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Senotherapy targeting for senescent cells is designed to attenuate age-related dysfunction. Senescent T cells, defined as CD4 + CD44 high CD62L low PD-1 + CD153 + cells, accumulate in visceral adipose tissues (VAT) in obese individuals. Here, we show the long-lasting effect of using CD153 vaccination to remove senescent T cells from high-fat diet (HFD)-induced obese C57BL/6J mice. We administered a CD153 peptide-KLH (keyhole limpet hemocyanin) conjugate vaccine with Alhydrogel (CD153-Alum) or CpG oligodeoxynucleotide (ODN) 1585 (CD153-CpG) and confirmed an increase in anti-CD153 antibody levels that was sustained for several months. After being fed a HFD for 10–11 weeks, adipose senescent T cell accumulation was significantly reduced in the VAT of CD153-CpG-vaccinated mice, accompanied by glucose tolerance and insulin resistance. A complement-dependent cytotoxicity (CDC) assay indicated that the mouse IgG2 antibody produced in the CD153-CpG-vaccinated mice successfully reduced the number of senescent T cells. The CD153-CpG vaccine is an optional tool for senolytic therapy. Senotherapy, the removal of aged T cells, is an effective approach to attenuate age-related diseases. Here the authors report a CD153 targeting vaccine that prevents the accumulation of senescent adipose tissue T cells in mice on high-fat diet, which is associated with improved glucose tolerance.

Modern spintronics relies on the generation of spin currents through spin-orbit coupling. The spin-current generation has been believed to be triggered by current-induced orbital dynamics, which governs the angular momentum transfer from the lattice to the electrons in solids. The fundamental role of the orbital response in the angular momentum dynamics suggests the importance of the orbital counterpart of spin currents: orbital currents. However, evidence for its existence has been elusive. Here, we demonstrate the generation of giant orbital currents and uncover fundamental features of the orbital response. We experimentally and theoretically show that orbital currents propagate over longer distances than spin currents by more than an order of magnitude in a ferromagnet and nonmagnets. Furthermore, we find that the orbital current enables electric manipulation of magnetization with efficiencies significantly higher than the spin counterpart. These findings open the door to orbitronics that exploits orbital transport and spin-orbital coupled dynamics in solid-state devices. The generation of spin-current is integral for the successful development of spintronic devices however the orbital counterpart is also expected to be potentially advantageous. Here, using Ni/Ti bilayers, in combination with tight binding calculations, the authors investigate the spin torque efficiency that occurs as a result of the orbital Hall effect, observing that orbital currents can propagate over longer distances than the spin currents.

1,2-Bis(diphenylphosphino)ethane (DPPE) and its synthetic analogues are important structural motifs in organic synthesis, particularly as diphosphine ligands with a C 2 -alkyl-linker chain. Since DPPE is known to bind to many metal centers in a bidentate fashion to stabilize the corresponding metal complex via the chelation effect originating from its entropic advantage over monodentate ligands, it is often used in transition-metal-catalyzed transformations. Symmetric DPPE derivatives (Ar 1 2 P−CH 2 −CH 2 −PAr 1 2 ) are well-known and readily prepared, but electronically and sterically unsymmetric DPPE (Ar 1 2 P−CH 2 −CH 2 −PAr 2 2 ; Ar 1 ≠Ar 2 ) ligands have been less explored, mostly due to the difficulties associated with their preparation. Here we report a synthetic method for both symmetric and unsymmetric DPPEs via radical difunctionalization of ethylene, a fundamental C 2 unit, with two phosphine-centered radicals, which is guided by the computational analysis with the artificial force induced reaction (AFIR) method, a quantum chemical calculation-based automated reaction path search tool. The obtained unsymmetric DPPE ligands can coordinate to several transition-metal salts to form the corresponding complexes, one of which exhibits distinctly different characteristics than the corresponding symmetric DPPE–metal complex. DPPEs are fundamental bidentate ligands with a C2-alkyl-linker chain for many transition-metal-catalyzed reactions. Here, authors utilize the AFIR method to develop a practical synthetic method for both symmetric and unsymmetric DPPEs with ethylene.

