The epithelial zinc transporter ZIP10 epigenetically regulates human epidermal homeostasis by modulating histone acetyltransferase activity.

BACKGROUND: The skin is the first organ that manifests changes in response to zinc deficiency. However, the molecular mechanism underlying how zinc is involved in skin homeostasis, especially its epigenetic regulation, is largely unknown. OBJECTIVES: In this study we demonstrate the importance of zinc levels and the zinc transporter ZIP10 in the epigenetic maintenance of human epidermal homeostasis. METHODS: Adult human skin, including skin appendages, were stained with anti-ZIP10 antibody. Histone acetyltransferase (HAT) activity was assessed after treating human keratinocytes with ZIP10 small interfering (si)RNAs or the zinc chelator TPEN. ZIP10- or HAT-regulated genes were analysed based on limma bioinformatics analysis for keratinocytes treated with ZIP10 siRNAs or a HAT inhibitor, or using a public database for transcription factors. A reconstituted human skin model was used to validate the role of ZIP10 in epidermal differentiation and the functional association between ZIP10 and HAT. RESULTS: ZIP10 is predominantly expressed in the interfollicular epidermis, epidermal appendages and hair follicles. ZIP10 depletion resulted in epidermal malformations in a reconstituted human skin model via downregulation of the activity of the epigenetic enzyme HAT. This decreased HAT activity, resulting from either ZIP10 depletion or treatment with the zinc chelator TPEN, was readily restored by zinc supplementation. Through bioinformatics analysis for gene sets regulated by knockdown of SLC39A10 (encoding ZIP10) and HAT inhibition, we demonstrated that ZIP10 and HATs were closely linked with the regulation of genes related to epidermal homeostasis, particularly filaggrin and metallothionein. CONCLUSIONS: Our study suggests that ZIP10-mediated zinc distribution is crucial for epidermal homeostasis via HATs. Therefore, zinc-dependent epigenetic regulation could provide alternatives to maintaining healthy skin or alleviating disorders with skin barrier defects.

Differences in the developmental origins of the periosteum may influence bone healing.

BACKGROUND AND OBJECTIVE: The jaw bone, unlike most other bones, is derived from neural crest stem cells, so we hypothesized that it may have different characteristics to bones from other parts of the body, especially in the nature of its periosteum. The periosteum exhibits osteogenic potential and has received considerable attention as a grafting material for the repair of bone and joint defects. MATERIAL AND METHODS: Gene expression profiles of jaw bone and periosteum were evaluated by DNA microarray and real-time polymerase chain reaction. Furthermore, we perforated an area 2 mm in diameter on mouse frontal and parietal bones. Bone regeneration of these calvarial defects was evaluated using microcomputed tomography and histological analysis. RESULTS: The DNA microarray data revealed close homology between the gene expression profiles within the ilium and femur. The gene expression of Wnt-1, SOX10, nestin, and musashi-1 were significantly higher in the jaw bone than in other locations. Microcomputed tomography and histological analysis revealed that the jaw bone had superior bone regenerative abilities than other bones. CONCLUSION: Jaw bone periosteum exhibits a unique gene expression profile that is associated with neural crest cells and has a positive influence on bone regeneration when used as a graft material to repair bone defects. A full investigation of the biological and mechanical properties of jaw bone as an alternative graft material for jaw reconstructive surgery is recommended.

Lin28a is a putative factor in regulating cancer stem cell-like properties in side population cells of oral squamous cell carcinoma.

Cancer stem cells (CSCs) are among the target cells of cancer therapy because they are uniquely involved in both cancer progression and sensitivity to chemotherapeutic agents. We identified side population (SP) cells, which are known to be an enriched population of CSC, in five oral squamous cell carcinoma (OSCC) cells (SCC9, SCC25, TOSCC7, TOSCC17, and TOSCC23). The percentages of SP cells ranged from 0% to 3.3%, with TOSCC23 cells showing the highest percentages of SP cells (3.3% of the total cell population). The SP cells isolated from TOSCC23 cells also showed greater cell proliferation and invasion compared to non-SP (MP) cells. Therefore, our initial findings suggested that SP cells were enriched for CSC-like cells. Furthermore, DNA microarray analysis revealed that the expression of cell proliferation-related and anti-apoptotic genes was greater in SP cells compared to MP cells. We focused on Lin28a, which showed the highest expression (approximately 22-fold) among the upregulated genes. The overexpression of Lin28a in TOSCC23 cells increased their proliferation, colony formation, and invasion. These findings suggest that Lin28a is an appropriate CSC target molecule for OSCC treatment.

