Bob1 maintains T follicular helper cells for long-term humoral immunity.

Humoral immunity is vital for host protection, yet aberrant antibody responses can trigger harmful inflammation and immune-related disorders. T follicular helper (Tfh) cells, central to humoral immunity, have garnered significant attention for unraveling immune mechanisms. This study shows the role of B-cell Oct-binding protein 1 (Bob1), a transcriptional coactivator, in Tfh cell regulation. Our investigation, utilizing conditional Bob1-deficient mice, suggests that Bob1 plays a critical role in modulating inducible T-cell costimulator expression and cellular respiration in Tfh cells. This regulation maintains the long-term functionality of Tfh cells, enabling their reactivation from central memory T cells to produce antibodies during recall responses. In a bronchial asthma model induced by house dust mite (HDM) inhalation, Bob1 is observed to enhance HDM-specific antibodies, including IgE, highlighting its pivotal function in Tfh cell regulation. Further exploration of Bob1-dependent mechanisms in Tfh cells holds promise for governing protective immunity and addressing immune-related disorders.

Symptomatic periesophageal vagal nerve injury by different energy sources during atrial fibrillation ablation.

Background: Symptomatic gastric hypomotility (SGH) is a rare but major complication of atrial fibrillation (AF) ablation, but data on this are scarce. Objective: We compared the clinical course of SGH occurring with different energy sources. Methods: This multicenter study retrospectively collected the characteristics and clinical outcomes of patients with SGH after AF ablation. Results: The data of 93 patients (67.0 ± 11.2 years, 68 men, 52 paroxysmal AF) with SGH after AF ablation were collected from 23 cardiovascular centers. Left atrial (LA) ablation sets included pulmonary vein isolation (PVI) alone, a PVI plus a roof-line, and an LA posterior wall isolation in 42 (45.2%), 11 (11.8%), and 40 (43.0%) patients, respectively. LA ablation was performed by radiofrequency ablation, cryoballoon ablation, or both in 38 (40.8%), 38 (40.8%), and 17 (18.3%) patients, respectively. SGH diagnoses were confirmed at 2 (1-4) days post-procedure, and 28 (30.1%) patients required re-hospitalizations. Fasting was required in 81 (92.0%) patients for 4 (2.5-5) days; the total hospitalization duration was 11 [7-19.8] days. After conservative treatment, symptoms disappeared in 22.3% of patients at 1 month, 48.9% at 2 months, 57.6% at 3 months, 84.6% at 6 months, and 89.7% at 12 months, however, one patient required surgery after radiofrequency ablation. Symptoms persisted for >1-year post-procedure in 7 patients. The outcomes were similar regardless of the energy source and LA lesion set. Conclusions: The clinical course of SGH was similar regardless of the energy source. The diagnosis was often delayed, and most recovered within 6 months, yet could persist for over 1 year in 10%.

Interface State Density Prediction between an Insulator and a Semiconductor by Gaussian Process Regression Models for a Modified Process.

During data-driven process condition optimization on a laboratory scale, only a small-size data set is accessible and should be effectively utilized. On the other hand, during process development, new operations are frequently inserted or current operations are modified. These accessible data sets are somewhat related but not exactly the same type. In this study, we focus on the prediction of the quality of the interface between an insulator and GaN as a semiconductor for the potential application of GaN power semiconductor devices. The quality of the interface was represented as the interface state density, Dit, and the inserted operation to the process was the ultraviolet (UV)/O3-gas treatment. Our retrospective evaluation of model-building approaches for Dit prediction from a process condition revealed that for the UV/O3-treated interfaces, data of interfaces without the treatment contributed to performance improvement. Such performance improvement was not observed when using a data set of Si as the semiconductor. As a modeling method, the automatic relevance vector-based Gaussian process regression with the prior distribution of the length-scale parameters exhibited a relatively high predictive performance and represented a reasonable uncertainty of prediction as reflected by the distance to the training data set. This feature is a prerequisite for a potential application of Bayesian optimization. Furthermore, hyperparameters in the prior distribution of the length-scales could be optimized by leave-one-out cross-validation.

