Genome-wide characterization of i-motifs and their potential roles in the stability and evolution of transposable elements in rice

I-motifs (iMs) are non-canonical DNA secondary structures that fold from cytosine (C)-rich genomic DNA regions termed putative i-motif forming sequences (PiMFSs).
The structure of iMs is stabilized by hemiprotonated C-C base pairs, and their functions are now suspected in key cellular processes in human cells such as genome stability and regulation of gene transcription. In plants, their biological relevance is still largely unknown.
Here, we Bio Med Frontiers characterized PiMFSs with high potential for i-motif formation in the rice genome by developing and applying a protocol hinging on an iMab antibody-based immunoprecipitation (IP) coupled with high-throughput sequencing (seq), consequently termed iM-IP-seq.
We found that PiMFSs had intrinsic subgenomic distributions, cis-regulatory functions and an intricate relationship with DNA methylation.
We indeed found that the coordination of PiMFSs with DNA methylation may affect dynamics of transposable elements (TEs) among different cultivated Oryza subpopulations or during evolution of wild rice species. Collectively, our study provides first and unique insights into the biology of iMs in plants, with potential applications in plant biotechnology for improving important agronomic rice traits.

The dynamic nature of the coronavirus receptor, angiotensin-converting enzyme 2 (ACE2) in differentiating airway epithelia.

  • Once inhaled, SARS-CoV-2 particles enter respiratory ciliated cells by interacting with angiotensin converting enzyme 2 (ACE2). Understanding the nature of ACE2 within airway tissue has become a recent focus particularly in light of the COVID-19 pandemic.
  • Airway mucociliary tissue was generated in-vitro using primary human nasal epithelial cells and the air-liquid interface (ALI) model of differentiation. About Using ALI tissue, three distinct transcript variants of ACE2 were identified. One transcript encodes the documented full-length ACE2 protein. The other two transcripts are unique truncated isoforms, that until recently had only been predicted to exist via sequence analysis software.
  • Quantitative PCR revealed that all three transcript variants are expressed throughout the differentiation of airway mucociliary epithelia. Immunofluorescence analysis of individual ACE2 protein isoforms exogenously expressed in cell lines revealed similar abilities to localize in the plasma membrane and interact with the SARS CoV 2 spike receptor-binding domain.
  • Immunohistochemistry on differentiated ALI tissue using antibodies to either the N-term or C-term of ACE2 revealed both overlapping and distinct signals in cells, most notably only the ACE2 C-term antibody displayed plasma-membrane localization.
  • We also demonstrate that ACE2 protein shedding is different in ALI Tissue compared to ACE2-transfected cell lines, and that ACE2 is released from both the apical and basal surfaces of ALI tissue. Together, our data highlights various facets of ACE2 transcripts and protein in airway mucociliary tissue that may represent variables which impact an individual’s susceptibility to SARS-CoV-2 infection, or the severity of Covid-19.

The Effect of TGF-β1 Reduced Functionality on the Expression of Selected Synaptic Proteins and Electrophysiological Parameters

  • Decreased platelet count represents a feature of acute liver failure (ALF) pathogenesis. Platelets are the reservoir of transforming growth factor 1 (TGF-β1), a multipotent cytokine involved in the maintenance of, i.a., central nervous system homeostasis.
  • Here, we analyzed the effect of a decrease in TGF-β1 active form on synaptic proteins levels, and brain electrophysiology, in mice after intraperitoneal (ip) administration of TGF-β1 antibody (anti-TGF-β1; 1 mg/mL).
  • Next, we correlated it with a thrombocytopenia-induced TGF-β1 decrease, documented in an azoxymethane-induced (AOM; 100 mM ip) model of ALF, and clarified the impact of TGF-β1 decrease on blood-brain barrier functionality.
  • The increase of both synaptophysin and synaptotagmin in the cytosolic fraction, and its reduction in a membrane fraction, were confirmed in the AOM mice brains. Both proteins’ decrease in analyzed fractions occurred in anti-TGF-β1 mice.
  • In turn, an increase in postsynaptic (NR1 subunit of N-methyl-D-aspartate receptor, postsynaptic density protein 95, gephyrin) proteins in the AOM brain cortex, but a selective compensatory increase of NR1 subunit in anti-TGF-β mice, was observed.
  • The alterations of synaptic proteins levels were not translated on electrophysiological parameters in the anti-TGF-β1 model.
  • The results suggest the impairment of synaptic vesicles docking to the postsynaptic membrane in the AOM model. Nevertheless, changes in synaptic protein level in the anti-TGF-β1 mice do not affect neurotransmission and may not contribute to neurologic deficits in AOM mice.