Comparison of short-term outcomes of robotic and laparoscopic transabdominal peritoneal repair for unilateral inguinal hernia: a propensity-score matched analysis.

PURPOSE: This study aimed to compare perioperative outcomes of robotic and laparoscopic transabdominal peritoneal repair (TAPP) for unilateral inguinal hernia. METHODS: This single institutional retrospective cohort study used de-identified data of patients who underwent robotic TAPP (R-TAPP) or laparoscopic TAPP (L-TAPP) for unilateral inguinal hernia between January 1, 2016 and October 31, 2021. Two cohorts were propensity matched, and data were analyzed. The learning curve was evaluated in the R-TAPP group. RESULTS: Among 938 patients analyzed, 704 were included. After propensity-score matching, 80 patients were included in each group. The difference in operative time between R-TAPP and L-TAPP groups was 10 min (99.5 and 89.5 min, p = 0.087); however, console/laparoscopic time was similar (67 and 66 min, p = 0.71). The dissection time for medial-type hernia in the R-TAPP group was marginally shorter than that in the L-TAPP group (17 and 27 min, p = 0.056); however, there was no difference for lateral-type hernia (38.5 and 40 min p = 0.37). Perioperative variables, including estimated blood loss, postoperative hospital stay, and postoperative pain, had no significant difference, and chronic pain, which needed medication or intervention, was not observed in each group. The number of cases needed to achieve plateau performance was 7-10 in the R-TAPP group. CONCLUSION: This study suggests that R-TAPP was safely introduced, and its perioperative outcomes were not inferior to those of L-TAPP. A shorter dissection time for medial-type hernia might be due to the robot's advantages, and a fast-learning curve could help with the early standardization of the procedure.

Zimmermann-Laband syndrome: a case report.

Zimmermann-Laband syndrome is a very rare disorder characterized by gingival fibromatosis, abnormalities of soft cartilages of the nose and/or ears, hypoplastic or absent nails and terminal phalanges, joint hypermobility, hypatoslenomegaly, mild hirsutism and learning difficulties. Early presentation of Zimmermann-Laband syndrome in a newborn has rarely been described. This paper describes a newborn patient with Zimmermann-Laband syndrome.

Early detection of Niemann-pick disease type C with cataplexy and orexin levels: continuous observation with and without Miglustat.

STUDY OBJECTIVES: Niemann-Pick type C (NPC) is an autosomal recessive and congenital neurological disorder characterized by the accumulation of cholesterol and glycosphingolipids. Symptoms include hepatosplenomegaly, vertical supranuclear saccadic palsy, ataxia, dystonia, and dementia. Some cases frequently display narcolepsy-like symptoms, including cataplexy which was reported in 26% of all NPC patients and was more often recorded among late-infantile onset (50%) and juvenile onset (38%) patients. In this current study, we examined CSF orexin levels in the 10 patients of NPC with and without cataplexy, which supports previous findings. METHODS: Ten patients with NPC were included in the study (5 males and 5 females). NPC diagnosis was biochemically confirmed in all 10 patients, from which 8 patients with NPC1 gene were identified. We compared CSF orexin levels among NPC, narcoleptic and idiopathic hypersomnia patients. RESULTS: Six NPC patients with cataplexy had low or intermediate orexin levels. In 4 cases without cataplexy, their orexin levels were normal. In 5 cases with Miglustat treatment, their symptoms stabilized or improved. For cases without Miglustat treatment, their conditions worsened generally. The CSF orexin levels of NPC patients were significantly higher than those of patients with narcolepsy-cataplexy and lower than those of patients with idiopathic hypersomnia, which was considered as the control group with normal CSF orexin levels. DISCUSSION: Our study indicates that orexin level measurements can be an early alert of potential NPC. Low or intermediate orexin levels could further decrease due to reduction in the neuronal function in the orexin system, accelerating the patients' NPC pathophysiology. However with Miglustat treatment, the orexin levels stabilized or improved, along with other general symptoms. Although the circuitry is unclear, this supports that orexin system is indeed involved in narcolepsy-cataplexy in NPC patients. CONCLUSION: The NPC patients with cataplexy had low or intermediate orexin levels. In the cases without cataplexy, their orexin levels were normal. Our study suggests that orexin measurements can serve as an early alert for potential NPC; furthermore, they could be a marker of therapy monitoring during a treatment.

