Lrig1-expressing epidermal progenitors require SCD1 to maintain the dermal papilla niche.

Niche cells are widely known to regulate stem/progenitor cells in many mammalian tissues. In the hair, dermal papilla niche cells are well accepted to regulate hair stem/progenitor cells. However, how niche cells themselves are maintained is largely unknown. We present evidence implicating hair matrix progenitors and the lipid modifying enzyme, Stearoyl CoA Desaturase 1, in the regulation of the dermal papilla niche during the anagen-catagen transition of the mouse hair cycle. Our data suggest that this takes place via autocrine Wnt signalling and paracrine Hedgehog signalling. To our knowledge, this is the first report demonstrating a potential role for matrix progenitor cells in maintaining the dermal papilla niche.

Wavy changes in the whiskers of domestic cats are correlated with feline leukemia virus infection.

BACKGROUND: Feline leukemia virus (FeLV) is a retrovirus with global impact on the health of domestic cats and is usually examined by serology. In our daily clinical practice, we noticed that cats infected with FeLV often possess wavy whiskers (sinus hairs on the face). To investigate the relationship between wavy whiskers (WW) and FeLV infection, the association between the presence or absence of wavy changes in whiskers and serological FeLV infection was examined in a total of 358 cats including 56 cats possessing WW, using the chi-square test. The results of blood tests from 223 cases were subjected to multivariate analysis (logistic analysis). Isolated whiskers were observed under light microscopy, and upper lip tissues (proboscis) were subjected to histopathological and immunohistochemical analyses. RESULTS: The prevalence of WW was significantly correlated with FeLV antigen positivity in the blood. Of 56 cases with WW, 50 (89.3%) were serologically positive for FeLV. The significant association between WW and serological FeLV positivity was also confirmed by multivariate analysis. In WW, narrowing, degeneration, and tearing of the hair medulla were observed. Mild infiltration of mononuclear cells in the tissues, but no degeneration or necrosis, was found. By immunohistochemistry, FeLV antigens (p27, gp70 and p15E) were observed in various epithelial cells including the sinus hair follicular epithelium of the whisker. CONCLUSIONS: The data suggest that the wavy changes in whiskers, a unique and distinctive external sign on a cat's face, were associated with FeLV infection.

[Levels of mercury in hair among pregnant women in Iceland].

INTRODUCTION: To limit exposure to methylmercury several countries have implimented specific advice on fish intake to pregnant women as well a measuring compliance through regular human biomonitoring. Despite fish intake being relatively high in Iceland, human biomonitoring data on mercury is scarce. MATERIALS AND MEHODS: We measured mercury in hair from 120 pregnant women recruited in 2021 from the the Reykjavik Capital area. At recruitment, information on fish intake during the past four months was recorded. Hair mercury concentrations were compared to existing health based guidance values and associatons with fish intake was explored. RESULTS: Mean (standard deviation) mercury concentration in hair was 0.48 µg/g (0.33). All participants had concentrations in hair below 1.8 µg/g, which corresponds to the hair value that the tolerable daily intake set by the European Food Safety Authority is derived from, while 5% had concentrations above 1.1 µg/g, which corresponds to the hair value that the US-EPA reference dose is derived from. Mean mercury concentrations in hair increased in a dose dependent manner (p for trend p<0.001) from 0.25 µg/g among women who consumed fish ≤ 3/month (n=24) and up to 0.80 mg/g among those consuming fish 3-4/ week (n=16). The few (n=3) women who reported to have eaten shark (p<1/month) were all at the higher end of the exposure distribution. CONCLUSION: Our results suggest that exposure is generally below the tolerable daily intake set by EFSA but may in some women exceed the reference dose established by the US-EPA.

Melatonin and the Human Hair Follicle.

