Solving a molecular cryptogram for the human fingerprint.

No two fingerprint patterns are exactly alike. In this issue of Cell, Glover et al. uncover the molecular and cellular mechanisms that result in patterned skin ridges over volar digits. This study reveals that the remarkable diversity of fingerprint configurations may originate from a common patterning code.

Dedifferentiation maintains melanocyte stem cells in a dynamic niche.

For unknow reasons, the melanocyte stem cell (McSC) system fails earlier than other adult stem cell populations1, which leads to hair greying in most humans and mice2,3. Current dogma states that McSCs are reserved in an undifferentiated state in the hair follicle niche, physically segregated from differentiated progeny that migrate away following cues of regenerative stimuli4-8. Here we show that most McSCs toggle between transit-amplifying and stem cell states for both self-renewal and generation of mature progeny, a mechanism fundamentally distinct from those of other self-renewing systems. Live imaging and single-cell RNA sequencing revealed that McSCs are mobile, translocating between hair follicle stem cell and transit-amplifying compartments where they reversibly enter distinct differentiation states governed by local microenvironmental cues (for example, WNT). Long-term lineage tracing demonstrated that the McSC system is maintained by reverted McSCs rather than by reserved stem cells inherently exempt from reversible changes. During ageing, there is accumulation of stranded McSCs that do not contribute to the regeneration of melanocyte progeny. These results identify a new model whereby dedifferentiation is integral to homeostatic stem cell maintenance and suggest that modulating McSC mobility may represent a new approach for the prevention of hair greying.

Coordinated activation of Wnt in epithelial and melanocyte stem cells initiates pigmented hair regeneration.

Melanocyte stem cells (McSCs) intimately interact with epithelial stem cells (EpSCs) in the hair follicle bulge and secondary hair germ (sHG). Together, they undergo activation and differentiation to regenerate pigmented hair. However, the mechanisms behind this coordinated stem cell behavior have not been elucidated. Here, we identified Wnt signaling as a key pathway that couples the behavior of the two stem cells. EpSCs and McSCs coordinately activate Wnt signaling at the onset of hair follicle regeneration within the sHG. Using genetic mouse models that specifically target either EpSCs or McSCs, we show that Wnt activation in McSCs drives their differentiation into pigment-producing melanocytes, while EpSC Wnt signaling not only dictates hair follicle formation but also regulates McSC proliferation during hair regeneration. Our data define a role for Wnt signaling in the regulation of McSCs and also illustrate a mechanism for regeneration of complex organs through collaboration between heterotypic stem cell populations.

The development of hair follicles and nail.

The hair follicle and nail unit develop and regenerate through epithelial-mesenchymal interactions. Here, we review some of the key signals and molecular interactions that regulate mammalian hair follicle and nail formation during embryonic development and how these interactions are reutilized to promote their regeneration during adult homeostasis and in response to skin wounding. Finally, we highlight the role of some of these signals in mediating human hair follicle and nail conditions.

Insights on hazardous metal bioaccessibility, and groundwater impacted by Zn residues from a legacy mine and risk evaluation of adjacent soils.