CD4+CD8+ T follicular helper cells regulate humoral immunity in chronic inflammatory lesions.

T follicular helper (Tfh) cells drive humoral immunity by facilitating B cell responses at the initial and recall phases. Recent studies have indicated the possible involvement of Tfh cells in the process of chronic inflammation. However, the functional role of Tfh cells in persistent immune settings remains unclear. Here, we report that CD4+CD8+ (double-positive, DP; CD3+CD4+CD8+CXCR5hiPD-1hi) Tfh cells, a subset of germinal-center-type Tfh cells, were abundantly present in the fibroinflammatory lesions of patients with immunoglobulin G4-related disease (IgG4-RD). Transcriptome analyses showed that these DP-Tfh cells in the lesions of IgG4-RD preferentially expressed signature genes characteristic of cytotoxic CD8+ T cells, such as Eomes, CRTAM, GPR56, and granzymes, in addition to CD70. Scatter diagram analyses to examine the relationships between tissue-resident lymphocytes and various clinical parameters revealed that the levels of DP-Tfh cells were inversely correlated to the levels of serum IgG4 and local IgG4-expressing (IgG4+) memory B cells (CD19+CD27+IgD-) in patients with IgG4-RD. Cell culture experiments using autologous tonsillar lymphocytes further suggested that DP-Tfh cells possess a poor B-cell helper function and instead regulate memory B cells. Since CD4+ (single positive, SP; CD3+CD4+CD8-CXCR5hiPD-1hi) Tfh cells differentiated into DP-Tfh cells under stimulation with IL-2 and IL-7 as assessed by in vitro experiments, these data imply that SP-Tfh cells are a possible origin of DP-Tfh cells under persistent inflammation. These findings highlight the potential feedback loop mechanism of Tfh cells in immune tolerance under chronic inflammatory conditions. Further studies on DP-Tfh cells may facilitate control of unresolved humoral responses in IgG4-RD pathological inflammation.

Internet use and physical activity of older adults during the COVID-19 pandemic: a cross-sectional study in a northern Japanese City.

BACKGROUND: Little is known of whether Internet use is associated with physical activity among socially isolated older adults during the coronavirus disease 2019 (COVID-19) pandemic. This study investigated the association between Internet use and physical activity, and whether this association differs depending on social isolation among community-dwelling Japanese older adults. METHODS: A cross-sectional study was conducted with 1048 community-dwelling residents aged 65-90 years. Data were obtained using a self-reported questionnaire in August 2020. Physical activity was assessed using the International Physical Activity Questionnaire-Short Form. Multivariable logistic regression analyses were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between Internet use and moderate-to-vigorous physical activity (MVPA). RESULTS: Internet use showed a significant association with MVPA (OR = 1.42, 95% CI: 1.06-1.90) after adjusting for age, sex, self-reported socioeconomic status, and other health-related characteristics. When the results were stratified by social participation and living status, Internet use was associated with a significantly higher likelihood of MVPA among participants with no social participation (OR = 1.81, 95% CI: 1.03-3.17) and living with family (OR = 1.40, 95% CI: 1.02-1.93). CONCLUSION: Internet use was associated with sufficient physical activity, and this association may differ depending on the social isolation among community-dwelling older adults in Japan.

Ataxia telangiectasia and Rad3-related inhibition by AZD6738 enhances gemcitabine-induced cytotoxic effects in bladder cancer cells.

The ataxia telangiectasia and rad3-related-checkpoint kinase 1 (ATR-CHK1) pathway is involved in DNA damage responses in many cancer cells. ATR inhibitors have been used in clinical trials in combination with radiation or chemotherapeutics; however, their effects against bladder cancer remain unclear. Here, the efficacy of combining gemcitabine with the novel ATR inhibitor AZD6738 was investigated in vitro in three bladder cancer cell lines (J82, T24, and UM-UC-3 cells). The effects of gemcitabine and AZD6738 on cell viability, clonogenicity, cell cycle, and apoptosis were examined. The combined use of gemcitabine and AZD6738 inhibited the viability and colony formation of bladder cancer cells compared to either treatment alone. Gemcitabine (5 nM) and AZD6738 (1 µM) inhibited cell cycle progression, causing cell accumulation in the S phase. Moreover, combined treatment enhanced cleaved poly[ADP-ribose]-polymerase expression alongside the number of annexin V-positive cells, indicating apoptosis induction. Mechanistic investigations showed that AZD6738 treatment inhibited the repair of gemcitabine-induced double-strand breaks by interfering with CHK1. Combining AZD6738 with gemcitabine could therefore be useful for bladder cancer therapy.

