Search

Abstract An aqueous solution of a common food dye, Fast Green FCF (FG), mimics cholyl-lysyl-fluorescein to visualize embryonic bile flow via single peritoneal injection into intrauterine mouse embryos. Despite its efficacy in embryos, its suitability for adult mice and small to medium-sized mammals remained uncertain. In this study, we investigated FG cholangiography in adult mice, dogs, and goats. The results demonstrate that FG injection enables progressive cholangiography in these species, highlighting its versatility across different animal models without necessitating specialized equipment. To further evaluate diagnostic utility, FG cholangiography was performed in various mouse models of bile flow disorders. FG successfully visualized dilated lumina in the extrahepatic bile duct of BDL mice and revealed aberrant luminal structures in the gallbladder walls of Sox17 +/− or Shh-cre; Sox17flox/− mice. In Mab21l1 −/− mice with contracted gallbladders, FG influx was limited to the gallbladder neck. Moreover, stereomicroscopic video analysis of FG influx into the gallbladder post-fasting revealed differences in gallbladder wall state and its bile composition between Sox17 +/− and wild-type mice, suggesting the potential for detecting variations in gallbladder stored bile properties. These findings underscore the efficacy of FG in facilitating progressive cholangiography across mammalian species.

Objectives: This study aimed to assess the safety and efficacy of cholic acid (CA) treatment over 74 weeks in Japanese patients with inherited enzymatic bile acid synthesis disorders (BASD). Methods: This phase 3, open-label, single-arm study enrolled four Japanese patients diagnosed with BASD, including two with 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase (HSD3B7) deficiency and two with Δ4–3-oxosteroid 5β-reductase (SRD5B1) deficiency. The patients had received chenodeoxycholic acid (CDCA) treatment but were switched to CA treatment. Treatment efficacy was evaluated by measuring serum and urinary bile acid levels and liver-related biomarkers, and adverse events were evaluated to monitor safety. Results: The daily CA doses ranged from 3.8 to 13.7 mg/kg/day. Laboratory values of liver-related biomarkers were maintained within normal ranges or improved. Bile acid analysis revealed CDCA replacement with CA in serum within the initial few weeks of CA treatment. Urinary concentrations of toxic bile acid metabolites associated with liver damage were higher than serum. Adverse effects from CA treatment were mild to moderate, and no treatment discontinuations were due to adverse events. Conclusions: CA treatment over 74 weeks resulted in favorable efficacy and safety outcomes in Japanese patients with BASD, consistent with previous studies. These results support the utility of CA as a therapeutic option for Japanese patients with BASD.

Abstract Electrophysiological studies have investigated predictive processing in music by examining event-related potentials (ERPs) elicited by the violation of musical expectations. While several studies have reported that the predictability of stimuli can modulate the amplitude of ERPs, it is unclear how specific the representation of the expected note is. The present study addressed this issue by recording the omitted stimulus potentials (OSPs) to avoid contamination of bottom-up sensory processing with top-down predictive processing. Decoding of the omitted content was attempted using a support vector machine, which is a type of machine learning. ERP responses to the omission of four target notes (E, F, A, and C) at the same position in familiar and unfamiliar melodies were recorded from 25 participants. The results showed that the omission N1 were larger in the familiar melody condition than in the unfamiliar melody condition. The decoding accuracy of the four omitted notes was significantly higher in the familiar melody condition than in the unfamiliar melody condition. These results suggest that the OSPs contain discriminable predictive information, and the higher the predictability, the more the specific representation of the expected note is generated.

Abstract Bile acids have received increasing attention as a marker of the long-term prognosis and a potential therapeutic target in patients with biliary atresia, which is a progressive disease of the hepatobiliary system. A detailed analysis of serum and urinary bile acid compositions was conducted to assess the characteristics of bile acid profiles and the correlation between bile acid profiles and liver fibrosis markers in adult patients with biliary atresia who achieved bilirubin normalization. Serum total bile acids and glucuronide-conjugated (glyco- and tauro-) cholic acids (GCA and TCA) and chenodeoxycholic acids (GCDCA and TCDCA) were significantly higher in patients with biliary atresia than in healthy controls, whereas unconjugated CA and CDCA showed no significant difference. There were no significant differences in CA to CDCA ratios and glycine-to-taurine-conjugated ratios. Urinary glycocholic acid 3-sulfate (GCA-3S) was significantly higher in patients with biliary atresia. Serum GCDCA showed a strong positive correlation with Mac-2 binding protein glycosylation isomer (M2BPGi). These results demonstrate that bile acid congestion persists into adulthood in patients with biliary atresia, even after cholestasis has completely improved after Kasai portoenterostomy. These fundamental data on bile acid profiles also suggest the potential value of investigating bile acid profiles in patients with biliary atresia.

Inborn errors of bile acid metabolism (IEBAM) cause cholestasis during the neonatal period, and 8 types of IEBAM have been reported to date. IEBAM accounts for approximately 2% of cases of cholestasis of unknown cause. As only 10 patients have been identified in Japan, IEBAM presents diagnostic challenges due to the similarity of clinical symptoms with biliary atresia, thus necessitating precise differentiation to avoid unnecessary invasive procedures. Laboratory tests in IEBAM are characterized by normal γ-glutamyltransferase (GGT) and serum total bile acid (STBA) levels despite the presence of cholestasis; therefore, measuring STBA and GGT is essential to distinguishing biliary atresia from IEBAM. With suspected IEBAM, liquid chromatography–mass spectrometry (LC/MS) analysis of urinary bile acids is needed to optimize diagnostic and therapeutic efficacy and avoid open cholangiography and initiate treatment for primary bile acids such as cholic acid or chenodeoxycholic acid. This prospective report aims to increase awareness of IEBAM by highlighting the characteristics of general blood test and bile acid profiles from LC/MS analyses of blood, urine, and stool samples.

