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.

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

Hair follicle neogenesis (HFN) occurs following 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 small skin excisions in mice result in scarring devoid of HFN, displaying features of non-regenerative 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, as this pathway is essential for HF development, but is also paradoxically well-characterized in fibrosis of adult wounds. By deletion of ß-catenin in large wound myofibroblasts, we show Wnt/ß-catenin signaling is required for endogenous mechanisms of HFN. Through utilizing a combined mouse model that simultaneously induces deletion of ß-catenin and constitutive activation of Smoothened (Smo) in myofibroblasts, we also found ß-catenin is required for Hh-driven DP formation. Transcriptome analysis confirms Wnt/ß-catenin and Hh pathways are activated in dermal papilla (DP) 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.

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.

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.

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.

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.

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.

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.

Reverse hybrid jig separation efficiency estimation of floating plastics using apparent specific gravity and concentration criterion.

We developed a technique called the reverse hybrid jig, an advanced physical separation technique that combines the principles of jig and flotation to separate floating plastics. This technique is a promising green technology that is more economical and environmentally friendly compared with the conventional flotation. Although the applicability of this technique to separate PP/PE have been reported, the index to illustrate the possibility of separation for the reverse hybrid jig is still not available. In this study, a reverse apparent concentration criterion (CC RA ) is proposed to estimate reverse hybrid jig separation efficiency. This modified concentration criterion can be calculated using the specific gravity (SG) of particle with attached bubbles called the apparent specific gravity (SG A ). To determine the volume of attached bubbles on plastic surfaces under water pulsation, a laser-assisted apparatus was used under various conditions, including plastic type, air flow rate, dosage, and type of wetting agent. The results of attached bubble volume measurements were used to calculate the SG A and CC RA . The estimated values were then compared with the results of reverse hybrid jig separation. It was found that higher CC RA resulted in better separation efficiency. In addition, an empirical linear equation for estimating the reverse hybrid jig separation efficiency is proposed.

Association between renal-limited vasculitis and relapse of antineutrophil cytoplasmic antibody-associated vasculitis: A single-center retrospective cohort study in Japan.

BACKGROUND: Several previous studies have evaluated the predictors of relapse in antineutrophil cytoplasmic antibody-associated vasculitis. Nonetheless, the association between renal-limited vasculitis and relapse has not been evaluated. OBJECTIVE: To assess the association between renal-limited vasculitis and the incidence of relapse in Japan among patients with microscopic polyangiitis/renal-limited vasculitis. METHODS: This retrospective cohort study included consecutive patients in remission at 6 months, with renal-limited vasculitis (n = 24, renal-limited vasculitis group) and microscopic polyangiitis with renal and extra-renal involvement (n = 56, non-renal-limited vasculitis group) between 2004 and 2020. RESULTS: During the median follow-up period of 35 (range, 15‒57) months, 28 (35.0%) patients had a relapse. Multivariable Cox proportional hazards models revealed that the lower estimated glomerular filtration rate (per -10 mL/min/1.73 m2; adjusted hazard ratio = 0.87, 95% confidence interval: 0.76-0.99; P =  0.043), renal-limited vasculitis (adjusted hazard ratio =  0.23, 95% confidence interval: 0.08-0.68; P =  0.008), and glucocorticoid combined with intravenous cyclophosphamide or rituximab (adjusted HR = 0.32, 95% CI: 0.11-0.96; P = 0.042) were associated with a decreased risk of relapse. Glucocorticoid dose during the observation period was lower in the renal-limited vasculitis group than in the non-renal-limited vasculitis group. CONCLUSIONS: Renal-limited vasculitis was associated with a lower risk of relapse than non-renal-limited vasculitis. Our data may contribute to the development of optimal management for renal-limited vasculitis, which may assist in minimizing the adverse effects of immunosuppressive therapy.

Wound-Induced Hair Neogenesis Model.

