Dynamical Rearrangement of Gauge Symmetry on the Orbifold S^1/Z_2

Gauge theory defined on the orbifold $M^4 \times (S^1/Z_2)$ is investigated from the viewpoint of the Hosotani mechanism. Rearrangement of gauge symmetry takes place due to the dynamics of Wilson line phases. The physical symmetry of the theory, in general, differs from the symmetry of the boundary conditions. Several sets of boundary conditions having distinct symmetry can be related by gauge transformations, belonging to the same equivalence class. The Hosotani mechanism guarantees the same physics in all theories in one equivalent class. Examples are presented in the SU(5) theory. Zero modes of the extra-dimensional components, $A_y$, of gauge fields acquire masses by radiative corrections. In the nonsupersymmetric SU(5) model the presence of bulk fermions leads to the spontaneous breaking of color SU(3). In the supersymmetric model with Scherk-Schwarz SUSY breaking zero modes of $A_y$'s acquire masses of order of the SUSY breaking.Comment: 57 pages, 4 figures. The error of a factor 2 in the effective potential in the supersymmetric SU(5) model was correcte

RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS

Repulsive guidance molecule A (RGMa) was originally identified as a neuronal growth cone–collapsing factor. Previous reports have demonstrated the multifunctional roles of RGMa mediated by neogenin1. However, the pathogenic involvement of RGMa in amyotrophic lateral sclerosis (ALS) remains unclear. Here, we demonstrated that RGMa concentration was elevated in the cerebrospinal fluid of both patients with ALS and transgenic mice overexpressing the mutant human superoxide dismutase1 (mSOD1 mice). Treatment with humanized anti-RGMa monoclonal antibody ameliorated the clinical symptoms in mSOD1 mice. Histochemical analysis revealed that the anti-RGMa antibody significantly decreased mutant SOD1 protein accumulation in the motor neurons of mSOD1 mice via inhibition of actin depolymerization. In vitro analysis revealed that the anti-RGMa antibody inhibited the cellular uptake of the mutant SOD1 protein, presumably by reinforcing the neuronal actin barrier. Collectively, these data suggest that RGMa leads to the collapse of the neuronal actin barrier and promotes aberrant protein deposition, resulting in exacerbation of the ALS pathology.Shimizu Mikito, Shiraishi Naoyuki, Tada Satoru, et al. RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS. Science Advances 9, 686 (2023); https://doi.org/10.1126/sciadv.adg3193

Incidence of seed migration to the chest, abdomen, and pelvis after transperineal interstitial prostate brachytherapy with loose 125I seeds

<p>Abstract</p> <p>Background</p> <p>The aim was to determine the incidence of seed migration not only to the chest, but also to the abdomen and pelvis after transperineal interstitial prostate brachytherapy with loose ¹²⁵I seeds.</p> <p>Methods</p> <p>We reviewed the records of 267 patients who underwent prostate brachytherapy with loose ¹²⁵I seeds. After seed implantation, orthogonal chest radiographs, an abdominal radiograph, and a pelvic radiograph were undertaken routinely to document the occurrence and sites of seed migration. The incidence of seed migration to the chest, abdomen, and pelvis was calculated. All patients who had seed migration to the abdomen and pelvis subsequently underwent a computed tomography scan to identify the exact location of the migrated seeds. Postimplant dosimetric analysis was undertaken, and dosimetric results were compared between patients with and without seed migration.</p> <p>Results</p> <p>A total of 19,236 seeds were implanted in 267 patients. Overall, 91 of 19,236 (0.47%) seeds migrated in 66 of 267 (24.7%) patients. Sixty-nine (0.36%) seeds migrated to the chest in 54 (20.2%) patients. Seven (0.036%) seeds migrated to the abdomen in six (2.2%) patients. Fifteen (0.078%) seeds migrated to the pelvis in 15 (5.6%) patients. Seed migration occurred predominantly within two weeks after seed implantation. None of the 66 patients had symptoms related to the migrated seeds. Postimplant prostate D90 was not significantly different between patients with and without seed migration.</p> <p>Conclusion</p> <p>We showed the incidence of seed migration to the chest, abdomen and pelvis. Seed migration did not have a significant effect on postimplant prostate D90.</p

Variations in Rectal Volumes and Dosimetry Values Including NTCP due to Interfractional Variability When Administering 2D-Based IG-IMRT for Prostate Cancer

