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2022 ◽  
Author(s):  
Grant M Zane ◽  
Mark A Silveria ◽  
Nancy L Meyer ◽  
Tommi A White ◽  
Michael S Chapman

Adeno-associated virus (AAV) is the vector of choice for several approved gene therapy treatments and is the basis for many ongoing clinical trials. Various strains of AAV exist (referred to as serotypes), each with their own transfection characteristics. Here, we present a high-resolution cryo-electron microscopy structure (2.2 Å) for AAV serotype 4 (AAV4). The receptor responsible for transduction of the AAV4 clade of AAV viruses (including AAV11, 12 and rh32.33) is unknown. Other AAVs interact with the same cell receptor, Adeno-associated virus receptor (AAVR), in one of two different ways. AAV5-like viruses interact exclusively with the polycystic kidney disease-like [PKD]-1 domain of AAVR while most other AAVs interact primarily with the PKD2 domain. A comparison of the present AAV4 structure with prior corresponding structures of AAV5, AAV2 and AAV1 in complex with AAVR, provides a foundation for understanding why the AAV4-like clade is unable to interact with either PKD1 or PKD2. The conformation of the AAV4 capsid in variable regions I, III, IV and V on the viral surface appears to be sufficiently different from AAV2 to ablate binding with PKD2. Differences between AAV4 and AAV5 in variable region VII appear sufficient to exclude binding with PKD1.


Diagnostics ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 147
Author(s):  
Sergei A. Kiryanov ◽  
Tatiana A. Levina ◽  
Maria V. Konopleva ◽  
Anatoly P. Suslov

Sensitive and reliable diagnostic test systems based on real-time PCR are of great importance in the fight against the ongoing SARS-CoV-2 pandemic. The genetic variability of the SARS-CoV-2 virus leads to the accumulation of mutations, some of which may affect the sensitivity of modern PCR assays. The aim of this study was to search in Russian clinical samples for new mutations in SARS-CoV-2 gene N that can affect the detection by RT-PCR. In this study, the polymorphisms in the regions of the target gene N causing failed or poor detection of the target N in the RT-PCR assay on 12 selected samples were detected. Sequencing the entire N and E genes in these samples along with other 195 samples that were positive for both target regions was performed. Here, we identified a number of nonsynonymous mutations and one novel deletion in the N gene that affected the ability to detect a target in the N gene as well a few mutations in the E gene of SARS-CoV-2 that did not affect detection. Sequencing revealed that majority of the mutations in the N gene were located in the variable region between positions 193 and 235 aa, inside and nearby the phosphorylated serine-rich region of the protein N. This study highlights the importance of the further characterization of the genetic variability and evolution of gene N, the most common target for detecting SARS-CoV-2. The use of at least two targets for detecting SARS-CoV-2, including one for the E gene, will be necessary for reliable diagnostics.


Biomolecules ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 61
Author(s):  
Valentyn Oksenych ◽  
Jeremy A. Daniel

B lymphocyte development has two DNA recombination processes: V(D)J recombination of the immunoglobulin (Igh) gene variable region, and class switching of the Igh constant regions from IgM to IgG, IgA, or IgE. V(D)J recombination is required for the successful maturation of B cells from pro-B to pre-B to immature-B and then to mature B cells in the bone marrow. CSR occurs outside of the bone marrow when mature B cells migrate to peripheral lymphoid organs, such as spleen and lymph nodes. Both V(D)J recombination and CSR depend on an open chromatin state that makes DNA accessible to specific enzymes, recombination activating gene (RAG), and activation-induced cytidine deaminase (AID). Acetyltransferases GCN5 and PCAF possess redundant functions acetylating histone H3 lysine 9 (H3K9). Here, we generated a mouse model that lacked both GCN5 and PCAF in B cells. Double-deficient mice possessed low levels of mature B cells in the bone marrow and peripheral organs, an accumulation of pro-B cells in bone marrow, and reduced CSR levels. We concluded that both GCN5 and PCAF are required for B-cell development in vivo.


2021 ◽  
Vol 10 (1) ◽  
pp. 88
Author(s):  
Songhee Lee ◽  
Heesang You ◽  
Yeongju Lee ◽  
Haingwoon Baik ◽  
Jeankyung Paik ◽  
...  

