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ApoA-I amyloidosis is an extremely rare form of systemic amyloidosis that commonly involves the heart, kidneys, and liver. ApoA-I amyloidosis is caused by amyloidogenic variants of APOA1 that are inherited in an autosomal dominant manner. Here, we report a 69-year-old man with sporadic cardiac amyloidosis who was born to consanguineous parents and carried a homozygous variant of p.Leu202Arg in APOA1., (© 2024. The Author(s).)

Information obtained via individual identification is invaluable for ecology and conservation. Physical tags, such as PIT tags and GPS, have been used for individual identification; however, these methods could impact on animal behavior and survival rates, and the tags may become lost. Although non-invasive methods that do not affect the target species (such as manual photoidentification) are available, these techniques utilize stripes and spots that are unique to the individual, which requires training, and applying them to large datasets is challenging. Many studies that have applied deep learning for identification have focused on species-level identification, but few have addressed individual-level identification. In this study, we developed an image-based identification method based on deep learning that uses the head spot pattern of the Japanese giant salamander (Andrias japonicus), an endemic and endangered species in Japan. We trained and evaluated a dataset collected over two days from 11 individuals in captivity, which included 7075 images taken by a smartphone camera. Individuals were photographed three times a day at approximately 11:00 (morning), 15:00 (afternoon), and 18:00 (evening). As a result, individual identification by our method, which used the EfficientNetV2 achieved 99.86% accuracy, kappa coefficient of 0.99, and an F1 score of 0.99. Performance was lower for the evening  model than for the morning and afternoon models, which were trained and evaluated using photographs taken at the corresponding time of the day. The proposed method does not require direct contact with the target species, and the effect on the animals is minimal; moreover, individual-level information can be obtained under natural conditions. In the future, smartphone images can be applied to citizen science surveys and individual-level big data collection, which is difficult using current methods., (© 2023. The Author(s).)

A major class of bispecific antibodies (BsAbs) utilizes heterodimeric Fc to produce the native immunoglobulin G (IgG) structure. Because appropriate pairing of heavy and light chains is required, the design of BsAbs produced through recombination or reassembly of two separately-expressed antigen-binding fragments is advantageous. One such method uses intein-mediated protein trans-splicing (IMPTS) to produce an IgG1-based structure. An extra Cys residue is incorporated as a consensus sequence for IMPTS in successful examples, but this may lead to potential destabilization or disturbance of the assay system. In this study, we designed a BsAb linked by IMPTS, without the extra Cys residue. A BsAb binding to both TNFR2 and CD30 was successfully produced. Cleaved side product formation was inevitable, but it was minimized under the optimized conditions. The fine-tuned design is suitable for the production of IgG-like BsAb with high symmetry between the two antigen-binding fragments that is advantageous for screening BsAbs., (© 2021. The Author(s).)

The identification and mapping of trees via remotely sensed data for application in forest management is an active area of research. Previously proposed methods using airborne and hyperspectral sensors can identify tree species with high accuracy but are costly and are thus unsuitable for small-scale forest managers. In this work, we constructed a machine vision system for tree identification and mapping using Red-Green-Blue (RGB) image taken by an unmanned aerial vehicle (UAV) and a convolutional neural network (CNN). In this system, we first calculated the slope from the three-dimensional model obtained by the UAV, and segmented the UAV RGB photograph of the forest into several tree crown objects automatically using colour and three-dimensional information and the slope model, and lastly applied object-based CNN classification for each crown image. This system succeeded in classifying seven tree classes, including several tree species with more than 90% accuracy. The guided gradient-weighted class activation mapping (Guided Grad-CAM) showed that the CNN classified trees according to their shapes and leaf contrasts, which enhances the potential of the system for classifying individual trees with similar colours in a cost-effective manner-a useful feature for forest management.

Although MUC13, a transmembrane mucin, is aberrantly expressed in pancreatic ductal adenocarcinoma (PDAC) and generally correlates with increased expression of HER2, the underlying mechanism remains poorly understood. Herein, we found that MUC13 co-localizes and interacts with HER2 in PDAC cells (reciprocal co-immunoprecipitation, immunofluorescence, proximity ligation, co-capping assays) and tissues (immunohistofluorescence). The results from this study demonstrate that MUC13 functionally interacts and activates HER2 at p1248 in PDAC cells, leading to stimulation of HER2 signaling cascade, including ERK1/2, FAK, AKT and PAK1 as well as regulation of the growth, cytoskeleton remodeling and motility, invasion of PDAC cells-all collectively contributing to PDAC progression. Interestingly, all of these phenotypic effects of MUC13-HER2 co-localization could be effectively compromised by depleting MUC13 and mediated by the first and second EGF-like domains of MUC13. Further, MUC13-HER2 co-localization also holds true in PDAC tissues with a strong functional correlation with events contributing to increased degree of disorder and cancer aggressiveness. In brief, findings presented here provide compelling evidence of a functional ramification of MUC13-HER2: this interaction could be potentially exploited for targeted therapeutics in a subset of patients harboring an aggressive form of PDAC.