Background Repeated action or inaction toward objects changes preferences for those objects. However, it remains unclear whether such training activates approach-avoidance motivation toward the objects, which leads to actual behavior. We conducted a pre-registered online experiment to examine whether approach and avoidance tendencies were affected by the experience of having executed or withheld a button-press response to a stimulus. Methods Participants (N = 236) performed a Go/NoGo task in which they were asked to repeatedly execute a response to a picture of a mug (i.e., Go-primed stimulus) and suppress a response to another picture of a mug (i.e., NoGo-primed stimulus). They then received one of two manikin tasks, which were implicit association tests designed to assess approach–avoidance tendencies. One manikin task measured the reaction times of moving a manikin toward or away from the Go-primed stimulus and the other picture of a mug (i.e., unprimed stimulus). The other manikin task measured the reaction times of moving a manikin toward or away from the NoGo-primed stimulus and the unprimed stimulus. The participants then rated their preference for the Go-primed, NoGo-primed, and unprimed items. Results The Go-primed item was evaluated as more highly preferable than the unprimed item in the Go condition, while the NoGo-primed item was evaluated as less preferable than the unprimed item in the NoGo condition. In contrast, the mean approach/avoidance reaction times in the manikin task showed no difference between the Go-primed and unprimed stimuli or between the NoGo-primed and unprimed stimuli. Conclusion When participants repeatedly responded or inhibited their responses to an object, their explicit preference for the object increased or decreased, respectively. However, the effect did not occur in approach-avoidance behaviors toward the object.

CYP7B1 catalyzes mitochondria-derived cholesterol metabolites such as (25R)26-hydroxycholesterol (26HC) and 3β-hydroxy-5-cholesten-(25R)26-oic acid (3βHCA) and facilitates their conversion to bile acids. Disruption of 26HC/3βHCA metabolism in the absence of CYP7B1 leads to neonatal liver failure. Disrupted 26HC/3βHCA metabolism with reduced hepatic CYP7B1 expression is also found in nonalcoholic steatohepatitis (NASH). The current study aimed to understand the regulatory mechanism of mitochondrial cholesterol metabolites and their contribution to onset of NASH. We used Cyp7b1−/− mice fed a normal diet (ND), Western diet (WD), or high-cholesterol diet (HCD). Serum and liver cholesterol metabolites as well as hepatic gene expressions were comprehensively analyzed. Interestingly, 26HC/3βHCA levels were maintained at basal levels in ND-fed Cyp7b1−/− mice livers by the reduced cholesterol transport to mitochondria, and the upregulated glucuronidation and sulfation. However, WD-fed Cyp7b1−/− mice developed insulin resistance (IR) with subsequent 26HC/3βHCA accumulation due to overwhelmed glucuronidation/sulfation with facilitated mitochondrial cholesterol transport. Meanwhile, Cyp7b1−/− mice fed an HCD did not develop IR or subsequent evidence of liver toxicity. HCD-fed mice livers revealed marked cholesterol accumulation but no 26HC/3βHCA accumulation. The results suggest 26HC/3βHCA-induced cytotoxicity occurs when increased cholesterol transport into mitochondria is coupled to decreased 26HC/3βHCA metabolism driven with IR. Supportive evidence for cholesterol metabolite-driven hepatotoxicity is provided in a diet-induced nonalcoholic fatty liver mouse model and by human specimen analyses. This study uncovers an insulin-mediated regulatory pathway that drives the formation and accumulation of toxic cholesterol metabolites within the hepatocyte mitochondria, mechanistically connecting IR to cholesterol metabolite-induced hepatocyte toxicity which drives nonalcoholic fatty liver disease.

The word “kawaii” is ubiquitous in contemporary Japan and has spread to the rest of the world with the dissemination of Japanese pop culture. Although the word is conventionally translated in English as “cute,” its meaning is more nuanced than “cute,” and it is used for a wider variety of objects. The primary aim of this study was to determine if Spanish has an equivalent to the word “kawaii”; additionally, similarities and differences across Japanese, English, and Spanish were explored. An internet survey was conducted in which respondents from Japan ( n = 486), the United States ( n = 365), and Argentina ( n = 303) were presented with various photographic images that were often described as “kawaii” in Japanese and asked to write three adjectives to describe the images. They were also instructed to rate their affective states when looking at each image in the valence and arousal dimensions. The results showed that babyish objects (e.g., human, animal, and toy) were most frequently defined as “kawaii” in Japanese, “cute” in English, and “tierno” in Spanish. The average frequency at which these words were used as primary adjectives was higher for “kawaii” (57.5%) than for “cute” (26.8%) or “tierno” (22.4%). All of these images were associated with positive and moderately-aroused affective states similarly across all three countries. The present study demonstrates that the adjectives “kawaii,” “cute,” and “tierno” can be used almost equivalently for describing babies and pets, but that the Japanese adjective “kawaii” encompasses wider categories than the other two words.