This study explored the legacy impact of Zinc plant residues (ZPRs) in Kabwe, Zambia, on the environment and human health, particularly in light of the town's reputation for Pb pollution. ZPRs solid samples and groundwater within and around ZPRs zone were collected from the legacy mine, along with soils in a 10 km radius from the mine site. Bioaccessible fractions of Pb and Zn were elucidated by Japanese leaching test (JLT) and simple bioaccessibility extraction test (SBET). Cationic speciation of Pb and Zn from inhalable and ingestible ZPRs particles was investigated via sequential extraction. Groundwater in the ZPRs area showed higher Zn levels (1490 mg/L) compared to Pb (1.7 mg/L). Elevated Zn concentration were facilitated by the presence of soluble Zn sulfates while Pb was constrained due to its precipitation as anglesite. Groundwater sampled outside the ZPRs area was within the Zambia regulatory limits (< 0.5 mg/L for Pb and < 1 mg/L for Zn). Inhalation exposure to < 30 µm dust particles from ZPRs and soils near the mine indicated negligible risk, with < 3% of bioaccessible Pb in artificial lysosomal fluid. Meanwhile, oral intake of ZPRs particles < 250 µm revealed elevated bioaccessible fractions (36% for Pb and 70% for Zn). ZPRs cationic speciation of ingestible particles < 30 µm, 30-75 µm, 75-150 µm and 150-250 µm indicated that the bioaccessible Pb predominantly emanated from labile Pb fractions under gastric conditions with pH < 1. This was due to the dissolution of Pb associated with the exchangeable phase, carbonates and iron/manganese oxides; however, only exchangeable/carbonate Pb was bioaccessible at pH < 2. Hazard quotients indicated increased risks of Pb intoxication through the ingestion of ZPRs and soils near the legacy mine, with higher risks observed in children, emphasizing the need to remediate legacy mine wastes to reduce health risks and protect groundwater through monitoring in mining-affected regions.

Time to normalisation of CRP and incidence of relapse in microscopic polyangiitis: A medical records review study in Japan.

OBJECTIVES: Despite the identification of risk factors for relapses in anti-neutrophil cytoplasmic antibody-associated vasculitis, the relationship between changes in C-reactive protein levels after initial treatment and incidence of relapse remains unknown. This study aimed to assess the association between the time taken for normalisation of C-reactive protein levels and the incidence of relapse in Japanese adult patients with microscopic polyangiitis. METHODS: This study included 85 consecutive patients with newly diagnosed microscopic polyangiitis who achieved remission after six months of immunosuppressive treatment at the Aichi Medical University Hospital, between 2009 and 2017. The relationship between the time to normalisation of C-reactive protein after initial immunosuppressive treatment and relapse incidences was evaluated using multivariable Cox proportional hazard models. RESULTS: During the follow-up period, 13 (30.2%), 7 (41.2%), and 16 (64.0%) patients relapsed (P=0.025) within 1-14, 15-28, and ≥29 days of normalisation, respectively. Hazard ratios (95% confidence intervals) of the time to normalisation of C-reactive protein of 1-14, 15-28, and ≥29 days were 1.00 (reference), 2.42 (95%CI: 0.92-6.39), and 3.48 (95%CI: 1.56-7.76), respectively. CONCLUSIONS: A significant association between the time to normalisation of C-reactive protein and relapse incidence in Japanese patients with microscopic polyangiitis was observed.

A novel arsenic immobilization strategy via a two-step process: Arsenic concentration from dilute solution using schwertmannite and immobilization in Ca-Fe-AsO4 compounds.

Acid mine drainage (AMD) with toxic arsenic (As) is commonly generated from the tailings storage facilities (TSFs) of sulfide mines due to the presence of As-bearing sulfide minerals (e.g., arsenopyrite, realgar, orpiment, etc.). To suppress As contamination to the nearby environments, As immobilization by Ca-Fe-AsO4 compounds is considered one of the most promising techniques; however, this technique is only applicable when As concentration is high enough (>1 g/L). To immobilize As from wastewater with low As concentration (~10 mg/L), this study investigated a two-step process consisting of concentration of dilute As solution by sorption/desorption using schwertmannite (Fe8O8(OH)8-2x(SO4)x; where (1 ≤ x ≤ 1.75)) and formation of Ca-Fe-AsO4 compounds. Arsenic sorption tests indicated that As(V) was well adsorbed onto schwertmannite at pH 3 (Qmax = 116.3 mg/g), but its sorption was limited at pH 13 (Qmax = 16.1 mg/g). A dilute As solution (~11.2 mg/L As) could be concentrated by sorption with large volume of dilute As solution at pH 3 followed by desorption with small volume of eluent of which pH was 13. The formation of Ca-Fe-AsO4 compounds from As concentrate solution (2 g/L As(V)) was strongly affected by temperature and pH. At low temperature (25-50 °C), amorphous ferric arsenate was formed, while at high temperature (95 °C), yukonite (Ca2Fe3-5(AsO4)3(OH)4-10·xH2O; where x = 2-11) and johnbaumite (Ca5(AsO4)3OH) were formed at pH 8 and 12, respectively. Among the synthesized products, johnbaumite showed strongest As retention ability even under acidic (pH < 2) and alkaline (pH > 9) conditions.