Because dementia is associated with both deterioration in the quality of life and poor prognosis, the prevention of cognitive impairment (CI) is a critical problem in public health promotion. Hypertension is a risk factor for the aggravation of CI, and the renin-angiotensin-aldosterone system (RAAS) is a key player in the increased incidence and development of hypertension. Therefore, the RAAS is considered to be a promoting factor for CI development. Conversely, recent studies have shown that lowering blood pressure with RAAS inhibitors decreases the incidence of CI, dementia and cardiovascular disease. Blood-brain barrier-penetrating RAAS inhibitors appear to have advantages in preventing cognitive decline because they can suppress the RAAS in the hippocampus, which has an important role in cognition. Thus, RAAS blockage is a notable strategy for preventing CI.

Thrombin has a crucial role in cardiac remodeling through protease-activated receptor-1 activation in cardiac fibroblasts and cardiomyocytes. As heparin cofactor II (HCII) inhibits the action of tissue thrombin in the cardiovascular system, it is possible that HCII counteracts the development of cardiac remodeling. We investigated the relationships between plasma HCII activity and surrogate markers of cardiac geometry, including left atrial volume index (LAVI), relative wall thickness (RWT) and left ventricular mass index, and deceleration time (DcT) and the ratio of peak E velocity to early diastolic mitral annulus velocity (E/e' ratio) as surrogate markers of left ventricular diastolic dysfunction measured using echocardiography in 304 Japanese elderly individuals without systolic heart failure (169 men and 135 women; mean age: 65.4 ± 11.8 years). Mean plasma HCII activity in all participants was 95.8 ± 17.0% and there was no difference between the mean plasma HCII activities in males and females. Multiple regression analysis revealed that there were significant inverse relationships between plasma HCII activity and LAVI (coefficient: -0.2302, P<0.001), between HCII activity and RWT (coefficient: -0.0007, P<0.05), between HCII activity and DcT (coefficient: -0.5189, P<0.05) and between HCII activity and E/e' ratio (coefficient: -0.0558, P<0.01). Plasma HCII activity was independently and inversely associated with the development of cardiac remodeling, including cardiac concentric change, left atrial enlargement and left ventricular diastolic dysfunction. These findings suggest that cardiac tissue thrombin inactivation by HCII is a novel therapeutic target for cardiac remodeling and atherosclerosis.

The purpose of this study was to elucidate the effects of dietary sodium restriction on diurnal blood pressure (BP) variation in primary aldosteronism. We studied the diurnal variation in the systemic hemodynamic indices and in baroreflex sensitivity (BRS). In 13 subjects with aldosterone-producing adenomas (2 males; mean age, 39+/-2 years), intra-arterial pressure was monitored telemetrically on a normal salt diet (NaCl 10-12 g/day). Non-dippers were defined as those with a nocturnal reduction in systolic BP (SBP) of less than 10% of daytime SBP. Ten subjects showed a non-dipper pattern. Six of these "non-dippers" underwent repetitive hemodynamic studies on the last day of a 1-week low salt diet regimen (NaCl 2-4 g/day). Stroke volume was determined using Wesseling's pulse contour method, calibrated with indocyanine green dilution. BRS was calculated every 30 min as delta pulse interval/delta SBP on spontaneous variations. Nocturnal reduction of SBP was 4.1% on the normal salt diet. With sodium restriction, urinary sodium excretion decreased from 187+/-8 to 46+/-8 mmol/day, and body weight decreased from 57.9+/-2.1 to 56.6+/-1.9 kg. Night-time BP significantly decreased with dietary modification from 154+/-7/88+/-4 to 140+/-6/78+/-4 mmHg, whereas daytime BP was unaltered. With sodium restriction, cardiac index and stroke index decreased throughout the day. No significant difference was seen in either daytime or nighttime BRS between the two diets. We conclude that the non-dipper pattern is common in patients with an aldosterone-producing adenoma on a normal salt intake, and under such conditions, volume expansion appears to play a major role in the impairment of nocturnal BP reduction.

