Interleukin‐37 improves T‐cell‐mediated immunity and chimeric antigen receptor T‐cell therapy in aged backgrounds

Aging‐associated declines in innate and adaptive immune responses are well documented and pose a risk for the growing aging population, which is predicted to comprise greater than 40 percent of the world''s population by 2050. Efforts have been made to improve immunity in aged populations; however, safe and effective protocols to accomplish this goal have not been universally established. Aging‐associated chronic inflammation is postulated to compromise immunity in aged mice and humans. Interleukin‐37 (IL‐37) is a potent anti‐inflammatory cytokine, and we present data demonstrating that IL‐37 gene expression levels in human monocytes significantly decline with age. Furthermore, we demonstrate that transgenic expression of interleukin‐37 (IL‐37) in aged mice reduces or prevents aging‐associated chronic inflammation, splenomegaly, and accumulation of myeloid cells (macrophages and dendritic cells) in the bone marrow and spleen. Additionally, we show that IL‐37 expression decreases the surface expression of programmed cell death protein 1 (PD‐1) and augments cytokine production from aged T‐cells. Improved T‐cell function coincided with a youthful restoration of Pdcd1, Lat, and Stat4 gene expression levels in CD4⁺ T‐cells and Lat in CD8⁺ T‐cells when aged mice were treated with recombinant IL‐37 (rIL‐37) but not control immunoglobin (Control Ig). Importantly, IL‐37‐mediated rejuvenation of aged endogenous T‐cells was also observed in aged chimeric antigen receptor (CAR) T‐cells, where improved function significantly extended the survival of mice transplanted with leukemia cells. Collectively, these data demonstrate the potency of IL‐37 in boosting the function of aged T‐cells and highlight its therapeutic potential to overcome aging‐associated immunosenescence.     

First total synthesis of prasinic acid and its anticancer activity

The first total synthesis of prasinic acid is being reported along with its biological evaluation. The ten step synthesis involved readily available and cheap starting materials and can easily be transposed to large scale manufacturing. The crucial steps of the synthesis included the formation of two different aromatic units (7 and 9) and their coupling reaction. The synthetic prasinic acid exhibited moderate antitumor activity (IC₅₀ 4.3–9.1 μM) in different lines of cancer cells.     

Deploying microbes as drivers and indicators in ecological restoration

Ecosystem degradation is a major environmental threat. Beyond conservation, restoration of degraded ecosystems is a prerequisite to reinstate their ability to provide essential services and benefits. Most of the restoration efforts focus on aboveground restoration, that is, plants, under the assumption that establishment of plant species will reestablish the faunal and microbial species. While this may be true for some cases, it is not a general rule. Reestablishment of microbial communities by dedicated efforts is also necessary for successful restoration, as cycling of essential nutrients for plant growth and decomposition of organic matter is dependent on them. The role of microbial fertilizers and efficient organisms used in agriculture needs to be explored in restoration. Testing of symbiotic interactions between potential plant growth-promoting Rhizobacteria and plants native to a degraded ecosystem can be conducted and utilized for successful establishment of plant species. However, utmost care must be taken while introducing new microbial species or non-native plant species to an area, as they can adversely affect the resident microbial community. Techniques like phospholipid fatty-acid analysis can be used for taxonomic identification of large microbial groups in non-degraded reference ecosystems before introducing microbial species into a degraded ecosystem. For use of microbes in restoration, more studies on microbe-plant interactions need to be conducted. For use of Soil Microbial Community (SMC) as indicators of restoration, their role and function in the ecology of the area need to be elucidated by employing all the available techniques.     

1,2,3-Triazole-nimesulide hybrid: Their design,synthesis and evaluation as potential anticancer agents

A new hybrid template has been designed by integrating the structural features of nimesulide and the 1,2,3-triazole moiety in a single molecular entity at the same time eliminating the problematic nitro group of nimesulide. The template has been used for the generation of a library of molecules as potential anticancer agents. A mild and greener CuAAC approach has been used to synthesize these compounds via the reaction of 4-azido derivative of nimesulide and terminal alkynes in water. Three of these compounds showed promising growth inhibition (IC₅₀ ～6–10 μM) of A549, HepG2, HeLa and DU145 cancer cell lines but no significant effects on HEK293 cell line. They also inhibited PDE4B in vitro (60–70% at 10 μM) that was supported by the docking studies (PLP score 87–94) in silico.     