Wnt activation in nail epithelium couples nail growth to digit regeneration.

The tips of mammalian digits can regenerate after amputation, like those of amphibians. It is unknown why this capacity is limited to the area associated with the nail. Here we show that nail stem cells (NSCs) reside in the proximal nail matrix and that the mechanisms governing NSC differentiation are coupled directly with their ability to orchestrate digit regeneration. Early nail progenitors undergo Wnt-dependent differentiation into the nail. After amputation, this Wnt activation is required for nail regeneration and also for attracting nerves that promote mesenchymal blastema growth, leading to the regeneration of the digit. Amputations proximal to the Wnt-active nail progenitors result in failure to regenerate the nail or digit. Nevertheless, ß-catenin stabilization in the NSC region induced their regeneration. These results establish a link between NSC differentiation and digit regeneration, and suggest that NSCs may have the potential to contribute to the development of novel treatments for amputees.

Adenosine A2a Receptor Blockade Diminishes Wnt/ß-Catenin Signaling in a Murine Model of Bleomycin-Induced Dermal Fibrosis.

Adenosine A2a receptor (A2aR) stimulation promotes the synthesis of collagens I and III, and we have recently demonstrated that there is crosstalk between the A2aR and WNT/ß-catenin signaling pathway. In in vitro studies, A2aR signaling for collagen III expression was mediated by WNT/ß-catenin signaling in human dermal fibroblasts; we further verified whether the crosstalk between A2aR and Wnt/ß-catenin signaling was involved in diffuse dermal fibrosis in vivo. Wnt-signaling reporter mice (Tcf/Lef:H2B-GFP) were challenged with bleomycin and treated with the selective A2aR antagonist istradefylline (KW6002) or vehicle. Dermal fibrosis was quantitated and nuclear translocation of ß-catenin in fibroblasts was assessed by double-staining for Green fluorescent protein or dephosphorylated ß-catenin or ß-catenin phosphorylated at Ser552, and vimentin. KW6002 significantly reduced skin thickness, skinfold thickness, breaking tension, dermal hydroxyproline content, myofibroblast accumulation, and collagen alignment in bleomycin-induced dermal fibrosis. Also, there was increased expression of Tcf/Lef:H2B-GFP reporter in bleomycin-induced dermal fibrosis, an effect that was diminished by treatment with KW6002. Moreover, KW6002 significantly inhibited nuclear translocation of Tcf/Lef:H2B-GFP reporter, as well as dephosphorylated ß-catenin and ß-catenin phosphorylated at Ser552. Our work supports the hypothesis that pharmacologic blockade of A2aR inhibits the WNT/ß-catenin signaling pathway, contributing to its capacity to inhibit dermal fibrosis in diseases such as scleroderma.

PAXgene-fixed paraffin-embedded sample is applicable to laser capture microdissection with well-balanced RNA quality and tissue morphology.

Assessing how gene expression analysis by RNA sequencing (RNA-Seq) correlates to a unique morphology is increasingly necessary, and laser capture microdissection (LCM) is a critical research tool for discovering the genes responsible in a region of interest (ROI). Because RNA-Seq requires high-quality RNA, a sample preparation procedure that can preserve morphology and give the required quality of RNA is essential. A PAXgene®-fixed paraffin-embedded (XFPE) block can satisfy the need for high-quality RNA, but there are few reports on adapting the method for LCM, such as how small an ROI is analyzable by RNA-Seq. In this study, we confirmed the morphology and preservation of RNA in XFPE and then assessed the relationship between the size of pieces cut by LCM and their RNA quality. In XFPE, the morphology was similar to that in alcohol-based fixed samples, the quality of the RNA extracted from a whole sample was excellent, that is equivalent to that of a fresh frozen sample, and the quality was maintained over one year later. Three sizes of pieces-large (25,000 µm2), medium (5,000 µm2), and small (1,000 µm2)-were cut by LCM so that the total areas of the sections cut per size were the same. RNA quality was found to be best preserved when tissue was cut into pieces of over 5,000 µm2. In summary, XFPE exhibits good morphology and excellent preservation of RNA quality. Furthermore, it can be a good tool when used with LCM and RNA-Seq, giving well-balanced RNA quality and tissue morphology in the ROI.