The purpose of this study was to elucidate the underlying mechanisms of blunted nocturnal blood pressure reduction in non-dipper hypertensive patients. We studied the diurnal variations in systemic hemodynamic indices and baroreflex sensitivity. In 45 subjects with essential hypertension (24 men; mean age, 49+/-1 years), intra-arterial pressure was monitored telemetrically. Non-dippers were defined as those with a nocturnal reduction of systolic blood pressure of less than 10% of daytime systolic blood pressure. Stroke volume was determined using Wesseling's pulse contour method, calibrated with indocyanine green dilution. Baroreflex sensitivity was calculated as deltapulse interval/deltasystolic blood pressure on spontaneous variations. The mean values of the hemodynamic parameters were calculated every 30 min. Twenty-six subjects were classified as non-dippers. Daytime blood pressure was not significantly different between dippers (149+/-4/87+/-3 mmHg) and non-dippers (147+/-3/82+/-2 mmHg), while the nighttime blood pressure was significantly reduced in dippers (131+/-3/77+/-2 mmHg) but not in non-dippers (145+/-3/80+/-2 mmHg). Nocturnal decreases in both cardiac index and stroke index were smaller in non-dippers (-12.0+/-1.2% and 1.5+/-1.0%) than in dippers (-17.5+/-1.4% and -2.2+/-1.1%). Baroreflex sensitivity significantly increased at nighttime both in dippers (6.5+/-0.6 to 8.0+/-0.7 ms/mmHg) and in non-dippers (5.1+/-0.3 to 6.4+/-0.4 ms/mmHg). Neither daytime nor nighttime baroreflex sensitivity was significantly different between the groups. We conclude that the hemodynamics of non-dipper essential hypertension are characterized by an inadequate nocturnal decrease in cardiac index and stroke index, suggestive of relative volume expansion or malsuppressed sympathetic activity.

The Y-box binding protein, YB-1, belongs to a family of multifunctional proteins which regulate gene expression on both transcriptional and translational levels. The tumor suppressor gene p53 displays growth suppressive properties by regulating gene expression through transcriptional regulation. We now demonstrate that YB-1 directly interacts with p53 using an in vitro pull-down assay. Using immunochemical co-precipitation methods, we also found that the two proteins are bound in vivo. Deletion analysis showed that three independent domains of YB-1, one at the N-terminal and two at the C-terminal, interact with p53. Conversely, a 14 amino acid sequence at the C-terminal of p53 was required for its interaction with YB-1. Gel mobility shift assays showed that the interaction of YB-1 with p53 stimulated the sequence-specific DNA binding of p53 to its consensus sequence. By contrast, this interaction inhibited the binding of YB-1. Using a p53-responsive p21 promoter linked to a reporter gene, it can be shown that antisense expression of YB-1 inhibits the induction of this promoter by p53 in transient transfection assays. These findings delineate a straightforward mechanism for gene expression through p53-YB-1 interaction.

To evaluate the role of volume expansion for prandial/postprandial natriuresis, we first determined spontaneous daily NaCl, H2O, and diet turnover and Evans blue and inulin spaces in male Wistar rats on various high-salt diets. Second, we measured the time course of Na and water clearance in chloralose/ketamine anesthetized rats over 270 minutes after a single intragastric Na load (0, 290.4, or 581 micromol/100 g body weight). Finally, similar measurements were made during and after a local [NaCl] increase in the left carotid artery supplying the brain for 60 minutes. Daily NaCl, H2O, and diet intake per rat was 2 to 74 mmol, 13 to 223 ml, and 1.5 to 33 g, respectively. Only inulin space and plasma [Na] correlated with daily Na uptake (X; regressions Y = 0.02X + 15.13, N = 99, r2 = 0.0716, P = 0.02; and Y = 141.7 + 0.1005X, N = 179, r2 = 0.104, P < 0.0001, respectively). Under chloralose/ketamine anesthesia, 86% to 102% of the total (i.v. plus i.g.) Na load and some 50% of the unilaterally administered intracarotid Na were excreted. Chloralose/ketamine anesthesia is thus suitable for studies on Na balance mechanisms. Plasma [Na] is under cerebral control. Because of its immediate onset, this mechanism might be the principal determinant of prandial and postprandial natriuresis and hence for the systemic Na balance.

