Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy

Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic Aciduria type C and Homocystinuria (MMACHC). Recently, mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) were shown to result in cellular phenocopies of cblC. Since HCFC1/RONIN jointly regulate MMACHC, patients with mutations in these factors suffer from reduced MMACHC expression and exhibit a cblC-like disease. However, additional de-regulated genes and the resulting pathophysiology is unknown. Therefore, we have generated mouse models of this disease. In addition to exhibiting loss of Mmachc, metabolic perturbations, and developmental defects previously observed in cblC, we uncovered reduced expression of target genes that encode ribosome protein subunits. We also identified specific phenotypes that we ascribe to deregulation of ribosome biogenesis impacting normal translation during development. These findings identify HCFC1/RONIN as transcriptional regulators of ribosome biogenesis during development and their mutation results in complex syndromes exhibiting aspects of both cblC and ribosomopathies.

Reduced sera neutralization to Omicron SARS-CoV-2 by both inactivated and protein subunit vaccines and the convalescents

Omicron variant continues to spread all over the world. There are lots of scientific questions remaining to be answered for such a devastating variant. There are a dozen of vaccines already in clinical use. The very urgent scientific question would be whether or not these vaccines can protect Omicron variant. Here, we tested the sera from both convalescents and vaccine recipients receiving either inactivated or protein subunits vaccines (CoronaVac from Sinovac, or BBIBP-CoV from Sinopharm, or ZF2001 from Zhifei longcom) for the binding antibody titers (ELISA) and neutralization antibodies titers (pseudovirus neutralization assay). We showed that Omicron do have severe immune escape in convalescents, with 15 of 16 were negative in neutralization. By contrast, in vaccinees who received three jabs of inactivated or protein subunit vaccine, the neutralizing activity was much better preserved. Especially in the ZF2001 group with an extended period of the second and third jab (4-6 months) remains 100% positive in Omicron neutralization, with only 3.1-folds reduction in neutralizing antibody (NAb) titer. In this case, we proposed that, the multi-boost strategy with an extended interval between the second and third jab for immune maturation would be beneficial for NAb against devastating variants such as Omicron.

Supramolecular assembly of chloroplast NAD(P)H dehydrogenase-like complex with photosystem I from Arabidopsis thaliana

Cyclic electron transport/flow (CET/CEF) in chloroplasts is a regulatory mechanism crucial for optimization of plant photosynthetic efficiency. CET is catalyzed by a membrane-embedded NAD(P)H dehydrogenase-like (NDH) complex containing at least 29 protein subunits and associating with photosystem I (PSI) to form the NDH-PSI supercomplex. Here we report the 3.9 angstrom resolution structure of Arabidopsis thaliana NDH-PSI (AtNDH-PSI) supercomplex. We have constructed structural models for 26 AtNDH subunits, among which 11 subunits are unique to chloroplast and stabilize the core part of NDH complex. In the supercomplex, one NDH can bind up to two PSI-LHCI complexes at both sides of its membrane arm. Two minor LHCIs, Lhca5 and Lhca6, each present in one PSI-LHCI, interact with NDH and contribute to the supercomplex formation and stabilization. Our results showed structural details of the supercomplex assembly and provide molecular basis for further investigation of the regulatory mechanism of CEF in plants.

The Potential of Snail Seromucous and Chitosan as Bioimunomodulator for Tuberculosis Therapy

Tuberculosis (TB) as a global emergency is a chronic disease caused by Mycobacterium tuberculosis (Mtb). Mtb plays an important role in inducing or suppressing the production of Interferon Gamma (IFNG) and IL-4 in the regulation of TB homeostasis and pathogenesis. The bioactive compounds of the snail seromucous (Achatina fulica Ferussac) and chitosan function as biological response modifiers. The study aimed to determine the potential effectiveness of snail seromucous and chitosan as bio-immunomodulator for TB therapy. The research method was based on the results of laboratory experiments with the physic-chemical, biochemical, microbiological examination, snail seromucous protein profile, lymphocyte proliferation, measurement of IFNG, and IL-4 levels. The results of the physic-chemical examination of the snail seromucous showed a specific gravity of 1.010; pH 8, glucose 16 mg/dL; cholesterol 9 mg/dL; protein 2.8 mg/dL and heavy metals (Pb, Cu, Hg, Al) negative. The results of microbiological tests showed that a 100% concentration of snail seromucous was antimicrobial against Staphylococcus aureus, Candida albicans, and Pseudomonas aeruginosa. The protein profile of snail seromucous shows that there are 3 protein subunits, namely the range 55 - 72 kDa and 1 specific protein sub-unit 43 kDa as a bioactive compound achasin sulfate. Addition of chitosan dose of 65 µg/mL; snail seromucous dose of 65 µg/mL and a mixture of chitosan (65 µg/mL): snail seromucous (65 µg/mL) ratio 1: 1, can increase lymphocyte proliferation; optimum levels of IFN-γ and IL-4. Snail seromucous and chitosan are effective immunomodulators and potential candidates for TB therapy.

Counting on COVID-19 Vaccine: Insights into the Current Strategies, Progress and Future Challenges

The emergence of a novel coronavirus viz., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019 and its subsequent substantial spread produced the coronavirus disease 2019 (COVID-19) pandemic worldwide. Given its unprecedented infectivity and pathogenicity, the COVID-19 pandemic had a devastating impact on human health, and its clinical management has been a great challenge, which has led to the development and speedy trials of several vaccine candidates against SARS-CoV-2 at an exceptional pace. As a result, several COVID-19 vaccines were made commercially available in the first half of 2021. Although several COVID-19 vaccines showed promising results, crucial insights into their epidemiology, protective mechanisms, and the propensities of reinfection are not largely reviewed. In the present report, we provided insights into the prospects of vaccination against COVID-19 and assessed diverse vaccination strategies including DNA, mRNA, protein subunits, vector-based, live attenuated, and inactivated whole/viral particle-based vaccines. Next, we reviewed major aspects of various available vaccines approved by the World Health Organization and by the local administrations to use against COVID-19. Moreover, we comprehensively assessed the success of these approved vaccines and also their untoward effects, including the possibility of reinfection. We also provided an update on the vaccines that are under development and could be promising candidates in the future. Conclusively, we provided insights into the COVID-19 vaccine epidemiology, their potency, and propensity for SARS-CoV-2 reinfection, while a careful review of their current status, strategies, success, and future challenges was also presented.