BACKGROUND: Melatonin, a pleiotropic hormone, affects the physiological processes including that of the hair follicle. We seek to identify the scientific evidence to support the potential benefits of melatonin in human hair growth. OBJECTIVE: To summarize the evidence on the association between melatonin and hair health, denoted by hair growth. METHODS: A literature review using 3 databases (PubMed, Google Scholar, and Cochrane) identified studies investigating the relationship between melatonin and hair loss (2022). The following search terms were used: (hair OR hair loss OR alopecia OR hair growth OR effluvium OR scalp) and (melatonin). Two independent reviewers screened studies for inclusion criteria, and data collection included demographics, melatonin intervention, study type, and effects on hair. RESULTS: A total of 11 human studies were identified with evidence of melatonin use in subjects with diagnosed alopecia (2,267 patients; 1,140M). Eight of the studies reviewed observed positive outcomes after topical melatonin use in subjects with androgenetic alopecia (AGA). Most studies report improved scalp hair growth (n=8), density (n=4), and hair shaft thickness (n=2) among melatonin users compared with controls. Effective topical melatonin dosage appears to be 0.0033% or 0.1% solution applied once-daily for 90 to 180 days vs 1.5 mg twice-daily oral melatonin supplementation for 180 days. CONCLUSION: There is evidence to support melatonin use to facilitate scalp hair growth, particularly in men with AGA. Further studies should include more patients and investigate the mechanism of action. J Drugs Dermatol. 2023;22(3): doi:10.36849/JDD.6921.

Discovering Hair Biomarkers of Alzheimer's Disease Using High Resolution Mass Spectrometry-Based Untargeted Metabolomics.

Hair may be a potential biospecimen to discover biomarkers for Alzheimer's disease (AD) since it reflects the integral metabolic profiles of body burden over several months. Here, we described the AD biomarker discovery in the hair using a high-resolution mass spectrometry (HRMS)-based untargeted metabolomics approach. A total of 24 patients with AD and 24 age- and sex-matched cognitively healthy controls were recruited. The hair samples were collected 0.1-cm away from the scalp and further cut into 3-cm segments. Hair metabolites were extracted by ultrasonication with methanol/phosphate-buffered saline 50/50 (v/v) for 4 h. A total of 25 discriminatory chemicals in hair between the patients with AD and controls were discovered and identified. The AUC value achieved 0.85 (95% CI: 0.72~0.97) in patients with very mild AD compared to healthy controls using a composite panel of the 9 biomarker candidates, indicating high potential for the initiation or promotion phase of AD dementia in the early stage. A metabolic panel combined with the nine metabolites may be used as biomarkers for the early detection of AD. The hair metabolome can be used to reveal metabolic perturbations for biomarker discovery. Investigating perturbations of the metabolites will offer insight into the pathogenesis of AD.

Extraction of Gallic Acid and Ferulic Acid for Application in Hair Supplements.

Food supplements based on antioxidants and vitamins are often prescribed to correct inefficiencies in the human diet and delay diseases such as premature aging and alopecia (temporary or permanent hair loss), given the free radical scavenging activity of these biomolecules. By reducing the concentration of reactive oxygen species (ROS), which promote abnormal hair follicle cycling and morphology, follicle inflammation and oxidative stress are reduced, minimising the effects of these health issues. Gallic acid (GA), which is significantly present in gallnuts and in pomegranate root bark, and ferulic acid (FA), commonly found in brown rice and coffee seeds, are very important antioxidants for the preservation of hair colour, strength and growth. In this work, these two secondary phenolic metabolites were successfully extracted in the Aqueous Two-Phase Systems (ATPS) {ethyl lactate (1) + trisodium citrate (2) + water (3)} and {ethyl lactate (1) + tripotassium citrate (2) + water (3)} at 298.15 K and 0.1 MPa, moving towards the application of these ternary systems in extracting antioxidants from biowaste and their a posteriori processing as food supplements for hair fortification. The studied ATPS provided biocompatible and sustainable media for the extraction of gallic acid and ferulic acid, yielding low mass losses (<3%) and contributing to an eco-friendlier production of therapeutics. The most promising results were obtained for ferulic acid, which attained maximum partition coefficients (K) of 15 ± 5 and (3 ± 2) · 101 and maximum extraction efficiencies (E) of (92.7 ± 0.4)% and (96.7 ± 0.4)% for the longest tie-lines (TLL = 69.68 and 77.66 m%) in {ethyl lactate (1) + trisodium citrate (2) + water (3)} and {ethyl lactate (1) + tripotassium citrate (2) + water (3)}, respectively. Moreover, the effect of pH on the UV-Vis absorbance spectra was studied for all the biomolecules to minimise errors in solute quantification. Both GA and FA were found to be stable at the used extractive conditions.

