Campylobacter jejuni (C. jejuni), Mycoplasma pneumoniae, and cytomegalovirus. C. jejuni is responsible for about a third of GBS cases. GBS due to C. jejuni is usually more severe than that due to other causes. Clinical presentation of GBS is highly dependent on the structure of pathogenic lipo-oligosaccharides (LOS) that trigger the innate immune system via Toll-like-receptor (TLR)-4 signalling. AIDP is due to demyelination, whereas in AMAN, structures of the axolemma are affected in the nodal or inter-nodal space. In conclusion, GBS is a neuro-immunological disorder caused by autoantibodies against components of the myelin sheath or axolemma. Molecular mimicry between surface structures of pathogens and components of myelin or the axon is one scenario that may explain the pathophysiology of GBS.Guillain–Barré syndrome (GBS) is a rare immune-mediated acute polyradiculo-neuropathy that typically develops after a previous gastrointestinal or respiratory infection. This narrative overview aims to summarise and discuss current knowledge and previous evidence regarding triggers and pathophysiology of GBS. A systematic search of the literature was carried out using suitable search terms. The most common subtypes of GBS are acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). The most common triggers of GBS, in three quarters of cases, are previous infections. The most common infectious agents that cause GBS include  Guillain–Barré syndrome (GBS) is a rare immune-mediated acute polyradiculo-neuropathy that typically develops after previous gastrointestinal or respiratory infection, which is why it is also referred to as post-infectious polyneuropathy ,2. It caClinical presentations of GBS are highly variable.Different subtypes of GBS are defined according to clinical presentation and findings from nerve conduction studies (NCSs) . The most common of these subtypes, particularly in the western hemisphere, is acute inflammatory demyelinating polyneuropathy (AIDP). The most common subtypes in the eastern hemisphere are acute motor axonal neuropathy (AMAN) and acute motor and sensory axonal neuropathy (AMSAN). Other subtypes include Miller–Fisher syndrome (MFS) , flail arm syndrome, flail leg syndrome, the pharyngo-cervico-brachial  subtype, mononeuritis cranialis (MNC), polyneuritis cranialis (PNC), acute bulbar palsy (ABP), and brainstem Bickerstaff encephalitis (BBE) ,2.The clinical presentation of GBS is diverse, depending on the GBS subtype. In most cases, GBS presents with progressive ascending muscle weakness of the limbs with or without involvement of sensory or autonomic fibers. Occasionally, axial, facial, or respiratory muscles are also affected. Tendon reflexes are usually reduced, but hyperreflexia has occasionally been reported . HyperreCerebrospinal fluid (CSF) investigations may show “dissociation cyto-albuminique”: a hallmark of GBS. CSF glucose and lactate are usually normal, and oligoclonal bands are negative. CSF tests can be normal at onset; therefore, normal findings in CSF investigations do not rule out GBS.Application of NCSs may show increased distal latencies of motor nerves, reduced nerve conduction velocities (NCVs) of motor or sensory nerves, or reduced amplitudes of compound muscle action potentials (CMAPs) or sensory nerve action potentials (SNAPs) . When seT1-weighted MRI with contrast medium of the cervical or lumbar spine can show thickening and enhancement of nerve roots or the cauda equine . T1-weigMycoplasma-pneumoniae-related AIDP are directed against galactocerebroside [Ganglioside antibodies are directed against gangliosides  that are predominantly located at the nodes of Ranvier and at nerve terminals . GM1-antebroside .The disease course is usually monophasic but can undulate. In up to one third of cases, respiratory muscles are involved, necessitating mechanical ventilation in up to one quarter of cases.There are no mandatory criteria for diagnosing GBS, but several approaches have been taken to provide efficient diagnostic criteria. These approaches led to the development of the Asbury and Cornblath criteria , the AshThe incidence of GBS is reported as 1–2/100,000/y . In thisCampylobacter jejuni (C. jejuni), Epstein–Barr virus (EBV), cytomegalovirus (CMV), or influenza in about two thirds of cases [C. jejuni and Mycoplasma pneumoniae [C. jejuni in 30%, M. pneumoniae in 10%, CMV in 4%, hepatitis-E in 3%, and EBV in 1% [C. jejuni infection [C. jejuni infection was more severe and required a longer time to regain the ability to walk independently [C. jejuni-positive patients [C. jejuni (27%), influenza-A (17%), influenza-B (16%), hepatitis-A (5%), dengue virus (3%), CMV (3%), EBV (3%), M. pneumoniae (2%), HSV (2%), VZV (1%), and rubella virus (1%) [Haemophilus influenzae, and Zika virus was negative [Infections are the most common triggers of GBS, preceding GBS in 75% of cases . Bacteriof cases . By far,eumoniae . The moseumoniae . An analBV in 1% . Six perBV in 1% . SymptomBV in 1% . ProportBV in 1% . The sennfection . GBS witendently . The purpatients . Time topatients . About hpatients . In a strus (1%) . Serolognegative .BacteriaCampylobacter jejuniC. jejuniCharacteristics of C. jejuni is a microaerophilic, oxygen-sensitive, gram-negative, and non-spore-forming bacterium of the genus Campylobacter and a common cause of gastroenteritis in humans [C. jejuni is unusual for an intestinal pathogen in its ability to coat (envelop) its surface with a polysaccharide capsule (CPS) [C. jejuni serotypes [n humans . The genle (CPS) . CPSs vale (CPS) . CPSs arle (CPS) . Structuerotypes . Differeerotypes .Transmission to humansC. jejuni to humans is usually through food consumption: particularly consumption of raw or undercooked poultry meat; unpasteurised, contaminated milk; or water-based environmental sources [C. jejuni colonises the distal ileum and colon [Transmission of  sources . After und colon .C. jejuniDiseases and complications caused by C. jejuni can cause various human diseases. The most common human disease caused by C. jejuni is foodborne enteritis. C. jejuni is the leading bacterial cause of foodborne gastroenteritis in developed countries [Campylobacter spp. are the leading cause of bacterium-derived gastroenteritis worldwide, affecting about 100 million individuals annually [C. jejuni, C. coli, and C. upsaliensis [C. jejuni is also considered the most common cause of GBS [C. jejuni infections are irritable bowel syndrome [ountries . Campyloannually . In contannually . In Germannually . The mosaliensis . Enteropaliensis . Infectie of GBS . Other csyndrome , reactivsyndrome , and Achsyndrome .PathophysiologyImportance of Lipo-OligosaccharidesC. jejuni infection is highly dependent on the structure of the pathogenic LOS, which trigger the innate immune system via Toll-like-receptor (TLR)-4 signalling [C. jejuni is explained by “molecular mimicry” between surface LOS antigens and ganglioside antigens (ceramides) on the surface of myelin sheaths or the axolemma. LOSs are an integral part of the C. jejuni cell membrane, with a structure of core oligosaccharides forming inner and outer core regions and a lipid-A moiety [Post-infectious morbidity of human gnalling . Toll-liA moiety . Outer mA moiety .C. jejuni strains elicit antibodies that recognise both bacterial molecules and gangliosides. They also elicit recognition of the latter biomolecules, which are abundantly expressed in the nervous system, where they are involved in neuro-transmission and cause neurological dysfunction [C. jejuni often produce structures that mimic the oligosaccharide moieties of GM1a and GD1a [Helicobacter pylori contributes to the pathophysiology of GBS remains unclear, but there is evidence that Helicobacter pylori antibodies are more common in GBS patients than in controls [Clinical and serologic data support a model in which LOSs of specific function . LOSs ofand GD1a . In addiand GD1a . Whethercontrols .The Classical Immune MechanismC. jejuni LOS antigens towards the cellular and humoral immune system induces release of C1q, macrophage activation, and production of antibodies in plasma cells. Due to molecular mimicry, these antibodies not only target LOS on C. jejuni but also ganglioside moieties on myelin or axons of peripheral nerves after crossing the blood nerve barrier (molecular mimicry) [C. jejuni without molecular mimicry of self-antigens, exist [Exposure of mimicry) . Howevers, exist . Accordis, exist . Complems, exist . Macrophs, exist . Infiltrs, exist . Alternas, exist . Whethers, exist .Alternative MechanismsC. jejuni. This interaction induces T-cell differentiation and autoantibody elicitation [Another pathophysiological mechanism that explains autoimmune demyelination of peripheral axons is interaction of the central antigen-presenting cell receptor Siglec-1 with the sialylated LOS motifs found specifically on surfaces of GBS-associated citation . In a mocitation .NOD1 genes were suspected to play a role in the pathophysiology of GBS [NOD1 and NOD2 genes conferred no risk to susceptibility or severity of GBS [Furthermore, nucleotide oligomerization domain (NOD) proteins, which are cytoplasmic receptors, seem to play an important role in host-innate immune responses to pathogens . NODs rey of GBS . Howevery of GBS .Difference between Axonal and Demyelinating LesionPathophysiology differs between demyelinating and axonal subtypes of GBS . AMAN isC. jejuni StrainsVariable Pathogenicity of C. jejuni is different between its various strains. The risk of GBS is estimated to be at least six times higher with strain C. jejuni Penner serotype HS:19 than is the average risk [C. jejuni HS:19 [Pathogenicity of age risk . The reaage risk . Additioni HS:19 .C. jejuni strains belonging to ST-2993, obtained from GBS patients during the large outbreak of GBS in Peru in 2019 and compared with four chicken C. jejuni strains via Illumina technology, LOS genes that were related to molecular mimicry with gangliosides in peripheral nerves were detected [LOS locus genes related to molecular mimicry with gangliosides in peripheral nerves [C. jejuni strains indicated chickens as a probable reservoir [In a study of 71 detected . Phylogel nerves . In addil nerves . The cloeservoir . Comparaeservoir .Why One Contracts GBS and Another Does NotThe question of why one can contract GBS from infection and another will not is