Ligand-based approaches to activity prediction for the early stage of structure-activity-relationship progression.

The retrospective evaluation of virtual screening approaches and activity prediction models are important for methodological development. However, for fair comparison, evaluation data sets must be carefully prepared. In this research, we compiled structure-activity-relationship matrix-based data sets for 15 biological targets along with many diverse inactive compounds, assuming the early stage of structure-activity-relationship progression. To use a large number of diverse inactive compounds and a limited number of active compounds, similarity profiles (SPs) are proposed as a set of molecular descriptors. Using these highly imbalanced data sets, we evaluated various approaches including SPs, under-sampling, support vector machine (SVM), and message passing neural networks. We found that for the under-sampling approaches, cluster-based sampling is better than random sampling. For virtual screening, SPs with inactive reference compounds and the under-sampling SVM also perform well. For classification, SPs with many inactive references performed as well as the under-sampling SVM trained on a balanced data set. Although the performance of SPs and the under-sampling SVM were comparable, SPs with many inactive references were preferable for selecting structurally distinct compounds from the active training compounds.

Prediction of Reaction Yield for Buchwald-Hartwig Cross-coupling Reactions Using Deep Learning.

Chemical reaction yield is one of the most important factors for determining reaction conditions. Recently, several machine learning-based prediction models using high-throughput experiment (HTE) data sets were reported for the prediction of reaction yield. However, none of them were at a practical level in terms of predictive ability. In this study, we propose a message passing neural network (MPNN) model for chemical yield prediction, focusing on the Buchwald-Hartwig cross-coupling HTE data set. As an initial atom embedding in MPNN model, we propose to use the Mol2Vec feature vectors pre-trained using a large compound database. Predictive ability of the proposed model was higher than that of previously reported five models for the three out of five data sets. Moreover, visualization of important atoms based on self-attention mechanism was in favor of Mol2Vec as an atom embedding rather than other embeddings including previously employed simple representations.

Incidence and Implications of J waves Observed During Coronary Angiography.

J waves may be observed during coronary angiography (CAG), but they have not been fully studied. We investigated the characteristics of J waves in 100 consecutive patients during CAG. The patients and their family members had no history of cardiac arrest. Approximately 60% of patients had ischemic heart disease, previous myocardial infarction, or angina pectoris, but at the time of this study, the right coronary artery was shown to be normal or patent after stenting. Electrocardiogram was serially recorded to monitor J waves and alteration of the QRS complex during CAG. In 12 patients (12%), J waves (0.249 ± 0.074 mV) newly appeared during right CAG, and in another 13 patients (13%), preexisting J waves increased from 0.155 ± 0.060 mV to 0.233 ± 0.133 mV during CAG. Left CAG induced no J waves or augmentation of J waves. Distinct alterations were observed in the QRS complex during CAG of both coronary arteries. Mechanistically, myocardial ischemia induced by contrast medium was considered to result in a local conduction delay, and when it occurred in the inferior wall, the site of the late activation of the ventricle, the conduction delay was manifested as J waves. In conclusion, J waves were confirmed to emerge or increase during angiography of the right but not the left coronary artery. Myocardial ischemia induced by contrast medium caused a local conduction delay that was manifested as J waves in the inferior wall, the site of the late activation of the ventricle.

The Dual Histone Deacetylase-Proteasome Inhibitor RTS-V5 Acts Synergistically With Ritonavir to Induce Endoplasmic Reticulum Stress in Bladder Cancer Cells.