Ancient lineages of the keratin-associated protein (KRTAP) genes and their co-option in the evolution of the hair follicle.

BLAST searches against the human genome showed that of the 93 keratin-associated proteins (KRTAPs) of Homo sapiens, 53 can be linked by sequence similarity to an H. sapiens metallothionein and 16 others can be linked similarly to occludin, while the remaining KRTAPs can themselves be linked to one or other of those 69 directly-linked proteins. The metallothionein-linked KRTAPs comprise the high-sulphur and ultrahigh-sulphur KRTAPs and are larger than the occludin-linked set, which includes the tyrosine- and glycine-containing KRTAPs. KRTAPs linked to metallothionein appeared in increasing numbers as evolution advanced from the deuterostomia, where KRTAP-like proteins with strong sequence similarity to their mammalian congeners were found in a sea anemone and a starfish. Those linked to occludins arose only with the later-evolved mollusca, where a KRTAP homologous with its mammalian congener was found in snails. The presence of antecedents of the mammalian KRTAPs in a starfish, a sea anemone, snails, fish, amphibia, reptiles and birds, all of them animals that lack hair, suggests that some KRTAPs may have a physiological role beyond that of determining the characteristics of hair fibres. We suggest that homologues of these KRTAPs found in non-hairy animals were co-opted by placodes, formed by the ectodysplasin pathway, to produce the first hair-producing cells, the trichocytes of the hair follicles.

Temporal and spatial assembly of inner ear hair cell ankle link condensate through phase separation.

Stereocilia are actin-based cell protrusions of inner ear hair cells and are indispensable for mechanotransduction. Ankle links connect the ankle region of developing stereocilia, playing an essential role in stereocilia development. WHRN, PDZD7, ADGRV1 and USH2A have been identified to form the so-called ankle link complex (ALC); however, the detailed mechanism underlying the temporal emergence and degeneration of ankle links remains elusive. Here we show that WHRN and PDZD7 orchestrate ADGRV1 and USH2A to assemble the ALC through liquid-liquid phase separation (LLPS). Disruption of the ALC multivalency for LLPS largely abolishes the distribution of WHRN at the ankle region of stereocilia. Interestingly, high concentration of ADGRV1 inhibits LLPS, providing a potential mechanism for ALC disassembly. Moreover, certain deafness mutations of ALC genes weaken the multivalent interactions of ALC and impair LLPS. In conclusion, our study demonstrates that LLPS mediates ALC formation, providing essential clues for understanding the pathogenesis of deafness.

In vitro hair follicle growth model for drug testing.

In vitro models of human hair follicle-like tissue could be fundamental tools to better understand hair follicle morphogenesis and hair drug screening. During prenatal development and postnatal cyclic hair regeneration, hair follicle morphogenesis is triggered by reciprocal interactions and the organization of the epithelial and mesenchymal cell populations. Given this mechanism, we developed an approach to induce hair peg-like sprouting in organoid cultures composed of epithelial and mesenchymal cells. Human fetal/adult epithelial and mesenchymal cells were cultured in a medium supplemented with a low concentration of either Matrigel or collagen I. These extracellular matrices significantly enhanced the self-organization capabilities of the epithelial and mesenchymal cells, resulting in spherical aggregation and subsequent hair peg-like sprouting. The length of the hair peg sprouting and associated gene expression significantly increased in the presence of a well-known hair drug, minoxidil. This approach may be beneficial for testing hair growth-promoting drug candidates.

Associations between chronic stress and hair cortisol in children: A systematic review and meta-analysis.

OBJECTIVES: This review systematically examined the associations between chronic stress and hair cortisol concentration (HCC) in children, and the potential modification effects of type, measurement period and scales of chronic stress, child age and sex, hair length and HCC measurement method, characteristics of study site, and congruence between time periods measured for chronic stress and HCC. METHODS: Pubmed, Wed of Science, and APA PsycINFO were systematically searched for articles examining the association between chronic stress and HCC. RESULTS: Thirteen studies from five countries with 1,455 participants were included in the systematic review and nine studies were included in the meta-analysis. Meta-analysis revealed that chronic stress was associated with HCC (pooled-r = 0.09, 95 % CI: 0.03, 0.16). Stratified analyses revealed that type, measurement time and scales of chronic stress, hair length and measurement method of HCC, and the congruence between time periods measured for chronic stress and HCC modified such correlations. The positive correlations between chronic stress and HCC were significant for studies measuring chronic stress as stressful life events, assessing chronic stress within the past six months, extracting HCC from 1 cm, 3 cm, or 6 cm of hair, measuring HCC by LC-MS/MS, or having congruence between time periods measured for chronic stress and HCC. The potential modifying effects of sex and country developmental status could not be concluded due to the limited number of studies included. CONCLUSIONS: Chronic stress was positively correlated with HCC, varying by characteristics and measurements of chronic stress and HCC. HCC could be a biomarker for chronic stress among children.