unresolved. However, some speculations can be made to answer this question.One explanation could be that coinfections are required to trigger the development of GBS. Since 6% of the GBS patients in the IGOS study showed co-infections , it is cC. jejuni has been largely ruled out.A second explanation could be that the immune reaction against associated bacteria is different in each individual due to genetic differences of the immune system. In a recent study that examined 422 GBS patients for polymorphisms rs153109 and rs785575 in interleukin 27 (IL-27), the G-allele of the rs153109 polymorphism was found to be more common in GBS patients than in controls . PatientC. jejuni were excluded.A third explanation could be that the blood nerve barrier is more permeable in some patients than in others. However, little evidence supports this assumption. Speculations that an immunoglobulin deficiency could explain the variable pathogenicity of C. jejuni genome. This decreases its phenotypic stability through reversible changes in the ON or OFF expression states they are in: a phenomenon called phase variation [C. jejuni [A fourth explanation could be high variability of surface antigens due to the relatively large number of hypermutable simple sequence repeat (SSR) tracts in the ariation . SSRs ar. jejuni . The pre. jejuni . ControlA fifth explanation could be variable affinity of antibodies to gangliosides . HoweverMycoplasma pneumoniaeMycoplasma pneumoniae [M. pneumoniae does not vary from that of GBS caused by to C. jejuni. It has been postulated that M. pneumoniae triggers GBS due to bacterial production of galacto-cerebroside [M. pneumoniae-associated GBS are similar to treatment and outcome of GBS triggered by alternative causes.Several cases have been reported showing that GBS can be preceded by pneumonia due to eumoniae . The cliebroside . TreatmeHaemophilus influenzaeHaemophilus influenzae has been rarely reported. In most of these cases, causality was suspected but confirmed only by exclusion of alternative causes [Haemophilus influenzae [Haemophilus influenzae was also reported in a 65-year-old male who developed quadriparesis one week following pneumonia [GBS following an infection with e causes . In a 24fluenzae . GBS trineumonia . His recneumonia .Erlichia chaffeenensisErlichia has been reported only in one patient [GBS triggered by an infection with  patient . A 71-ye patient . Despite patient . She sta patient .Orientia tsutsugamushiOrientia tsutsugamushi is the causative agent of scrub typhus [b typhus . Clinicab typhus . Meningob typhus . In a 7-b typhus . Single VirusesViruses are well-known causes of GBS. Types of viruses that triggered GBS varied significantly between cohorts investigated and depended strongly on presence or absence of a virus epidemic.Cytomegalovirus (CMV)In a retrospective study of 86 GBS patients from Italy, 6% of patients had a concomitant infection with CMV . CMV-relZika VirusDuring the 2013–2016 outbreak in the Americas and the Pacific, Zika virus infection also resulted in GBS . In one SARS-CoV-2n = 118), AMAN (n = 13), AMSAN (n = 11), MFS (n = 7), PNC (n = 2), PCB (n = 1), and BFE (n = 0) [n = 191), plasmapheresis (n = 15), steroids (n = 2), or no therapy (n = 7) [There is an ongoing debate as to whether SARS-CoV-2 can cause GBS, but an increasing number of patients; the temporal relation between onset of infection and onset of GBS; ruling out of alternative causes; and elevated cytokines, chemokines, and glial fibrillary acidic protein in the CSF argue in favour of a causal relation . In a st (n = 0) . SARS-Co (n = 0) . Therapy (n = 7) . Mechani (n = 7) .Other VirusesDengue is not as common as a trigger of GBS as CMV or Zika. In a study of 5821 patients with dengue and from India, 3.2% were diagnosed with GBS . Some ofAlthough GBS has been causally related to several vaccinations , other sSeveral non-infectious and non-vaccine-related triggers of GBS have been reported. In a male in his 80s, GBS was triggered by angio-immunoblastic T-cell lymphoma . The patIVIGs and plasma exchange (PE) are the mainstay treatments of GBS, especially in the first four weeks after onset of weakness . AccordiC jejuni infection, need for mechanical ventilation, and axonal subtype [Most patients with GBS respond favourably to immunotherapy, but a substantial proportion are left with disability, and death can occur . Accordi subtype . Prognos subtype . Accordi subtype .A search of the literature in the databases PubMed, Google Scholar, and Scopus was conducted using the search terms “Guillain-Barre syndrome”, “acute, inflammatory demyelinating polyneuropathy”, “acute, motor, axonal neuropathy”, “acute, motor, sensory, axonal neuropathy”, “Miller Fisher syndrome”, and “brainstem Bickerstaff encephalitis” in combination with “infection”, “C jejuni”, “hemophilus influenzae”, “mycoplasma pneumoniae”, “cytomegalovirus”, “Epstein-Barr virus”, “measles virus”, “influenza-A virus”, “hepatitis E”, “enterovirus”, “swine influenza“, Zika”, and “SARS-CoV-2”. In addition, reference lists were searched for additional articles that matched the search criteria. Only original articles published between 1966 and September 2022 were included. Reviews, abstracts, proceedings, and editorials were excluded from the review.C. jejuni. C. jejuni is highly pathogenic to humans, most commonly causes enteritis, and more rarely causes GBS. In about one third of GBS patients, a previous infection with C. jejuni can be identified. C. jejuni is less likely to cause GBS than CMV and causes a more severe course than other infectious agents. AIDP is caused by demyelination, whereas AMAN is antibody-mediated, attacking structures of the axolemma in the nodal or inter-nodal space. Post-infectious morbidity of human C. jejuni infection is strongly dependent on structure of pathogenic LOSs that trigger the innate immune system and possibly ganglioside pattern on myelin membranes and axons. Despite recent progress in clarifying pathophysiology of GBS, further advances are urgently needed to provide more effective treatments and improve outcome.GBS is a neuro-immunological disorder caused by an autoimmune reaction against components of the myelin membrane or the axolemma. This abnormal immune reaction is most commonly triggered by antecedent gastrointestinal or pulmonary infection; by vaccination; or by other non-infectious, non-vaccine-related conditions. The most common triggering infectious agent is bacterium


Piper nigrum and Piper longum are the most popular and economically essential spice crops globally valued for their aromatic alkaloids, especially Piperine. However, Piperine synthesis pathway mechanisms are not yet well known. This work was aimed to generate the full-length comparative berry transcriptome analysis dataset of P. nigrum and P. longum by Illumina and Nanopore sequencing platforms. While short-read sequencing technology is widely using to capture transcriptome profiles, there are still some limitations due to the read length. We used Oxford Nanopore technology for long reads and the Illumina sequencing platform for short reads to generate a hybrid transcriptome assembly from half matured and fully matured berries of P. nigrum and P. longum. From P. nigrum and P. longum 37.3 million and 38.1 million raw reads were generated respectively. A total of 308369 contigs from P. nigrum and 267715 contigs from P. longum were obtained and successfully annotated. The transcriptome data revealed gene families involved in piperine and other secondary metabolite biosynthetic pathways. The raw data were uploaded to NCBI database. This dataset shed light on the further exploration of the piperine biosynthetic pathway, its transcriptomic changes, and evolution. Data generated has been submitted to SRA of NCBI with Bio samples accession: . They would be valuable resources to examine molecular characteristics of genes that play a role in the biosynthesis of beneficial secondary metabolites in both plants.•in silico comparative genomics studies.Meta-analysis of the raw sequencing data may be carried out for further 1P. nigrum and 267715 unigenes from P. longum with an average length of 1120 were obtained. Using KOG, NR, KEGG, Pfam databases, all the unigenes were successfully annotated (Piper nigrum and Piper longum samples are provided in https://data.mendeley.com/datasets/vyr4r7mxj8/draft?a=a8fd91d3-2868-4ae5-bf3d-d6ab370ab792).Statistical report and other details of transcripts and unigenes for the full-length berry transcriptome are provided in nnotated . The wor21.Sample collectionP. nigrum variety IISR-Thevam and P. longum were collected from ICAR-Indian Institute of Spices Research, Experimental Farm, Kozhikode, Kerala, IndiaHalf matured and fully matured berry samples of 2.Total RNA ExtractionThe modified Spectrum Plant Total RNA Kit (STRN50-Sigma) protocol was used to extract the total RNA. Bioanalyzer 2100  was used to assess RNA integrity. An equivalent amount of RNA was pooled from three different berry samples from three different plants. Sequencing was performed on samples with an RNA integrity score of at least six.3.Transcriptome sequencing and De novo assemblyde novo transcriptome sequencing of berry samples. The Illumina data were demultiplexed using bcl2fastq, and nanopore fast5 data were base-called using Albacore de novo hybrid transcriptome assembly pipeline is illustrated in Illumina and Nanopore sequencing were used to perform 4.Functional AnnotationThe full-length contigs were annotated by homology searches using the NR database Nil.Johnson K. George: Conceptualization, Methodology, Software, Funding acquisition; M.A. Fayad: Visualization, Investigation, Writing- Reviewing and Editing, Software, Validation; S. Shelvy Validation, Investigation, Visualization, Writing- Reviewing and Editing, Software, Validation; T.E. Sheeja: Visualization, Investigation, Data curation, Writing- Original draft preparation; Santhosh J. Eapen: Supervision, Data curation, Visualization, Investigation; Sona Charles: Visualization, Investigation, Data curation, Writing- Original draft preparation, Software, Validation; Anil Rai: Visualization, Software; Dinesh Kumar: Visualization, Software.The authors declare that they have no known competing financial interests or personal relationships which have or could be perceived to have influenced the work reported in this article.