The current empirical evidence regarding the effects of personality on physical attractiveness is limited to adult faces. In two preregistered studies, we demonstrated that personality descriptions influenced perceived cuteness, warmth, competence of young children, and female adults’ nurturing motivation toward them. Study 1 showed that participants rated children accompanied by positive personality descriptions as cuter, friendlier, and more intelligent than their initial ratings. Negative personality descriptions reduced perceived cuteness in children, which in turn reduced nurturing motivation. Study 2 showed that negative personality descriptions consistently reduced perceived cuteness and warmth ratings after manipulation, regardless of the initial level of perceived cuteness. After one week, cuteness and warmth ratings in the positive personality condition tended to return to their initial ratings. However, the effect of negative personality descriptions on cuteness ratings persisted for all children. Together, our findings suggest that female adults’ perception of cuteness and nurturing motivation are induced not only by children’s appearance but also their personality.

The gut microbiome of vertebrates is capable of numerous biotransformations of bile acids, which are responsible for intestinal lipid digestion and function as key nutrient-signaling molecules. The human liver produces bile acids from cholesterol predominantly in the A/B-cis orientation in which the sterol rings are “kinked”, as well as small quantities of A/B-trans oriented “flat” stereoisomers known as “primary allo-bile acids”. While the complex multi-step bile acid 7α-dehydroxylation pathway has been well-studied for conversion of “kinked” primary bile acids such as cholic acid (CA) and chenodeoxycholic acid (CDCA) to deoxycholic acid (DCA) and lithocholic acid (LCA), respectively, the enzymatic basis for the formation of “flat” stereoisomers allo-deoxycholic acid (allo-DCA) and allo-lithocholic acid (allo-LCA) by Firmicutes has remained unsolved for three decades. Here, we present a novel mechanism by which Firmicutes generate the ”flat” bile acids allo-DCA and allo-LCA. The BaiA1 was shown to catalyze the final reduction from 3-oxo-allo-DCA to allo-DCA and 3-oxo-allo-LCA to allo-LCA. Phylogenetic and metagenomic analyses of human stool samples indicate that BaiP and BaiJ are encoded only in Firmicutes and differ from membrane-associated bile acid 5α-reductases recently reported in Bacteroidetes that indirectly generate allo-LCA from 3-oxo-Δ4-LCA. We further map the distribution of baiP and baiJ among Firmicutes in human metagenomes, demonstrating an increased abundance of the two genes in colorectal cancer (CRC) patients relative to healthy individuals.

Konrad Lorenz, an ethologist, proposed that certain physical elements are perceived as cute and induce caretaking behavior in other individuals, with the evolutionary function of enhancing offspring survival. He called these features Kindchenschema, baby schema. According to his introspection, these include a large forehead, chubby round features, and chubby cheeks. Previous studies are limited to examining the effects of these facial features on perceived cuteness. However, other morphological factors may be related to perceived cuteness. This study uses Bayesian optimization, one of the global sequential optimization methods for estimating unknown functions, to search for facial morphological features that enhance the perceptions of facial cuteness. We applied Bayesian optimization incorporating Gaussian process ordinal regression (GPOR), which allows an estimation of the latent cuteness function based on evaluations using the Likert scale. A total of 96 preschool children provided the facial images used in this study. We summarized the facial shape variations using methodologies of geometric morphometrics and principal component analysis (PCA) up to the third principal component (PC), which we refer to as the face space. A total of 40 participants evaluated the images created by warping the average facial texture of the children's faces with randomly generated parameters in the face space. Facial traits related to perceived cuteness were estimated based on the averaged cuteness function. Perceived cuteness was linked to the relative lower position of facial components and narrower jawline but not to the forehead height.

Although most bile acids (BAs) in feces are present in noncovalent forms that can be extracted with ethanol, non-negligible amounts of saponifiable BAs are also present. It is a major concern that such saponifiable BAs are routinely omitted from fecal BA measurements. We compared the BA profiles of healthy stools that were obtained with/without alkaline hydrolysis and found that as much as 29.7% (2.1–67.7%) of total BAs were saponifiable. Specifically, alkaline treatment led to significant elevations of isodeoxycholic acid (isoDCA) and isolithocholic acid (isoLCA) concentrations, suggesting that considerable proportions of isoDCA and isoLCA were esterified. Precursor ion scan data from LC/MS suggested the presence of long-chain FA-linked BAs. We chemically synthesized a series of fatty acid 3β-acyl conjugates of isoDCA and isoLCA as analytical standards and analyzed their fecal profiles from newborns to adults (n = 64) by LC/MS. FA-conjugated isobile acids (FA-isoBAs) were constantly present from 2 years of age to adulthood. C16- and C18-chain FA-isoBA esters were predominantly found regardless of age, but small amounts of acetic acid esters were also found. FA-isoBA concentrations were not correlated to fecal FA concentrations. Interestingly, there were some adults who did not have FA-isoBAs. Gut bacteria involved in the production of FA-isoBAs have not been identified yet. The present study provides insight into the establishment of early gut microbiota and the interactive development of esterified BAs.The contribution of FA-isoBAs to gut physiology and their role in pathophysiologic conditions such as inflammatory bowel disease are currently under investigation.

Organic anion transporting polypeptide (OATP) 1B1 (gene, solute carrier organic anion transporter family member 1B1 [SLCO1B1]) and OATP1B3 (SLCO1B3) serve as transporters for hepatic uptake of important endogenous substances and several commonly prescribed drugs. Inactivation of both proteins together causes Rotor syndrome. How this OATP1B1/1B3 defect disturbs bile acid (BA) metabolism is largely unknown. In this study, we performed detailed BA analysis in 3 patients with genetically diagnosed Rotor syndrome. We found that BAs glucuronidated at the C‐3 position (BA‐3G) accounted for 50% or more of total BAs in these patients. In contrast but similarly to healthy controls, only trace amounts of BA‐3G were detected in patients with constitutional indocyanine green excretory defect (OATP1B3 deficiency) or sodium‐taurocholate cotransporting polypeptide (NTCP; gene, solute carrier family 10 member 1 [SLC10A1]) deficiency. Therefore, substantial amounts of BA‐3G are synthesized in hepatocytes. The cycling pathway of BA‐3G, consisting of excretion from upstream hepatocytes and uptake by downstream hepatocytes by OATP1B1/1B3 may exist to reduce the burden on upstream hepatocytes. Conclusion: Detailed BA analysis revealed glucuronidated bile acidemia in patients with Rotor syndrome. Further exploration of the physiologic role of glucuronidated BAs is necessary.