Arsenic in drinking water, hair, and prevalence of arsenicosis in Perak, Malaysia.

Arsenic is a carcinogen element that occurs naturally in our environment. Humans can be exposed to arsenic through ingestion, inhalation, and dermal absorption. However, the most significant exposure pathway is via oral ingestion. Therefore, a comparative cross-sectional study was conducted to determine the local arsenic concentration in drinking water and hair. Then, the prevalence of arsenicosis was evaluated to assess the presence of the disease in the community. The study was conducted in two villages, namely Village AG and Village P, in Perak, Malaysia. Socio-demographic data, water consumption patterns, medical history, and signs and symptoms of arsenic poisoning were obtained using questionnaires. In addition, physical examinations by medical doctors were performed to confirm the signs reported by the respondents. A total of 395 drinking water samples and 639 hair samples were collected from both villages. The samples were analyzed using Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) to determine arsenic concentration. The results showed that 41% of water samples from Village AG contained arsenic concentrations of more than 0.01 mg/L. In contrast, none of the water samples from Village P exceeded this level. Whilst, for hair samples, 85 (13.5%) of total respondents had arsenic levels above 1 µg/g. A total of 18 respondents in Village AG had at least one sign of arsenicosis and hair arsenic levels of more than 1 µg/g. Factors significantly associated with increased arsenic levels in hair were female, increasing age, living in Village AG and smoking. The prevalence of arsenicosis in the exposed village indicates chronic arsenic exposure, and immediate mitigation action needs to be taken to ensure the wellbeing of the residents in the exposed village.

Comparative ultrastructure of the antennae and sensory hairs in six species of crayfish.

Background: Antennae in crayfish are essential for gaining information about the local topography and localising food, chemicals, conspecifics or predator. There are still gaps in the research on the morphology of antennae in decapods compared to other arthropods. Methodology: Biometrical and ultrastructural methods were applied using light and cryo-scanning electron microscopies to study the morphology of antennae in six different crayfish species, including marbled crayfish Procambarus virginalis, Mexican dwarf crayfish Cambarellus patzcuarensis, red swamp crayfish Procambarus clarkii, signal crayfish Pacifastacus leniusculus, common yabby Cherax destructor, and spiny-cheek crayfish Faxonius limosus to find their potential morphological differences. Results: Significant differences in the antenna length, length and width of each segment to carapace length ratios, and the number of segments were found in the six crayfish species. The ultrastructure revealed differences in the distribution of sensory hairs on the antenna and the morphology of the antennal surface. Conclusions: The different morphology of antennae might reflect adaptation to the conditions of their specific habitats. In addition, results showed that a combination of differences in the morphological features and biometrical measurements of antennae could be used for the distinguishment of different studied crayfish species.

Hair embedding after transperineal prostate biopsy: two case reports.

BACKGROUND: Transperineal prostate biopsy is gradually becoming the standard methodology for diagnosing prostate cancer because of its high accuracy and low risk of infection, but careful preparation is not always highlighted before a transperineal biopsy. we reported two cases of hair embedding during transurethral resection of the prostate following transperineal puncture biopsy with a Bard MC1820 disposable biopsy needle. Histological examination did not find the hair follicle structure required for hair growth. The hair source was suspected to be percutaneously brought in by needle during the biopsya simulated experiment was used to analyze and reconstruct the process of hair embedding in prostate tissue. CONCLUSION: Hair embedding caused by perineal prostate biopsy is a consumable-related adverse event, and skin preparation before a transperineal prostate biopsy is recommended.

Investigation of Glypican-4 and -6 by Infrared Spectral Imaging during the Hair Growth Cycle.

