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We use the framework of asymptotically safe quantum gravity to derive predictions for scalar leptoquark solutions to the b→s and b→c flavor anomalies. The presence of an interactive UV fixed point in the system of gauge and Yukawa couplings imposes a set of boundary conditions at the Planck scale, which allows one to determine low-energy values of the leptoquark Yukawa matrix elements. As a consequence, the allowed leptoquark mass range can be significantly narrowed down. We find that a consistent gravity-driven solution to the b→s anomalies predicts a leptoquark with the mass of 4–7 TeV, entirely within the reach of a future hadron-hadron collider with s=100TeV. Conversely, in the case of the b→c anomalies the asymptotically safe gravity framework predicts a leptoquark mass at the edge of the current LHC bounds. Complementary signatures appear in flavor observables, namely the (semi)leptonic decays of B and D mesons and kaons.

Autophagy regulates primary cilia formation, but the underlying mechanism is not fully understood. In this study, we identify NIMA-related kinase 9 (NEK9) as a GABARAPs-interacting protein and find that NEK9 and its LC3-interacting region (LIR) are required for primary cilia formation. Mutation in the LIR of NEK9 in mice also impairs in vivo cilia formation in the kidneys. Mechanistically, NEK9 interacts with MYH9 (also known as myosin IIA), which has been implicated in inhibiting ciliogenesis through stabilization of the actin network. MYH9 accumulates in NEK9 LIR mutant cells and mice, and depletion of MYH9 restores ciliogenesis in NEK9 LIR mutant cells. These results suggest that NEK9 regulates ciliogenesis by acting as an autophagy adaptor for MYH9. Given that the LIR in NEK9 is conserved only in land vertebrates, the acquisition of the autophagic regulation of the NEK9–MYH9 axis in ciliogenesis may have possible adaptive implications for terrestrial life. Ciliogenesis is a tightly regulated process, although the role of selective autophagy is unclear. Here, the authors show NIMA-related kinase 9 controls actin network stabilization and subsequently ciliogenesis by targeting myosin MYH9 for autophagic degradation via GABARAP interaction.

In the development of atomic clocks, some atomic transition frequencies are measured with remarkable precision. These measured spectra may include the effects of a new force mediated by a weakly interacting boson. Such effects might be distilled out from possible violation of a linear relation in isotope shifts between two transitions, as known as King’s linearity, with relatively suppressed theoretical uncertainties. We discuss the experimental sensitivity to a new force in the test of the linearity as well as the linearity violation owing to higher-order effects within the Standard Model. The sensitivity to new physics is limited by such effects. We have found that, for Yb + , the higher-order effect is in the reach of future experiments. The sensitivity to a heavy mediator is also discussed. It is analytically clarified that the sensitivity becomes weaker than that in the literature. Our numerical results of the sensitivity are compared with other weak force search experiments.

The Atomiki anomaly can be interpreted as a new light vector boson. If such a new particle exists, it could be a mediator between the Standard Model sector and the dark sector including the dark matter. We discussed some simple effective models with these particles. In the models, the secluded dark matter models are good candidates to satisfy the thermal relic abundance. In particular, we found that the dark matter self-interaction can be large enough to solve the small scale structure puzzles if the dark matter is a fermion.

Prostaglandins (PGs) are divided into conventional PGs, e.g., PGD2, and cyclopentenone-type PGs, e.g., 15-deoxy-Δ12,14 prostaglandin J2 (15d-PGJ2). PGD2 is non-enzymatically metabolized to PGJ2, Δ12-PGJ2, and 15d-PGJ2. In the central nervous system, 15d-PGJ2 differentiates embryonic midbrain cells into dopaminergic neuronal cells via its nuclear peroxysome proliferator-activated receptor-γ (PPARγ). 15d-PGJ2 exerts conflict actions: proinflammatory and anti-inflammatory activities. In the brain, 15d-PGJ2 possesses opposite functions as a neuroprotectant at low concentrations and a neurotoxicant at high concentrations in the brain. PPARγ contributes to the neuroprotective effect of 15d-PGJ2 but not to the neurotoxic effect. Its membrane receptor, chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTH2), is not also involved in the neurotoxicity of 15d-PGJ2. 15d-PGJ2 induces neuronal apoptosis via inactivating ubiquitin proteasome pathway and activating caspase cascade. Alternatively, 15d-PGJ2 downregulates phosphoinositide 3-kinase (PI3K)-Akt pathway and suppresses neurite outgrowth. 15d-PGJ2 possesses α,β-unsaturated ketone moiety in its cyclopentenone ring and acts an endogenous electrophile. By the Michael addition reaction, 15d-PGJ2 is covalently bound to cellular nucleophiles, such as free cysteine residues of proteins that regulate intracellular signaling pathways. There are specific binding sites of [3H]15d-PGJ2 in the plasma membrane of cerebral cortices. Besides CRTH2, plasmalemmal glycolytic enzymes, respiratory chain enzymes, molecular chaperones, adaptor proteins and cytoskeletons are identified as membrane targets for 15d-PGJ2. In the present review, we provide evidences for pathophysiological roles of 15d-PGJ2 in the central nervous system and neurological diseases.