Free-time and fixed end-point optimal control theory in quantum mechanics: application to entanglement generation.

We have constructed free-time and fixed end-point optimal control theory for quantum systems and applied it to entanglement generation between rotational modes of two polar molecules coupled by dipole-dipole interaction. The motivation of the present work is to solve optimal control problems more flexibly by extending the popular fixed time and fixed end-point optimal control theory for quantum systems to free-time and fixed end-point optimal control theory. As a demonstration, the theory that we have constructed in this paper will be applied to entanglement generation in rotational modes of NaCl-NaBr polar molecular systems that are sensitive to the strength of entangling interactions. Our method will significantly be useful for the quantum control of nonlocal interaction such as entangling interaction, which depends crucially on the strength of the interaction or the distance between the two molecules, and other general quantum dynamics, chemical reactions, and so on.

Free-time and fixed end-point optimal control theory in dissipative media: application to entanglement generation and maintenance.

We develop monotonically convergent free-time and fixed end-point optimal control theory (OCT) in the density-matrix representation to deal with quantum systems showing dissipation. Our theory is more general and flexible for tailoring optimal laser pulses in order to control quantum dynamics with dissipation than the conventional fixed-time and fixed end-point OCT in that the optimal temporal duration of laser pulses can also be optimized exactly. To show the usefulness of our theory, it is applied to the generation and maintenance of the vibrational entanglement of carbon monoxide adsorbed on the copper (100) surface, CO/Cu(100). We demonstrate the numerical results and clarify how to combat vibrational decoherence as much as possible by the tailored shapes of the optimal laser pulses. It is expected that our theory will be general enough to be applied to a variety of dissipative quantum dynamics systems because the decoherence is one of the quantum phenomena sensitive to the temporal duration of the quantum dynamics.

Delta 9-tetrahydrocannabinol-induced catalepsy-like immobilization is mediated by decreased 5-HT neurotransmission in the nucleus accumbens due to the action of glutamate-containing neurons.

Delta(9)-tetrahydrocannabinol (THC) has been reported to induce catalepsy-like immobilization, but the mechanism underlying this effect remains unclear. In the present study, in order to fully understand the neural circuits involved, we determined the brain sites involved in the immobilization effect in rats. THC dose-dependently induced catalepsy-like immobilization. THC-induced catalepsy-like immobilization is mechanistically different from that induced by haloperidol (HPD), because unlike HPD-induced catalepsy, animals with THC-induced catalepsy became normal again following sound and air-puff stimuli. THC-induced catalepsy was reversed by SR141716, a selective cannabinoid CB(1) receptor antagonist. Moreover, THC-induced catalepsy was abolished by lesions in the nucleus accumbens (NAc) and central amygdala (ACE) regions. On the other hand, HPD-induced catalepsy was suppressed by lesions in the caudate putamen (CP), substantia nigra (SN), globus pallidus (GP), ACE and lateral hypothalamus (LH) regions. Bilateral microinjection of THC into the NAc region induced catalepsy-like immobilization. This THC-induced catalepsy was inhibited by serotonergic drugs such as 5-hydroxy-L-tryptophan (5-HTP), a 5-HT precursor, and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), a 5-HT receptor agonist, as well as by anti-glutamatergic drugs such as MK-801 and amantadine, an N-methyl-d-aspartate (NMDA) receptor antagonist. THC significantly decreased 5-HT and glutamate release in the NAc, as shown by in vivo microdialysis. SR141716 reversed and MK-801 inhibited this decrease in 5-HT and glutamate release. These findings suggest that the THC-induced catalepsy is mechanistically different from HPD-induced catalepsy and that the catalepsy-like immobilization induced by THC is mediated by decreased 5-HT neurotransmission in the nucleus accumbens due to the action of glutamate-containing neurons.

