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Heart rate variability (HRV) is believed to possess the potential for disease detection. However, early identification of heart disease remains challenging, as HRV analysis in dogs primarily reflects the advanced stages of the disease. The aim of this study is to compare 24-h HRV with sleep HRV to assess the potential utility of sleep HRV analysis. Thirty healthy dogs with no echocardiographic abnormalities were included in the study, comprising 23 females and 7 males ranging in age from 2 months to 8 years (mean [standard deviation], 1.4 [1.6]). This study employed a cross-sectional study. 24-h HRV and sleep HRV were measured from 48-h Holter recordings. Both linear analysis, a traditional method of heart rate variability analysis, and nonlinear analysis, a novel approach, were conducted. Additionally, circadian rhythm parameters were assessed. In frequency analysis of linear analysis, the parasympathetic index nHF was significantly higher during sleep compared to the mean 24-h period (mean sleep HRV [standard deviation] vs. mean 24 h [standard deviation], 95% confidence interval, value, r-family: 0.24 [0.057] vs. 0.23 [0.045], 0.006-0.031,  = 0.005,  = 0.49). Regarding time domain analysis, the parasympathetic indices SDNN and RMSSD were also significantly higher during sleep (SDNN: 179.7 [66.9] vs. 156.6 [53.2], 14.5-31.7,  < 0.001,  = 0.71 RMSSD: 187.0 [74.0] vs. 165.4 [62.2], 13.2-30.0,  < 0.001,  = 0.70). In a geometric method of nonlinear analysis, the parasympathetic indices SD1 and SD2 showed significantly higher values during sleep (SD1: 132.4 [52.4] vs. 117.1 [44.0], 9.3-21.1,  < 0.001,  = 0.70 SD2: 215.0 [80.5] vs. 185.9 [62.0], 17.6-40.6,  < 0.001,  = 0.69). Furthermore, the circadian rhythm items of the parasympathetic indices SDNN, RMSSD, SD1, and SD2 exhibited positive peaks during sleep. The findings suggest that focusing on HRV during sleep can provide a more accurate representation of parasympathetic activity, as it captures the peak circadian rhythm items.

Echocardiography is the first choice for assessing the structure and function of the heart, but it is unclear for detecting subclinical changes. In recent years, abnormal heart rate variability (HRV) has received attention for its ability to identify patients at risk for developing heart failure. HRV analysis in veterinary medicine is predominantly limited to linear analysis, which primarily reflects advanced heart disease. In contrast, nonlinear HRV analysis holds the potential for early detection of heart disease, but its quantitative evaluation remains rare. This study aimed to evaluate the feasibility of using HRV for the early heart disease detection in clinical settings, with a focus on doxorubicin (DXR)-induced myocardial damage in dogs. Six healthy female dogs with no abnormalities on physical examination, blood pressure, electrocardiography (ECG) and echocardiography were selected in this study. The dogs had an average age of 1.2 years and an average body weight of 8.1 kg. After recording blood pressure, ECG and echocardiography, the dogs were fitted with a Holter ECG, and measurements were taken for 2 days. Following the removal of the Holter ECG, DXR at 30 mg/m was administered over 30 min, repeated every 3 weeks, up to a maximum cumulative dose of 180 mg/m . Each measurement was taken before the first and after the final DXR dose. There were no changes in recommended parameters of left ventricular systolic function (FS: 34.4% [33.9-42.8] vs. 37.8% [34.7-42.8],  = 0.73, GLS EN: -19.1% [-21.3 - -17.5] vs. -18.0% [-19.3 - -17.3],  = 0.68). However, the Poincaré plot of nonlinear HRV significantly reflected increased sympathetic activity (SD1/SD2: 0.58% [0.57-0.60] vs. 0.42% [0.40-0.45],  = 0.008, SD2/SD1: 1.8% [1.76-1.82] vs. 2.5% [2.3-2.7],  = 0.008). The finding that nonlinear HRV analysis reflected early increased sympathetic activity associated with DXR administration in dogs is an important step forward in enhancing the clinical application potential of HRV.

Background Hypertension is the prime risk factor for stroke, and primary aldosteronism (PA) is the most common cause of secondary hypertension. The prevalence of PA in stroke patients has never been reported. The aim of this study was to elucidate the prevalence of PA. Methods A total of 427 consecutive patients with acute stroke were prospectively enrolled for this study. The screening tests were performed at the initial visit and a week after admission by measuring plasma aldosterone concentration and plasma renin activity. The rapid adrenocorticotropic hormone (ACTH) test was performed as the confirmatory test when both screening tests were positive. The primary endpoint was a final diagnosis of PA. Results The sensitivity of the dual screening system for the diagnosis of PA was 88.2 %, and PA was finally diagnosed in 4.0 % of acute stroke patients and in 4.9 % of stroke patients with a history of hypertension. Patients with PA were less likely to be male and have diabetes, and they had higher blood pressure at the initial visit, lower potassium concentration, and more intracerebral hemorrhage. The rapid ACTH test was performed safely even in acute stroke patients. Conclusions The prevalence of PA is not low among acute stroke patients. Efficient screening of PA should be performed particularly for patients with risk factors. Trial registration UMIN-CTR; UMIN000011021 . Trial registration date: June 23, 2013 (retrospectively registered).