Apodemus agrarius mouse infected with Rickettsia conorii, indicating a natural Mediterranean spotted fever foci exists in East China and that the range of R. conorii could be expanding.We sequenced DNA from spleens of rodents captured in rural areas of Qingdao, East China, during 2013–2015. We found 1  Rickettsia conorii that is transmitted to humans by the brown dog tick, Rhipicephalus sanguineus (R. conorii (R. conorii ITT has been detected in ticks in Xinjiang Province in West China (Mediterranean spotted fever (MSF) is an acute febrile, zoonotic disease caused by the bacterium Rickettsia spp., Orientia tsutsugamushi, and severe fever with thrombocytopenia syndrome virus . We initially performed nested PCR on all rodents with 17-kDa antigen (htrA), then we further tested the PCR-positive samples by using primers of 16S ribosomal RNA (rrs) and outer membrane protein A and B (ompA and ompB) genes (https://tsingke.com). We cloned purified PCR products into T-Vector pMD19 . Both strands were sequenced by Sangon Biotech (https://www.sangon.com).We extracted DNA from homogenized rodent spleen tissues by using the QIAamp DNA Mini Kit  genes . We usedhttps://www.dnastar.com) to remove primers and analyzed sequences in BLAST (https://blast.ncbi.nlm.nih.gov/Blast.cgi) to compare with GenBank sequences. We constructed a phylogenetic tree by using the maximum-likelihood method with the Kimura 2-parameter model in MEGA version 7 (https://www.megasoftware.net), and we calculated bootstrap values with 1,000 replicates to determine the relative support for clades in the trees.We edited DNA sequences by using DNAStar software (Apodemus agrarius), 19 house mice (Mus musculus), 16 Chinese hamsters (Cricetulus barabensis), 10 brown rats (Rattus norvegicus), 8 greater long-tailed hamsters (Cricetulus triton), and 8 Chinese white-bellied rats (Niviventer confucianus)  . Among tA. agrarius mouse captured outdoors was positive for a Rickettsia species and the other 120 rodents were negative for Rickettsia by htrA primers. We further amplified the spleen tissue of the PCR-positive mouse by using rrs, ompA, and ompB primers. All 3 pairs of primers generated positive PCR products. Because the PCR fragment was too short and the sequence was conserved, we could not differentiate Rickettsia species by phylogenetic analysis of the htrA gene. However, the rrs gene sequence obtained in this study was 100% identical to R. conorii strains in GenBank  that were obtained from Rh. turanicus ticks in Xinjiang, China. The obtained rrs sequence also matched 100%  with a GenBank R. conorii strain from India (accession no. L36107), and an R. conorii Malish 7 strain (accession no. NR_041934). The ompA sequence from the mouse was 100% identical to R. conorii strains from Rh. turanicus ticks (494/494 bp for GenBank accession nos. MF002512 and KY069258) and an R. conorii strain from a human blood sample (449/449 bp for accession no. MG190328) from Xinjiang, China. The obtained ompA sequence was also 100% (494/494 bp) identical to GenBank R. conorii strains from India (accession no. U43794) and Italy (accession no. JN944636). The ompB amplified from the mouse was 99.87% (798/799 bp) homologous to the corresponding sequences of R. conorii from Rh. turanicus ticks from Xinjiang, China (GenBank accession nos. MF002514 and KY069249) and an R. conorii strain from India (GenBank accession no. AF123726).PCR amplification indicated that 1 rrs , htrA (169 bp), ompA (494 bp), and ompB (844 bp), showed that the rickettsial sequence from this study clustered with R. conorii ITT from ticks in India (GenBank accession no. AJHC01000000) and within the same clade as the R. conorii Malish 7 strain (GenBank accession no. AE006914), R. conorii Israel tick typhus strain (GenBank accession no. AJVP01000000), and R. conorii Astrakhan strain (GenBank accession no. AJUR01000000) .A phylogenetic tree of the concatenated sequences of the 4 genes, 1000000) . We depoRickettsia spp. in a striped field mouse captured in Qingdao in East China. Phylogenetic analysis showed that the Rickettsia species we detected was identical in multiple gene sequences to R. conorii ITT, indicating the strain we identified is R. conorii. Our results could not be caused by PCR contamination because we do not have an R. conorii strain nor its DNA in our laboratory.We identified R. conorii is the brown dog tick, Rh. sanguineus (R. conorii might be related to the worldwide spread of its vector tick among dogs (R. conorii ITT sequences have been reported in Rh. turanicus ticks from Xinjiang Province in West China (R. conorii in 1 rodent in Qingdao, located in the eastern part of Shandong Province. Another recent study reported R. conorii genomic sequences in a patient in the western part of Shandong Province (R. conorii either recently expanded into Shandong Province in East China or R. conorii has existed in East China but was not detected before.The prevailing vector of R. conorii. The tick vector of R. conorii in Shandong Province has not been identified.We speculate that the expansion of MSF foci in China is caused by transportation of dogs from West China to East China (R. conorii infection in 1 rodent from Qingdao in East China. Further studies are needed to determine the epidemiology of R. conorii in East China. Our study increases our knowledge about the distribution of R. conorii. Identification of MSF foci in East China could indicate that the range of R. conorii and its tick vector are expanding. In conclusion, we confirmed


Helicobacter pylori eradication on metachronous gastric neoplasm prevention after endoscopic submucosal dissection (ESD) of gastric adenoma is unclear. This study included patients with confirmed H. pylori infection after ESD with curative resection for gastric adenoma. Patients were divided based on the success of H. pylori eradication treatment into two groups: eradication and non-eradication. Patients with any newly detected lesion within 1 year after ESD and recurrence at the ESD site were excluded from the analysis. Further, 1:1 propensity score matching was also performed to eliminate baseline differences between the two groups. H. pylori eradication treatment was administered to 673 patients after ESD (163 in the successful eradication group and 510 in the non-eradication group). During the median follow-up periods of 25 and 39 months in the eradication and non-eradication groups, metachronous gastric neoplasm was identified in 6 (3.7%) and 22 patients (4.3%), respectively. Adjusted Cox analysis revealed that H. pylori eradication was not associated with increased risk of metachronous gastric neoplasm after ESD. Kaplan–Meier analysis in the matched population yielded similar findings (p = 0.546). H. pylori eradication treatment was not associated with metachronous gastric neoplasm after ESD with curative resection for gastric adenoma.The long-term effect of  Helicobacter pylori is a strong risk factor in gastric cancer [H. pylori may prevent gastric cancer [H. pylori eradication can prevent progression to advanced precancerous lesions in a gastric carcinogenesis model with atrophic gastritis and intestinal metaplasia. Thus, eradication treatment for H. pylori is recommended for gastric cancer prevention [c cancer ,2; hencec cancer ,4,5,6. Ic cancer . H. pyloevention ,9,10.H. pylori eradication treatment [H. pylori eradication treatment when histological changes in the gastric mucosa, such as atrophic gastritis and intestinal metaplasia, are already evident. However, studies involving patients with atrophic gastritis and intestinal metaplasia demonstrated that H. pylori eradication treatment reduced the incidence of gastric cancer [In contrast, the “point of no return” theory explains that gastric cancer might develop after reatment ,12. Thisc cancer . Similarc cancer .H. pylori eradication treatment lowers the incidence of metachronous gastric cancer in patients with early gastric cancer [H. pylori eradication treatment after the resection of early gastric cancer is highly recommended; however, the recommendations are unclear for gastric adenomas [H. pylori eradication treatment influences metachronous gastric neoplasm in patients with gastric adenomas after ESD with curative resection using real-world data collected over 15 years at a single center.Gastric adenomas are precancerous lesions that can be eradicated with endoscopic submucosal dissection (ESD) ,16,17. Hc cancer ; howeverc cancer ,20,21. Iadenomas . TherefoH. pylori in the initial workup, (4) patients who tried H. pylori eradication treatment but successful eradication was not confirmed, and (5) incomplete resection. Incomplete resection was defined when one of the following conditions was not satisfied: En-bloc resection (single-piece specimen) and a negative resection margin . The enrolled patients were assigned to eradication and non-eradication groups based on the H. pylori eradication treatment results. The Ajou University Hospital Institutional Review Board approved protocol of this study . Because this study was a retrospective study, the process of obtaining informed consent was waived.This retrospective, single-center study included patients who underwent ESD for gastric adenoma at Ajou University Hospital  between 1 January 2005 and 31 December 2020. Exclusion criteria involved patients who met the following conditions: (1) previous history of gastric adenoma or cancer, (2) previous history of other malignancies and/or multiple gastric lesions in the initial workup, (3) patients who were