Abstract Diagnosis of biliary atresia (BA) can involve uncertainties. In the present prospective multicenter study, we considered whether urinary oxysterols represent a useful marker for diagnosis of BA in Japanese children. Subjects under 6 months old at 7 pediatric centers in Japan were prospectively enrolled, including patients with cholestasis and healthy controls (HC) without liver disease. Patients with cholestasis constituted 2 groups representing BA patients and others with cholestasis from other causes (non-BA). We quantitatively analyzed 7 oxysterols including 4β-, 20(S)-, 22(S)-, 22(R)-, 24(S)-, 25-, and 27-hydroxycholesterol by liquid chromatography/electrospray ionization-tandem mass spectrometry. Enrolled subjects included 14 with BA (median age 68 days; range 26–170) and 10 non-BA cholestatic controls (59; 14–162), as well as 10 HC (57; 25–120). Total urinary oxysterols were significantly greater in BA (median, 153.0 μmol/mol creatinine; range 24.1–486.7; P

Abstract. Rationale:. Congenital bile acid synthesis defect (BASD) is a rare disease caused by mutations in the aldo-keto reductase 1D1 gene, which encodes the primary Δ4-3-oxosteroid 5β-reductase enzyme. Early disease diagnosis is critical for early treatment with bile acid replacement therapy, with an excellent chance for recovery. In contrast, protracted diagnosis and treatment may lead to poor outcomes, including decompensated hepatic cirrhosis, liver transplant, and even death. Patient concerns:. Three clinical congenital bile acid synthesis defect cases in the Vietnamese population are herein reported. These pediatric patients presented with symptoms of prolonged postpartum jaundice and abnormal loose stool (mucus, lipids, and white). The clinical examinations showed hepatosplenomegaly. Urinalysis showed a very low fraction of primary bile acids and atypical 3-oxo-Δ4- bile acids in all three patients. Diagnoses:. The patients were diagnosed with primary Δ4-3-oxosteroid 5β-reductase deficiency. Next-generation gene sequencing revealed two homozygous mutations in the aldo-keto reductase family 1 member D1 gene. The first is a documented variant, c.797G>A (p.Arg266Gln), and the second is a novel mutation at c.155T>C (p.Ile52Thr). Interventions:. Immediately after diagnosis, patients were treated with oral chenodeoxycholate 5 mg/kg/d. Outcomes:. The patients’ symptoms, signs, and primary bile acids levels improved significantly. Lessons:. Clinicians should consider genetic disorders related to cholestasis for effective and life-saving treatment. A prompt genetic analysis by next-generation gene sequencing enables patients to access bile acid replacement therapy earlier, significantly improving short- and long-term outcomes.

Abstract Background Berberine (BBR) is a plant-based nutraceutical that has been used for millennia to treat diarrheal infections and in contemporary medicine to improve patient lipid profiles. Reduction in lipids, particularly cholesterol, is achieved partly through up-regulation of bile acid synthesis and excretion into the gastrointestinal tract (GI). The efficacy of BBR is also thought to be dependent on structural and functional alterations of the gut microbiome. However, knowledge of the effects of BBR on gut microbiome communities is currently lacking. Distinguishing indirect effects of BBR on bacteria through altered bile acid profiles is particularly important in understanding how dietary nutraceuticals alter the microbiome. Results Germfree mice were colonized with a defined minimal gut bacterial consortium capable of functional bile acid metabolism (Bacteroides vulgatus, Bacteroides uniformis, Parabacteroides distasonis, Bilophila wadsworthia, Clostridium hylemonae, Clostridium hiranonis, Blautia producta; B4PC2). Multi-omics (bile acid metabolomics, 16S rDNA sequencing, cecal metatranscriptomics) were performed in order to provide a simple in vivo model from which to identify network-based correlations between bile acids and bacterial transcripts in the presence and absence of dietary BBR. Significant alterations in network topology and connectivity in function were observed, despite similarity in gut microbial alpha diversity (P = 0.30) and beta-diversity (P = 0.123) between control and BBR treatment. BBR increased cecal bile acid concentrations, (P

Abstract High-resolution digital audio is believed to produce a better listening experience than the standard quality audio, such as compact disks (CDs) and digital versatile disks (DVDs). One common belief is that high-resolution digital audio is superior due to the higher frequency (> 22 kHz) of its sound components, a characteristic unique to this audio. This study examined whether sounds with high-frequency components were processed differently from similar sounds without these components in the auditory cortex. Mismatch negativity (MMN), an electrocortical index of auditory deviance detection in sensory memory, was recorded in young adults with normal hearing (N = 38) using two types of white noise bursts: original sound and digitally filtered sound from which high-frequency components were removed. The two sounds did not produce any MMN response and could not be discriminated behaviourally. In conclusion, even if high-resolution audio is superior to the standard format, the difference is apparently not detectable at the cortical level.

