The human intestinal microbiota is a plethora of diverse microbial species, wherein certain bacteria considered as driver bacteria with procarcinogenic features contribute directly toward colonic epithelium cell damage to initiate colorectal carcinogenesis. However, some bacteria, in particular Fusobacterium nucleatum, which is otherwise a normal resident of the oral microflora and a relatively poor colonizer of the healthy gut, have also been considered to play a role in the development of colorectal cancer. Many studies have reported that F. nucleatum is associated with colorectal adenomas and advanced-stage colorectal cancer, but its precise role in the early stages of colorectal tumorigenesis is poorly understood. Here, we review some of the important features of F. nucleatum, its association with inflammatory bowel disease, modulation of the tumor-immune microenvironment, and E-cadherin/β-catenin signaling.

Alpha1-antitrypsin (α1AT) is an abundant serine-protease inhibitor in circulation. It has an important role in neutralizing the neutrophil elastase activity. Different pathogenic point mutations like Z^(E342K)-α1AT have been implicated in the development of liver cirrhosis and Chronic Obstructive Pulmonary Disease (COPD), the latter being a cluster of progressive lung diseases including chronic bronchitis and emphysema. M3-α1AT (376Glu > Asp) is another variant of α1AT which so far is largely being considered as normal though increased frequency of the variant has been reported in many human diseases including COPD. We also observed increased frequency of M3-α1AT in COPD cases in Kashmiri population. The frequency of heterozygous (AC) genotype in cases and controls was 58.57% and 27.61% (odds-ratio 6.53 (2.27–15.21); p < 0.0001) respectively, while homozygous CC genotype was found to be 21.42% and 6.66% (odds-ratio 10.56 (3.63–18.64); p < 0.0001) respectively. Comparative in vitro investigations that include trypsin‒antitrypsin assay, Circular Dichroism spectroscopy and dynamic light scattering performed on wild-type (M-α1AT), M3-α1AT, and Z-α1AT proteins along with the molecular dynamics simulations revealed that M3-α1AT has properties similar to Z-α1AT capable of forming aggregates of varied size. Our maiden observations suggest that M3-α1AT may contribute to the pathogenesis of COPD and other disorders by mechanisms that warrant further investigations.

Furin cleavage-site (CS) present between the S1/S2 junction in SARS-CoV2 spike (S) protein is critical to drive the fusion of SARS-CoV2 with the host cell. SARS-CoV2 falls in the sarbecovirus lineage that doesn’t comprise of furin CS and therefore makes its origin enigmatic. The available wild-type (Wt) SARS-CoV2 S protein with PDB ID: 6yvb lacks a stretch of amino acid including furin CS as well. All investigators till date have shown this stretch existing in the form of a loop. We are for the first time reporting that this stretch comprises of 14 amino acid residues (677QTNSPRRARSVASQ689), forming an antiparallel β-sheet comprising of PRRAR furin CS. We observed the presence of this antiparallel β-sheet in MERS spike protein as well. While switching over from Wt. SARS-CoV2 with PRRAR furin CS to B.1.1.7 variant with HRRAR furin CS, we found 3% increase in the percentage content of β stands. Interestingly, we found that the change of B.1.1.7 to B.1.617 variant comprising of RRRAR furin CS shifted the percentage secondary structure back to that found in Wt. SARS-CoV2. We anticipate that this β-sheet is used as a docking site by host cell proteases to act on furin-CS. Additionally, we studied the interaction of modeled SARS-CoV2 S protein with transmembrane protease, serine 2 (TMPRSS2), and furin proteases, which clearly highlighted that these proteases exclusively uses furin CS located in β-sheet to cleave the SARS-CoV2 S protein at its S1/S2 junction.

Furin cleavage-site (CS) present between the S1/S2 junction in SARS-CoV2 spike (S) protein is critical to drive the fusion of SARS-CoV2 with the host cell. SARS-CoV2 falls in the sarbecovirus lineage that doesn’t comprise of furin CS and therefore makes its origin enigmatic. The available wild-type (Wt) SARS-CoV2 S protein with PDB ID: 6yvb lacks a stretch of amino acid including furin CS as well. All investigators till date have shown this stretch existing in the form of a loop. We are for the first time reporting that this stretch comprises of 14 amino acid residues (677QTNSPRRARSVASQ689), forming an antiparallel β-sheet comprising of PRRAR furin CS. We observed the presence of this antiparallel β-sheet in MERS spike protein as well. While switching over from Wt. SARS-CoV2 with PRRAR furin CS to B.1.1.7 variant with HRRAR furin CS, we found 3% increase in the percentage content of β stands. Interestingly, we found that the change of B.1.1.7 to B.1.617 variant comprising of RRRAR furin CS shifted the percentage secondary structure back to that found in Wt. SARS-CoV2. We anticipate that this β-sheet is used as a docking site by host cell proteases to act on furin-CS. Additionally, we studied the interaction of modeled SARS-CoV2 S protein with transmembrane protease, serine 2 (TMPRSS2), and furin proteases, which clearly highlighted that these proteases exclusively uses furin CS located in β-sheet to cleave the SARS-CoV2 S protein at its S1/S2 junction.