Background Lower limb lymphedema (LLL) is a chronic and incapacitating condition afflicting patients who undergo lymphadenectomy for gynecologic cancer. This study aimed to identify risk factors for LLL and to develop a prediction model for its occurrence. Methods Pelvic lymphadenectomy (PLA) with or without para-aortic lymphadenectomy (PALA) was performed on 366 patients with gynecologic malignancies at Yaizu City Hospital between April 2002 and July 2014; we retrospectively analyzed 264 eligible patients. The intervals between surgery and diagnosis of LLL were calculated; the prevalence and risk factors were evaluated using the Kaplan-Meier and Cox proportional hazards methods. We developed a prediction model with which patients were scored and classified as low-risk or high-risk. Results The cumulative incidence of LLL was 23.1% at 1 year, 32.8% at 3 years, and 47.7% at 10 years post-surgery. LLL developed after a median 13.5 months. Using regression analysis, body mass index (BMI) ≥25 kg/m 2 (hazard ratio [HR], 1.616; 95% confidence interval [CI], 1.030–2.535), PLA + PALA (HR, 2.323; 95% CI, 1.126–4.794), postoperative radiation therapy (HR, 2.469; 95% CI, 1.148–5.310), and lymphocyst formation (HR, 1.718; 95% CI, 1.120–2.635) were found to be independently associated with LLL; age, type of cancer, number of lymph nodes, retroperitoneal suture, chemotherapy, lymph node metastasis, herbal medicine, self-management education, or infection were not associated with LLL. The predictive score was based on the 4 associated variables; patients were classified as high-risk (scores 3–6) and low-risk (scores 0–2). LLL incidence was significantly greater in the high-risk group than in the low-risk group (HR, 2.19; 95% CI, 1.440–3.324). The cumulative incidence at 5 years was 52.1% [95% CI, 42.9–62.1%] for the high-risk group and 28.9% [95% CI, 21.1–38.7%] for the low-risk group. The area under the receiver operator characteristics curve for the prediction model was 0.631 at 1 year, 0.632 at 3 years, 0.640 at 5 years, and 0.637 at 10 years. Conclusion BMI ≥25 kg/m 2 , PLA + PALA, lymphocyst formation, and postoperative radiation therapy are significant predictive factors for LLL. Our prediction model may be useful for identifying patients at risk of LLL following lymphadenectomy. Providing an intensive therapeutic strategy for high-risk patients may help reduce the incidence of LLL and conserve the quality of life.

Suppression of ubiquitin proteasome pathway (UPP) and stimulation of caspase-3 are involved in neurodegeneration. Can UPP activators and caspase-3 inhibitors ameliorate neurodegeneration? Here, we found a novel neuronal cell death accompanied with UPP activation and caspase-3 inhibition. Recently, plasmalemmal neuron-specific enolase (NSE) has been identified as one of membrane targets of 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2). 15d-PGJ2 induces neuronal apoptosis via activating caspase-3 and inactivating UPP, whereas the anti-NSE antibody inactivated caspase-3, activated UPP, and caused neuronal cell death. The anti-NSE antibody activated caspase-1 (pyroptosis marker), but not condense chromatin (apoptosis marker). The anti-NSE antibody declined intracellular level of ATP, which is not altered in pyroptosis. The intracellular level of calcium is elevated in necrosis and pyroptosis, but its chelator did not ameliorate the neurotoxicity of anti-NSE. Thiol antioxidants such as N-acetyl cysteine and glutathione reduced the neurotoxicity of 15d-PGJ2 but enhanced that of the anti-NSE antibody. The anti-NSE antibody incorporated propidium iodide into neurons through the disrupted plasma membrane, which are not observed in ferroptosis and autophagic cell death. Thus, the anti-NSE antibody induced neuronal cell death in a novel fashion distinguished from necrosis, necroptosis, apoptosis, pyroptosis, ferroptosis, and autophagic cell death.