BACKGROUND/AIM: Simultaneous inhibition of histone deacetylase and proteasomes induces endoplasmic reticulum (ER) stress efficiently. RTS-V5 is the first dual histone deacetylase-proteasome inhibitor, and we anticipated that combining it with the cytochrome P450 family 3 subfamily A member 4 inhibitor ritonavir would enhance its activity in bladder cancer cells. MATERIALS AND METHODS: Using bladder cancer cells (human T-24, J-82, murine MBT-2), we evaluated the ability and mechanism by which the combination of RTS-V5 and ritonavir induced ER stress and killed cancer cells. RESULTS: The combination of RTS-V5 and ritonavir triggered robust apoptosis and inhibited bladder cancer growth effectively in vitro and in vivo. It caused ubiquitinated protein accumulation and induced ER stress synergistically. The combination inhibited the mammalian target of rapamycin pathway by increasing the expression of AMP-activated protein kinase. We also found that the combination caused histone and tubulin hyperacetylation. CONCLUSION: Ritonavir enhances the ability of RTS-V5 to cause ER stress in bladder cancer cells.

Using ultra-widefield red channel images to improve the detection of ischemic central retinal vein occlusion.

PURPOSE: To examine the usefulness of red channel fundus imaging to detect the ischemic status in eyes with central retinal vein occlusion (CRVO). METHODS: Ultra-widefield (UWF) fundus images were obtained from 42 eyes with CRVO. Twenty-one eyes were ischemic, and 21 eyes were non-ischemic. Rubeosis was found in 11 ischemic eyes. UWF images were split into red and green channels using ImageJ software. Both the color and red channel images were used to predict the presence or absence of ischemia when examined by masked graders. The sensitivity and specificity of UWF imagings for the detection of ischemia were calculated in Group A (total 42 eyes), Group B (32 eyes excluding non-rubeotic ischemic CRVO) and Group C (31 eyes excluding rubeotic ischemic CRVO), respectively. Moreover, a linear mixed model was conducted to investigate the relationship between the type of images and the accuracy of prediction in each group. RESULTS: No significant difference in the sensitivity of color fundus imaging was seen between Group A and Group B. By contrast, a significant difference in the sensitivity of red channel imaging was seen between Group A and Group B (p = 0.031). The accuracies of the predictions were not associated with the type of image in Group A and Group B, but were significantly associated in Group C (p = 0.026). CONCLUSIONS: UWF red channel imaging enabled more accurate detection of the ischemic status, compared with color fundus images, especially in non-rubeotic CRVO eyes.

Noradrenaline modulates neuronal and perceptual visual detectability via ß-adrenergic receptor.

RATIONALE: Noradrenaline (NA) is a neuromodulator secreted from noradrenergic neurons in the locus coeruleus to the whole brain depending on the physiological state and behavioral context. It regulates various brain functions including vision via three major adrenergic receptor (AR) subtypes. Previous studies investigating the noradrenergic modulations on vision reported different effects, including improvement and impairment of perceptual visual sensitivity in rodents via ß-AR, an AR subtype. Therefore, it remains unknown how NA affects perceptual visual sensitivity via ß-AR and what neuronal mechanisms underlie it. OBJECTIVES: The current study investigated the noradrenergic modulation of perceptual and neuronal visual sensitivity via ß-AR in the primary visual cortex (V1). METHODS: We performed extracellular multi-point recordings from V1 of rats performing a go/no-go visual detection task under the head-fixed condition. A ß-AR blocker, propranolol (10 mM), was topically administered onto the V1 surface, and the drug effect on behavioral and neuronal activities was quantified by comparing pre-and post-drug administration. RESULTS: The topical administration of propranolol onto the V1 surface significantly improved the task performance. An analysis of the multi-unit activity in V1 showed that propranolol significantly suppressed spontaneous activity and facilitated the visual response of the recording sites in V1. We further calculated the signal-to-noise ratio (SNR), finding that the SNR was significantly improved after propranolol administration. CONCLUSIONS: Pharmacological blockade of ß-AR in V1 improves perceptual visual detectability by modifying the SNR of neuronal activity.

