Chimeric Antigen Receptor T Cell Bearing Herpes Virus Entry Mediator Co-stimulatory Signal Domain Exhibits High Functional Potency

Chimeric antigen receptor (CAR) is a hybrid molecule consisting of an antigen-binding domain and a signal transduction domain. The artificial T cells expressing CAR (CAR-T cells) are expected to be a useful tool for treatment of various diseases, such as cancer. The addition of a co-stimulatory signal domain (CSSD) to CAR is shown to be critical for modulating CAR-T cell activities. However, the interplay among types of CSSDs, effector functions, and characteristics of CAR-T cells is largely unknown. To elucidate the interplay, we analyzed effector functions, differentiation to memory T cell subsets, exhaustion, and energy metabolism of the CAR-T cells with different CSSDs. Comparing to the CAR-T cells bearing a CD28- or 4-1BB-derived CSSD, which are currently used for CAR-T cell development, we found that the CAR-T cells with a herpes virus entry mediator (HVEM)-derived CSSD exhibited enhanced effector functions and efficient and balanced differentiation to both central and effector memory subsets, associated with an elevated energy metabolism and a reduced level of exhaustion. Thus, we developed the CAR-T cells bearing the CSSD derived from HVEM with high functional potency. The HVEM-derived CSSD may be useful for developing effective CAR-T cells

Recombinant human soluble thrombomodulin is associated with attenuation of sepsisinduced renal impairment by inhibition of extracellular histone release

感染症によって重篤な臓器障害が引き起こされて敗血症に至る過程でDAMPs（damage － associated molecular patterns）の関与が注目されている．今回，ヒストンH3に着目し，ラット腹膜炎敗血症モデルを用いてリコンビナントトロンボモジュリン（rhTM）とその抗炎症作用をもつD1がヒストンH3濃度と腎障害に与える影響を検討した．rhTMとD1の投与は，ヒストンH3濃度上昇と血清クレアチニン値上昇を抑制し腎の組織障害が軽減し，生存率改善との関連が示唆された．これらの結果は臨床応用を見据えた場合，rhTMのD1領域が細胞外ヒストンH3蛋白を制御し，敗血症での治療戦略の一つとなる可能性が示唆された

Predisposition for borderline personality disorder with comorbid major depression is associated with that for polycystic ovary syndrome in female Japanese population

Polycystic ovary syndrome (PCOS) is a common lifestyle-related endocrinopathy in women of reproductive age and is associated with several mental health problems. We examined the genotypic distributions of IRS-1 Gly972Arg and CYP11B2 -344T/C, which were previously described as influencing PCOS, and assayed the serum levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), in a set of female patients with borderline personality disorder (BPD) with comorbid major depressive disorder (MDD) (n = 50) and age-matched control subjects (n = 100), to investigate the predisposition for BPD with MDD. The results showed that the patients were more frequently IRS-1 972Arg variant allele carriers (P = 0.013; OR 6.68; 95% CI = 1.30–34.43) and homozygous for the CYP11B2 −344C variant allele (P = 0.022; OR = 3.32; 95% CI = 1.18–9.35) than the control subjects. The IL-6 level was significantly higher in the patients than in the controls (P < 0.0001). There was no significant difference in the serum TNF-α level between patients with BPD with MDD and the healthy comparison group (P = 0.5273). In conclusion, the predisposition for BPD with MDD is associated with that for PCOS, in the female Japanese population. An elevated serum IL-6 level is considered to be a possible biomarker of BPD with MDD

Interplay of a non-conjugative integrative element and a conjugative plasmid in the spread of antibiotic resistance via suicidal plasmid transfer from an aquaculture Vibrio isolate