Human gut microbiota are involved in different metabolic processes, such as digestion and nutrient synthesis, among others. For the elderly, supplements are a major means of maintaining health and improving intestinal homeostasis. In this study, 51 elderly women were administered MPRO3 (n = 17), a placebo (n = 16), or both (MPRO3: 1 week, placebo: 3 weeks; n = 18) for 4 weeks. The fecal microbiota were analyzed by sequencing the 16S rRNA gene V3–V4 super-variable region. The dietary fiber intake increased, and glucose levels decreased with 4-week MPRO3 intake. Reflux, indigestion, and diarrhea syndromes gradually improved with MPRO3 intake, whereas constipation was maintained. The stool shape also improved. Bifidobacterium animalis, B. pseudolongum, Lactobacillus plantarum, and L. paracasei were relatively more abundant after 4 weeks of MPRO3 intake than in those subjects after a 1-week intake. Bifidobacterium and B. longum abundances increased after 1 week of MPRO3 intake but decreased when the intake was discontinued. Among different modules and pathways, all 10 modules analyzed showed a relatively high association with 4-week MPRO3 intake. The mineral absorption pathway and cortisol biosynthesis and secretion pathways correlated with the B. animalis and B. pseudolongum abundances at 4 weeks. Therefore, 4-week MPRO3 intake decreased the fasting blood glucose level and improved intestinal health and metabolism.


Author(s):  
Adeyinka Adedeji ◽  
Anvou Jambol ◽  
R. Weka ◽  
Muwanika V.B. ◽  
Pam Luka ◽  
...  

African swine fever (ASF) is the most lethal disease of pigs caused by ASF virus (ASFV) with severe economic implications and threat to food security in endemic countries. Between 2016 and 2018, several ASF outbreaks were reported throughout pig producing States in Nigeria. This study was designed to identify the ASFV genotypes responsible for these outbreaks and the transmission pathways of the virus during this period. Twenty-two ASFV-positive samples collected during passive surveillance in eight States of Nigeria were characterized using 3 partial genes sequences of the virus. The genes were: p72 capsid protein of the B646L, p54 envelope protein of E183L, and the central variable region (CVR) within B602L of ASFV. Phylogenetic analysis based on p72 and p54 revealed ASFV genotype I as the circulating virus. Sequence analysis of the CVR of B602L revealed genetic variations with six ASFV variants namely: Tet-15, Tet-20a, Tet-21b, Tet-27, Tet-31 and Tet-34, thus increasing the overall genetic diversity of ASFV in Nigeria. Three of these variants: Tet-21b, Tet-31 and Tet-34 were identified for the first time in Nigeria. The new variants of ASFV genotype I were identified in the States of Enugu, Imo, Plateau and Taraba, while co-circulation of multiple variants of ASFV genotype I were recorded in Plateau and Benue States. The high genetic diversity, emergence and increasing recovery of new variants of genotype I in Nigeria should be a concern given that ASFV is a relatively stable DNA virus. The epidemiological implications of these findings require further investigation.


Author(s):  
Valentyn Oksenych ◽  
Dan Su ◽  
Jeremy A. Daniel

B lymphocyte development has two DNA recombination processes: V(D)J recombination of the immunoglobulin (Igh) gene variable region and class switching of the Igh constant regions from IgM to IgG, IgA, or IgE. V(D)J recombination is required for successful maturation of B cells from pro-B to pre-B to immature-B and then to mature B cells in the bone marrow. CSR occurs outside of the bone marrow when mature B cells migrate to peripheral lymphoid organs, such as spleen and lymph nodes. Both V(D)J recombination and CSR depend on an “open chromatin” state that makes DNA accessible to specific enzymes, recombination activating gene (RAG), and activation-induced cytidine deaminase (AID). Acetyltransferases GCN5 and PCAF possess redundant functions acetylating histone H3 lysine 9 (H3K9). Here, we generated a mouse model that lacks both GCN5 and PCAF in B cells. We found that double-deficient mice possess low levels of mature B cells in the bone marrow and peripheral organs, an accumulation of pro-B cells in bone marrow, and reduced CSR levels. We conclude that both GCN5 and PCAF are required for B cell development in vivo.