A pathological evaluation is one of the most important methods for the diagnosis of malignant lymphoma. A standardized diagnosis is occasionally difficult to achieve even by experienced hematopathologists. Therefore, established procedures including a computer-aided diagnosis are desired. This study aims to classify histopathological images of malignant lymphomas through deep learning, which is a computer algorithm and type of artificial intelligence (AI) technology. We prepared hematoxylin and eosin (H&E) slides of a lesion area from 388 sections, namely, 259 with diffuse large B-cell lymphoma, 89 with follicular lymphoma, and 40 with reactive lymphoid hyperplasia, and created whole slide images (WSIs) using a whole slide system. WSI was annotated in the lesion area by experienced hematopathologists. Image patches were cropped from the WSI to train and evaluate the classifiers. Image patches at magnifications of ×5, ×20, and ×40 were randomly divided into a test set and a training and evaluation set. The classifier was assessed using the test set through a cross-validation after training. The classifier achieved the highest levels of accuracy of 94.0%, 93.0%, and 92.0% for image patches with magnifications of ×5, ×20, and ×40, respectively, in comparison to diffuse large B-cell lymphoma, follicular lymphoma, and reactive lymphoid hyperplasia. Comparing the diagnostic accuracies between the proposed classifier and seven pathologists, including experienced hematopathologists, using the test set made up of image patches with magnifications of ×5, ×20, and ×40, the best accuracy demonstrated by the classifier was 97.0%, whereas the average accuracy achieved by the pathologists using WSIs was 76.0%, with the highest accuracy reaching 83.3%. In conclusion, the neural classifier can outperform pathologists in a morphological evaluation. These results suggest that the AI system can potentially support the diagnosis of malignant lymphoma. This study aims to classify histopathological images of malignant lymphoma through deep learning. The classifier achieved the high levels of accuracy in comparison to diffuse large B-cell lymphoma, follicular lymphoma, and reactive lymphoid hyperplasia, which were higher than those of pathologists. Artificial intelligence can potentially support diagnosis of malignant lymphoma.

We examined the effects of meal timing on postprandial glucose metabolism, including the incretin response and metabolites in healthy adults. Nineteen healthy young men completed two trials involving blood collection in a fasting state and at 30, 60 and 120 min after meal provision in a random order: (1) morning (~0900 h) and (2) evening (~1700 h). The blood metabolome of eight participants was analyzed using capillary electrophoresis-mass spectrometry. Postprandial glucose concentrations at 120 min (p = 0.030) and glucose-dependent insulinotropic polypeptide concentrations (p = 0.005) at 60 min in the evening trials were higher than those in the morning trials. The incremental area under the curve values of five glycolysis, tricarboxylic acid cycle and nucleotide-related metabolites and 18 amino acid-related metabolites were higher in the morning trials than those in the evening trials (p < 0.05). Partial least-squares analysis revealed that the total metabolic change was higher in the morning. Our study demonstrates that a meal in the evening exacerbates the state of postprandial hyperglycemia in healthy adults. In addition, this study provides insight into the difference of incretion and blood metabolites between breakfast and dinner, indicating that the total metabolic responses tends to be higher in the morning.

Intrahepatic cholangiocarcinoma and combined hepatocellular cholangiocarcinoma show varying degrees of biliary epithelial differentiation, which can be defined as liver cancer displaying biliary phenotype (LCB). LCB is second in the incidence for liver cancers with and without chronic hepatitis background and more aggressive than hepatocellular carcinoma (HCC). To gain insight into its molecular alterations, we performed whole-genome sequencing analysis on 30 LCBs. Here we show, the genome-wide substitution patterns of LCBs developed in chronic hepatitis livers overlapped with those of 60 HCCs, whereas those of hepatitis-negative LCBs diverged. The subsequent validation study on 68 LCBs identified recurrent mutations in TERT promoter, chromatin regulators ( BAP1 , PBRM1 and ARID2 ), a synapse organization gene ( PCLO ), IDH genes and KRAS . The frequencies of KRAS and IDHs mutations, which are associated with poor disease-free survival, were significantly higher in hepatitis-negative LCBs. This study reveals the strong impact of chronic hepatitis on the mutational landscape in liver cancer and the genetic diversity among LCBs. Intrahepatic cholangiocarcinoma and combined hepatocellular cholangiocarcinoma displaying biliary phenotypes are aggressive cancers. Fujimoto et al. characterize the mutational profile of chronic hepatitis and identify mutations in KRAS and IDH associated with poor survival.