Molecular diversity in the primary and secondary gene pools of genus Oryza

The objective of the present investigation was to assess the genetic relationships among the species of Oryza that belong to the primary gene pool (sativa complex) and the secondary gene pool (officinalis complex) using three marker systems such as RAPDs, ISSRs and SSRs. A total of 432 clear and reproducible bands were amplified from 18 RAPD primers; 113 bands were detected from 8 ISSR primers and 78 alleles were found to be amplified across the Oryza species from 13 SSR primer pairs. All the three dendrograms constructed, using UPGMA from the genetic similarity matrices based on the three marker data sets, were similar in their groupings. In all the three trees, two accessions of Oryza sativa formed an exclusive group indicating its genomic differentiation from its wild ancestors through the process of domestication. Distinctness between the wild species of the sativa and officinalis complexes was evident in all the trees derived from different markers. The groupings obtained among the species of the sativa complex were in perfect concordance with the species relationships established through classical crossability and cytogenetic analysis. This study has brought out some information on the species relationship between the diploid and tetraploid genomes of the officinalis complex possessing BB, CC and DD genomes. The higher level of similarity observed between the species possessing C and D genomes supports the view of many earlier authors that these two genomes might have originated from a single hybridization event. The results of this study also show that the diploid species possessing C genomes such as Oryza officinalis, Oryza rhizomatis and Oryza eichingeri are distinct from their allotetraploid counterparts possessing BBCC and CCDD genomes indicating a wider genomic differentiation in their evolutionary process.     

Differences in clinical features according to Boryoung and Karp genotypes of Orientia tsutsugamushi

Background

Scrub typhus is an infectious disease caused by Orientia tsutsugamushi. The differences in virulence of O. tsutsugamushi prototypes in humans are still unknown. We investigated whether there are any differences in the clinical features of the Boryoung and Karp genotypes.

Methodology/Principal Findings

Patients infected with O. tsutsugamushi, as Boryoung and Karp clusters, who had visited 6 different hospitals in southwestern Korea were prospectively compared for clinical features, complications, laboratory parameters, and treatment responses. Infected patients in the Boryoung cluster had significantly more generalized weakness, eschars, skin rashes, conjunctival injection, high albumin levels, and greater ESR and fibrinogen levels compared to the Karp cluster. The treatment response to current antibiotics was significantly slower in the Karp cluster as compared to the Boryoung cluster.

Conclusion

The frequency of occurrence of eschars and rashes may depend on the genotype of O. tsutsugamushi.     

Is the mechanism of COVID-19 coagulopathy still a rabbit’s hole?

The pathophysiology of COVID-19 is an enigma with its severity often determined by the extent of coagulopathy. Several regulatory pathways targeted by the SARS-CoV-2 include the renin-angiotensin system, von Willebrand Factor, and most importantly, the complement pathway. This article discusses these pathways to help design potential future therapies.     

Secretome analysis of Magnaporthe oryzae using in vitro systems

Magnaporthe oryzae is a devastating blast fungal pathogen of rice (Oryza sativa L.) that causes dramatic decreases in seed yield and quality. During the early stages of infection by this pathogen, the fungal spore senses the rice leaf surface, germinates, and penetrates the cell via an infectious structure known as an appressorium. During this process, M. oryzae secretes several proteins; however, these proteins are largely unknown mainly due to the lack of a suitable method for isolating secreted proteins during germination and appressoria formation. We examined the secretome of M. oryzae by mimicking the early stages of infection in vitro using a glass plate (GP), PVDF membrane, and liquid culture medium (LCM). Microscopic observation of M. oryzae growth revealed appressorium formation on the GP and PVDF membrane resembling natural M. oryzae-rice interactions; however, appresorium formation was not observed in the LCM. Secreted proteins were collected from the GP (3, 8, and 24 h), PVDF membrane (24 h), and LCM (48 h) and identified by two-dimensional gel electrophoresis (2DE) followed by tandem mass spectrometry. The GP, PVDF membrane, and LCM-derived 2D gels showed distinct protein patterns, indicating that they are complementary approaches. Collectively, 53 nonredundant proteins including previously known and novel secreted proteins were identified. Six biological functions were assigned to the proteins, with the predominant functional classes being cell wall modification, reactive oxygen species detoxification, lipid modification, metabolism, and protein modification. The in vitro system using GPs and PVDF membranes applied in this study to survey the M. oryzae secretome, can be used to further our understanding of the early interactions between M. oryzae and rice leaves.