Skin wounds in adult mammals typically heal with a fibrotic scar and fail to restore ectodermal appendages, such as hair follicles or adipose tissue. Intriguingly, new hair follicles regenerate in the center of large full-thickness wounds of mice in a process called wound-induced hair neogenesis (WIHN). WIHN is followed by neogenesis of dermal adipose tissue. Both neogenic events reactivate embryonic-like cellular and molecular programs. The WIHN model provides a platform for studying mammalian regeneration, and findings from this model could instruct future regenerative medicine interventions for treating wounds and alopecia. Since Ito et al. rediscovered WIHN 15 years ago, numerous investigators have worked on the WIHN model using varying wounding protocols and model interpretations. Because a variety of factors, including environmental variables and choice of mouse strains, can affect the outcomes of a WIHN study, the purpose of this article is to provide an overview of the experimental variables that impact WIHN so that experiments between laboratories can be compared in a meaningful manner.

Anti-neutrophil cytoplasmic antibody-associated vasculitis complicated by thrombotic microangiopathy with posterior reversible encephalopathy syndrome successfully treated with eculizumab: A case report.

Thrombotic microangiopathy is characterised by endothelial cell injury, intravascular platelet-fibrin thrombi, and vascular damage, leading to acute kidney injury, thrombocytopenia, and microangiopathic haemolytic anaemia. Among the autoimmune diseases related to thrombotic microangiopathy, anti-neutrophil cytoplasmic antibody-associated vasculitis-related thrombotic microangiopathy cases have been rarely reported; therefore, the optimal treatment for associated vasculitis-related thrombotic microangiopathy remains unknown. An 84-year-old woman without significant medical history presented with a 1-month history of general fatigue, fever, and deteriorating bilateral leg numbness and was admitted to our hospital. She had elevated myeloperoxidase anti-neutrophil cytoplasmic antibody levels, polyneuropathy, and rapid progressive glomerulonephritis because of pauci-immune crescentic glomerulonephritis, as revealed by a kidney biopsy. Accordingly, we diagnosed her with microscopic polyangiitis. After administering methylprednisolone pulse therapy, rituximab, and intravenous immunoglobulin, the patient's mental state deteriorated, presenting signs of thrombotic microangiopathy with posterior reversible encephalopathy syndrome. Intermittent haemodialysis and plasma exchange were initiated; however, her condition did not improve, and eculizumab administration was initiated thereafter. The patient's symptoms showed a remarkable response to eculizumab; thrombotic microangiopathy findings, kidney function, and neurological symptoms improved after only two doses of eculizumab, and she achieved sustained remission. The extremely effective course of eculizumab treatment indicated that overt complement activation affected the development of thrombotic microangiopathy. Anti-neutrophil cytoplasmic antibody-associated vasculitis-related thrombotic microangiopathy may be mediated by complement activation, and prompt induction of eculizumab therapy may be a superior strategy to prevent organ damage. Further studies should elucidate the role of complement activation in associated vasculitis-related thrombotic microangiopathy and the efficacy of eculizumab treatment.

Solid-Phase Partitioning and Leaching Behavior of Pb and Zn from Playground Soils in Kabwe, Zambia.

Zambia's Kabwe mine wastes (KMWs) are responsible for contaminating the surrounding soil and dust in the Kabwe district. Unfortunately, these wastes arise from the historical mining activities of lead (Pb) and Zinc (Zn), which lacked adequate waste management strategies. As a result, potentially toxic elements (PTEs) (Pb and Zn) spread across the Kabwe district. To assess the soil pollution derived from previous mining activities, we studied topsoil samples (n = 8) from the school playground soils (SPs). In this study, the degree of contamination, geochemical partitioning, and leachability, coupled with the release and retention of Pb and Zn, were studied. The SPs were classified as extremely enriched (EF > 40) and contaminated with Pb (Igeo > 5). On average, Pb (up to 89%) and Zn (up to 69%) were bound with exchangeable, weak acid-soluble, reducible and oxidizable phases, which are considered as 'geochemically mobile' phases in the environment. The leachates from the soils (n = 5) exceeded the Zambian standard (ZS: 190:2010) for Pb in potable drinking water (Pb < 0.01 mg/L). Furthermore, the spatial distribution of Pb and Zn showed a significant reduction in contents of Pb and Zn with the distance from the mine area.