Semi-dwarf traits have been widely introgressed into cereal crops to improve lodging resistance. In sorghum ( Sorghum bicolor L. Moench), four major unlinked dwarfing genes, Dw1-Dw4 , have been introduced to reduce plant height, and among them, Dw3 and Dw1 have been cloned. Dw3 encodes a gene involved in auxin transport, whereas, Dw1 was recently isolated and identified as a gene encoding a protein of unknown function. In this study, we show that DW1 is a novel component of brassinosteroid (BR) signaling. Sorghum possessing the mutated allele of Dw1 ( dw1 ), showed similar phenotypes to rice BR-deficient mutants, such as reduced lamina joint bending, attenuated skotomorphogenesis, and insensitivity against feedback regulation of BR-related genes. Furthermore, DW1 interacted with a negative regulator of BR signaling, BRASSINOSTEROID INSENSITIVE 2 (BIN2), and inhibited its nuclear localization, indicating that DW1 positively regulates BR signaling by inhibiting the function of BIN2. In contrast to rice and wheat breeding which used gibberellin (GA) deficiency to reduce plant height, sorghum breeding modified auxin and BR signaling. This difference may result from GA deficiency in rice and wheat does not cause deleterious side effects on plant morphology, whereas in sorghum it leads to abnormal culm bending.

Intestinal microfold (M) cells actively capture luminal antigens and move them by transcytosis to initiate immune responses. Ohno and colleagues show that the Ets transcription factor Spi-B is necessary for M-cell differentiation. Intestinal microfold cells (M cells) are an enigmatic lineage of intestinal epithelial cells that initiate mucosal immune responses through the uptake and transcytosis of luminal antigens. The mechanisms of M-cell differentiation are poorly understood, as the rarity of these cells has hampered analysis. Exogenous administration of the cytokine RANKL can synchronously activate M-cell differentiation in mice. Here we show the Ets transcription factor Spi-B was induced early during M-cell differentiation. Absence of Spi-B silenced the expression of various M-cell markers and prevented the differentiation of M cells in mice. The activation of T cells via an oral route was substantially impaired in the intestine of Spi-B-deficient ( Spib −/− ) mice. Our study demonstrates that commitment to the intestinal M-cell lineage requires Spi-B as a candidate master regulator.

Maternal immunoglobulin transfer plays a key role in conferring passive immunity to neonates. Maternal blood immunoglobulin Y (IgY) in avian species is transported to newly-hatched chicks in two steps: 1) IgY is transported from the maternal circulation to the yolk of maturing oocytes, 2) the IgY deposited in yolk is transported to the circulation of the embryo via the yolk sac membrane. An IgY-Fc receptor, FcRY, is involved in the second step, but the mechanism of the first step is still unclear. We determined whether FcRY was also the basis for maternal blood IgY transfer to the yolk in the first step during egg development. Immunohistochemistry revealed that FcRY was expressed in the capillary endothelial cells in the internal theca layer of the ovarian follicle. Substitution of the amino acid residue in Fc region of IgY substantially changed the transport efficiency of IgY into egg yolks when intravenously-injected into laying quail; the G365A mutant had a high transport efficiency, but the Y363A mutant lacked transport ability. Binding analyses of IgY mutants to FcRY indicated that the mutant with a high transport efficiency (G365A) had a strong binding activity to FcRY; the mutants with a low transport efficiency (G365D, N408A) had a weak binding activity to FcRY. One exception, the Y363A mutant had a remarkably strong binding affinity to FcRY, with a small dissociation rate. The injection of neutralizing FcRY antibodies in laying quail markedly reduced IgY uptake into egg yolks. The neutralization also showed that FcRY was engaged in prolongation of half-life of IgY in the blood; FcRY is therefore a multifunctional receptor that controls avian immunity. The pattern of the transport of the IgY mutants from the maternal blood to the egg yolk was found to be identical to that from the fertilized egg yolk to the newly-hatched chick blood circulation, via the yolk sac membrane. FcRY is therefore a critical IgY receptor that regulates the IgY uptake from the maternal blood circulation into the yolk of avian species, further indicating that the two steps of maternal–newly-hatched IgY transfer are controlled by a single receptor.

The older adult population in Japan is expected to increase. Therefore, long-term care and frailty prevention are important. However, the relationship between masticatory performance, nutritional intake, and frailty remains unclear. This cross-sectional study aimed to examine energy, protein, and vitamin D intake and its association with frailty and masticatory performance in older adults. Patients between January 2022 and January 2023 were recruited and divided into robust and frail groups. Masticatory performance, nutrition, frailty, and other data, such as age and sex, were evaluated through onsite measurements and a questionnaire. Logistic regression analysis was conducted with frailty as a dependent variable and masticatory performance as an independent variable, adjusting for age, sex, skeletal muscle mass, living alone, energy intake, protein–energy ratio, and vitamin D intake. No significant differences were observed between the groups regarding age or sex. The robust group showed significantly better results for protein–energy ratio, vitamin D intake, and subjective and objective masticatory performance than the frail group. Logistic regression analysis revealed a significant correlation between skeletal muscle mass, protein–energy ratio, and objective masticatory performance with frailty. Masticatory performance was associated with frailty, independent of the intake of nutrients such as energy, protein, and vitamin D.