not confirmed to be infected with Five highly experienced expert endoscopists  conducted ESD at our center. Before resecting the lesions, the entire stomach was inspected for additional lesions, and the lesion margins were evaluated. After observing all lesions with white light endoscopy and narrow-band imaging, an indigo carmine solution was applied to establish accurate margins. Subsequently, a needle knife  was used to mark 5 mm outside the lesion margin. To reduce bleeding during incision and submucosal dissection, epinephrine mixed with saline was injected into the submucosal layer; therefore, the lesion was sufficiently lifted from the proper muscle layer. After inducing a circumferential incision 5 mm from the marked site, a needle or an insulated-tip knife  was used to dissect the submucosal layer and separate the lesion from the proper muscle layer. The specimen was removed from the body, pinned to a plate, and immersed in a 10% buffered formalin solution. Subsequently, the specimen was forwarded to the pathology department for histopathologic confirmation.Tumor characteristics were evaluated through endoscopic and pathologic findings. The lesion size was determined by measuring the long diameter of the tumor with an endoscopic ruler, and the specimen size was measured after plate fixation. Gross morphology was divided into elevated, flat, or depressed according to the dominant type . We cateH. pylori infection was confirmed using a urea breath test, a rapid urease test, or pathologic evaluation (hematoxylin and eosin and Wright–Giemsa stain) during the initial workup. The success of the eradication treatment was defined as a negative result of rapid urease test or urea breath test after three or four weeks after standard triple therapy  [14 days) .Definite surveillance guideline after ESD with curative resection in patients with gastric adenoma does not exist. According to our center protocol, we performed follow-up endoscopies on all patients 3, 6, 12, 18, and 24 months after ESD and annually. Additionally, a biopsy was performed at the ESD sites at each follow-up examination, and an additional biopsy was performed at the operator’s discretion when a new lesion was suspected.H. pylori infection were matched in a 1:1 ratio. Standardized mean differences were calculated to measure covariate balance before and after propensity score matching. All statistical analyses were performed using R software, version 3.6.2 , and SAS software, version 9.4 . Statistical significance was defined as two-sided p-values < 0.05.Categorical variables were analyzed using Pearson chi-square or Fisher’s exact test, while continuous variables were analyzed using independent t-test or Wilcoxon rank sum test. Log-rank test was used for the evaluation of differences in disease-free probability between the two groups. The Kaplan–Meier method was used for plotting survival curves for gastric adenoma, cancer, and neoplasm. Hazard ratios (HRs) were estimated using the Cox proportional hazard model to assess the incidence risk of metachronous gastric neoplasm. Propensity score matching was performed to reduce selection bias in this retrospective study. The propensity score was estimated with 11 matching variables, including age, sex, pathology, chronic atrophic gastritis, intestinal metaplasia, lesion size, tumor location, gross morphology, familial history of gastric cancer, smoking, and ASA physical status classification system score. Using these scores, the eradication and non-eradication groups of H. pylori infection or who were not tested for H. pylori infection were excluded. Among 1065 patients with confirmed H. pylori infection, 48 patients were excluded because successful eradication was not confirmed after H. pylori eradication treatment. In addition, 67 patients were excluded due to incomplete resection, and 216 patients were excluded due to multiple lesions during the initial workup. A total of 30 patients were excluded because of previous history of gastric neoplasm or other malignancies. Hence, 163 and 510 patients were assigned to the eradication and non-eradication groups, respectively. n = 338, 50.2%), and the mean (standard deviation) size of the lesion was 11.7 mm (7.8 mm). The lesion was in the lower third of the stomach in 42.2% (n = 284) of the total patients, and 15.8% (n = 106) had high-grade dysplasia. Less than 10% of the total patients had a familial history of gastric cancer , and less than 50% of the total patients were smokers . Patients with 1 point of ASA physical status score were more than 80% of the total patients , and the proportion of alcohol drinkers was also revealed to be similar to that of smokers . A comparison of the baseline characteristics of the eradication and non-eradication groups revealed that most investigated variables, including clinical parameters and pathologic information, did not differ between the groups. However, smoking history and tumor gross morphology differed between the two groups . In the eradication group, less than 30% were smokers . However, the proportion of smokers in the non-eradication group was up to 40% . In the eradication group, the rates of elevated and flat morphologies were similar. In contrast, more than half of the non-eradication group had superficial elevated morphology . In addition, the eradication group had a 1.60 times higher proportion of tumors with depressed morphology than the non-eradication group . Of the 2403 patients who underwent ESD for gastric adenoma, 1338 patients who tested negative for p = 0.825). In the non-eradication group, all metachronous gastric adenoma cases had low-grade dysplasia (n = 13). Metachronous gastric cancer was observed in three (1.8%) and nine (1.8%) patients of the eradication and non-eradication groups, respectively, and the incidence rate of metachronous gastric cancer was similar between the two groups (The mean follow-up period was 25 (interquartile range (IQR): 18–35 months) and 39 months (IQR: 27–57 months) in the eradication and non-eradication groups, respectively. In the total patient population, there were 28 cases (4.2%) of metachronous gastric neoplasm after ESD. The incidence rate of metachronous gastric neoplasm did not differ significantly between the two groups (6 (3.7%) vs. 22 (4.3%), o groups .H. pylori eradication treatment after ESD for gastric adenoma resection was not a risk factor for metachronous gastric neoplasm  (p = 0.090)  . Kaplan–= 0.090) .p = 0.546)  .H. pylori is a well-known risk factor in gastric cancer [H. pylori infection is growing. In different randomized studies, H. pylori eradication treatment reduced the incidence of metachronous cancer after endoscopic resection of early gastric cancer [H. pylori eradication treatment in gastric adenoma, a precancerous lesion, is lacking. Herein, we used single-center data accumulated over 15 years to investigate the effects of H. pylori eradication treatment on metachronous lesions after gastric adenoma resection. Local recurrence and synchronous lesions that were observed within a year after ESD were excluded. Only cases where lesions resected through ESD could undergo full histopathologic evaluation were enrolled for analysis. Therefore, our findings revealed that H. pylori eradication treatment after gastric adenoma resection did not affect the incidence of metachronous gastric neoplasm. Intriguingly, the replication of these results, even after propensity score matching, confirmed that H. pylori eradication could not influence metachronous gastric neoplasm after ESD.Eliminating risk factors is the most basic strategy for preventing gastric cancer. As c cancer , the impc cancer ,26,27. HH. pylori is a risk factor in gastric cancer. Thus, eradication treatment was reported to lower incidence and mortality in patients with gastric cancer [H. pylori a human carcinogen [H. pylori eradication treatment is debatable in conditions with or without atrophy/intestinal metaplasia after gastric adenoma resection. Resecting gastric adenoma lesions does not change the status of the gastric mucosa. In the stepwise progression from normal to gastric cancer, gastric adenoma is an intermediate neoplasm. Thus, resecting the lesion is not a fundamental treatment for gastric mucosa, and these theoretical bases suggest that H. pylori eradication treatment must be performed after resecting gastric adenoma.According to Correa’s multi-stage cascade of gastric oncogenesis, prolonged mucosal inflammation causes changes in atrophy and intestinal metaplasia . Furtherc cancer ,31,32,33rcinogen . The necH. pylori eradication treatment cannot reverse the progressive histological changes [H. pylori eradication treatment reduced the risk of future gastric cancer in patients without precancerous lesions or with atrophy. However, H. pylori eradication did not reduce the risk of gastric cancer in patients with intestinal metaplasia or gastric adenoma [H. pylori eradication treatment. H. pylori eradication treatment was more effective in preventing gastric cancer in patients with mild atrophy than in patients with extensive atrophy [H. pylori eradication treatment did not improve molecular changes related to carcinogenesis [However, in the “point of no return” theory, where gastric mucosa with atrophy/intestinal metaplasia is present in the stepwise progression,  changes . Accordi adenoma ,35. More atrophy . These fogenesis . This isH. pylori eradication treatment reduced the risk of gastric cancer in patients with intestinal metaplasia or gastric adenoma [H. pylori