We measure isotope shifts for neutral Yb isotopes on an ultranarrow optical clock transitionS10−P03with an accuracy of a few hertz. Combined with one of the recently reported isotope-shift measurements ofYb+on two optical transitions, the result allows us to construct the King plots—a set of scaled isotope shifts data on two different optical transitions plotted in two-dimensional plane. When only the leading-order terms of isotope shifts are taken into account, a King plot should exhibit a linear relation as a result of elimination of the leading nuclear-size dependence. Extremely large nonlinearity unexplainable by a quadratic field shift is revealed, which was proposed previously as a source of the observed nonlinearity of the King plot. We further construct the generalized King plot with three optical transitions so that we can eliminate the contribution arising from a higher-order effect within the standard model. Our analysis of the generalized King plot shows a deviation from linearity at the3σlevel, indicating that there exist at least two higher-order contributions in the measured isotope shifts. Under reasonable assumptions, we obtain the upper bound of the product of the couplings for a new boson, mediating a force between electrons and neutrons—|yeyn|/(ℏc)<1×10−10for the mass less than 1 keV—with the 95% confidence level, providing an important step toward probing new physics via isotope-shift spectroscopy.

Understanding the mechanisms of non-T cell inflamed tumor microenvironment (TME) and their modulation are important to improve cancer immunotherapies such as immune checkpoint inhibitors. The involvement of various immunometabolisms has recently been indicated in the formation of immunosuppressive TME. In this study, we investigated the immunological roles of stearoyl-CoA desaturase 1 (SCD1), which is essential for fatty acid metabolism, in the cancer immune response. We investigated the roles of SCD1 by inhibition with the chemical inhibitor or genetic manipulation in antitumor T cell responses and the therapeutic effect of anti-programmed cell death protein 1 (anti-PD-1) antibody using various mouse tumor models, and their cellular and molecular mechanisms. The roles of SCD1 in human cancers were also investigated by gene expression analyses of colon cancer tissues and by evaluating the related free fatty acids in sera obtained from patients with non-small cell lung cancer who were treated with anti-PD-1 antibody. Systemic administration of a SCD1 inhibitor in mouse tumor models enhanced production of CCL4 by cancer cells through reduction of Wnt/β-catenin signaling and by CD8 effector T cells through reduction of endoplasmic reticulum stress. It in turn promoted recruitment of dendritic cells (DCs) into the tumors and enhanced the subsequent induction and tumor accumulation of antitumor CD8 T cells. SCD1 inhibitor was also found to directly stimulate DCs and CD8 T cells. Administration of SCD1 inhibitor or SCD1 knockout in mice synergized with an anti-PD-1 antibody for its antitumor effects in mouse tumor models. High SCD1 expression was observed in one of the non-T cell-inflamed subtypes in human colon cancer, and serum SCD1 related fatty acids were correlated with response rates and prognosis of patients with non-small lung cancer following anti-PD-1 antibody treatment. SCD1 expressed in cancer cells and immune cells causes immunoresistant conditions, and its inhibition augments antitumor T cells and therapeutic effects of anti-PD-1 antibody. Therefore, SCD1 is an attractive target for the development of new diagnostic and therapeutic strategies to improve current cancer immunotherapies including immune checkpoint inhibitors.

Exposure of testes to high-temperature environment results in defective spermatogenesis. Zebrafish exposed to high temperature exhibited apoptosis not only in germ cells but also in Leydig cells, as expected from studies using mice or salmon. However, the role of testicular somatic cells in spermatogenesis defects remains unclear. We found that in Leydig cells the Trpv4 gene encoding the temperature sensitive ion channel was specifically upregulated in high temperature. High temperature also reduced hormone synthesis in Leydig cells and led to a prompt downregulation of sperm motility. In the Trpv4 null mutant, neither Leydig cell-specific apoptosis nor decreased sperm motility was observed under high temperature. These results indicate that Leydig cell specific-apoptosis is induced via Trpv4 by high temperature. Notably this Trpv4 -dependent mechanism was specific to Leydig cells and did not operate in germ cells. Because sperm exposed to high temperature exhibited compromised genome stability, we propose that temperature sensing leading to apoptosis in Leydig cells evolved to actively suppress generation of offspring with unstable genome. Under high temperature in zebrafish, the temperature sensitive ion channel Trpv4 is upregulated in Leydig cells, inducing apoptosis. Leydig cell-specific apoptosis decreases steroid hormone synthesis, impairing the motility of sperm with compromised genome integrity.