Drying-Induced Self-Similar Assembly of Megamolecular Polysaccharides through Nano and Submicron Layering.

We propose a self-similar assembly to generate planar orientation of megamolecular polysaccharides on the nanometer scale and submicron scale. Evaporating the aqueous liquid crystalline (LC) solution on a planar air-LC interface induces polymer layering by self-assembly and rational action of macroscopic capillary forces between the layers. To clarify the mechanisms of nanometer- and submicron-scale layering, the polymer films are investigated by electron microscopy.

Dermal ß-Catenin Is Required for Hedgehog-Driven Hair Follicle Neogenesis.

Hair follicle neogenesis (HFN) occurs after large skin excisions in mice, serving as a rare regenerative model in mammalian wound healing. Wound healing typically results in fibrosis in mice and humans. We previously showed that small skin excisions in mice result in scarring devoid of HFN, displaying features of nonregenerative healing, and hedgehog (Hh) activation in the dermis of such wounds can induce HFN. In this study, we sought to verify the role of dermal Wnt/ß-catenin signaling in HFN because this pathway is essential for hair follicle development but is also paradoxically well-characterized in fibrosis of adult wounds. By deletion of ß-catenin in large wound myofibroblasts, we show that Wnt/ß-catenin signaling is required for endogenous mechanisms of HFN. By utilizing a combined mouse model that simultaneously induces deletion of ß-catenin and constitutive activation of Smoothened in myofibroblasts, we also found that ß-catenin is required for Hh-driven dermal papilla formation. Transcriptome analysis confirms that Wnt/ß-catenin and Hh pathways are activated in dermal papilla cells. Our results indicate that Wnt-active fibrotic status may also create a permissive state for the regenerative function of Hh, suggesting that activation of both Wnt and Hh pathways in skin wound fibroblasts must be ensured in future strategies to promote HFN.

Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding.

The mammalian hair follicle is a complex 'mini-organ' thought to form only during development; loss of an adult follicle is considered permanent. However, the possibility that hair follicles develop de novo following wounding was raised in studies on rabbits, mice and even humans fifty years ago. Subsequently, these observations were generally discounted because definitive evidence for follicular neogenesis was not presented. Here we show that, after wounding, hair follicles form de novo in genetically normal adult mice. The regenerated hair follicles establish a stem cell population, express known molecular markers of follicle differentiation, produce a hair shaft and progress through all stages of the hair follicle cycle. Lineage analysis demonstrated that the nascent follicles arise from epithelial cells outside of the hair follicle stem cell niche, suggesting that epidermal cells in the wound assume a hair follicle stem cell phenotype. Inhibition of Wnt signalling after re-epithelialization completely abrogates this wounding-induced folliculogenesis, whereas overexpression of Wnt ligand in the epidermis increases the number of regenerated hair follicles. These remarkable regenerative capabilities of the adult support the notion that wounding induces an embryonic phenotype in skin, and that this provides a window for manipulation of hair follicle neogenesis by Wnt proteins. These findings suggest treatments for wounds, hair loss and other degenerative skin disorders.

Conventional and recent advances in gravity separation technologies for coal cleaning: A systematic and critical review.