NAFLD is an important public health issue closely associated with the pervasive epidemics of diabetes and obesity. Yet, despite NAFLD being among the most common of chronic liver diseases, the biological factors responsible for its transition from benign nonalcoholic fatty liver (NAFL) to NASH remain unclear. This lack of knowledge leads to a decreased ability to find relevant animal models, predict disease progression, or develop clinical treatments. In the current study, we used multiple mouse models of NAFLD, human correlation data, and selective gene overexpression of steroidogenic acute regulatory protein (StarD1) in mice to elucidate a plausible mechanistic pathway for promoting the transition from NAFL to NASH. We show that oxysterol 7α-hydroxylase (CYP7B1) controls the levels of intracellular regulatory oxysterols generated by the “acidic/alternative” pathway of cholesterol metabolism. Specifically, we report data showing that an inability to upregulate CYP7B1, in the setting of insulin resistance, results in the accumulation of toxic intracellular cholesterol metabolites that promote inflammation and hepatocyte injury. This metabolic pathway, initiated and exacerbated by insulin resistance, offers insight into approaches for the treatment of NAFLD.

The formation of secondary bile acids by gut microbes is a current topic of considerable biomedical interest. However, a detailed understanding of the biology of anaerobic bacteria in the genus Clostridium that are capable of generating secondary bile acids is lacking. We therefore sought to determine the transcriptional responses of two prominent secondary bile acid producing bacteria, Clostridium hylemonae and Clostridium hiranonis to bile salts (in vitro) and the cecal environment of gnotobiotic mice. The genomes of C. hylemonae DSM 15053 and C. hiranonis DSM 13275 were closed, and found to encode 3,647 genes (3,584 protein-coding) and 2,363 predicted genes (of which 2,239 are protein-coding), respectively, and 1,035 orthologs were shared between C. hylemonae and C. hiranonis. RNA-Seq analysis was performed in growth medium alone, and in the presence of cholic acid (CA) and deoxycholic acid (DCA). Growth with CA resulted in differential expression (>0.58 log2FC; FDR

Background: Inborn errors of bile acid metabolism (IEBAM) cause rare but treatable genetic disorders that can present as neonatal cholestasis or neurological diseases. Without timely primary bile acid treatment, patients may develop liver failure early in life. This study aimed to analyze the types and treatment outcomes of IEBAM in Taiwanese infants and document the allele frequency of CYP7B1 hot spot mutations in the population. Methods: Urine samples from patients with infantile intrahepatic cholestasis and suspected IEBAM were subjected to urinary bile acid analysis by gas chromatography-mass spectrometry (GC/MS). Genetic diagnoses were made using direct sequencing or next-generation sequencing. We also tested healthy control subjects for a probable hot spot point mutation of CYP7B1. Results: Among the 75 patients with infantile intrahepatic cholestasis tested during 2000 –2016, three had ∆4-3-oxosteroid 5β-reductase deficiency with AKR1D1 mutations, and three had oxysterol-7α-hydroxylase deficiency with CYP7B1 mutation. Two patients with ∆4-3-oxosteroid 5β-reductase deficiency were successfully treated with cholic acid. The three unrelated infants with oxysterol 7α-hydroxylase deficiencies had the same p.R112X homozygous CYP7B1 mutation. Two had mild renal or neurological involvement. Among 608 healthy control subjects, the allele frequency of the heterozygous mutation for p.R112X was 2/1216 (0.16%). The only surviving patient with oxysterol 7α-hydroxylase deficiency recovered from liver failure after chenodeoxycholic acid (CDCA) treatment beginning at 3 months of age. Conclusion: Distinct types of IEBAM disease were found in the Taiwanese population. Patients with early diagnosis and early treatment had a favorable outcome. IEBAM prevalence rates may be higher than expected due to the presence of heterozygous mutations in the general population. Key Words: chenodeoxycholic acid, cholic acid, inborn errors of bile acid metabolism, neonatal cholestasis, oxysterol 7α-hydroxylase deficiency

Research interest in cuteness perception and its effects on subsequent behavior and physiological responses has recently been increasing. The purpose of the present study was to produce a dataset of Japanese infant faces that are free of portrait rights and can be used for cuteness research. A total of 80 original facial images of 6-month-old infants were collected from their parents. The cuteness level of each picture was rated on a 7-point scale by 200 Japanese people (100 men and 100 women in their 20s–60s). Prototypical high- and low-cuteness faces were created by averaging the top 10 and bottom 10 faces according to the mean cuteness ratings. Then, 50 composite faces were made by mixing two faces randomly chosen from the 60 unused middle-cuteness faces. The normative cuteness ratings of these composite faces were obtained from 229 Japanese men and women in their 20s–60s. The shape of each composite face was transformed to be cuter (+50%) or less cute (–50%) along a continuum between the high- and low-cuteness prototypical faces. A two-alternative forced-choice task (N = 587) confirmed that cuteness discrimination was better than the chance level for all 50 face pairs. Moreover, the results showed that young men had poorer sensitivity to cuteness differences in infant faces than older men and women of any age. This Japanese Cute Infant Face (JCIF, “jay-sif”) dataset, including composite face images and normative rating scores, is publicly available online.