We estimated variations in rectal volumes and dosimetry values including NTCP with interfractional motion during prostate IG-IMRT. Rectal volumes, DVH parameters, and NTCPs of 20 patients were analyzed. For this patient population, the median (range) volume on the initial plan for the rectum was 45.6 cc (31.3–82.0), showing on-treatment spread around the initial prediction based on the initial plan. DVH parameters of on-treatment CBCT analyses showed systematic regularity shift from the prediction based on the initial plan. Using the Lyman-Kutcher-Burman model, NTCPs of predicted late rectal bleeding toxicity of rectal grade ≥ 2 (RTOG) and the QUANTEC update rectal toxicity for the prediction based on the initial plan were 0.09% (0.02–0.24) and 0.02% (0.00–0.07), respectively, with NTCPs from on-treatment CBCT analyses being 0.35% (0.01–6.16) and 0.12% (0.00–4.11), respectively. Using the relative seriality model, for grade ≥ 2 bleeding rectal toxicity, NTCP of the prediction based on the initial plan was 0.64% (0.15–1.22) versus 1.48% (0.18–7.66) for on-treatment CBCT analysis. Interfraction variations in rectal volumes occur in all patients due to physiological changes. Thus, rectal assessment during 2D-based IG-IMRT using NTCP models has the potential to provide useful and practical dosimetric verification

TAK-652 Inhibits CCR5-Mediated Human Immunodeficiency Virus Type 1 Infection In Vitro and Has Favorable Pharmacokinetics in Humans

The first small-molecule CCR5 antagonist, TAK-779, could not be developed as an anti-human immunodeficiency virus type (anti-HIV-1) agent because of its poor oral bioavailability. TAK-652 is an orally bioavailable TAK-779 derivative with potent anti-HIV-1 activity. TAK-652 inhibited the binding of RANTES (regulated on activation, normal T-cell expressed and secreted), macrophage inflammatory protein 1α (MIP-1α), and MIP-1β to CCR5-expressing cells at nanomolar concentrations. TAK-652 could also suppress the binding of monocyte chemotactic protein 1 (MCP-1) to CCR2b-expressing cells. However, its inhibitory effect on ligand binding to other chemokine receptors was limited. TAK-652 was active against CCR5-using (R5) HIV-1 but totally inactive against CXCR4-using (X4) HIV-1. The compound was active against R5 HIV-1 clinical isolates containing reverse transcriptase and protease inhibitor-resistant mutations, with a mean 50% effective concentration (EC(50)) and EC(90) of 0.061 and 0.25 nM, respectively. In addition, recombinant R5 viruses carrying different subtype (A to G) envelope proteins were equally susceptible to TAK-652. A single oral administration of TAK-652 up to 100 mg was safe and well tolerated in humans. The compound displayed favorable pharmacokinetics, and its plasma concentration was 7.2 ng/ml (9.1 nM) even 24 h after the administration of 25 mg. Thus, TAK-652 is a promising candidate as a novel entry inhibitor of HIV-1

Outcomes following iodine-125 prostate brachytherapy with or without neoadjuvant androgen deprivation

AbstractPurposeTo report the biochemical failure-free survival (BFFS), cause-specific survival (CSS), and overall survival (OS) outcomes of patients treated with iodine-125 (I-125) brachytherapy for clinically localized prostate cancer.Methods and materialsBetween 2003 and 2009, I-125 permanent prostate brachytherapy without supplemental external-beam radiotherapy was performed for 663 patients with low-risk and low-tier intermediate-risk (defined as organ-confined disease, PSA <10ng/mL, and Gleason score 3+4 with biopsy positive core rate <33%) prostate cancer. Early in the study period, the preplanning method was used in the first 104 patients, and later the real-time planning method was used. Biochemical failure was determined using the American Society for Therapeutic Radiology Oncology (ASTRO) and Phoenix definitions.ResultsThe 7-year BFFS rates for the ASTRO and Phoenix definitions were 96.1% and 95.9%, respectively. The corresponding BFFS rates by risk group were 97.6% and 96.7% for low-risk, and 91.8% and 93.6% for low-tier intermediate-risk disease (p=0.007 and 0.08, respectively). The median times to biochemical failure in those who failed were 29.5 and 43.9months according to the ASTRO and Phoenix definitions, respectively. The 7-year CSS and OS were 99.1% and 96.4%. There was no significant difference in CSS or OS between the low-risk and low-tier intermediate-risk groups. In multivariate Cox regression analysis, risk group and prostate D90 were independent predictors of BFFS for the ASTRO definition, while only the prostate D90 was significant for the Phoenix definition.ConclusionI-125 prostate brachytherapy results in excellent 7-year BFFS, CSS, and OS for low-risk and low-tier intermediate-risk prostate cancer