eradication treatment. In a study that analyzed the effects of H. pylori eradication treatment on the incidence of metachronous gastric cancer after endoscopic resection of gastric cancer, the eradication group showed histological improvement of atrophy/metaplasia after 3 years of follow-up [In contrast, in a large cohort study of the general population conducted in China,  adenoma . In thatollow-up . The effollow-up , but aftollow-up . This imH. pylori eradication treatment after gastric adenoma resection included cases of newly observed lesions within a year [H. pylori eradication on the incidence of metachronous gastric neoplasm. Additionally, unlike previous studies that compared the incidence of metachronous gastric neoplasm by comparing eradication and non-eradication groups without confirming the success of eradication treatment [In our study, a synchronous lesion was defined as a newly observed lesion at a site other than the ESD site within a year of the procedure. Along with cases that recurred at the ESD site , synchronous lesions were excluded from the final analysis. This was because cases of newly observed lesions within a year may be newly developed cancer or possibly missed cancer. Previous studies that evaluated the effects of n a year ,26,38. Ireatment , we onlyreatment ,40. HereH. pylori after ESD were conducted under the same conditions, limiting the effects of various confounding variables. Second, this study was retrospective; hence, various confounding factors might have interfered with interpreting the results. Therefore, to minimize baseline differences between the eradication and non-eradication groups, we removed known risk factors for gastric neoplasm development through matching. Nevertheless, factors such as the degree of gastric atrophy, gastric hypoacidity, and secondary cancer risk should be analyzed as factors that could affect eradication treatment. Given the retrospective design of this study, it was not possible to evaluate the above factors. Third, this study did not evaluate H. pylori re-infection following eradication treatment. This study only analyzed patients who had successful eradication treatment to clarify the effects after eradication treatment. However, some patients may have been reinfected with H. Pylori after successful eradication treatment. H. pylori re-infection was not evaluated; however, the annual rate of H. Pylori infection in South Korea is approximately 3.5%, which would have had minimal effects on the study results [H. pylori eradication on metachronous gastric neoplasm.This study had some limitations. First, this study was conducted in a single center. However, the pathological evaluation and detection of  results . FinallyH. pylori eradication treatment after ESD with curative resection of gastric adenoma did not show difference in the incidence of metachronous gastric neoplasm. In addition, our findings were reported after removing baseline differences between the eradication and non-eradication groups through propensity score matching analysis. However, future studies should include a longer follow-up period, because eradication treatment eliminates H. pylori, a major risk factor in gastric cancer, and the effects of eradication treatment may appear after a long period of time.In conclusion, our results demonstrate that the success of


We further review the neutralisation of these snake venoms by selected antivenoms widely used within the African continent. The profiling of African snake venom proteomes will aid in the development of effective antivenom against snakebite envenoming and, additionally, could possibly reveal therapeutic applications of snake venom proteins.Snakebite envenoming is a neglected tropical disease (NTD) that results from the injection of snake venom of a venomous snake into animals and humans. In Africa (mainly in sub-Saharan Africa), over 100,000 envenomings and over 10,000 deaths per annum from snakebite have been reported. Difficulties in snakebite prevention and antivenom treatment are believed to result from a lack of epidemiological data and underestimated figures on snakebite envenoming-related morbidity and mortality. There are species- and genus-specific variations associated with snake venoms in Africa and across the globe. These variations contribute massively to diverse differences in venom toxicity and pathogenicity that can undermine the efficacy of adopted antivenom therapies used in the treatment of snakebite envenoming. There is a need to profile all snake venom proteins of medically important venomous snakes endemic to Africa. This is anticipated to help in the development of safer and more effective antivenoms for the treatment of snakebite envenoming within the continent. In this review, the proteomes of 34 snake venoms from the most medically important snakes in Africa, namely the Viperidae and Elipdae, were extracted from the literature. The toxin families were grouped into dominant, secondary, minor, and others based on the abundance of the protein families in the venom proteomes. The Viperidae venom proteome was dominated by snake venom metalloproteinases (SVMPs–41%), snake venom serine proteases (SVSPs–16%), and phospholipase A Snakebite envenoming is a neglected tropical disease (NTD) that causes serious public health issues. Snakebite envenoming mainly affects people from poorly developed and politically marginalised rural tropical and subtropical communities in India, Southeast Asia, sub-Saharan Africa, and Latin America ,2. AccorLack of epidemiological data and underestimated figures on snakebite envenoming-related morbidity and mortality impedes snakebite prevention and antivenom treatment . The menBitis arietans, within sub-Saharan Africa [Naja spp.) and mambas (Dendroaspis spp.), while the viperids include adders (Bitis spp.) and saw-scaled/carpet vipers (Echis spp.) [The snake venom toxins cause diverse clinical manifestations ranging from local tissue damage to life-threatening systemic effects, including neurotoxicity , haemotoxicity (haemorrhage and coagulopathy), and/or cytotoxicity  ,9,10. Thn Africa . In Afriis spp.) . Snakebiis spp.) . Elapidais spp.) .https://www.who.int/teams/control-of-neglected-tropical-diseases/snakebite-envenoming/snakebite-information-and-data-platform/overview#tab=tab_1 accessed on 29 August 2022). The platform also helps in data sharing, collaboration, awareness and the education of people. Future directives to better understand and eradicate snakebite envenomation in Africa require multidisciplinary approaches alongside preclinical evaluation and production of multi-antivenoms across Africa [In 2017, following a recommendation by the WHO’s strategic and technical advisory group for NTD, snakebite envenoming was listed as an NTD. In 2018, this recommendation was adopted by the 71st World Health Assembly. Later, in 2019, the WHO provided its 2019–2030 global strategy for the prevention and control of snakebite envenoming aimed at reducing deaths and disabilities by 50% before 2030 . The key2 (PLA2s), metalloproteases, serine proteases, L-amino acid oxidases (LAAO), disintegrins (DIS) and C-type lectins (CTL) [2s, snake venom metalloproteinases (SVMPs), and snake venom serine proteases (SVSPs) encoded by multilocus gene families are the most abundant protein families component of snake venom, which exhibit multifunctionality [Snake venom contains several compounds dominated by protein mixtures that include phospholipase Ans (CTL) ,19. Threionality ,20,21,222s are enzymes that play major toxic roles in envenomation. These enzymes have been identified in the venoms of all kinds of snake families, including Viperidae and Elapidae [2+ for activities [2s catalyse the hydrolysis of glycerophospholipids at the sn-2 position of the glycerol backbone, releasing lysophospholipids and fatty acids [2s induce several pharmacological effects in victims, such as neurotoxicity, cytotoxicity, cardiotoxicity, myotoxicity, oedema, and anticoagulation. These effects are linked to their multiple functional sites and diverse receptors [2s that disrupt the integrity of the plasma membrane of muscle fibres [2 has both monomeric and dimeric enzymatic forms. The monomeric PLA2 has cytotoxicity activities, while the dimeric form possesses both cytotoxicity and neurotoxicity activities [2 with neurotoxicity activities have been identified [2 exist, but they are classified into group I and group II based on the disulphide bond. Group II is further classified into Asp49 PLA2 and Lys49 PLA2 myotoxins involved in cytotoxicity activities in Viperidae venom [2 is a potential target for a wide spectrum of antivenom drug development [2 activity and, as such, reduced the lethal effects of Protobothrops mucrosquamatus snake venom in a mouse model [Snake venom PLAElapidae   are non-enzymatic protein components of snake venom found mainly in the Elipdae with 60–74 amino acid residues containing three β strand loops linked to 4–5 disulphide bridges . These tomponent . These tomponent . Cytotoxse model .2+-dependent manner which plays a role in adhesion, endocytosis and pathogen neutralisation [1 and β3 integrin receptors [The activities of other selected snake venom protein components, such as LAAO, CTL, DIS, KUN, and CYS, are shown in lisation . These plisation ,63. DIS lisation . These neceptors ,64. DIS eceptors .