Transport of angular momentum is a key concept in condensed-matter physics. In solids, electrons can carry both spin and orbital angular momentum, leading to various applications in spintronics and orbitronics. A key difference between spin and orbital transport lies in their characteristic length scales in ferromagnets in which the dynamic orbital response is significantly long ranged compared with its spin counterpart. However, a comprehensive understanding of the physics behind the long-range nature of the orbital response is lacking. Here we demonstrate that the long-range dynamic orbital response in ferromagnets can be controlled by crystal symmetry. Our results manifest a clear difference in the characteristic length scale of orbital torque generation in atomically ordered and disordered CoPt alloys. This observation indicates that the long-range dynamic orbital response relies on the orbital-dependent energy splittings and hybridizations governed by crystal symmetry, which can be manipulated by atomic arrangements. Our results suggest the possibility of simultaneously controlling dynamic and static magnetic phenomena by manipulating orbital hybridization, which could be tailored for spintronic and orbitronic devices. Manipulation of the electron’s orbital contribution to transport experiments is important for potential orbitronics device applications. Now the long-range dynamic orbital response is shown to be controlled by the arrangement of atoms in ferromagnets.

The aim of this study is to understand adaptive immunity to SARS-CoV-2 through the analysis of B cell epitope and neutralizing activity in coronavirus disease 2019 (COVID-19) patients. We obtained serum from forty-three COVID-19 patients from patients in the intensive care unit of Osaka University Hospital (n = 12) and in Osaka City Juso Hospital (n = 31). Most individuals revealed neutralizing activity against SARS-CoV-2 assessed by a pseudotype virus-neutralizing assay. The antibody production against the spike glycoprotein (S protein) or receptor-binding domain (RBD) of SARS-CoV-2 was elevated, with large individual differences, as assessed by ELISA. We observed the correlation between neutralizing antibody titer and IgG, but not IgM, antibody titer of COVID-19 patients. In the analysis of the predicted the linear B cell epitopes, hot spots in the N-terminal domain of the S protein were observed in the serum from patients in the intensive care unit of Osaka University Hospital. Overall, the analysis of antibody production and B cell epitopes of the S protein from patient serum may provide a novel target for the vaccine development against SARS-CoV-2.

Background The systemic inflammatory response and nutritional status of patients with malignant tumors are related to postoperative results. We examined the usefulness of the prognostic nutritional index (PNI) as a prognostic tool in patients with oral squamous cell carcinoma who underwent radical surgery. Methods From 2008 to 2019, 102 patients (73 males, 29 females; age, 65.6 ± 9.8 years) who visited our hospital and underwent surgical therapy were included in this study. The endpoint was the total survival period, and the evaluation markers included the lymphocyte count and albumin level in peripheral blood obtained 4 weeks preoperatively, age, sex, alcohol consumption, smoking history, site of the tumor, pathological stage, and surgery status. The PNI was calculated using serum albumin levels and the peripheral blood lymphocyte count. The relationship between the PNI and patient characteristics were analyzed using Fisher's exact test. The Kaplan–Meier method was used to evaluate the survival rate. The survival periods were compared using the log-rank method. We evaluated the prognostic factors for overall survival (OS) and disease-free survival (DFS) in a logistic regression model. Results The tumor sites included the maxilla (n = 12), buccal mucosa (n = 11), mandible (n = 17), floor of the mouth (n = 9), and tongue (n = 53). The number of patients with stage I, II, III, and IV oral cancers was 28 (27.5%), 34 (27.5%), 26 (33.3%), and 14 (13.7%), respectively. During the observation period, 21 patients died of head and neck cancer. The optimal cut-off PNI value was 42.9, according to the receiver operating characteristic analysis. The proportion of patients with a short OS was lower in those with PNI higher than 42.9, and the 5-year OS in patients with PNI higher and lower than the cut-off value was 62.3% and 86.0%, respectively (P = 0.0105). Conclusions The OS of patients with PNI < 42.9 was lower than that of patients with PNI ≥ 42.9. The PNI, which is a preoperative head-to-foot inflammatory marker, can help in estimating the prognosis of oral cancer.

There is currently a respiratory disease outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). After rapid development, RNA vaccines and adenoviral vector vaccines were approved within a year, which has demonstrated the strong impact of preventing infectious diseases using gene therapy technology. Furthermore, intensive immunological analysis has been performed to evaluate the efficiency and safety of these vaccines, potentially allowing for rapid progress in vaccine technology. After the coronavirus disease 2019 (COVID-19) era, the novel vaccine technology developed will expand to other vaccines. We have been developing vaccines for chronic diseases, such as hypertension, for >10 years. Regarding the development of vaccines against self-antigens (i.e., angiotensin II), the vaccine should efficiently induce a blocking antibody response against the self-antigen without activating cytotoxic T cells. Therefore, the epitope vaccine approach has been proposed to induce antibody production in response to a combination of a B cell epitope and exogenous T cell epitopes through major histocompatibility complex molecules. When these vaccines are established as therapeutic options for hypertension, their administration regimen, which might be a few times per year, will replace daily medication use. Thus, therapeutic vaccines for hypertension may be a novel option to control the progression of cerebrovascular diseases. Hopefully, the accumulation of immunological findings and vaccine technology advances due to COVID-19 will provide a novel concept for vaccines for chronic diseases.