Unsuspected small ameloblastoma in the alveolar bone: a collaborative study of 14 cases with discussion of their cellular sources.

BACKGROUND: Intraosseous ameloblastoma (IA) is the quintessence of epithelial odontogenic tumor and histologically and behaviorally defined as an undoubted neoplastic process. Current information must lead to the consensus that IA arises from the embryologic inclusions of odontogenic epithelium within the jawbone. Nevertheless, clinically oriented evidence is limited to this day. METHODS: The clinical and radiographic features, behavior, and pathology of 14 cases of small IA confined to the alveolar region were systematically examined. RESULTS: Six cases were a chance finding. There was no gender predilection and half of the lesions clustered in middle age (>40 years). The posterior region of the mandible (n = 7) and the anterior segment of the maxilla (n = 4) were favored. Five radiographic characteristics were recognized: interradicular (n = 5) and periradicular (n = 3), and periapical, residual and pericoronal (n = 2 each). They showed solid (n = 12) or unicystic (n = 2) growth pattern and 12 lesions were divided into seven follicular, three desmoplastic, and two plexiform subtypes. The main location of tumor was microscopically traceable in six cases; three interradicular type outside the periodontal ligament space and two periradicular and one periapical variants inside. CONCLUSION: By in-depth evaluation of the spatial relationship between tumor and its surrounding structure, the alveolar process, periodontal ligament space, and pericoronal area are all the likely starting points of IA. This report re-awakens the oral pathologist to the histogenetic significance of incipient IA as the only available human specimen for reappraisal of their origin.

Perivascular myoid tumors of the oral region: a clinicopathologic re-evaluation of 35 cases.

BACKGROUND: Myopericytoma (MPC) is a generic denomination to describe tumors showing differentiation toward perivascular myoid cells /myopericytes. It has been suggested that MPC forms a morphologic continuum with glomus tumor (GT), solitary myofibroma (SMF), and angioleiomyoma (ALM). This proposed relationship has not yet been assessed in the oral region. METHODS: We reviewed our 28-year experience with 35 oral tumors, originally diagnosed as ALM (n = 28), SMF (n = 4), GT (n = 2), and MPC (n = 1) to analyze their overlapping microscopic features, with the assistance of immunohistochemistry. RESULTS: Myopericytoma showed a wide range of growth patterns; concentric perivascular whorls, hemangiopericytomatous areas, glomangiopericytoma (GPC)-type vessels and leiomyomatous foci. Intravascular growth was also seen. Among 28 cases studied, three ALM were reclassified as MPC (n = 2) and SMF (n = 1), based on the present diagnostic criteria. Additional MPC-type components, at varying degrees, were similarly found in four ALM and three SMF, at least focally. One GT featured intravascular whorls of spindle cells. These four interrelated groups of tumors had in common GPC-type vasculature and intraluminal cellular proliferation was nearly ubiquitously present. Diffuse immunoreactivity for alpha-smooth muscle actin and less staining intensity of muscle-specific actin were observed in all tumors. Only ALM displayed desmin positivity of variable extent. Neither case tested expressed CD34. CONCLUSIONS: Our data matches with the recent results in extraoral sites that MPC, GT, SMF, and ALM exhibit histologic and immunohistochemical overlap with each other. A common perivascular myoid differentiation between these tumor types is further reinforced by the present oral series.

Effects of urine pH modification on pharmacokinetics of phenobarbital in healthy dogs.