+ and Ca2+ channel activities [KUN belongs to the functionally diverse bovine pancreatic trypsin inhibitor (BPTI) family characterised by a conserved fold of 50–60 amino acid residues cross-linked by three disulphide bridges ,66. Theytivities ,38,67,68tivities ,70. It itivities . In thistivities .Advancements in the ‘omics’ technologies, especially proteomics, accompanied by databases and bioinformatics tools, have been excellent in the identification of protein toxins and analysis of their relative abundance ,73. SnakThe lyophilised snake venom can be separated into various fractions using chromatography techniques, including reverse-phase (RP), ion-exchange or size-exclusion high-performance liquid chromatography (HPLC). Most snake venom proteomics has adopted sample fractionation with the use of the C18 RP column coupled to the HPLC (RP-HPLC) ,76,77. TSnake venom comprises a mixture of proteins and peptides of different toxins. There are inter- and intraspecific variations of venom components due to the influence of genetic mutations, genetic drift, diet, season and natural selection that moulds the venom of each species for optimal adaptation ,19. Tranhttps://www.google.com/ accessed on 8 August 2022), Google Scholar (https://scholar.google.com/ accessed on 8 August 2022), PubMed (https://pubmed.ncbi.nlm.nih.gov accessed on 8 August 2022) and ScienceDirect (https://www.sciencedirect.com/ accessed on 8 August 2022) databases using the keywords “African snake venom proteome”, “African snake venomics”, “snake protein components”, and “African antivenoms”. Also, different African snake genera and species names were included in the search. The results were screened manually for the venom proteome data of Viperidae and Elapidae. Proteomic studies without quantified protein family abundance were excluded from the analyses. For comparison purposes, snake species with more than one proteomic data set were included in the analysis. For simplicity, the families that represent major protein abundance of total venom proteome are represented here.Here, an online search was conducted using search engines such as Google  from snake venoms of Viperidae  and metalloproteinases (21.1%) dominated the venom of the former while metalloproteinases (34.8%), phospholipase A2s (21.2%) and serine proteases (15.5%) dominated the later [SVMPs, PLAt toxins . Amongst victims ,75. The cellatus , B. caudcaudalis  and B. ggabonica . Proteomhe later . Intereshe later .Cerastes cerastes snake venom but was, however, lower (1%) in the C. vipera species [E. ocellatus and Ghanaian B. arietans [C. cerastes, C. vipera and Nigerian B. arietans  in the Tunisian  species . DIS is arietans ,85, thusarietans . KUN wasMacrovipera and Cerastes genera, albeit (<1%) in the Moroccan C. cerestas. VEGF was fairly present in venoms of Bitis, Echis and Macroviperan genera but not in the Cerestas. CYS was identified in the Bitis genera only, which may be an indicator of intra- and inter-species variation in the Viperidae snake venoms.Minor toxin families are CRISP, VEGF and CYS, with a 4% average protein abundance in Viperidae . CRISP w2 receptors, phospholipase B (PLB), phospholipase A2 inhibitor, globins, DC-fragment, SVMP inhibitors, peptides, and unknown (Bitis and Echis genera and most likely play various roles in snakebite envenomation.These toxin families were present in low abundance and were grouped as ‘others’. They include snake venom natriuretic peptides (NPs), 5′-nucleotidase (5′N), three-finger toxins (3FTxs), nerve growth factor (NGF), bradykinin-potentiating peptides (BPP), peroxiredoxin, snake venom glutaminyl cyclases, secretory phospholipase A unknown . All oth2 and SVMPs. These three toxins were also reported as the most dominant proteins from Elapidae from other continents [2 was not detected in the venom proteome of the Senegalese Cobra  [Naja annulifera (African cobra) [2 in the venoms of cobras in the Uraeus subgenus.These include 3FTxs, PLA2 and SVMPs, and make up an average of 87% of Elapidae venom   and Najan cobra) , consist2 was not identified in the venom of Dendroaspis angusticeps [D. polylepis [D. polylepis venom but was lacking in D. angusticeps [Naja melanoleuca), amongst others, was dominated by 3FTx, which includes post-synaptically acting α-neurotoxin [2 in the African spitting cobras may be the major contributor to the toxic effects of these venoms, such as local tissue necrosis [Aspidelaps) such as intermediate shield-nose snake (Aspiderlaps scutatus intermedius), Cowle’s shield snake (Aspiderlaps lubricus cowlesi) and Cape coral snake (Aspiderlaps lubricus) shows cross-genus dominance of 3FTxs and PLA2s with various isoforms of the former linked to interspecies variation. The proteome analysis of the venoms of three African spitting cobras  and one non-spitting snouted cobra (N. annulifera) reported that while 3FTxs and PLA2s were the most abundant proteins in the spitting cobras, 3FTxs and SVMP were dominant in the non-spitting cobra, amongst others [Similarly, PLAusticeps  and witholylepis , indicatusticeps . It is iurotoxin . The domnecrosis . Proteomt others .D. polylepis (61.1%) and the second most abundant in D. angusticeps (16.3%). This suggests that the KUN toxin contributes massively to the envenomation caused by the Dendroaspis genera. While D. polylepis venom was dominated by KUN, D. angusticeps was dominated by the 3FTxs. The toxin variations observed can be a result of dietary variations due to the divergent terrestrial ecology of black mamba (D. polylepsis) compared to the arboreal niche of green mambas  [Secondary toxins comprise the CRISP and KUN family proteins which are made up of an average of 8% in Elapidae venom proteomes . In the aimosae) .Haemachatus haemachatus and Dendroaspis species, albeit 0.1% of PDE was observed in D. polylepis  or divalent fragment antibody F(ab’)2 from venom-immunised horses or other animals. The snake venom used as an immunogen in antivenom production is mixed with adjuvants to enhance the immune system response . While c2 fragments [The animals  are quarantined and vaccinated against specific diseases and treated against diseases . The aniragments ,104,105.ragments . Furtherragments .B. arietans venom in the L6 rat skeletal muscle cells [Aspidelaps) was not included in the venoms used to immunise horses for the manufacturing of regional SAIMR polyvalent antivenom due to the snake’s uncommon bites. Nevertheless, the antivenom was effective in neutralising the venoms from the A. s. intermidius, A. l. cowlesi and A. l. lubricus, comparable to those observed in the cape cobra (N. nivea), suggesting a wider than anticipated clinical utility of the antivenom [le cells . Howeverntivenom .Echis sp.  and Bitis spp.  from Nigeria and other sub-Saharan African locations [E. ocellatus, B. arietans and N. nigricollis) [2 and LAAO in snake venoms of Echis and Bitis genera [2 activities of N. nigricollis and N. mossambica, lethal and PLA2 activities of N. palliada and finally, the PLA2 activities of N. katiensis and N. nubiae [B. arietans, N. mossambica, N. annulifera, H. haemachatus) from the southern region (Swaziland) to obtain expanded-scope antivenom called EchiTAb-P + ICP antivenom [A whole IgG polyspecific EchiTAb-Plus-ICP antivenom designed for the treatment of snakebite envenomings in sub-Saharan Africa was effective in neutralising Viperid venoms for both ocations . The Echicollis) . This ans genera . In anot. nubiae . The expntivenom .N. senegalensis (predominated with cardiotoxin/cytotoxin) and α-neurotoxin, with no PLA2) [E. leucogaster, E. ocellatus, B. arietans, B. gabonica) and six African Elapids  snake species [N. annulifera venom, with PANAF being marginally more potent [D. polylepis and D. angusticeps venoms were neutralised by three polyvalent antivenoms: (a) SAIMR antivenom from South African vaccine producers, (b) Snake venom antivenom  and (c) Snake venom antivenom (Africa) from VINS Bioproducts Ltd. [D. polylepis venom, albeit in different potencies [D. angusticeps venom, while the VINS central African antivenom failed to neutralise the lethality of the venom with the lowest antivenom ratio tested (1.0 mg venom/mL) [D. angusticeps was not included in the immunisation mixture used in the production of the VINS central African antivenom.The hetero-specific VINS African Polyvalent Antivenom (VAPAV) was immunoreactive and cross-neutralised the venom of no PLA2) . It show species . Both the potent . D. polycts Ltd. ,89. In totencies ,97. SAIMHemachatus-ICP antivenom produced by Costa Rican Instituto Clodomiro Picado was able to neutralise the toxicity and lethality of three spitting cobras . Nevertheless, it was not effective against the toxicity and lethality of the non-spitting cobra, N. annulifera. This suggests a closer relationship between Haemachatus and Naja spitting cobra than the Naja non-spitting cobra [C. cerastes (CcMo_AV) and the Gamma-VIP divalent antivenom had similar immunocapturing capability toward snake venom proteins of C. cerastes from Morocco, Tunisia and Egypt [M. mauritanica (MmMo_AV) and commercially available Gamma-VIP divalent antivenom show great immunoreactivity towards Moroccan M. mauritanica and Tunisian M. labetina venoms [The monospecific anti-ng cobra . Monospend Egypt . In addia venoms .E. ocellatus venoms from Mali, Cameroon and Nigeria were neutralised by antivenoms distributed in sub-Saharan Africa, such as EchiTAb-Plus-ICP, EchiTAb-G, FAV Afrique and Inoserp Panafricain antivenoms [E. ocellatus. A preclinical efficacy study comparing four tests  and two gold standard antivenoms  against medically important snake venoms in East Africa revealed PANAF as the most effective and affordable of the tested