Author(s):  
Valentyn Oksenych ◽  
Dan Su ◽  
Jeremy Austin Daniel

B lymphocyte development has two DNA recombination processes: V(D)J recombination of the immunoglobulin (Igh) gene variable region and class switching of the Igh constant regions from IgM to IgG, IgA, or IgE. V(D)J recombination is required for successful maturation of B cells from pro-B to pre-B to immature-B and then to mature B cells in the bone marrow. CSR occurs outside of the bone marrow when mature B cells migrate to peripheral lymphoid organs, such as spleen and lymph nodes. Both V(D)J recombination and CSR depend on an “open chromatin” state that makes DNA accessible to specific enzymes, recombination activating gene (RAG), and activation-induced cytidine deaminase (AID). Acetyltransferases GCN5 and PCAF possess redundant functions acetylating histone H3 lysine 9 (H3K9). Here, we generated a mouse model that lacks both GCN5 and PCAF in B cells. We found that double-deficient mice possess low levels of mature B cells in the bone marrow and peripheral organs, an accumulation of pro-B cells in bone marrow, and reduced CSR levels. We conclude that both GCN5 and PCAF are required for B cell development in vivo.


2021 ◽  
Vol 12 ◽  
Author(s):  
Ajay Kumar ◽  
Vivek P. Varma ◽  
Kavela Sridhar ◽  
Mohd Abdullah ◽  
Pallavi Vyas ◽  
...  

Leptospira, a zoonotic pathogen, is known to infect various hosts and can establish persistent infection. This remarkable ability of bacteria is attributed to its potential to modulate (activate or evade) the host immune response by exploiting its surface proteins. We have identified and characterized the domain of the variable region of Leptospira immunoglobulin-like protein A (LAV) involved in immune modulation. The 11th domain (A11) of the variable region of LigA (LAV) induces a strong TLR4 dependent innate response leading to subsequent induction of humoral and cellular immune responses in mice. A11 is also involved in acquiring complement regulator FH and binds to host protease Plasminogen (PLG), there by mediating functional activity to escape from complement-mediated killing. The deletion of A11 domain significantly impaired TLR4 signaling and subsequent reduction in the innate and adaptive immune response. It also inhibited the binding of FH and PLG thereby mediating killing of bacteria. Our study discovered an unprecedented role of LAV as a nuclease capable of degrading Neutrophil Extracellular Traps (NETs). This nuclease activity was primarily mediated by A11. These results highlighted the moonlighting function of LigA and demonstrated that a single domain of a surface protein is involved in modulating the host innate immune defenses, which might allow the persistence of Leptospira in different hosts for a long term without clearance.


Author(s):  
Valentyn Oksenych

B lymphocyte development includes two DNA recombination processes, the V(D)J recombination of immunoglobulin (Igh) gene variable region and class switching when the Igh constant regions are changed from IgM to IgG, IgA, or IgE. The V(D)J recombination is required for successful maturation of B cells from pro-B to pre-B to immature-B and then to mature B cells in the bone marrow. The CSR occurs outside the bone marrow when mature B cells migrate to peripheral lymphoid organs, such as spleen and lymph nodes. Both V(D)J recombination and CSR depend on an “open chromatin” state that makes DNA accessible to specific enzymes, recombination activating gene (RAG), and activation-induced cytidine deaminase (AID). Acetyltransferases GCN5 and PCAF possess redundant functions acetylating histone H3 lysine 9 (H3K9). Here, we generated by complex breeding a mouse model with B cells lacking both GCN5 and PCAF. We found that double-deficient mice possess low levels of mature B cells in the bone marrow and peripheral organs, accumulation of pro-B cells in bone marrow, and reduced CSR levels. We concluded that both GCN5 and PCAF are required for B cell development in vivo.


2021 ◽  
Author(s):  
Valentyn Oksenych

B lymphocyte development includes two DNA recombination processes, the V(D)J recombina-tion of immunoglobulin (Igh) gene variable region and class switching when the Igh constant regions are changed from IgM to IgG, IgA, or IgE. The V(D)J recombination is required for suc-cessful maturation of B cells from pro-B to pre-B to immature-B and then to mature B cells in the bone marrow. The CSR occurs outside the bone marrow when mature B cells migrate to periph-eral lymphoid organs, such as spleen and lymph nodes. Both V(D)J recombination and CSR de-pend on an open chromatin state that makes DNA accessible to specific enzymes, recombina-tion activating gene (RAG), and activation-induced cytidine deaminase (AID). Acetyltransferases GCN5 and PCAF possess redundant functions acetylating histone H3 lysine 9 (H3K9). Here, we generated by complex breeding a mouse model with B cells lacking both GCN5 and PCAF. We found that double-deficient mice possess low levels of mature B cells in the bone marrow and peripheral organs, accumulation of pro-B cells in bone marrow, and reduced CSR levels. We concluded that both GCN5 and PCAF are required for B cell development in vivo.


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