The possible role of extracellular volume (ECV) expansion in prandial/postprandial natriuresis was evaluated in control, sham-operated (SO), and uninephrectomized (UNX) male Wistar rats fed a 0.64 (normal salt, NS) or 8 (high salt, HS) g% NaCl diet for seven days after UNX. We thus determined daily NaCl, diet, and water intake and Evans blue and inulin spaces on day 7. Finally, we determined Na and water clearance after a single i.g. Na load (581 micromol/100 g body weight) under chloralose/ketamine anesthesia in UNX and control HS rats. NaCl, diet, and water intakes were comparable beyond day 5. Plasma volume and ECV were similar in all groups. With NS diet, glomerular filtration rate (GFR) in UNX was compensated but lower than that of SO rats (0.55 vs. 0.74 ml/min per 100 g body weight). Blood pressure (BP) was 111 mm Hg in SO controls and 112 mm Hg in the UNX group. After oral Na loading, BP rose in both groups and remained higher in UNX (134 vs. 126 mm Hg at 15 minutes, 130 vs. 118 mm Hg at 225 minutes). Cumulative Na and water excretions were similar (513 and 610 micromol/100 g body weight, 1.97 and 2.35 ml/100 g body weight in SO and UNX, respectively). Chronically salt-loaded UNX rats seem to maintain dietary Na balance by mechanism(s) other than volume expansion.

To elucidate the roles of endogenous endothelin (ET) and nitric oxide (NO) in tubuloglomerular feedback (TGF), the effects of FR139317, a specific ET-A receptor antagonist, and NG-nitro-L-arginine (L-NNA), a NO synthase inhibitor on TGF were studied in Sprague-Dawley rats. FR139317 (1.5 mg/kg/hr i.v.) reversed the systemic pressor and renal vasoconstrictor responses induced by ET-1 (2 nmol/kg/hr i.v.), but did not alter the early proximal flow rate (EPFR) reduction in response to a loop perfusion with an artificial tubular fluid at 40 nl/min (47 +/- 3 vs. 47 +/- 3% in controls). L-NNA (0.2 mg/kg + 2 micrograms/kg/min i.v.) had no effect on systemic blood pressure (BP), renal hemodynamics or EPFR measured at zero perfusion (31 +/- 2 vs. 31 +/- 2 nl/min in controls), but enhanced the EPFR reduction during loop perfusion to 77 +/- 3%. Loop perfusion with 10(-3) M L-NNA in perfusate also increased the EPFR reduction to 70 +/- 7%. In conclusion, inhibition of NO synthesis enhances the TGF-mediated reduction of nephron GFR. This indicates an active participation of endogenous NO in the control of afferent arteriolar tone. endogenous ET does not influence TGF via the ET-A receptor.

It has been reported that glucose intolerance is occasionally found in primary aldosteronism. In this study, we measured insulin sensitivity by the euglycaemic hyperinsulinaemic glucose clamp technique and ability to release insulin by 75 g oral glucose tolerance test (OGTT) in primary aldosteronism. Seven patients with primary aldosteronism (PA) (53.7 +/- 3.4 years; mean +/- SEM) and eight normotensive subjects (NS) (57.5 +/- 2.6 years) were employed in this study. The two-hour euglycemic hyperinsulinaemic glucose clamp technique was performed in seven PA before adrenalectomy, six PA after adrenalectomy and eight NS. The 75 g OGTT was also done in five PA before and after adrenalectomy and eight NS. The mean rate of glucose infusion to maintain euglycemia for the last 30 minutes of the clamp technique was used as an indicator of insulin sensitivity (M-value). The total blood glucose levels during 75 g OGTT (area under the curves) (sigma blood glucose) were significantly higher in PA than those in NS, and the total insulin levels during 75 g OGTT (area under the curves) (sigma IRI) were significantly lower in PA than those in NS. After adrenalectomy in PA, blood glucose levels were significantly decreased and IRI were significantly increased compared with the normal range. There was a significant positive correlation (P < 0.05, r = 0.71) between serum potassium levels and IRI in PA which were determined before and after adrenalectomy. In PA, M-values (240.7 +/- 14.6 mg/m2/min) were significantly higher than those in NS (199.0 +/- 12.3 mg/m2/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of our data in conjunction with other recent literature allows the following conclusions regarding the role of endothelin in the tubuloglomerular feedback control mechanism and in the pathogenesis of acute ischemic renal failure: (1) Endothelin reduces nephron filtration rate in the nephrons with interrupted signal perception at the macula densa, in accord with preglomerular arteriolar constriction. Yet, the increase in filtration fraction in the whole kidney clearance study suggests a preferential postglomerular arteriolar constriction. Taken together, endothelin, which is a very potent renal vasoconstrictor, seems to constrict both preglomerular and postglomerular arterioles with a predominant constriction of the latter at the doses employed. (2) The endothelin-induced natriuresis is due to a fall in tubular reabsorption, reflecting a direct tubular action, possibly related to an elevation in blood pressure. (3) At the doses of endothelin used and under the present experimental conditions, changes in the magnitude of tubuloglomerular feedback (TGF) response or the feedback characteristic could not be detected. (4) No evidence was found for a participation of endothelin in the pathogenesis of acute postischemic renal failure, as evidenced by the absence of an improvement in glomerular filtration after treatment with endothelin antiserum.