antivenoms [tivenoms . Potet etivenoms  reportedtivenoms . The oveThere is a need to intensify clinical testing for all antivenoms in the African market space and also advance research to develop African-specific antivenoms with the most medically important snake venoms from all regions, which will alleviate snakebite envenomation within the continent.E. coli host systems within antivenom research [The immunoglobulin-based antivenom produced from livestock has lots of drawbacks, including allergic reactions and hypersensitive reactions in patients, batch variability, lack of specificity and complex manufacturing process . Alternaresearch . Optimisresearch .E. ocellatus and C. cerastes venoms [Didelphis virginiana) serum inhibited the lethality of snake venoms [E. coli expression of this short peptide yielded a recombinant LTNF that neutralised rattlesnake  venom [2 inhibitor Varespladib was effective in counteracting the lethal effects of vipers from South Asia, sub-Saharan Africa and Central America [2, anti-SVSP, anti-SVMP), antibody fragments and small molecule inhibitors  [E. ocellatus venoms from Cameroon and Ghana in the mouse model [2, 3FTx, SVSP and SVMP are the major snake venom toxin targeted for next-generation therapeutics due to their dominant abundance and major pathological implication in snakebite victims [Sequences encoding the epitopes of venom toxin (SVMP) cDNA library obtained from an expressed sequence tag database and engineered into a single synthetic multiepitope DNA immunogen (a string of SVMP epitopes) neutralised haemorrhage induced by s venoms . Lethal e venoms . The E. x) venom . A combi America . Next-gespladib) ,125. Twose model . PLA2, 32 and SVSP were the most abundant proteins in the former, while 3FTxs and PLA2 were the dominant protein families in the latter. Protein components were classified as dominant, secondary, minor and other toxins based on the toxin abundance in the venoms. We also reviewed the activities of selected antivenom used in the treatment of snakebite envenomation in Africa. In conclusion, the African Viperidae and Elapidae snake venoms have diverse protein components that can be used to develop more robust antivenom in the treatment of snakebite envenomation and as prospective therapeutic treatment of other diseases.Snakebite envenomation is an NTD that massively affects poorer communities and causes morbidity and mortality. There are species- and genus-specific variations in the toxins of snake venom, which leads to distinct toxicity and pathological effects thereof. Proteomic profiling of the medically important African snake venoms will contribute to the production of safer and more effective antivenom to treat snakebite envenomation in Africa. There is a low supply of antivenom in Africa, which needs to be upscaled to alleviate the effect of snakebite envenomation. The data obtained from proteome analyses of the African Viperidae and Elapidae snake venoms showed that SVMP, PLA


Leishmania. The visceral form of this disease caused by Leishmania donovani continues to constitute a major public health crisis, especially in countries of endemicity. In some cases, it is asymptomatic and comes with acute and chronic clinical outcomes such as weight loss, pancytopenia, hepatosplenomegaly, and death if left untreated. Over the years, the treatment of VL has relied solely on chemotherapeutic agents, but unfortunately, these drugs are now faced with challenges. Despite all efforts, no successful vaccine has been approved for VL. This could be as a result of limited knowledge/understanding of the immune mechanisms necessary to regulate parasite growth. Using a computational approach, this study explored the prospect of harnessing the properties of a disulfide isomerase protein of L. donovani amastigotses to develop a multi-epitope subunit vaccine candidate against the parasite. We designed a 248-amino acid multi-epitope vaccine with a predicted antigenicity probability of 0.897372. Analyses of immunogenicity, allergenicity, and multiple physiochemical parameters indicated that the constructed vaccine candidate was stable, non-allergenic, and immunogenic, making it compatible with humans and hence, a potentially viable and safe vaccine candidate against Leishmania spp. Parasites.Leishmaniasis is a neglected tropical disease caused by parasitic intracellular protozoa of the genus  Phlebotomus or Lutzomyia during a blood meal [Leishmania spp. Infections and 70,000 deaths occur annually worldwide, with the majority of cases affecting resource-constrained regions, including African countries [Leishmaniasis is a vector-borne disease transmitted to humans by female phlebotomine sandflies of the genus ood meal . The infountries .Leishmania spp. Are known, and one of these, Leishmania donovani, causes VL, a fatal disease in over 95% of reported cases [Leishmania parasites, such as sodium stibogluconate (SSG), amphotericin B (AMB), paromomycin (PMM), and miltefosine (MIL), treatment failure has become increasingly common with the use of these drugs [The disease commonly manifests in three main forms that are: visceral leishmaniasis (VL), cutaneous leishmaniasis (CL), and mucocutaneous leishmaniasis (MCL), all of which are highly endemic in several countries . Over 20ed cases . Cases oed cases . Amongstse drugs ,4. In VLse drugs . Vaccinese drugs ,8. MoreoUpon infection, T and B cells are responsible for recognising the pathogen and sharing information about shaping an appropriate immune response against the pathogen. T and B cells migrate to the site of infection and produce chemokines to recruit granulocytes, monocytes, and natural killer cells to eliminate infected cells, after which a small fraction of the cells mature into memory T and B cells which protect against host reinfection . This loL. donovani has been reported to play a significant role in its virulence and survival. The protein has also been identified as pivotal to the induction of immune response of macrophages and neutrophils via the stimulation of T helper type 1 cells [L. donovani. Consequently, this study aimed to explore the disulfide isomerase proteins to design a multi-epitope subunit vaccine capable of targeting L. donovani amastigotes using an immunoinformatics approach.The protein disulfide isomerase of  1 cells . Furtherhttps://www.ncbi.nlm.nih.gov/ (accessed on 1 May 2022)) using the search method under the category of protein and downloaded in FASTA format along with other details such as the accession number, name of protein, and the organism from which the sequence was acquired, which is in this case the L. donovani parasite. The protein sequence was further subjected to antigenicity testing on the online platform ANTIGENpro (http://scratch.proteomics.ics.uci.edu/ (accessed on 1 May 2022)) to determine if the protein sequence can trigger an immune response when ingested into a patient. In other words, ANTIGENpro was used to predict protein antigenicity [The protein sequence to be subjected to multi-epitope vaccine design was retrieved from the protein database, NCBI (genicity .http://www.cbs.dtu.dk/services/NetCTL/ (accessed on 2 May 2022)) to check for the ability of the protein sequence epitopes to elicit an immunogenic response and for memory cells [https://www.iedb.org/ (accessed on 2 May 2022)) for MHC class I immunogenicity prediction. The MHC-I binding predictions were made using the IEDB analysis resource NetMHCpan (ver. 4.0) tool (http://tools.iedb.org/mhci/ (accessed on 2 May 2022)) [To predict the CTL epitopes of the antigenic protein sequences selected, the selected sequences were inputted into the freely accessible NETCTL 1.2 server ) . To seley 2022)) , the lowhttp://www.imtech.res.in/raghava/abcpred/ (accessed on 3 May 2022)) was used to predict the B-cell epitope. While maintaining a default threshold of 0.51 [A B-cell epitope is the part of the antigen responsible for binding to the immunoglobulin or antibody . Its pre of 0.51 , the amiTo obtain a strong vaccine capable of inducing innate immune responses which will in turn lead to the attainment of adaptive immune responses, the cytotoxic T lymphocytes’ (CTLs) epitopes with a high score of >0.75 and the HTL epitopes with high affinity (with a percentile rank score of ≤1.5) were selected and used in developing a vaccine sequence comprising a TLR-4 agonist adjuvant , AAY, and GPGPG linkers used in the intra-epitope region, thus joining the CTL and HTL epitopes together, respectively . The TLRhttp://scratch.proteomics.ics.uci.edu/ (accessed on 5 May 2022)). For the allergenicity of the vaccine, the platform AllerTOP v2.0 (http://www.ddg-pharmfac.net/AllerTOP/ (accessed on 5 May 2022)) and AllergenFP (http://ddg-pharmfac.net/AllergenFP/ (accessed on 5 May 2022)) were used. AllerTOP is a bioinformatics tool used for the prediction of allergenicity by making use of factors such as amino acid E-descriptors, auto and cross-covariance transformation, and the k-nearest neighbours machine-learning methods in allergen classification. AllergenFP functions by employing an alignment-free, descriptor-based fingerprint in the identification of allergens and non-allergens [The vaccine sequence developed was further tested for its antigenicity property on the ANTIGENpro server (https://web.expasy.org/protparam/ (accessed on 5 May 2022)).Further analysis of other physiochemical properties of the sequence included amino acid composition, theoretical isoelectric point (pI) value, instability index, in vitro and in vivo half-life, aliphatic