We investigated how a presenter's touching behaviors of an object during its explanation affect the observer's perceived feelings of kawaii, a Japanese word that means "cute," toward the object and the presenter. We conducted a face-to-face experiment with a robot presenter as well as a web survey experiment with both robot and human presenters. Based on the phenomenon that people more firmly touch an object when their perceived kawaii feeling is overwhelmingly strong, we investigated the effects of touching behavior with emphasized styles. First, we conducted a face-to-face experiment with a robot presenter where participants observed their presentations about an object to explain its characteristics. The results showed that participants who observed the robot's touch behaviors perceived the object to be more kawaii and thought that the robot also felt the object was more kawaii. On the other hand, the results did not effectively show any increase in the participant's feelings of kawaii toward the robot or the emphasized touch style. Based on these results, we next conducted a web survey experiment to investigate whether such knowledge about touching effects is applicable for human presenters. The results resembled those obtained when the presenter was a robot, i.e., viewing a touch behavior increased both the presenter's perceived feelings of kawaii toward the object and the participant's feelings of kawaii toward it. These results suggest that viewing the touch behaviors of others influenced the perceived emotional feelings toward both presenters and objects.

Although it is well established that cosmetic makeup enhances perceived facial attractiveness, few studies have examined whether facial makeup modulates neural responses to face images. This study investigated behavioral and attractiveness-related brain responses to self-applied makeup, focusing on the N170, early posterior negativity, P300, and late positive potential components of event-related brain potentials. A total of 77 Japanese women participated in two experiments (N = 34 and 43 for Experiments 1 and 2, respectively). Experiment 1 assessed the effects of self-applied makeup on attractiveness-related event-related potential amplitudes using facial images during a makeup identification task in which makeup was directly relevant to task demands. Experiment 2 examined the effects of self-applied makeup using images of one's own face and another female's face when performing a gender classification task, where the presence of makeup had no explicit connection to facial gender classification. In both experiments, faces with makeup were rated as more attractive and elicited more negative early posterior negativity and more positive late positive potential components, regardless of the participant's own face or another person's face. These findings suggest that people are spontaneously motivated to pay visual attention to faces with makeup, which supports the idea that makeup adds reward value to the facial appearance of the human. Moreover, neural evidence empirically confirmed that the benefits of makeup are not just limited to how others see your face but also extend to how you see your own face.

The display duration of stimuli is overestimated due to the increase in phasic arousal induced by the stimuli or high levels of background arousal. A previous study demonstrated that display duration of items (2 s) was overestimated when a participant attempted to conceal one of the items so as not to be detected in the concealed information test (CIT). As the time perception remained the same between the item to be concealed and the other items, the overestimation was thought to be due to the high level of background arousal under the conceal condition. Duration of 2 s may be too long to examine the phasic arousal effect induced by the concealed item. The present study conducted three online experiments with shorter durations, that is, each of three items was presented with duration of 1, 0.5, and 2 s in Experiments 1, 2, and 3, respectively. The participants were instructed to conceal one of the three items under the conceal condition and did not conceal any item in the innocent condition. The difference in time perception between the conceal and innocent conditions or between items under the conceal condition was observed in none of the three experiments. The result indicates that temporal overestimation does not occur when a participant is only concealing an object. Rather, temporal overestimation would occur only when the level of background arousal is amplified by the concealment.

We investigated the age-dependent changes in urinary excretion of glucuronidated bile acids at the C-3 position. Bile acid 3-glucuronides accounted for 0.5% of urinary bile acids in neonates, and the proportion of bile acid 3-glucuronides plateaued at 1–3 years of age. The 3-glucuronides of secondary bile acids were first secreted at 3 months of age, the same time as the establishment of the gut bacterial flora in infants. A considerable portion of bile acid 3-glucuronides were present as non-amidated forms. Our results indicate dynamic hepatic enzyme activity in which the levels of uridine 5′-diphospho-glucuronosyltransferases (UGTs) differ by age group, with higher glucuronidation activity of UGTs towards nonamidated bile acids than amidated bile acids.

Niemann-Pick disease type C (NPC) is an autosomal recessive disorder characterized by progressive nervous degeneration. Because of the diversity of clinical symptoms and onset age, the diagnosis of this disease is difficult. Therefore, biomarker tests have attracted significant attention for earlier diagnostics. In this study, we developed a simultaneous analysis method for five urinary conjugated cholesterol metabolites, which are potential diagnostic biomarkers for a rapid, convenient, and noninvasive chemical diagnosis, using LC/MS/MS. By the method, their urinary concentrations were quantified and the NPC diagnostic performances were evaluated. The developed LC/MS/MS method showed high accuracy and satisfied all analytical method validation criteria. When the urine of healthy controls and patients with NPC was analyzed, three of five urinary conjugated cholesterol metabolite concentrations corrected by urinary creatinine were significantly higher in the patients with NPC. As a result of receiver operating characteristics analysis, these urinary metabolites might have excellent diagnostic marker performance. 3β-Sulfooxy-7β-hydroxy-5-cholenoic acid showed particularly excellent diagnostic performance with both 100% clinical sensitivity and specificity, suggesting that it is a useful NPC diagnostic marker. The urinary conjugated cholesterol metabolites exhibited high NPC diagnostic marker performance and could be used for NPC diagnosis.

Internal tibial torsion is more common in the Asian population than in Western populations. Generally, surgery should be considered for the treatment of severe internal tibial torsion. As an alternative approach, the usefulness of a tibia counter rotator (TCR), a corrective orthosis based on the theory of the tibia torsional transformer, has been demonstrated, but the evidence is limited. In the present study, the efficacy and safety of TCR treatment were investigated in pediatric patients with internal tibial torsion. The subjects were 124 pediatric patients with internal tibial torsion who were between 3 and 15 years of age and had no underlying diseases. The severity of tibial intorsion was evaluated by the tibial transmalleolar angle (TMA). A TMA less than 5° was defined as internal tibial torsion, and less than −20° was defined as severe in this study. The median duration of TCR use was 11 (9, 12) (median (IQR: interquartile range)) months, and the treatment completion rate was 94.4% (117/124). The TMA at 12 months from the start of treatment in patients who completed treatment was 5° (0°, 10°) on the right (n = 66) (p < 0.01 vs. pretreatment) and 0° (−5°, 8°) on the left (n = 71) (p < 0.01 vs. pretreatment). The tibial torsional transformer used in this study is effective in the initial treatment of mild to severe internal tibial torsion, with no adverse effects. Although internal tibial torsion is generally expected to resolve spontaneously, TCR treatment may be an effective alternative to surgical therapy in the Asian pediatric population.