Association Between Retinal Artery Angle and Visual Function in Eyes With Idiopathic Epiretinal Membrane.

Purpose: This study investigated the relationship between retinal artery angle and visual function in eyes with idiopathic epiretinal membrane (ERM). Methods: Ultra-wide field fundus imaging was conducted to analyze ERM and normal contralateral eyes. In addition to the logMAR visual acuity (VA) measurement, the average of the vertical and horizontal metamorphopsia scores (Mave) was measured using m-Charts for each eye. We calculated the retinal artery angle (Yugami correlated angle [YCA]) in all the examined eyes using ImageJ software. The YCAs were then compared between the ERM and normal contralateral eyes. Additionally, the relationship between YCA and visual function was investigated in the ERM eyes. Results: Data from 40 patients with ERM were analyzed. The mean age of the participants was 67.1 ± 8.1 years. The YCA was significantly smaller in the ERM eyes, compared with the contralateral eyes (P < 0.001, respectively; Wilcoxon signed rank test). Among age, axial length, YCAs, central retinal thickness (CRT), and central choroidal thickness (CCT), the optimal model for logMAR VA included age, YCA, and CRT. On the other hand, the optimal model for Mave included YCA and CCT. Conclusions: The retinal artery angle may be useful for predicting visual function in eyes with ERM. Translational Relevance: Our established quantitative measurements in fundus photography have potential clinical use in predicting visual function in ERM.

Acetylcholine from the nucleus basalis magnocellularis facilitates the retrieval of well-established memory.

Retrieval deficit of long-term memory is a cardinal symptom of dementia and has been proposed to associate with abnormalities in the central cholinergic system. Difficulty in the retrieval of memory is experienced by healthy individuals and not limited to patients with neurological disorders that result in forgetfulness. The difficulty of retrieving memories is associated with various factors, such as how often the event was experienced or remembered, but it is unclear how the cholinergic system plays a role in the retrieval of memory formed by a daily routine (accumulated experience). To investigate this point, we trained rats moderately (for a week) or extensively (for a month) to detect a visual cue in a two-alternative forced-choice task. First, we confirmed the well-established memory in the extensively trained group was more resistant to the retrieval problem than recently acquired memory in the moderately trained group. Next, we tested the effect of a cholinesterase inhibitor, donepezil, on the retrieval of memory after a long no-task period in extensively trained rats. Pre-administration of donepezil improved performance and reduced the latency of task initiation compared to the saline-treated group. Finally, we lesioned cholinergic neurons of the nucleus basalis magnocellularis (NBM), which project to the entire neocortex, by injecting the cholinergic toxin 192 IgG-saporin. NBM-lesioned rats showed severely impaired task initiation and performance. These abilities recovered as the trials progressed, though they never reached the level observed in rats with intact NBM. These results suggest that acetylcholine released from the NBM contributes to the retrieval of well-established memory developed by a daily routine.

Simvastatin-romidepsin combination kills bladder cancer cells synergistically.

The HMG-CoA reductase inhibitor simvastatin activates AMP-activated protein kinase (AMPK) and thereby induces histone acetylation. We postulated that combining simvastatin with the histone deacetylase (HDAC) inhibitor romidepsin would kill bladder cancer cells by inducing histone acetylation cooperatively. The combination of romidepsin and simvastatin induced robust apoptosis and killed bladder cancer cells synergistically. In murine subcutaneous tumor models using MBT-2 cells, a 15-day treatment with 0.5 mg/kg romidepsin and 15 mg/kg simvastatin was well tolerated and inhibited tumor growth significantly. Mechanistically, the combination induced histone acetylation by activating AMPK. The combination also decreased the expression of HDACs, thus further promoting histone acetylation. This AMPK activation was essential for the combination's action because compound C, an AMPK inhibitor, suppressed the combination-induced histone acetylation and the combination's ability to induce apoptosis. We also found that the combination increased the expression of peroxisome proliferator-activated receptor (PPAR) γ, leading to reactive oxygen species production. Furthermore, the combination induced endoplasmic reticulum (ER) stress and this ER stress was shown to be associated with increased AMPK expression and histone acetylation, thus playing an important role in the combination's action. Our study also suggests there is a positive feedback cycle between ER stress induction and PPARγ expression.