Nonischemic cardiomyopathy (NICM) resulting from long-standing hypertension, valvular disease, and genetic mutations is a major cause of heart failure worldwide. Recent observations suggest that myeloid cells can impact cardiac function, but the role of tissue-intrinsic vs. tissue-extrinsic myeloid cells in NICM remains poorly understood. Here, we show that cardiac resident macrophage proliferation occurs within the first week following pressure overload hypertrophy (POH; a model of heart failure) and is requisite for the heart’s adaptive response. Mechanistically, we identify Kruppel-like factor 4 (KLF4) as a key transcription factor that regulates cardiac resident macrophage proliferation and angiogenic activities. Finally, we show that blood-borne macrophages recruited in late-phase POH are detrimental, and that blockade of their infiltration improves myocardial angiogenesis and preserves cardiac function. These observations demonstrate previously unappreciated temporal and spatial roles for resident and nonresident macrophages in the development of heart failure.

Despite the recent therapeutic developments for the treatment of pulmonary fibrosis, its prognosis is still not well controlled, and a novel therapeutic agent is needed. Recently, the critical role of Toll-like receptors (TLRs) in the pathophysiology of pulmonary fibrosis has been reported; however, the effects of multiple TLR signaling inhibition are still unknown. Here, we examined how the inhibition of multiple TLRs affects pulmonary fibrosis using a novel synthetic receptor activator of nuclear factor κB ligand (RANKL) partial peptide, MHP1-AcN, which could suppress TLR2, 3, 4, 7, and 9 signaling through CD14 and RANK. When MHP1-AcN was administered in the bleomycin-induced lung fibrosis model, reduced collagen deposition was observed, with suppressed fibrosis-related gene expression including Col1a1 , Col1a2 , Acta2 , Tgfb1 and Tgfbr2 . MHP1-AcN also decreased proinflammatory M1 and profibrotic M2 macrophage marker expression. Furthermore, MHP1-AcN treatment inhibited transforming growth factor (TGF-β)-induced Smad2/3 phosphorylation and myofibroblast differentiation in human fetal lung fibroblast (MRC-5) cells. This effect was associated with decreased TGF-β receptor levels and the upregulated Bmp7 and Smad7 expression. These findings suggest that MHP1-AcN protects mice against bleomycin-induced pulmonary fibrosis. MHP1-AcN might provide a novel therapeutic strategy for the pulmonary fibrosis.

Prorenin is viewed as an ideal target molecule in the prevention of diabetic retinopathy. However, no drugs are available for inhibiting activation of prorenin. Here, we tested the effect of a prorenin peptide vaccine (V P ) in the retina of a murine model of type 2 diabetes (T2D). To choose the optimal vaccine, we selected three different epitopes of the prorenin prosegment (E1, E2, and E3) and conjugated them to keyhole limpet hemocyanin (KLH). We injected C57BL/6J mice twice with KLH only (as a control vaccine), E1 conjugated with KLH (E1-KLH), E2-KLH, or E3-KLH and compared antibody titers. E2-KLH showed the highest antibody titer and specific immunoreactivity of anti-sera against prorenin, so we used E2-KLH as V P . Then, we administered injections to the non-diabetic db/m and diabetic db/db mice, as follows: db/m + KLH, db/db + KLH, and db/db + V P . Retinal blood flow measurement with laser speckle flowgraphy showed that the impaired retinal circulation response to both flicker light and systemic hyperoxia in db/db mice improved with V P . Furthermore, the prolonged implicit time of b-wave and oscillatory potentials in electroretinography was prevented, and immunohistochemical analysis showed reduced microglial activation, gliosis, and vascular leakage. The enzyme-linked immunosorbent spot assay confirmed vaccinated mice had no auto-immune response against prorenin itself. The present data suggest that vaccination against prorenin is an effective and safe measure against the early pathological changes of diabetic retinopathy in T2D.