"Affordable and clean energy" is enshrined in the UN Sustainable Development Goals (SDGs; #7) because of its importance in supporting the sustainable development of society. As an energy source, coal is widely used because it is abundant and its utilization for electricity and heat generation do not require complex infrastructures and technologies, which makes it ideal for the energy needs of low-income and developing countries. Coal is also essential in steel making (as coke) and cement production and will continue to be on high demand for the foreseeable future. However, coal is naturally found with impurities or gangue minerals like pyrite and quartz that could create by-products (e.g., ash) and various pollutants (e.g., CO2, NOX, SOX). To reduce the environmental impacts of coal during combustion, coal cleaning-a kind of pre-combustion clean coal technology-is essential. Gravity separation, a technique that separates particles based on their differences in density, is widely used in coal cleaning due to the simplicity of its operation, low cost, and high efficiency. In this paper, recent studies (from 2011 to 2020) related to gravity separation for coal cleaning were systematically reviewed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 1864 articles were screened after removing duplicates, and after a thorough evaluation 189 articles were reviewed and summarized. Among of conventional separation techniques, dense medium separator (DMS), particularly dense medium cyclone (DMC), is the most popular technologies studied, which could be attributed to the growing challenges of cleaning/processing fine coal-bearing materials. In recent years, most of works focused on the development of dry-type gravity technologies for coal cleaning. Finally, gravity separation challenges and future applications to address problems in environmental pollution and mitigation, waste recycling and reprocessing, circular economy, and mineral processing are discussed.

Social cost of mining-related lead (Pb) pollution in Kabwe, Zambia, and potential remediation measures.

Lead (Pb) pollution has been one of the major environmental problems of worldwide significance. It is a latent factor for several fatal illnesses, whereas the exposure to lead in early childhood causes a lifetime IQ loss. The social cost is the concept to aggregate various adverse effects in a single monetary unit, which is useful in describing the pollution problem and provides foundation for the design of interventions. However, the assessment of the social cost is scarce for developing countries. In this study, we focus on the lead pollution problem of a former mining town, Kabwe, Zambia, where mining wastes abandoned near residential areas has caused a critical pollution problem. We first investigated the social cost of lead pollution that future generations born in 2025-2049 would incur in their lifetime. As the channels of the social cost, we considered the lost income from the IQ loss and the lost lives from lead-related mortality. The results showed that the social cost would amount to 224-593 million USD (discounted to the present value). Our results can be considered conservative, lower bound estimates because we focused only on well-identified effects of lead, but the social cost was still substantial. Then we examined several engineering remediation measures. The results showed that the social cost can be reduced (the benefits of remediations) more than the costs of implementing remediation measures. This study is the first to investigate the social cost of mining-related lead pollution problem in developing countries. Our interdisciplinary approach utilises the micro-level economic, health and pollution data and integrates the techniques in economics, toxicology and engineering.

A case of 2,8-DHA crystalline nephropathy caused by adenine phosphoribosyltransferase deficiency: diagnosis and treatment.

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder that leads to the accumulation of poorly soluble 2,8-dihydroxyadenine (DHA) in the kidneys, resulting in a variety of renal presentations including nephrolithiasis, acute kidney injury, and chronic kidney disease (CKD) caused by crystal nephropathy. Here, we report a case of a 43-year-old man with 2,8-DHA crystalline nephropathy caused by APRT deficiency strongly suspected by renal biopsy results and definitively diagnosed by a urine gas chromatography-mass spectrometry (GC/MS)-based plasma metabolomic assessment. This case represents the importance of awareness and recognition of the signs and symptoms of this rare condition and its progression to CKD, which can be prevented by the early administration of xanthine oxidoreductase inhibitors.

Mepolizumab administration for eosinophilic granulomatosis with polyangiitis in an elderly patient with an abrupt onset of limb ischaemia and peripheral neuropathy: A case-based literature review.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a type of anti-neutrophil cytoplasmic antibody-associated vasculitis characterised by small- to medium-sized vessel vasculitis and is typically associated with eosinophilic granulomatous inflammation. EGPA can affect any organ system, most commonly the lungs, skin, and the nervous system. However, limb ulcers are rare complications and have only been described in few case reports. Furthermore, no documented cases of EGPA have been treated with mepolizumab. Herein, we report a case of an 86-year-old Japanese woman with anti-neutrophil cytoplasmic antibody-negative EGPA, who had an abrupt onset of upper limb ulcers and bilateral foot drop due to multiple mononeuropathy. Clinicopathological sural nerve biopsy showed eosinophil-associated vascular damage. The patient was administered steroids, intravenous immunoglobulin, vasodilators, and mepolizumab; this resulted in clinical improvement of her finger ulcers and peripheral neuropathy without any adverse effects. In cases of an abrupt onset of limb ischaemia and peripheral neuropathy, physicians should consider the possibility of EGPA as a differential diagnosis. Furthermore, the early administration of mepolizumab might yield better outcomes in terms of improving limb ischaemia and peripheral neuropathy.