An online survey was conducted to clarify the connotative meanings of the cute and the attitudes toward cuteness in three countries: Japan ( n = 1,000), the United States ( n = 718), and Israel ( n = 437). The results show a remarkable resemblance in respondents’ conceptions of the cute ( kawaii in Japanese and hamud in Hebrew) across countries. Except for slight cultural differences, the following common tendencies were found: (a) Cuteness is highly appreciated and believed to induce positive affective responses, (b) women tend to find things cute more frequently and strongly than men do, (c) animal babies are thought to be cuter than human babies, and (d) infants are found to be cuter when people get older, while older people generally show less positive attitudes toward cuteness. This study provides some evidence that the concept of cuteness and the feelings connected to its perception are universal.

We investigated if viewing cute pictures could improve fine motor skills and prolong quiet eye (QE) duration. QE is a gaze phenomenon, and its duration (i.e., the period between fixation onset preceding a critical movement and fixation offset) is thought to represent attention control. As it has been reported that QE duration is longer for expert athletes than for novice athletes in various sports and becomes shorter even for experts who choke under pressure during games, resulting in performance deterioration, QE prolongation is important to prevent choking under pressure. Separately, several studies have confirmed that viewing cute pictures can induce focal attention, thus improving performance in fine motor tasks. We hypothesized that viewing cute pictures may modulate attention control and prolong QE duration. We also tested if the beneficial effects of viewing cute pictures could be obtained in a high-pressure situation in which participant performance was evaluated by an experimenter. We used a fine-motor task requiring participants to use a pair of tweezers to remove 12 small pieces from holes in a game board. We randomly assigned participants to either the baby-animal pictures group or the adult-animal pictures group, based on pictures viewed prior to the task. Participants executed the task in a pre-test, post-test, and pressure test. In both the post-test and the pressure test, participants viewed seven photographs of either baby animals or adult animals before execution of the task. In accordance with previous research, task precision increased after viewing pictures of baby animals in both the post-test and pressure test. Furthermore, QE duration was also prolonged after viewing cute pictures in the post-test, but not in the pressure test. Neither performance improvement nor QE prolongation was found after viewing pictures of adult animals. These results suggested that simply viewing cute pictures could prolong QE duration without pressure and might provide a beneficial effect on performance, even in a high-pressure situation.

Tetrahydroxy bile acids (THBAs) are hydrophilic and are present at minimal or undetectable levels in healthy human adults, but are present at high levels in bile salt export pump (abcb11)-knockout mice. The roles of THBAs in human cholestatic diseases are unclear. We aimed to investigate the presence of THBAs in patients with infantile intrahepatic cholestasis and its correlation with outcome. Urinary bile acids (BAs) were analyzed by GC-MS. Data were compared between good (n = 21) (disease-free before 1 year old) and poor prognosis groups (n = 19). Good prognosis patients had a higher urinary THBA proportion than poor prognosis patients [25.89% (3.45–76.73%) vs. 1.93% (0.05–48.90%)]. A urinary THBA proportion >7.23% predicted good prognosis with high sensitivity (95.24%), specificity (84.21%), and area under the curve (0.91) (P < 0.0001). A THBA proportion ≤7.23% was an independent factor for decreased transplant-free survival (hazard ratio = 7.16, confidence interval: 1.24–41.31, P = 0.028). Patients with a confirmed ABCB11 or tight junction protein 2 gene mutation (n = 7) had a minimally detectable THBA proportion (0.23–2.99% of total BAs). Three patients with an ATP8B1 mutation had an elevated THBA proportion (7.51–37.26%). In conclusion, in addition to disease entity as a major determinant of outcome, a high THBA level was associated with good outcome in the infantile intrahepatic cholestasis patients.

In Japan, many products contain the characteristics of small, round, bright colors, and are adorable and sweet, in short kawaii (“cute” in direct translation into English). Over the years, the mass production of kawaii goods has made its way to the West, initially through visual media and later on through consumption goods. This exposure has brought increased interest in Japan and its culture among young Westerners as well as a rise in familiarity with everyday Japanese words like kawaii . This study illuminates how non-Japanese people, in this case Israelis, define and treat the term kawaii . The results of the survey showed that a high number of respondents were familiar with the term kawaii , were able to define it in their own words, and had a positive approach toward it. This article provides some empirical evidence of a successful penetration of the Japanese consumer-related culture and popular words in Israel.

An oblique view of three-dimensional objects is preferred over a frontal or lateral view, partly because it is more familiar and easily recognizable. However, which side of a symmetric object looks better remains unsolved. Reading direction, handedness, and the functionality of objects have been suggested as the potential sources of directional bias. In this study, participants of three online surveys (total N = 1082) were asked to choose one item that looked better or was more aesthetically pleasing; the test was performed between 100 pairs of left- and right-facing mirror-images. The results showed that Japanese participants (both vertical and left-to-right readers) and Israeli participants (right-to-left readers) preferred left-facing images over right-facing images, whereas American participants (left-to-right readers) preferred right-facing images over left-facing images. Weak effects of handedness and object functionality were also found: Left-handers tended to choose right-facing images more than right-handers, and the view of objects with a handle that is graspable by the dominant hand was more likely to be chosen over the opposite side view, regardless of culture. Although previous studies have emphasized the role of reading direction, a close look at the results suggests that it cannot fully account for the preferred facing direction of oblique objects.