The expression of glypicans in different hair follicle (HF) compartments is still poorly understood. Heparan sulfate proteoglycans (HSPGs) distribution in HF is classically investigated by conventional histology, biochemical analysis, and immunohistochemistry. Our previous study proposed a novel approach to assess hair histology and glypican-1 (GPC1) distribution changes in the HF at different phases of the hair growth cycle using infrared spectral imaging (IRSI). We show in the present manuscript for the first time complementary data on the distribution of glypican-4 (GPC4) and glypican-6 (GPC6) in HF at different phases of the hair growth cycle using IR imaging. Findings were supported by Western blot assays focusing on the GPC4 and GPC6 expression in HFs. Like all proteoglycan features, the glypicans are characterized by a core protein to which sulfated and/or unsulfated glycosaminoglycan (GAG) chains are covalently linked. Our study demonstrates the capacity of IRSI to identify the different HF tissue structures and to highlight protein, proteoglycan (PG), GAG, and sulfated GAG distribution in these structures. The comparison between anagen, catagen, and telogen phases shows the qualitative and/or quantitative evolution of GAGs, as supported by Western blot. Thus, in one analysis, IRSI can simultaneously reveal the location of proteins, PGs, GAGs and sulfated GAGs in HFs in a chemical and label-free manner. From a dermatological point of view, IRSI may constitute a promising technique to study alopecia.

Clinical and dermatoscopic features of temporal triangular alopecia in infants.

OBJECTIVE: To summarize the clinical and dermatoscopic features of temporal triangular alopecia in infants and explore the clinical significance of dermatoscopy in the diagnosis of triangular alopecia temporalis in infants. METHODS: A retrospective analysis was performed on 20 children with temporal triangular alopecia diagnosed in the dermatology clinic of Tianjin Children's Hospital from January 2015 to December 2021. Dermatoscopy was performed on all children, and images were collected. RESULTS: The clinical features of 20 children were 15 males and five females, all of which were born immediately after birth; There were eight cases (40%) in the left temporal region, 10 cases (50%) in the right temporal region, one case (5%) in the head region, and one case (5%) in the occipital region; 19 cases were single (95%), one case was multiple (5%); There were 21 skin lesions, 15 triangular lesions (71.4%), four quasi-circular lesions (19%), and two lance-shaped lesions (9.5%). Trichoscopic features: The hair follicle opening in all skin lesions is normal, and the hair follicle opening can be seen with fluffy hair (vellus hair). The vellus hair is evenly distributed, and the length is diverse (both short and long vellus hair exist in the same hair loss area). There are 14 cases of white vellus hair (70%), five cases of white spots (25%), one case of honeycomb pigment pattern (5%), and one case of vascular dilation pattern (5%). CONCLUSION: Temporal triangular alopecia in infants has typical clinical and dermatoscopic characteristics, and the dermatoscopy can provide clinical basis for its diagnosis and differential diagnosis.

Stress and reproductive hormones in hair associated with contaminant metal(loid)s of European brown bear (Ursus arctos).

Environmental contaminants like arsenic (As), cadmium (Cd), mercury (Hg) or lead (Pb) may disrupt hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes due to their endocrine toxicity potential. Resulting long-term physiological stress or adverse effects on wildlife reproduction and ontogeny may cause detrimental effects at the individual and population levels. However, data on environmental metal(loid)s' impact on reproductive and stress hormones in wildlife, especially large terrestrial carnivores, are scarce. Hair cortisol, progesterone and testosterone concentrations were quantified and modelled with hair As, Cd, total Hg, Pb, biological, environmental and sampling factors to test for potential effects in free-ranging brown bears (Ursus arctos) from Croatia (N = 46) and Poland (N = 27). Testosterone in males (N = 48) and females (N = 25) showed positive associations with Hg and an interaction between Cd and Pb, but a negative association with interaction between age and Pb. Higher testosterone was found in hair during its growth phase compared to quiescent phase. Body condition index was negatively associated with hair cortisol and positively associated with hair progesterone. Year and conditions of sampling were important for cortisol variation, while maturity stage for progesterone variation (lower concentrations in cubs and yearlings compared to subadult and adult bears). These findings suggest that environmental levels of Cd, Hg and Pb might influence the HPG axis in brown bears. Hair was shown to be a reliable non-invasive sample for investigating hormonal fluctuations in wildlife while addressing individual and sampling specificities.