The RapidIO Routing Strategy Based on the Double-Antibody Group Multi-Objective Artificial Immunity Algorithm

The RapidIO standard is a packet-switching interconnection technology similar to the Internet Protocol (IP) conceptually. It realizes the high-speed transmission of RapidIO packets at the transport layer, but this greatly increases the probability of network blocking.
Therefore, it is of great significance to optimize the RapidIO routing strategy. For this problem, this paper proposes a Double-Antibody Group Multi-Objective Artificial Immune Algorithm (DAG-MOAIA), which improves the local search and global search ability of the population by adaptive crossover and adaptive mutation of the double-antibody groups, and uses co-competition of multi-antibody groups to increase the diversity of the population. Through DAG-MOAIA, an optimal transmission path from the source node to multiple destination nodes can be selected to solve the Quality Of Service (QoS) problem during data transmission and ensure the QoS of the RapidIO network.
Simulation results show that DAG-MOAIA could obtain high-quality solutions to select better routing transmission paths, and exhibit better comprehensive performance in all simulated test networks, which plays a certain role in solving the problem of the RapidIO routing strategy.

Anti-PD-L1 F(ab) Conjugated PEG-PLGA Nanoparticle Enhances Immune Checkpoint Therapy.

 Immune checkpoint therapies are effective in the treatment of a subset of patients in many different cancers. Immunotherapy offers limited efficacy in part because of rapid drug clearance and off-target associated toxicity. PEG-PLGA is a FDA approved, safe, biodegradable polymer with flexible size control. The delivery of immune checkpoint inhibitors such as anti-PD-L1 (α-PD-L1) via PEG-PLGA polymer has the potential to increase bioavailability and reduce immune clearance to enhance clinical efficacy and reduce toxicity.
The Fc truncated F(ab) portion of α-PD-L1 monoclonal antibody (α-PD-L1 mAb) was attached to a PEG-PLGA polymer.
α-PD-L1 F(ab)-PEG-PLGA polymers were incubated in oil-in-water emulsion to form a α-PD-L1 F(ab)-PEG-PLGA nanoparticle (α-PD-L1 NP). α-PD-L1 NP was characterized for size, polarity, toxicity and stability. The relative efficacy of α-PD-L1 NP to α-PD-L1 mAb was measured when delivered either intraperitoneally (IP) or intravenously (IV) in a subcutaneous mouse colon cancer model (MC38).
 Antibody retention was measured using fluorescence imaging. Immune profile in mice was examined by flow cytometry and immunohistochemistry.  
Engineered α-PD-L1 NP was found to have pharmacological properties that are potentially advantageous compared to α-PD-L1 mAb. The surface charge of α-PD-L1 NP was optimal for both tumor cell uptake and reduced self-aggregation.

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The modified size of α-PD-L1 NP reduced renal excretion and mononuclear phagocyte uptake, which allowed the NP to be retained in the host system longer. α-PD-L1 NP was non-toxic in vitro and in vivo. α-PD-L1 NP comparably suppressed MC38 tumor growth. α-PD-L1 NP appeared to elicit an increased immune response as measured by increase in germinal center area in the spleen and in innate immune cell activation in the tumor.
Finally, we observed that generally, for both α-PD-L1 NP and α-PD-L1 mAb, the IP route was more effective than IV route for tumor reduction. α-PD-L1 NP is a non-toxic, biocompatible synthetic polymer that can extend α-PD-L1 antibody circulation and reduce renal clearance while retaining anti-cancer activity and potentially enhancing immune activation.

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