Explore the vast range of titles available.

CSMD1 ( Cub and Sushi Multiple Domains 1 ) is a well-recognized regulator of the complement cascade, an important component of the innate immune response. CSMD1 is highly expressed in the central nervous system (CNS) where emergent functions of the complement pathway modulate neural development and synaptic activity. While a genetic risk factor for neuropsychiatric disorders, the role of CSMD1 in neurodevelopmental disorders is unclear. Through international variant sharing, we identified inherited biallelic CSMD1 variants in eight individuals from six families of diverse ancestry who present with global developmental delay, intellectual disability, microcephaly, and polymicrogyria. We modeled CSMD1 loss-of-function (LOF) pathogenesis in early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells (hESCs). We show that CSMD1 is necessary for neuroepithelial cytoarchitecture and synchronous differentiation. In summary, we identified a critical role for CSMD1 in brain development and biallelic CSMD1 variants as the molecular basis of a previously undefined neurodevelopmental disorder.

Recent advances in protein design have opened avenues for the creation of artificial enzymes needed for biotechnological and pharmaceutical applications. However, designing efficient enzymes remains an unrealized ambition, as the design must incorporate a catalytic apparatus specific for the desired reaction. Here we present a de novo design approach to evolve a minimal carbonic anhydrase mimic. We followed a step-by-step design of first folding the main chain followed by sequence variation for substrate binding and catalysis. To optimize the fold, we designed an αββ protein based on a Zn-finger. We then inverse-designed the sequences to provide stability to the fold along with flexibility of linker regions to optimize Zn binding and substrate hydrolysis. The resultant peptides were synthesized and assessed for Zn and substrate binding affinity by fluorescence and ITC followed by evaluation of catalytic efficiency with UV-based enzyme kinetic assays. We were successful in mimicking carbonic anhydrase activity in a peptide of twenty two residues, using p-nitrophenyl acetate as a CO2 surrogate. Although our design had modest activity, being a simple structure is an advantage for further improvement in efficiency. Our approach opens a way forward to evolving an efficient biocatalyst for any industrial reaction of interest.

Plastic materials are recalcitrant in the open environment, surviving for longer without complete remediation. The current disposal methods of used plastic material are inefficient; consequently, plastic wastes are infiltrating the natural resources of the biosphere. The mixed composition of urban domestic waste with different plastic types makes them unfavorable for recycling; however, natural assimilation in situ is still an option to explore. In this research work, we have utilized previously published reports on the biodegradation of various plastics types and analyzed the pattern of microbial degradation. Our results demonstrate that the biodegradation of plastic material follows the chemical classification of plastic types based on their main molecular backbone. The clustering analysis of various plastic types based on their biodegradation reports has grouped them into two broad categories of C-C (non-hydrolyzable) and C-X (hydrolyzable). The C-C and C-X groups show a statistically significant difference in their biodegradation pattern at the genus level. The Bacilli class of bacteria is found to be reported more often in the C-C category, which is challenging to degrade compared to C-X. Genus enrichment analysis suggests that Pseudomonas and Bacillus from bacteria and Aspergillus and Penicillium from fungi are potential genera for the bioremediation of mixed plastic waste. The lack of uniformity in reporting the results of microbial degradation of plastic also needs to be addressed to enable productive growth in the field. Overall, the result points towards the feasibility of a microbial-based biodegradation solution for mixed plastic waste.

Prion diseases, like Alzheimer’s disease and Parkinson disease, are rapidly progressive neurodegenerative disorders caused by misfolding followed by aggregation and accumulation of protein deposits in neuronal cells. Here we measure intramolecular polypeptide backbone reconfiguration as a way to understand the molecular basis of prion aggregation. Our hypothesis is that when reconfiguration is either much faster or much slower than bimolecular diffusion, biomolecular association is not stable, but as the reconfiguration rate becomes similar to the rate of biomolecular diffusion, the association is more stable and subsequent aggregation is faster. Using the technique of Trp–Cys contact quenching, we investigate the effects of various conditions on reconfiguration dynamics of the Syrian hamster and rabbit prion proteins. This protein exhibits behavior in all three reconfiguration regimes. We conclude that the hamster prion is prone to aggregation at pH 4.4 because its reconfiguration rate is slow enough to expose hydrophobic residues on the same time scale that bimolecular association occurs, whereas the rabbit sequence avoids aggregation by reconfiguring 10 times faster than the hamster sequence.

Recent advances in protein design have opened avenues for the creation of artificial enzymes needed for biotechnological and pharmaceutical applications. However, designing efficient enzymes remains an unrealized ambition, as the design must incorporate a catalytic apparatus specific for the desired reaction. Here we present a de novo design approach to evolve a minimal carbonic anhydrase mimic. We followed a step-by-step design of first folding the main chain followed by sequence variation for substrate binding and catalysis. To optimize the fold, we designed an [alpha][beta][beta] protein based on a Zn-finger. We then inverse-designed the sequences to provide stability to the fold along with flexibility of linker regions to optimize Zn binding and substrate hydrolysis. The resultant peptides were synthesized and assessed for Zn and substrate binding affinity by fluorescence and ITC followed by evaluation of catalytic efficiency with UV-based enzyme kinetic assays. We were successful in mimicking carbonic anhydrase activity in a peptide of twenty two residues, using p-nitrophenyl acetate as a CO.sub.2 surrogate. Although our design had modest activity, being a simple structure is an advantage for further improvement in efficiency. Our approach opens a way forward to evolving an efficient biocatalyst for any industrial reaction of interest.