Novel Insights into the Role of Keratinocytes-Expressed TRPV3 in the Skin.

TRPV3 is a non-selective cation channel that is highly expressed in keratinocytes in the skin. Traditionally, keratinocytes-expressed TRPV3 is involved in multiple physiological and pathological functions of the skin, such as itching, heat pain, and hair development. Although the underlying mechanisms by which TRPV3 functions in vivo remain obscure, recent research studies suggest that several cytokines and EGFR signaling pathways may be involved. However, there have also been other studies with opposite results that question the role of TRPV3 in heat pain. In addition, an increasing number of studies have suggested a novel role of TRPV3 in promoting skin regeneration, indicating that TRPV3 may become a new potential target for regulating skin regeneration. This paper not only reviews the role of keratinocytes-expressed TRPV3 in the physiological and pathological processes of itching, heat pain, hair development, and skin regeneration, but also reviews the relationship between TRPV3 gene mutations and skin diseases such as atopic dermatitis (AD) and Olmsted syndrome (OS). This review will lay a foundation for further developing our understanding of the mechanisms by which TRPV3 is involved in itching, heat pain, and hair development, as well as the treatments for TRPV3-related skin diseases.

Human Stem Cell Use in Androgenetic Alopecia: A Systematic Review.

Androgenetic alopecia is a condition that results in hair loss in both men and women. This can have a significant impact on a person's psychological well-being, which can lead to a decreased quality of life. We conducted a systematic review to evaluate the efficacy of using stem cells in androgenic alopecia. The search was conducted in MEDLINE via PubMed, Web of Science, and Scopus databases. The review was performed on data pertaining to the efficacy of using different types of stem cells in androgenic alopecia: quantitative results of stem cell usage were compared to the control treatment or, different types of treatment for female and male androgenetic alopecia. Of the outcomes, the density of hair was analyzed. Fourteen articles were selected for this review. During and after treatment with stem cells, no major side effects were reported by patients with alopecia. The use of stem cells in androgenic alopecia seems to be a promising alternative to the standard treatment or it could play the role of complementary therapy to improve the effect of primary treatment. However, these results should be interpreted with caution until they can be reproduced in larger and more representative samples.

Skin aging associated with chromium among rural housewives in northern China.

Previous studies have found associations between chromium exposure and skin damage. However, few studies have focused on both chromium and skin aging. This study aimed to assess the degree of skin aging symptoms and estimate the relationship between hair chromium and skin aging among rural housewives. We recruited 405 subjects in Shanxi Province of northern China and analyzed 397 eligible hair samples with inductively coupled plasma-mass spectrometry (ICP-MS). The subjects' skin aging symptoms were assessed with SCINEXA™ (SCore of INtrinsic and EXtrinsic skin Aging). After adjusting for age and other important covariates, the regression results showed more severe skin aging symptoms in women with a higher level of hair chromium and presented an increasing linear trend. Vegetables, fruits, and beans might be a source of chromium exposure. We concluded that skin aging might be positively associated with hair chromium. It is necessary to take measures to reduce chromium exposure to prevent skin aging.

Keratin 79 is a PPARA target that is highly expressed by liver damage.

Keratins are key structural proteins found in skin and other epithelial tissues. Keratins also protect epithelial cells from damage or stress. Fifty-four human keratins were identified and classified into two families, type I and type II. Accumulating studies showed that keratin expression is highly tissue-specific and used as a diagnostic marker for human diseases. Notably, keratin 79 (KRT79) is type II cytokeratin that was identified as regulator of hair canal morphogenesis and regeneration in skin, but its role in liver remains unclear. KRT79 is undetectable in normal mouse but its expression is significantly increased by the PPARA agonist WY-14643 and fenofibrate, and completely abolished in Ppara-null mice. The Krt79 gene has functional PPARA binding element between exon 1 and exon 2. Hepatic Krt79 is regulated by HNF4A and HER2. Moreover, hepatic KRT79 is also significantly elevated by fasting- and high-fat diet-induced stress, and these increases are completely abolished in Ppara-null mice. These findings suggest that hepatic KRT79 is controlled by PPARA and is highly associated with liver damage. Thus, KRT79 may be considered as a diagnostic marker for human liver diseases.