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Fulltext A pan-specific antiserum produced by a novel immunization strategy shows a high spectrum of neutralization against neurotoxic snake venoms

Ratanabanangkoon K, Tan KY, Pruksaphon K, Klinpayom C, Gutiérrez JM, Quraishi NH, et al.

Sci Rep, 2020 07 09;10(1):11261.
PMID: 32647261 DOI: 10.1038/s41598-020-66657-8

Snakebite envenomation is a neglected tropical disease of high mortality and morbidity largely due to insufficient supply of effective and affordable antivenoms. Snake antivenoms are mostly effective against the venoms used in their production. It is thus crucial that effective and affordable antivenom(s) with wide para-specificity, capable of neutralizing the venoms of a large number of snakes, be produced. Here we studied the pan-specific antiserum prepared previously by a novel immunization strategy involving the exposure of horses to a 'diverse toxin repertoire' consisting of 12 neurotoxic Asian snake toxin fractions/ venoms from six species. This antiserum was previously shown to exhibit wide para-specificity by neutralizing 11 homologous and 16 heterologous venoms from Asia and Africa. We now show that the antiserum can neutralize 9 out of 10 additional neurotoxic venoms. Altogether, 36 snake venoms belonging to 10 genera from 4 continents were neutralized by the antiserum. Toxin profiles previously generated using proteomic techniques of these 36 venoms identified α-neurotoxins, β-neurotoxins, and cytotoxins as predominant toxins presumably neutralized by the antiserum. The bases for the wide para-specificity of the antiserum are discussed. These findings indicate that it is feasible to generate antivenoms of wide para-specificity against elapid neurotoxic venoms from different regions in the world and raises the possibility of a universal neurotoxic antivenom. This should reduce the mortality resulting from neurotoxic snakebite envenomation.
Venom proteome of Bungarus sindanus (Sind krait) from Pakistan and in vivo cross-neutralization of toxicity using an Indian polyvalent antivenom

Oh AMF, Tan CH, Tan KY, Quraishi NH, Tan NH

J Proteomics, 2019 02 20;193:243-254.
PMID: 30385415 DOI: 10.1016/j.jprot.2018.10.016

The proteome of the Pakistani B. sindanus venom was investigated with reverse-phase HPLC and nano-ESI-LCMS/MS analysis. At least 36 distinct proteins belonging to 8 toxin protein families were identified. Three-finger toxin (3FTx), phospholipase A2 (including β-bungarotoxin A-chains) and Kunitz-type serine protease inhibitor (KSPI) were the most abundant, constituting ~95% of total venom proteins. The other toxin proteins of low abundance are snake venom metalloproteinase (SVMP), L-amino acid oxidase (LAAO), acetylcholinesterase (AChE), vespryn and cysteine-rich secretory protein (CRiSP). The venom was highly lethal to mice with LD50 values of 0.04 μg/g (intravenous) and 0.15 μg/g (subcutaneous). The 3FTx proteins are diverse, comprising kappa-neurotoxins, neurotoxin-like protein, non-conventional toxins and muscarinic toxin-like proteins. Kappa-neurotoxins and β-bungarotoxins represent the major toxins that mediate neurotoxicity in B. sindanus envenoming. Alpha-bungarotoxin, commonly present in the Southeast Asian krait venoms, was undetected. The Indian VINS Polyvalent Antivenom (VPAV) was immunoreactive toward the venom, and it moderately cross-neutralized the venom lethality (potency = 0.25 mg/ml). VPAV was able to reverse the neurotoxicity and prevent death in experimentally envenomed mice, but the recovery time was long. The unique toxin composition of B. sindanus venom may be considered in the formulation of a more effective pan-regional, polyspecific antivenom. BIOLOGICAL SIGNIFICANCE: Bungarus sindanus, an endemic krait species distributed mainly in the Sindh Province of Pakistan is a cause of snake envenomation. Its specific antivenom is, however, lacking. The proteomic study of its venom revealed a substantial presence of κ-bungarotoxins and β-bungarotoxins. The toxin profile corroborates the potent neurotoxicity and lethality of the venom tested in vivo. The heterologous Indian VINS polyvalent antivenom (VPAV) cross-reacted with B. sindanus venom and cross-neutralized the venom neurotoxicity and lethality in mice, albeit the efficacy was moderate. The findings imply that B. sindanus and the phylogenetically related B. caeruleus of India share certain venom epitopes. Research should be advanced to improve the efficacy spectrum of a pan-regional polyspecific antivenom.
Elucidating the biogeographical variation of the venom of Naja naja (spectacled cobra) from Pakistan through a venom-decomplexing proteomic study

Wong KY, Tan CH, Tan KY, Quraishi NH, Tan NH

J Proteomics, 2018 03 20;175:156-173.
PMID: 29278784 DOI: 10.1016/j.jprot.2017.12.012

