, meropenem, doxycycline, minocycline, gentamicin, kanamycin, streptomycin. Also, these strains were sensitive to four kinds of aminoglycosides . Six strains isolated from patients of Laizhou, China in 2015 were multi-drug resistant (insensitive to three or more types of antibiotics).S. algae at the intra-species level by sequencing 12 new S. algae strains and performed pan-, core- and accessory-genome analysis together with another 43 S. algae strains available in GenBank.Our study firstly provided a finer-scale comparison of S. algae has great diversity in terms of genomic characteristics. The phylogenetic tree based on core genome demonstrated that the 55 S. algae strains were clustered into three separate clades, with most strains in China in clade 1 and 2. Compared with the report by Fang et al. [S. algae in our study was consistent with the topological structure and evolutionary relationship of the phylogenetic tree constructed by MLSA method. When comparing the type strain of S. algae with those of other phylogenetically closed Shewanella species based on genome alignments, we observed that there were a large number of rearrangement and duplication events within different Shewanella species. The COG function annotation showed that the unique genes of S. algae were mainly related to signal transduction and transcription mechanisms, which may also indicate that accessory genes, especially the unique genes acquired from different environments, could be important for S. algae strains to increase their survival ability .Pan-genome analysis explored the gene pool, unique genes and functional information underlying bacterial diversification. The number of accessory genes was 5.2 times that of core genes, which demonstrated that g et al. , the phyS. algae is not clear. Wu et al. found homologous genes of hlyA, hlyB, hlyD and tolC in the genome of S. algae STY3, which encoded hemolysin and transport functions, and speculated that the hemolytic activity may be an important virulence factor of S. algae [et al. confirmed that S. algae begins to produce tetrodotoxin after 12 h of culture [S. algae strains isolated from food poisoning specimens by Wang et al., which suggests the possibility of TTX as a pathogenic substance of S. algae [et al. have discovered and proposed candidate virulence factors of S. algae, including hemolysin, the type VI secretion system (T6SS), microbial collagenase, DNase, type IV pili, curli, twin-arginine translocation system, ClpP and urease [Currently, the pathogenic mechanism of  algae . Gallach culture . Also, T algae . Alazea d urease .S. algae, 142 potential virulence-associated genes were extracted against the VFDB online database, showing a rich diversity of virulence-associated factors. There were significant differences in the virulence genes carried by strains in different groups  HlyA in E. coli [S. algae. In addition, the common genes related to type IV pili, which are regulated by external stimuli for directed movement, provided a fresh perspective on pathogenicity [vasF, which was related to VAS type VI secretion system (T6SS), was specific for S. algae strains in group 2  contained urease-related genes ureB and ureG. Fu et al. demonstrated that the products of ureB and ureG genes are important virulence factors of Vibrio harveyi and enhance the pathogenicity to fish [et al. confirmed ureG gene could encode urease, which was essential for the colonization of Helicobacter pylori in stomach [Brucella spp. also show strong urease activity. The products encoded by ureB and ureG are involved in protecting Brucella spp. from gastric acid and thus contribute to the pathogenicity [S. algae. O-antigen, a virulence factor of Gram-negative bacteria, is the outermost structure of lipopolysaccharide. O-antigen is important for environmental adaptability because it is the main target of bacteriophages and the host immune system. O-antigen can induce a strong immune response in the host [S. algae strains, suggesting that there may be minimal difference between clinical and environmental stains in terms of virulence-associated genes. Thus, we inferred that the pathogenicity of S. algae is affected by many factors such as complex interaction between the host and the environment, which is in accordance with the report of Janda et al. [Different bacteria in the gut flora could compete with other species through contact-dependent mechanisms, such as the T6SS. For example,  ability . Vibribacteria . In thisthe host . Most ofsistance . In our philia . Our stu to fish . Also, M stomach . Most Brgenicity . Therefothe host . In our S. algae is a dominant human pathogen in the genus Shewanella when people are exposed to marine niches containing this pathogen through occupational or recreational activities. Documented illnesses linked to S. algae included skin and soft tissue infections, bacteremia, and otitis media. Generally, S. algae mostly infect people with an impaired immune system [S. algae, which suggests that most S. algae strains may only cause opportunistic infections. Accordingly, we could reasonably speculate that the infection of S. algae is a preliminary condition rather than a decisive factor for human disease, and the pathogenic process is the result of the synergistic effect of multiple factors.It is increasingly agreed that e system . Also, wHalomonas meridiana Eplume2 and Alcanivorax N3-2A. Also, two GIs, which were detected in strains RQs-106 and CCU101 respectively, were highly homologous to those in Aeromonas hydrophila ONP3.1 and Marinobacter hydrocarbonoclasticus VT8 respectively. The sequences of prophage-related elements detected in strain 18064-CSB-B-B were 100 % similar to those in E. coli AR435 and Salmonella SL131. The GIs carried a suite of virulence genes and mobile elements, and the prophages contained genes encoding transposase and integrase. The horizontal gene transfer across species breaks down the boundaries of kinship and makes gene flow more complex. Therefore, we speculated that the cross-species gene transfer caused by GIs or prophage-related elements contributes to the evolution and independent acquisitions of virulence factors of S. algae. In addition, strains 2NE11, VGH117 and RQs-106 harboured GIs that encode several acyltransferases. Acyltransferases are enzymes which transfer acyl groups to specific targets and may be an important factor regulating the production of virulence factors, motility and biofilm formation.GIs harbouring a cluster of genes, are defined as probable horizontal origins in bacterial or archaeal genomes . As one The CRISPR-Cas system is a prokaryotic adaptive immune system which has evolved to get rid of foreign invading genes from viruses. The system is found in many bacteria, showing great complexity and diversity . In our Shewanella was a reservoir for MCR-4 mobile colistin resistance [S. algae was the source of plasmid-mediated QnrA determinants [Shewanella spp. with environmental or clinical origins, highlighting that the genus is probably a vehicle and a reservoir of antibiotic resistance genes [S. algae strains were found to carry antibiotic resistance genes, among which the carriage rate of blaOXA gene was 100 %, and that of qnr gene followed. It is worth noting that the plasmids of strains 18064-CSB-B-B and CCU101 were proved to carry RTFs, which contribute to the spread of antibiotic-resistance genes. Over the past few years, various investigations have extensively reported drug-resistant (XDR) Shewanella species from environmental and human infection samples, like XDR S. xiamenensis . Among the 55 S. algae strains in our study, 67.3 % contained genes associated with resistance to more than one class of antibiotics (strain KC-NA-R1 carried the most number: 14). In addition, clinical strains have a higher frequency of carrying resistance genes of aminoglycosides (21.9%) compared with environmental strains (8.7 %), which may reveal an early warning for clinical surveillance and treatment of S. algae infection, since aminoglycosides are more often preferred in the treatment of severe infection caused by aerobic Gram-negative bacteria.Related literature reported that the aquatic bacterium sistance , and Srminants . A variece genes . These get al. discovered that the blaA gene was strongly induced by ampicillin at high (50 µg ml−1), but not at low levels (2.5 µg ml−1) [It is worth noting that, the drug-resistant phenotype of the 55 strains in our study did not match the drug-resistant genes carried in their genomes. Several reasons may account for this phenomenon. First, the genomes of most strains were not complete so the drug-resistant genes may be interrupted. Also, although the antimicrobial resistant phenotypes were determined by the corresponding genotypes, there was no absolute consistency between them . Jianhuaµg ml−1) . These rClick here for additional data file.