Palasuberniam, P. | bioRxiv Science

bioRxiv2025

Antigenic Divergence of Cobra Short-chain α-Neurotoxins: Implications for Regional Antivenom Effectiveness in Southeast Asia

Short-chain -neurotoxins (SNTXs) are the principal neurotoxic components in several Asiatic cobras, including Naja atra, Naja philippinensis, and N. samarensis. Although structurally conserved, SNTXs exhibit marked antigenic variation that can limit the effectiveness of regional antivenoms used for snakebite envenoming in Asia. Here, we evaluated the immunoreactivity of the Philippine Cobra Antivenom (PCAV) and three regional products--Naja kaouthia Monovalent Antivenom (NkMAV), Neuro Bivalent Antivenom (NBAV), and Indonesian SABU--against a panel of cobra venoms and purified -neurotoxins. PCAV bound strongly to homologous N. philippinensis SNTX but showed weak cross-reactivity with SNTXs from N. kaouthia, N. sputatrix, and N. atra, and minimal recognition of marine elapid SNTXs and long-chain -neurotoxins (LNTXs) of Monocled Cobra as well as King Cobra. Conversely, NkMAV and NBAV recognized mainland Asian SNTXs more broadly but reacted poorly with the Philippine cobra toxin. Hierarchical clustering of normalized immunoreactivity delineated two major SNTX antigenic subtypes corresponding to Philippine versus continental Asian lineages. Peptide sequence analysis unmasked two distinct loop-II motifs (28WWS-TII37 and 28RWR-YRT37) associated with these divergent immunotypes. Phylogenetic reconstruction suggests that the Philippine cobras retain an ancestral SNTX motif, while Sundaic and East Asian cobras have diversified to employ another major SNTX form. Epitope prediction further revealed differences in surface exposure and accessibility that help explain the limited cross-neutralization across antivenoms. These findings demonstrate a clear antigenic dichotomy among Asian cobra SNTXs, which underlies species-specific antivenom effectiveness and highlights the need to incorporate representative SNTX variants into immunogen formulations to improve regional antivenom coverage.

biochemistry↗

bioRxiv2017

Building a schizophrenia genetic network: Evidence that Transcription Factor 4 regulates schizophrenia risk genes.

The transcription factor 4 (TCF4) locus is a robust association finding with schizophrenia (SZ), but little is known about the genes regulated by the encoded transcription factor. Therefore, we conducted chromatin immunoprecipitation sequencing (ChIP-seq) of TCF4 in neural-derived (SH-SY5Y) cells to identify genome-wide TCF4 binding sites, followed by data integration with SZ association findings. We identified 11,322 TCF4 binding sites overlapping in two ChIP-seq experiments. These sites are significantly enriched for the TCF4 Ebox binding motif (>85% having [≥]1 Ebox) and implicate a gene set enriched for genes down-regulated in TCF4 siRNA knockdown experiments, indicating the validity of our findings. The TCF4 gene set was also enriched among 1) Gene Ontology categories such as axon/neuronal development, 2) genes preferentially expressed in brain, in particular pyramidal neurons of the somatosensory cortex, and 3) genes down-regulated in post-mortem brain tissue from SZ patients (OR=2.8, permutation p<4x10-5). Considering genomic alignments, TCF4 binding sites significantly overlapped those for neural DNA binding proteins such as FOXP2 and the SZ-associated EP300. TCF4 binding sites were modestly enriched among SZ risk loci from the Psychiatric Genomic Consortium (OR=1.56, p=0.03). In total, 130 TCF4 binding sites occurred in 39 of the 108 regions published in 2014. Thirteen genes within the 108 loci had both a TCF4 binding site {+/-}10kb and were differentially expressed in siRNA knockdown experiments of TCF4, suggesting direct TCF4 regulation. These findings confirm TCF4 as an important regulator of neural genes and point towards functional interactions with potential relevance for SZ.

genetics↗