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Phosphorylation of the serine 139 of the histone variant H2AX (γH2AX) is a DNA damage marker that regulates DNA damage response and various diseases. However, whether γH2AX is involved in neuropathic pain is still unclear. We found the expression of γH2AX and H2AX decreased in mice dorsal root ganglion (DRG) after spared nerve injury (SNI). Ataxia telangiectasia mutated (ATM), which promotes γH2AX, was also down-regulated in DRG after peripheral nerve injury. ATM inhibitor KU55933 decreased the level of γH2AX in ND7/23 cells. The intrathecal injection of KU55933 down-regulated DRG γH2AX expression and significantly induced mechanical allodynia and thermal hyperalgesia in a dose-dependent manner. The inhibition of ATM by siRNA could also decrease the pain threshold. The inhibition of dephosphorylation of γH2AX by protein phosphatase 2A (PP2A) siRNA partially suppressed the down-regulation of γH2AX after SNI and relieved pain behavior. Further exploration of the mechanism revealed that inhibiting ATM by KU55933 up-regulated extracellular-signal regulated kinase (ERK) phosphorylation and down-regulated potassium ion channel genes, such as potassium voltage-gated channel subfamily Q member 2 (Kcnq2) and potassium voltage-gated channel subfamily D member 2 (Kcnd2) in vivo, and KU559333 enhanced sensory neuron excitability in vitro. These preliminary findings imply that the down-regulation of γH2AX may contribute to neuropathic pain.

Objective: Delirium is a common postoperative complication in elderly patients with intertrochanteric femur fracture. This study aimed at analyzing risk factors for postoperative delirium (POD) in patients after proximal femoral nail anti-rotation (PFNA). Methods: From February 2017 to February 2021, we included elderly patients with intertrochanteric fractures who underwent PFNA. The predictive ability and cut-off value of neutrophil/lymphocyte ratio (NLR) for POD were evaluated using receiver operating characteristic (ROC) curve. Univariate and multivariate analyses were used to investigate the association between NLR and POD. Results: We enrolled 315 patients. The ROC curve suggested that NLR ≥ 4.85 was the optimal cut-off value for POD. The POD and non-POD groups differed significantly in age, diabetes, time from injury to operation, preoperative albumin level, neutrophil count, and NLR (P < 0.05). Logistic regression indicated that NLR ≥ 4.85 (odds ratio [OR] = 3.491; 95% confidence interval [CI]: 1.731-5.982; P < 0.001), old age (OR = 1.921; 95% CI: 1.267-4.125; P < 0.001), time from injury to operation ≥ 48 h (OR = 1.733; 95% CI: 1.212-3.542; P = 0.007), and preoperative albumin level ≤ 35 g/L (OR = 2.274; 95% CI: 1.662-4.846; P = 0.001) increased the risk of POD. Conclusion: Old age, time from injury to operation ≥ 48 h, preoperative albumin level ≤ 35 g/L, and NLR ≥ 4.85 were independent risk factors for POD. Thus, NLR may predict POD in elderly patients with intertrochanteric femur fractures after PFNA.

Mass spectrometry (MS)-based analysis of RNA oligonucleotides (oligos) plays an increasingly important role in the development of RNA therapeutics and in epitranscriptomic studies. However, MS fragmentation behaviors of RNA oligos are understood insufficiently. In this study, we characterized the negative-ion-mode fragmentation behaviors of 26 synthetic RNA oligos of four to eight nucleotides (nt) in length by collision-induced dissociation (CID) using a high-resolution, accurate-mass instrument. We find that in the CID spectra acquired under the normalized collisional energy of 35%, ∼70% of the total peak intensity belonged to sequencing ions (a-B, a, b, c, d, w, x, y, z), ∼25% belonged to precursor ions with either complete or partial loss of a nucleobase in the form of a neutral or an anion, and the remainder were internal ions and anionic nucleobases. Of the sequencing ions, the most abundant species werey, c, w, a-B, andaions. The charge state of the RNA precursor ions strongly affected their fragmentation behaviors. As the precursor charge increased from -1 to -5, the fractional intensity of sequencing ions in the CID spectra decreased, whereas the fractional intensity of precursor ions with neutral and/or charged losses of a nucleobase increased. Moreover, RNA oligos containing U, especially at the 3′ terminus, tended to produce precursors that lost HNCO and/or NCO-, which presumably corresponded to isocyanic acid and cyanate anion, respectively. These findings build a strong foundation for mechanistic understanding of RNA fragmentation by MS/MS, contributing to future automated identification of RNA oligos from their CID spectra in a more efficient way.

Aiming at the problems of the destroyed structure, the decreased capacitance retention rate and the bad cycle stability of polyaniline (PANI) during the continuous charge/discharge due to the irreversible deformation of PANI, this article proposes that the TEMPO-oxidized cellulose nanofiber (TOCNF), doping sulfonated multi-walled carbon nanotube (SMWCNT) enhances its electrical conductivity, the microstructure of the polymer is controlled via in-situ polymerization of the aniline on the surface of TOCNF-SMWCNT, the composite electrode materials PANI/(TOCNF-SMWCNT) is synthesized. The composite electrode materials were characterized by SEM, TEM, XRD, XPS, FTIR, and Raman, and the structure-activity relationship of the enhanced electrical properties was also clarified. The test results showed that the specific capacitance of PANI/(TOCNF-SMWCNT) is 546.0 F/g at a current density of 1.0 A/g. In addition, the composite electrode exhibited good cyclic stability with retention of 82.4% even after 5000 cycles when the current density is 1.0 A/g.

The bispecific T-cell engager (BiTE) blinatumomab against CD19 and CD3 has emerged as the most successful bispecific antibody (bsAb) to date; however, a significant proportion of patients do not respond to the treatments or eventually experience relapse after an initial response, and the recurrence rate increases significantly due to escape or downregulation of the CD19 antigen. To enhance antitumor efficacy and overcome potential immune escape, we developed a novel approach to design a CD19/CD22/CD3 trispecific antibody (tsAb) by site-specifically fusing anti-CD19 scFv (FMC63) and anti-CD22 nanobody (Nb25) to the defined sites of the CD3 antigen-binding fragment (Fab, SP34). This strategy allows for the optimal formation of immune synapses mediated by CD19/CD22/CD3 between target cells and T cells. Optimized tsAb can be superior for inducing T-cell−specific cytotoxicity and cytokine production against CD19+ and/or CD22+ tumor cells compared to other tsAb formats, and demonstrated significantly enhanced antitumor efficacy and the ability to overcome immune escape compared with the corresponding bsAbs alone or in combination, as well as with blinatumomab. In addition, tsAb treatment can lead to the long-term elimination of primary B-ALL patient samples in the PDX model and significantly prolong survival. This novel approach provides unique insight into the structural optimization of T-cell−redirected multispecific antibodies using site-specific recombination, and may be broadly applicable to heterogeneous and resistant tumor populations as well as solid tumors.