The interaction between stromal and tumor cells in tumor microenvironment is a crucial factor in Mantle cell lymphoma (MCL) progression and therapy resistance. We have identified a long non-coding RNA, CERS6-AS1, upregulated in MCL and associated with poor overall survival. CERS6-AS1 expression was elevated in primary MCL within stromal microenvironment and in a subset of MCL cells adhered to stromal layer. These stromal-adhered MCL-subsets exhibited cancer stem cell signatures than suspension counterparts. Mechanistically, we found that downregulating CERS6-AS1 in MCL reduced Fibroblast Growth Factor Receptor-1 (FGFR1), expression attributed to loss of its interaction with RNA-binding protein nucleolin. In addition, using in-silico approach, we have discovered a direct interaction between nucleolin and 5’UTR of FGFR1, thereby regulating FGFR1 transcript stability. We discovered a positive association of CERS6-AS1 with cancer stem cell signatures, and Wnt signaling. Building on these, we explored potential therapeutic strategies where combining nucleolin-targeting agent with FGFR1 inhibition significantly contributed to reversing cancer stem cell signatures and abrogated primary MCL cell growth on stromal layer. These findings provide mechanistic insights into regulatory network involving CERS6-AS1, nucleolin, and FGFR1 axis-associated crosstalk between tumor cells and stromal cell interaction and highlights therapeutic potential of targeting a non-coding RNA in MCL.

Medical genomics research performed in diverse population facilitates a better understanding of the genetic basis of developmental disorders, with regional implications for community genetics. Autosomal recessive mitochondrial complex I deficiency (MCID) accounts for a constellation of clinical features, including encephalopathies, myopathies, and Leigh Syndrome. Using whole-exome sequencing, we identified biallelic missense variants in NDUFV1 that encodes the 51-kD subunit of complex I (NADH dehydrogenase) NDUFV1. Mapping the variants on published crystal structures of mitochondrial complex I demonstrate that the novel c.1118T > C (p.(Phe373Ser)) variant is predicted to diminish the affinity of the active pocket of NDUFV1 for FMN that correlates to an early onset of debilitating MCID symptoms. The c.1156C > T (p.(Arg386Cys)) variant is predicted to alter electron shuttling required for energy production and correlate to a disease onset in childhood. NDUFV1 c.1156C > T (p.(Arg386Cys)) represents a founder variant in South Asian populations that have value in prioritizing this variant in a population-specific manner for genetic diagnostic evaluation. In conclusion, our results demonstrate the advantage of analyzing population-specific sequences to understand the disease pathophysiology and prevalence of inherited risk variants in the underrepresented populations.

N-terminal acetyltransferases (NATs) are overexpressed in various cancers. Specifically in lung cancer, human N-α-acetyltransferase D (hNatD) is upregulated and prevents the histone H4 N-terminal serine phosphorylation, leading to the epithelial-to-mesenchymal transition (EMT) of cancer cells. hNatD facilitates histone H4 N-α-terminal serine acetylation and halts the CK2α-mediated serine phosphorylation. In the present study, we report the effects of four N-terminal mutant (S1C, R3C, G4D and G4S) histone H4 peptides on their bindings with hNatD by employing a molecular dynamics simulation. We also used graph theory-based analyses to understand residue correlation and communication in hNatD under the influence of WT and MT H4 peptides. Results show that S1C, R3C and G4S mutant peptides have significant stability at the catalytic site of hNatD. However, S1C, G4D and G4S peptides disrupt hNatD structure. Additionally, intramolecular hydrogen bond analysis reveals greater stability of hNatD in complex with R3C peptide. Further, intermolecular hydrogen bond analysis of acetyl-CoA with hNatD and its RMSD analysis in five complexes indicate that cofactor has greater stability in WT and R3C complexes. Our findings support previously reported experimental study on impacts of H4 mutations on its hNatD-mediated acetylation catalytic efficiency. The betweenness centrality (BC) analysis further gives insight into the hNatD residue communication dynamics that can be exploited to target hNatD using existed or novel drug candidates therapeutically. Competing Interest Statement The authors have declared no competing interest.

The plastic materials are recalcitrant in the open environment, surviving longer without complete remediation. The current disposal methods of used plastic material are not efficient; consequently, plastic wastes are infiltrating the natural resources of the biosphere. A sustaining solution for plastic waste is either recycling or making it part of the earth's biogeochemical cycle. We have collected, manually mined, and analyzed the previous reports on plastic biodegradation. Our results demonstrate that the biodegradation pattern of plastics follows the chemical classification of plastic types. Based on clustering analysis, the distant plastic types are grouped into two broad categories of plastic types, C-C (non-hydrolyzable) and C-X (hydrolyzable). The genus enrichment analysis suggests that Pseudomonas and Bacillus from bacteria and Aspergillus and Penicillium from fungal are potential genera for bioremediation of mixed plastic waste. Overall results have pointed towards a possible solution of mixed plastic waste either in a circular economy or open remediation. The meta-analysis of the reports revealed a historical inclination of biodegradation studies towards C-X type of plastic; however, the C-C class is dominated in overall plastic production. An interactive web portal of reports is hosted at plasticbiodegradation.com for easy access by other researchers for future studies. Competing Interest Statement The authors have declared no competing interest. Footnotes * http://www.plasticbiodegradation.com/