Baby schema has been considered a key stimulus that triggers feelings and thoughts of cuteness. Kawaii is a Japanese word that roughly translates to cute in English, but its meaning appears to be broader than cute. Specifically, cuteness is often regarded as synonymous with infant physical attractiveness, whereas kawaii is used not only for babies but also for noninfantile objects. In this study, psychophysiological responses were compared between two types of kawaii pictures: human babies and animals ( kawaii with baby schema) or objects such as desserts and dress accessories ( kawaii without baby schema). Twenty female university students were asked to view various pictures twice. Both types of kawaii pictures were rated to be more pleasant than neutral pictures, elicited a greater activation of the zygomaticus major muscles associated with smiling, and were viewed for a longer period when the same pictures were presented again. The effect of baby schema appeared in the zygomaticus major muscle activity, which was greater for pictures with baby schema. The findings suggest that the word kawaii expresses positive feelings that are more generic than infant attractiveness and that are associated with a motivation to approach a preferable object.

We have developed a simple and accurate HPLC method for measurement of fecal bile acids using phenacyl derivatives of unconjugated bile acids, and applied it to the measurement of fecal bile acids in cirrhotic patients. The HPLC method has the following steps: 1) lyophilization of the stool sample; 2) reconstitution in buffer and enzymatic deconjugation using cholylglycine hydrolase/sulfatase; 3) incubation with 0.1 N NaOH in 50% isopropanol at 60°C to hydrolyze esterified bile acids; 4) extraction of bile acids from particulate material using 0.1 N NaOH; 5) isolation of deconjugated bile acids by solid phase extraction; 6) formation of phenacyl esters by derivatization using phenacyl bromide; and 7) HPLC separation measuring eluted peaks at 254 nm. The method was validated by showing that results obtained by HPLC agreed with those obtained by LC-MS/MS and GC-MS. We then applied the method to measuring total fecal bile acid (concentration) and bile acid profile in samples from 38 patients with cirrhosis (17 early, 21 advanced) and 10 healthy subjects. Bile acid concentrations were significantly lower in patients with advanced cirrhosis, suggesting impaired bile acid synthesis.

The effects of makeup on attractiveness have been evaluated using mainly subjective measures. In this study, event-related brain potentials (ERPs) were recorded from a total of 45 Japanese women (n = 23 and n = 22 for Experiment 1 and 2, respectively) to examine the neural processing of faces with no makeup, light makeup, and heavy makeup. To have the participants look at each face carefully, an identity judgement task was used: they were asked to judge whether the two faces presented in succession were of the same person or not. The ERP waveforms in response to the first faces were analyzed. In two experiments with different stimulus probabilities, the amplitudes of N170 and vertex positive potential (VPP) were smaller for faces with light makeup than for faces with heavy makeup or no makeup. The P1 amplitude did not differ between facial types. In a subsequent rating phase, faces with light makeup were rated as more attractive than faces with heavy makeup and no makeup. The results suggest that the processing fluency of faces with light makeup is one of the reasons why light makeup is preferred to heavy makeup and no makeup in daily life.

Kawaii (a Japanese word meaning "cute") things are popular because they produce positive feelings. However, their effect on behavior remains unclear. In this study, three experiments were conducted to examine the effects of viewing cute images on subsequent task performance. In the first experiment, university students performed a fine motor dexterity task before and after viewing images of baby or adult animals. Performance indexed by the number of successful trials increased after viewing cute images (puppies and kittens; M ± SE=43.9 ± 10.3% improvement) more than after viewing images that were less cute (dogs and cats; 11.9 ± 5.5% improvement). In the second experiment, this finding was replicated by using a non-motor visual search task. Performance improved more after viewing cute images (15.7 ± 2.2% improvement) than after viewing less cute images (1.4 ± 2.1% improvement). Viewing images of pleasant foods was ineffective in improving performance (1.2 ± 2.1%). In the third experiment, participants performed a global-local letter task after viewing images of baby animals, adult animals, and neutral objects. In general, global features were processed faster than local features. However, this global precedence effect was reduced after viewing cute images. Results show that participants performed tasks requiring focused attention more carefully after viewing cute images. This is interpreted as the result of a narrowed attentional focus induced by the cuteness-triggered positive emotion that is associated with approach motivation and the tendency toward systematic processing. For future applications, cute objects may be used as an emotion elicitor to induce careful behavioral tendencies in specific situations, such as driving and office work.

Manual responses are often facilitated when the handle direction of a tool is aligned with the response hand in two-choice reaction-time tasks. This effect is discussed in terms of affordance perception, but that is still controversial. If manual responses are promoted by perceived affordance of grasping, the responses would conversely be suppressed when the danger of grasping is perceived. In this study, 36 right-handed university students performed a discrimination task using blades and non-bladed tools on a tablet screen by tapping on the left or right position near the tool with the left or right index finger. The results showed that the responses were not facilitated even when the direction of the handle was aligned with the response hand. The responses were quicker to blades than to non-bladed tools and especially facilitated when the direction of the edge of the blade and the response position coincided. These results do not support the prediction from affordance perception and can be interpreted as a Simon-type spatial compatibility effect caused by the proximity of attention-grabbing blades to response positions. [ABSTRACT FROM AUTHOR]