Methylmercury chronic exposure affects the expression of DNA single-strand break repair genes, induces oxidative stress, and chromosomal abnormalities in young dyslipidemic APOE knockout mice.

Mercury (Hg) is one of the most toxic environmental pollutants, especially when methylated, forming methylmercury (MeHg). MeHg affects DNA repair, increases oxidative stress, and predisposes to cancer. MeHg neurotoxicity is well-known, but recently MeHg-associated cardiovascular effects were recognized. This study evaluated circulating lipids, oxidative stress, and genotoxicity after MeHg-chronic exposure (20 mg/L in drinking water) in C57BL/6J wild-type and APOE knockout (ko) mice, the latter, being spontaneously dyslipidemic. Experimental mice were assigned to four groups: non-intoxicated and MeHg-intoxicated wild-type mice and non-intoxicated and MeHg-intoxicated APOE ko mice. Plasma levels of triglycerides, total cholesterol (TC), HDL, and LDL were analyzed. Liver lipid peroxidation and splenic gene expression of xeroderma pigmentosum complementation groups A, C, D, and G (XPA, XPC, XPD, and XPG), X-ray repair cross-complementing protein 1 (XRCC1), and telomerase reverse transcriptase (TERT) were measured. Fur Hg levels confirmed chronic MeHg intoxication. MeHg exposure raises TC levels both in wild-type and APOE ko mice. HDL and LDL-cholesterol levels were increased only in the MeHg-challenged APOE ko mice. MeHg increased liver lipid peroxidation, regardless of the genetic background. Unintoxicated APOE ko mice showed higher expression of TERT than all other groups. APOE deficiency increases XPA expression, regardless of MeHg intoxication. Furthermore, MeHg-intoxicated mice had more cytogenetic abnormalities, effect which was independent of APOE deficiency. More studies are needed to dissect the interactions between circulating lipids, MeHg intoxication, and DNA-repair pathways even at young age, interactions that likely play critical roles in cell senescence and the risk for chronic disorders later in life.

Enhanced pyrite passivation by carrier-microencapsulation using Fe-catechol and Ti-catechol complexes.

Acid mine drainage (AMD) formation is mainly caused by the oxidation of pyrite. Carrier-microencapsulation (CME) using metal-catecholate complexes has been proposed to passivate sulfide minerals by forming surface-protective coatings on their surfaces. Among the various metal-catecholate complexes, Ti-catecholate formed stable coatings having superior acid-resistance, but a thick enough passivating film required considerable time (ca. 14 days) to grow. Meanwhile, Fe-catecholates can form Fe-oxyhydroxide coatings within 2 days, however, they are less stable than Ti-based coating. To address these drawbacks of using a single metal-complex, this study investigated the concurrent use of Fe-catechol and Ti-catechol complexes for accelerating the formation of stable passivating coating on pyrite. Compared with a single metal-complex system, the coating formation was significantly accelerated in mixed system. Linear sweep voltammetry showed the simultaneous decomposition of [Fe(cat)]+ and [Ti(cat)3]2- as the main reason for improved coating formation. Electrochemical properties of coatings formed by single and mixed complex systems, confirmed by electrochemical impedance spectroscopy and cyclic voltammetry, indicated the coating formed in the mixed system had higher resistance and more electrochemically inert than the other cases. The simultaneous use of Fe-catechol and Ti-catechol complexes enhanced pyrite passivation by accelerating metal-complex decomposition and forming more stable coating composed of Fe2TiO5.