Core and rod structures of a thermophilic cyanobacterial light-harvesting phycobilisome

Cyanobacteria, glaucophytes, and rhodophytes utilize giant, light-harvesting phycobilisomes (PBSs) for capturing solar energy and conveying it to photosynthetic reaction centers. PBSs are compositionally and structurally diverse, and exceedingly complex, all of which pose a challenge for a comprehensive understanding of their function. To date, three detailed architectures of PBSs by cryo-electron microscopy (cryo-EM) have been described: a hemiellipsoidal type, a block-type from rhodophytes, and a cyanobacterial hemidiscoidal-type. Here, we report cryo-EM structures of a pentacylindrical allophycocyanin core and phycocyanin-containing rod of a thermophilic cyanobacterial hemidiscoidal PBS. The structures define the spatial arrangement of protein subunits and chromophores, crucial for deciphering the energy transfer mechanism. They reveal how the pentacylindrical core is formed, identify key interactions between linker proteins and the bilin chromophores, and indicate pathways for unidirectional energy transfer.

Rapid cell-free characterization of multi-subunit CRISPR effectors and transposons

CRISPR-Cas biology and technologies have been largely shaped to-date by the characterization and use of single-effector nucleases. In contrast, multi-subunit effectors dominate natural systems, represent emerging technologies, and were recently associated with RNA-guided DNA transposition. This disconnect stems from the challenge of working with multiple protein subunits in vitro and in vivo. Here, we apply cell-free transcription-translation (TXTL) to radically accelerate the characterization of multi-subunit CRISPR effectors and transposons. Numerous DNA constructs can be combined in one TXTL reaction, yielding defined biomolecular readouts in hours. Using TXTL, we mined phylogenetically diverse I-E effectors, interrogated extensively self-targeting I-C and I-F systems, and elucidated targeting rules for I-B and I-F CRISPR transposons using only DNA-binding components. We further recapitulated DNA transposition in TXTL, which helped reveal a distinct branch of I-B CRISPR transposons. These capabilities will facilitate the study and exploitation of the broad yet underexplored diversity of CRISPR-Cas systems and transposons.

Matrix-GLA-Protein and Vascular Calcification: Can Diet Influence the Consequences of Matrix GLA Protein Inactivation? A Review

In vascular calcification, as a physiological process, intimal arterial calcification (IAC) associated with increased cardiovascular risk is distinguished from medial arterial calcification (MAC) localized mainly in the lamina elatica interna, which are not only based on different pathophysiological mechanisms. They also lead to different cardiovascular diseases. While intimal arterial calcification involves inflammation and lipid accumulation, a calcification process similar to desmal ossification plays the main role in medial arterial calcification. In this context, the phenotype change of smooth muscle cells from muscular type to synthesizing form in the tunica media is considered to be of great importance, which puts the matrix GLA protein, mainly involved in bone metabolism, in the center of interest. The present review work elucidates the molecular biological basis of interaction of matrix GLA protein subunits in the pathogenesis of vascular calcifications and the influence of diet on the consequences of underactivation of matrix GLA protein.

Celiac Disease and Its Association with Organ-Specific Auto-Immune Diseases

Wheat is one of the most consumed foods in the world. Although it is extremely nutrient rich for us humans, some of us have great difficulties in completely digesting its protein subunits. This review aims to understand the onset of Celiac Disease and its association with several other auto-immune diseases. The gliadin molecule, undigested in the small intestine, over time, ruptures the villi lining of the intestinal wall and enters the bloodstream which in turn activates the body's immune response. In some patients with the presence of HLA DQ2/DQ8 genes, this immune response results in Celiac Disease. Notably, researchers over the past several decades have found several links between Celiac Disease and multiple auto-immune diseases. Diabetes is one such auto-immune disease which has shown multiple associations with Celiac Disease. Similarly, in this review paper, we are critically analyzing the association of Celiac Disease with some of the most common autoimmune diseases namely Type-1 Diabetes, Multiple Sclerosis, Autism and Inflammatory Bowel Disease. In this paper, we have shown a clear correlation of celiac disease with several other auto-immune diseases. Further study is needed to understand the bidirectional association of Celiac Disease with different auto-immune diseases.

Optical Detection of SARS-CoV-2 Utilizing Antigen-Antibody Binding Interactions

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease (COVID-19) pandemic, is sweeping the world today. This study investigates the optical detection of SARS-CoV-2, utilizing the antigen-antibody binding interactions utilizing a light source from a smart phone and a portable spectrophotometer. The proof-of-concept is shown by detecting soluble preparations of spike protein subunits from SARS-CoV-2, followed by detection of the actual binding potential of the SARS-CoV-2 proteins with their corresponding antigens. The measured binding interactions for RBD and NCP proteins with their corresponding antibodies under different conditions have been measured and analyzed. Based on these observations, a “hump or spike” in light intensity is observed when a specific molecular interaction takes place between two proteins. The optical responses could further be analyzed using the principle component analysis technique to enhance and allows precise detection of the specific target in a multi-protein mixture.