Naja naja is a medically important species that is distributed widely in South Asia. Its venom lethality and neutralization profile have been reported to vary markedly, but the understanding of this phenomenon has been limited without a comprehensive venom profile for the Pakistani N. naja. This study set to investigate the venom proteome of Pakistani N. naja applying reverse-phase HPLC, SDS-PAGE, mass spectrometry and data-mining approaches. The venom enzymatics and antigen binding activities were also studied. A total of 55 venom proteins comprising 11 toxin families were identified, with three-finger toxins (75.29%) being the predominant component, followed by phospholipase A2 (14.24%) and other proteins (<5%). The enzyme activities of most of the venom components were also detected in this work. The high abundance of long neurotoxins (LNTX, 21.61%) in the Pakistani N. naja venom is varied from that reported for N. naja venoms from other geographical origins. The venom exhibited high immunoreactivity toward Naja kaouthia monovalent antivenom (NKMAV), which was raised against the LNTX-predominated heterologous Thai N. kaouthia venom. Together, the findings show that the Pakistani N. naja venom is predominated by LNTX, and this unique property correlates with its high lethality and effective neutralization by the heterologous NKMAV.
BIOLOGICAL SIGNIFICANCE: This study reveals the compositional details of the venom proteome of Pakistani spectacled cobra (Naja naja). The protein subtypes, proteoforms, and relative abundances of individual proteins were comprehensively revealed in this study, following a venom decomplexing proteomic approach. The Pakistani cobra venom is unique among the rest of the N. naja venom composition reported thus far, as it contains a high abundance of alpha-neurotoxins (predominated by long neurotoxins); these are highly potent post-synaptic neuromuscular blockers that cause paralysis and are principal toxins that account for the high lethality of the venom (LD50=0.2μg/g in mice). In contrast, previous reports showed that the N. naja venoms of India and Sri Lanka had a lower content of neurotoxins and a relatively higher value of LD50. The Pakistani cobra venom demonstrated sufficient immunoreactivity toward three antivenom products manufactured outside Pakistan (including the Indian product VINS), however the potency of antigen binding was the highest toward Naja kaouthia monovalent antivenom, a heterologous antivenom raised against a long neurotoxin-predominated venom of the Thai monocled cobra. From the practical standpoint, the findings indicate that the treatment of N. naja envenomation in Pakistan may be improved by the production of a locale-specific antivenom, in which the antivenom produced contains more antibodies that can target and react more specifically with the highly abundant lethal neurotoxins in the Pakistani N. naja venom.
Fulltext Efficient models for enhancing the link adaptation performance of LTE/LTE-A networks

Bin-Salem AA, Wan TC, Naeem H, Anbar M, Hanshi SM, Redjaimia A

EURASIP J Wirel Commun Netw, 2022;2022(1):10.
PMID: 35132311 DOI: 10.1186/s13638-022-02091-w

Link adaptation (LA) is the ability to adapt the modulation scheme (MS) and the coding rate of the error correction in accordance with the quality of the radio link. The MS plays an important role in enhancing the performance of LTE/LTE-A, which is typically dependent on the received signal to noise ratio (SNR). However, using the SNR to select the proper MSs is not enough given that adaptive MSs are sensitive to error. Meanwhile, non-optimal MS selection may seriously impair the system performance and hence degrades LA. In LTE/ LTE-A, the LA system must be designed and optimized in accordance with the characteristics of the physical (e.g., MSs) and MAC layers (e.g., Packet loss) to enhance the channel efficiency and throughput. Accordingly, this study proposes using two LA models to overcome the problem. The first model, named the cross-layer link adaptation (CLLA) model, is based on the downward cross-layer approach. This model is designed to overcome the accuracy issue of adaptive modulation in existing systems and improve the channel efficiency and throughput. The second model, named the Markov decision process over the CLLA (MDP-CLLA) model, is designed to improve on the selection of modulation levels. Besides that, our previous contribution, namely the modified alpha-Shannon capacity formula, is adopted as part of the MDP-CLLA model to enhance the link adaptation of LTE/LTE-A. The effectiveness of the proposed models is evaluated in terms of throughput and packet loss for different packet sizes using the MATLAB and Simulink environments for the single input single output (SISO) mode for transmissions over Rayleigh fading channels. In addition, phase productivity, which is defined as the multiplication of the total throughput for a specific modulation with the difference between adjacent modulation SNR threshold values, is used to determine the best model for specific packet sizes in addition to determine the optimal packet size for specific packet sizes among models. Results generally showed that the throughput improved from 87.5 to 89.6% for (QPSK → 16-QAM) and from 0 to 43.3% for (16-QAM → 64-QAM) modulation transitions, respectively, using the CLLA model when compared with the existing system. Moreover, the throughput using the MDP-CLLA model was improved by 87.5-88.6% and by 0-43.2% for the (QPSK → 16-QAM)and (16-QAM → 64-QAM) modulation transitions, respectively, when compared with the CLLA model and the existing system. Results were also validated for each model via the summation of the phase productivity for every modulation at specific packet sizes, followed by the application one-way analysis of variance (ANOVA) statistical analysis with a post hoc test, to prove that the MDP-CLLA model improves with best high efficiency than the CLLA model and the existing system.