Ubiquitin-proteasome System Is a Promising Target for Killing Cisplatin-resistant Bladder Cancer Cells.

BACKGROUND/AIM: Activation of the ubiquitin-proteasome system (UPS) has been shown to be associated with drug resistance in cancer. Using bladder cancer cells, we investigated the association between UPS activation and cisplatin resistance and also the efficacy of UPS-targeting drugs. MATERIALS AND METHODS: We established cisplatin-resistant bladder cancer cells (J82-cisR, T24-cisR) and examined the activation status of the UPS and the efficacy of MLN7243, oprozomib, ixazomib, and RTS-V5. RESULTS: The UPS in cisplatin-resistant bladder cancer cells was activated compared to that in their parental controls. All the UPS-targeting drugs induced apoptosis and inhibited growth more effectively in the cisplatin-resistant bladder cancer cells than they did in the parental controls. Furthermore, these UPS-targeting drugs induced endoplasmic reticulum stress by causing unfolded protein accumulation at lower concentrations in the cisplatin-resistant bladder cancer cells. CONCLUSION: Targeting the UPS could be an effective strategy for treating cisplatin-resistant bladder cancer.

Inhibition of checkpoint kinase 1 potentiates anticancer activity of gemcitabine in bladder cancer cells.

Checkpoint kinases (CHKs) are involved in the DNA damage response in many cancer cells. CHK inhibitors have been used in clinical trials in combination with chemotherapeutics; however, their effect against bladder cancer remains unclear. Here, we investigated the efficacy of combining gemcitabine with MK-8776, a novel CHK1 inhibitor, in four bladder cancer cell lines. The effects of gemcitabine and MK-8776 on cell viability, clonogenicity, cell cycle, and apoptosis were examined alongside in vivo efficacy using murine xenograft tumor models. Combined treatment inhibited the viability and colony formation of bladder cancer cells compared to either single treatment. Although gemcitabine (10 nM) alone increased the cell number in S-phase, it increased the cell number in sub-G1 phase when combined with MK-8776 (0.5 µM). Combined treatment enhanced cleaved poly[ADP-ribose]-polymerase expression alongside the number of annexin-V-positive cells, indicating the induction of apoptosis. In vivo, administration of gemcitabine and MK-8776 was well tolerated and suppressed tumor growth. Mechanistically, the combined treatment elevated γH2A.X and suppressed Rad51 expression. Our study demonstrates that MK-8776 and gemcitabine combined induces apoptosis and suppresses proliferation in bladder cancer cells by inhibiting CHKs and DNA repair. Therefore, CHK1 inhibition combined with gemcitabine may be a potential treatment for bladder cancer.

Associations between Socioeconomic Status, Social Participation, and Physical Activity in Older People during the COVID-19 Pandemic: A Cross-Sectional Study in a Northern Japanese City.

Physical activity (PA) is a key determinant of health in older adults. However, little is known about the effect of social factors on PA among older adults during the coronavirus disease 2019 (COVID-19) pandemic. Therefore, we aimed to clarify the association between socioeconomic status, social participation, and PA during the pandemic. A cross-sectional study was conducted on 999 community-dwelling residents aged 65-90 years. A self-administered questionnaire was used to collect socioeconomic status, social participation, and PA data in August 2020. Multivariable logistic regression analyses were used to calculate the odds ratios (ORs) for the associations between socioeconomic status, social participation, and maintaining PA. For both sexes, PA was reduced by approximately 5%-10% after the onset of COVID-19-related distancing restrictions. Men with a low socioeconomic status were less physically active (OR = 0.49, 95% CI: 0.30-0.82). Women who reported social participation had higher odds of maintaining PA (OR = 1.67, 95% CI: 1.13-2.45) during the restrictions. Higher socioeconomic status and social participation levels before the COVID-19 pandemic may have helped older adults to maintain PA during the COVID-19 pandemic. Further research is needed to clarify the potential effects of these factors on the health of older adults.