index, molecular weight, and grand average of hydropathicity (GRAVY) . These ahttp://raptorx.uchicago.edu/ (accessed on 6 May 2022)) [p-values which depict the quality of the predicted structures. The model with the lowest p-value is considered the best model.The tertiary structure of a protein, also known as the 3D structure of a protein, is the level at which a protein becomes functional. This structure can be predicted from the primary structure of a protein. The tertiary structure of the vaccine construct was predicted from its amino acid sequence using the RaptorX structure prediction server (y 2022)) ,25. Rapthttp://galaxy.seoklab.org/ (accessed on 9 May 2022)) [https://servicesn.mbi.ucla.edu/PROCHECK/ (accessed on 9 May 2022)). It provides an easy way to visualize energetically allowed and disallowed dihedral angles psi (Φ) and phi (Ψ) [https://prosa.services.came.sbg.ac.at/prosa.php (accessed on 9 May 2022)) uses statistical methods to generate a z-score that expresses the quality of the predicted protein structure and was also used for the validation [Following the prediction of the tertiary structure of the vaccine construct by the RaptorX server, the model with the best quality was selected for further analysis. The selected model was refined using the GalaxyRefine module of the GalaxyWEB server (y 2022)) ,27. Thisy 2022)) ,29. Furt phi (Ψ) . ProSA-wlidation .https://www.rcsb.org/ (accessed on 9 May 2022)) in PDB format while the predicted 3D structure of the vaccine was used as the ligand. The docking was carried out using three different online servers. ClusPro 2.0 (https://cluspro.bu.edu/login.php (accessed on 9 May 2022)) was first used for the protein-protein docking study [https://bioinfo3d.cs.tau.ac.il/PatchDock/php.php (accessed on 9 May 2022)) with all the parameters kept at their default values [https://bioinfo3d.cs.tau.ac.il/FireDock/php.php (accessed on 9 May 2022)) [Recognition of an antigen by the immune system is critical for the generation of an immune response. This recognition is done by a family of proteins known as pattern recognition receptors (PRRs) to which toll-like receptors (TLRs) belong . The abing study . Furthert values . The resy 2022)) . The reshttps://imods.iqfr.csic.es/ (accessed on 16 May 2022)) was used in this study to analyse the complex’s stability. Parameters used in this study included deformability, eigenvalues, covariance, and the B-factors. Deformability measures the ability of the molecule to deform at each of its residues. The eigenvalues are directly proportional to the energy required to deform the structure [The stability of the complex formed from the docking study was evaluated using molecular dynamics. The iMODS server’s normal mode analysis (NMA) ) database was screened for sequences of the disulfide proteins from L. donovani. A total of four protein sequences were identified and retrieved. Each sequence represented a different disulfide isomerase target ). Previous studies have shown that protein sequences with antigenicity scores ≥0.8 could bind to antibodies [To evaluate the probability of these vaccine protein candidates binding to host antibodies , the distibodies , with a tibodies . The rem+ T lymphocytes (CTLs) are potentially vaccine-induced immune effectors due to their killing action on contact with infectious pathogens and through cytokine secretion to activate helper T cells (HTL) [http://www.cbs.dtu.dk/services/NetCTL/ (accessed on 2 May 2022)). A total of 17 CTL epitopes clustered into 9 amino acid sequences was predicted with a COMB (combined) score of greater than 0.75  . As suchhan 0.75 .https://www.iedb.org/ (accessed on 2 May 2022 )) was probed to evaluate specific mouse antigenic sequences with the major histocompatibility (MHC) alleles H-2-Qa2, H-2-Qa1, and H-2-Db. Epitope sequences measuring 14 amino acids long were considered robust, based on a percentile rank score of below 1.5 as previously described [To predict HTL epitopes, the IEDB server  was evaluated since the expression of TLR-4 increases during  epitope . There w epitope . The HTL epitope . Similar epitope . The finhttp://www.imtech.res.in/aghava/abcpred/ (accessed on 3 May 2022)) for B cell epitope prediction under the name LdV. With a set threshold of 0.51, the protein sequence was found to have 235 14mers. All peptides chosen in the sequence were above the threshold value set, as previously described [The constructed vaccine protein was submitted to the ABCpred server  simulation is a technique that provides information about the time-dependent behaviour of any molecular complex by incorporating Newton’s laws of motion. The results of the MD simulation are depicted in −5 and 9.173423 × 10−5 for the vaccine-TLR2 and vaccine-TLR4 complexes, respectively (The eigenvalue of the complexes was predicted to be 1.476206 × 10ectively B. This vectively C. The coectively E represeL. donovani. Imperatively, several studies have employed in silico techniques in the design of potential vaccines/drugs against various diseases [Leishmaniasis is a debilitating and potentially fatal disease, with over 90% seen in Africa . The absdiseases ,54,55,56L. donovani was identified as a potential vaccine candidate. Virtual antigenicity tests of the disulfide isomerase protein sequence indicated that our proposed candidate could be a robust antigenic compound, similar to previous findings [The disulfide isomerase protein sequence from findings ,20,57. Wfindings . Of the L. donovani [L. donovani infection [Epitopes with good immunogenicity scores can trigger immune responses from CTLs . These idonovani . Additiodonovani . HTL epidonovani ,61. Earlnfection . Hence, nfection . Additio+ T cells differentiation, a successful adjuvant must be constructed with a protein developed to facilitate entry into the MHC class I processing pathway [Drosophila [In addition, adjuvants are critical components of vaccine formulations. Adjuvants can facilitate the induction of non-specific innate immunity, leading to the uptake of vaccine antigens by antigen-presenting cells. Antigen-presenting cells then move to secondary lymphoid organs where the long-lasting memory immune responses are inducted and maintained. Coffman and coworkers suggested that for the promotion of functional CD8 pathway . This woosophila . It funcosophila ,66. The To validate the structure and functionality of our proposed vaccine candidate protein, we used GalaxyRefine and PROCHECK . The PROL. donovani. The designed vaccine was highly antigenic, non-allergenic, and possessed desirable physicochemical properties. Molecular docking simulation showed the vaccine could interact with the innate immune response via recognition by the TLRs, while molecular dynamics simulation of the vaccine-TLRs complex also showed the complex formed was stable. The designed vaccine could emerge as a viable option in the development of prophylactic and curative treatments against L. donovani. However, further in vitro and in vivo studies are needed to validate the findings of this study.This study employed immunoinformatics techniques to design an epitope-based vaccine against


Geobacter sulfurreducens biofilms. They state that “In this study, we examined all three nanowires in the anode biofilm of G. sulfurreducens with the goal of defining both their structural and conductive contributions.” (G. sulfurreducens that they studied did not express two of the three nanowire types under consideration. Furthermore, the authors misrepresent previously published studies of their own, as well as other investigators.Ye et al.  present utions.” . Howeverutions.”  did not c-type cytochromes, either OmcS or OmcZ (G. sulfurreducens expressed thin filaments (c-type cytochromes in their ΔPilB strain under the same growth conditions (G. sulfurreducens produced cytochrome-based filaments, but they also presented data that suggested that the outer-surface cytochromes that were expressed were not assembled into filaments.The three nanowires that Ye et al.  consider or OmcZ . Ye et a or OmcZ  demonstrilaments . Howeverilaments  deleted ilaments . Accordiilaments , deletinilaments  previousnditions . Thus, nnditions  fail to G. sulfurreducens (Although OmcS nanowires emanating from cells grown under similar conditions were previously demonstrated in another strain of reducens , it is areducens , 5, thatreducens  had no dG. sulfurreducens biofilms because strains expressing poorly conductive pili were defective in current production (–G. sulfurreducens that can express OmcS nanowires continued to produce OmcS nanowires in the same abundance when it was genetically modified to express poorly conductive pili (G. sulfurreducens strains expressing poorly conductive pili.Previous studies concluded that e-pili plays an important role in long-range electron transport through current-producing oduction –10. Ye eduction – stated tduction –. Ye et aduction –, which dduction –. The mosive pili . Ye et aive pili , as wellG. sulfurreducens and G. metallireducens were defective in current production (Liu et al.  previousoduction . Yet nowoduction  claim thoduction  refutes G. sulfurreducens could express the OmcZ nanowires emanating from cells that their model required.Ye et al.  presenteG. sulfurreducens strain not relevant to their strain without acknowledging that the prior studies also analyzed a ΔPilB mutation made in the type strain background. Ye et al. (Word limit restrictions prevent full discussion of the failure of Ye et al.  to propee et al.  also faie et al. , as welle et al. .