Malnutrition according to the GLIM criteria with kidney dysfunction is associated with increased mortality in hospitalized patients with cardiovascular disease: A retrospective cohort study.

BACKGROUND & AIMS: Cardiovascular disease (CVD) is a significant cause of mortality and rising healthcare costs, involving numerous chronic and nutritional risk. Although several studies have reported that malnutrition based on the Global Leadership Initiative on Malnutrition (GLIM) criteria is associated with mortality in patients with CVD, they have not evaluated this association in terms of malnutrition severity (moderate or severe). Furthermore, the relationship between malnutrition combined with renal dysfunction, a risk factor for death in CVD patients, and mortality has not been previously evaluated. Thus, we aimed to assess the association between malnutrition severity and mortality, as well as malnutrition status stratified by kidney function and mortality, in patients hospitalized due to CVD events. METHODS: This single-centre, retrospective cohort study included 621 patients with CVD aged ≥18 years admitted to Aichi Medical University between 2019 and 2020. The relationship between nutritional status based on the GLIM criteria (without malnutrition, moderate malnutrition, or severe malnutrition) and the incidence of all-cause mortality was evaluated by multivariable Cox proportional hazards models. RESULTS: Patients with moderate and severe malnutrition were significantly more prone to mortality than those without malnutrition (adjusted hazard ratio [HR] of patients without, with moderate, and with severe malnutrition: 1.00 [reference], 1.94 [1.12-3.35], and 2.63 [1.53-4.50], respectively). Furthermore, we found the highest all-cause mortality rate in patients with malnutrition and a lower estimated glomerular filtration rate (eGFR <30 mL/min/1.73 m2) (adjusted HR, 10.1; confidence interval, 3.90-26.4) than in patients without malnutrition and normal eGFR (eGFR ≥60 mL/min/1.73 m2). CONCLUSIONS: The present study indicated that malnutrition according to the GLIM criteria was associated with increased all-cause mortality in patients with CVD, and malnutrition associated with kidney dysfunction was associated with a higher risk of mortality. These findings provide clinically relevant information to identify high mortality risk in patients with CVD and highlight the need for giving careful attention to malnutrition with kidney dysfunction among patients with CVD.

Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis.

The discovery of long-lived epithelial stem cells in the bulge region of the hair follicle led to the hypothesis that epidermal renewal and epidermal repair after wounding both depend on these cells. To determine whether bulge cells are necessary for epidermal renewal, here we have ablated these cells by targeting them with a suicide gene encoding herpes simplex virus thymidine kinase (HSV-TK) using a Keratin 1-15 (Krt1-15) promoter. We show that ablation leads to complete loss of hair follicles but survival of the epidermis. Through fate-mapping experiments, we find that stem cells in the hair follicle bulge do not normally contribute cells to the epidermis which is organized into epidermal proliferative units, as previously predicted. After epidermal injury, however, cells from the bulge are recruited into the epidermis and migrate in a linear manner toward the center of the wound, ultimately forming a marked radial pattern. Notably, although the bulge-derived cells acquire an epidermal phenotype, most are eliminated from the epidermis over several weeks, indicating that bulge stem cells respond rapidly to epidermal wounding by generating short-lived 'transient amplifying' cells responsible for acute wound repair. Our findings have implications for both gene therapy and developing treatments for wounds because it will be necessary to consider epidermal and hair follicle stem cells as distinct populations.