The capture of antimicrobial resistance genes (ARGs) by mobile genetic elements (MGEs) plays a critical role in resistance acquisition for human-associated bacteria. Although aquaculture environments are recognized as important reservoirs of ARGs, intra- and intercellular mobility of MGEs discovered in marine organisms is poorly characterized. Here, we show a new pattern of interspecies ARGs transfer involving a ‘non-conjugative’ integrative element. To identify active MGEs in a Vibrio ponticus isolate, we conducted whole-genome sequencing of a transconjugant obtained by mating between Escherichia coli and Vibrio ponticus. This revealed integration of a plasmid (designated pSEA1) into the chromosome, consisting of a self-transmissible plasmid backbone of the MOBH group, ARGs, and a 13.8-kb integrative element Tn6283. Molecular genetics analysis suggested a two-step gene transfer model. First, Tn6283 integrates into the recipient chromosome during suicidal plasmid transfer, followed by homologous recombination between the Tn6283 copy in the chromosome and that in the newly transferred pSEA1. Tn6283 is unusual among integrative elements in that it apparently does not encode transfer function and its excision barely generates unoccupied donor sites. Thus, its movement is analogous to the transposition of insertion sequences rather than to that of canonical integrative and conjugative elements. Overall, this study reveals the presence of a previously unrecognized type of MGE in a marine organism, highlighting diversity in the mode of interspecies gene transfer

Interplay of a non-conjugative integrative element and a conjugative plasmid in the spread of antibiotic resistance via suicidal plasmid transfer from an aquaculture Vibrio isolate

<div><p>The capture of antimicrobial resistance genes (ARGs) by mobile genetic elements (MGEs) plays a critical role in resistance acquisition for human-associated bacteria. Although aquaculture environments are recognized as important reservoirs of ARGs, intra- and intercellular mobility of MGEs discovered in marine organisms is poorly characterized. Here, we show a new pattern of interspecies ARGs transfer involving a ‘non-conjugative’ integrative element. To identify active MGEs in a <i>Vibrio ponticus</i> isolate, we conducted whole-genome sequencing of a transconjugant obtained by mating between <i>Escherichia coli</i> and <i>Vibrio ponticus</i>. This revealed integration of a plasmid (designated pSEA1) into the chromosome, consisting of a self-transmissible plasmid backbone of the MOB_H group, ARGs, and a 13.8-kb integrative element Tn<i>6283</i>. Molecular genetics analysis suggested a two-step gene transfer model. First, Tn<i>6283</i> integrates into the recipient chromosome during suicidal plasmid transfer, followed by homologous recombination between the Tn<i>6283</i> copy in the chromosome and that in the newly transferred pSEA1. Tn<i>6283</i> is unusual among integrative elements in that it apparently does not encode transfer function and its excision barely generates unoccupied donor sites. Thus, its movement is analogous to the transposition of insertion sequences rather than to that of canonical integrative and conjugative elements. Overall, this study reveals the presence of a previously unrecognized type of MGE in a marine organism, highlighting diversity in the mode of interspecies gene transfer.</p></div

Recombinant human soluble thrombomodulin is associated with attenuation of sepsis-induced renal impairment by inhibition of extracellular histone release.

Multiple organ dysfunction induced by sepsis often involves kidney injury. Extracellular histones released in response to damage-associated molecular patterns are known to facilitate sepsis-induced organ dysfunction. Recombinant human soluble thrombomodulin (rhTM) and its lectin-like domain (D1) exert anti-inflammatory effects and neutralize damage-associated molecular patterns. However, the effects of rhTM and D1 on extracellular histone H3 levels and kidney injury remain poorly understood. Our purpose was to investigate the association between extracellular histone H3 levels and kidney injury, and to clarify the effects of rhTM and D1 on extracellular histone H3 levels, kidney injury, and survival in sepsis-induced rats. Rats in whom sepsis was induced via cecal ligation and puncture were used in this study. Histone H3 levels, histopathology of the kidneys, and the survival rate of rats at 24 h after cecal ligation and puncture were investigated. Histone H3 levels increased over time following cecal ligation and puncture. Histopathological analyses indicated that the distribution of degeneration foci among tubular epithelial cells of the kidney and levels of histone H3 increased simultaneously. Administration of rhTM and D1 significantly reduced histone H3 levels compared with that in the vehicle-treated group and improved kidney injury. The survival rates of rats in rhTM- and D1-treated groups were significantly higher than that in the vehicle-treated group. The results of this study indicated that rhTM and its D1 similarly reduce elevated histone H3 levels, thereby reducing acute kidney injury. Our findings also proposed that rhTM and D1 show potential as new treatment strategies for sepsis combined with acute kidney injury