Although pH modification is one of the effective strategies for dissolving or preventing uroliths, little is known about its effects on the pharmacokinetics of phenobarbital in dogs. Five spayed, female Beagles were fed with a twice-daily diet that included potassium citrate and ammonium chloride for urine alkalinization and acidification, respectively. After a stabilizing period of 7 days, a single clinical dose of phenobarbital (3 mg/kg) was orally administered, and time-course changes in its serum and urine concentrations were determined by high-performance liquid chromatography. Total amounts of unchanged phenobarbital excreted into urine for 216 h were decreased by urine acidification and increased by urine alkalinization. The elimination half-life of serum phenobarbital in dogs with urine alkalinization was shortened and Cl(R) increased when compared with dogs with urine acidification. Other pharmacokinetic parameters, including C(max), T(max), AUC(0-216), Cl/F, and A(e0-216) were not changed by modification of the urine pH. These results suggest that the pH of urine is likely to be a determinant of the pharmacokinetics, especially urine excretion rate, of a clinical dose of oral phenobarbital. It is possible that the serum concentration of phenobarbital might be altered when a pH modifying-diet is administered for the purpose of dissolving or preventing uroliths.

Pharmacokinetics of zonisamide and drug interaction with phenobarbital in dogs.

The purposes of the present study were to elucidate the pharmacokinetics of zonisamide, determine the presence of a drug interaction with phenobarbital, and evaluate how long any interaction lasted after discontinuation of phenobarbital in dogs. Five dogs received zonisamide (5 mg/kg, p.o. and i.v.) before and during repeated oral administration of phenobarbital (5 mg/kg, bid, for 30-35 days). Zonisamide (5 mg/kg, p.o.) was also administered 8, 10, and 12 weeks after discontinuation of phenobarbital. Blood was sampled until 24 h after each zonisamide administration and serum concentrations of zonisamide were determined. Repeated phenobarbital decreased the maximum serum concentration, area under the serum concentration vs. time curve, apparent elimination half-life, and bioavailability of zonisamide. Total clearance increased. Time to maximum serum concentration and volume distribution were not changed. The maximum serum concentration and area under the serum concentration vs. time curve of zonisamide continued to be low until 10 weeks after the discontinuation of phenobarbital. They were restored to the same serum concentration as before phenobarbital administration 12 weeks after the discontinuation of phenobarbital. These data suggested that repeated administration of a clinical dose of phenobarbital enhanced the clearance of zonisamide and the enhanced clearance lasted at least 10 weeks after the discontinuation of phenobarbital. Caution may be necessary when zonisamide is given with phenobarbital and when antiepileptic therapy is changed from phenobarbital to zonisamide.

Evaluation of circadian phenotypes utilizing fibroblasts from patients with circadian rhythm sleep disorders.

We evaluated the circadian phenotypes of patients with delayed sleep-wake phase disorder (DSWPD) and non-24-hour sleep-wake rhythm disorder (N24SWD), two different circadian rhythm sleep disorders (CRSDs) by measuring clock gene expression rhythms in fibroblast cells derived from individual patients. Bmal1-luciferase (Bmal1-luc) expression rhythms were measured in the primary fibroblast cells derived from skin biopsy samples of patients with DSWPD and N24SWD, as well as control subjects. The period length of the Bmal1-luc rhythm (in vitro period) was distributed normally and was 22.80±0.47 (mean±s.d.) h in control-derived fibroblasts. The in vitro periods in DSWPD-derived fibroblasts and N24SWD-derived fibroblasts were 22.67±0.67 h and 23.18±0.70 h, respectively. The N24SWD group showed a significantly longer in vitro period than did the control or DSWPD group. Furthermore, in vitro period was associated with response to chronotherapy in the N24SWD group. Longer in vitro periods were observed in the non-responders (mean±s.d.: 23.59±0.89 h) compared with the responders (mean±s.d.: 22.97±0.47 h) in the N24SWD group. Our results indicate that prolonged circadian periods contribute to the onset and poor treatment outcome of N24SWD. In vitro rhythm assays could be useful for predicting circadian phenotypes and clinical prognosis in patients with CRSDs.

Growth suppression of intracranial xenografted glioblastomas overexpressing mutant epidermal growth factor receptors by systemic administration of monoclonal antibody (mAb) 806, a novel monoclonal antibody directed to the receptor.

A mutant epidermal growth factor receptor (variously called DeltaEGFR, de2-7 EGFR, or EGFRvIII) containing a deletion of 267 amino acids of the extracellular domain is frequently highly expressed in human malignant gliomas and has been reported for cancers of the lung, breast, and prostate. We tested the efficacy of a novel monoclonal anti-DeltaEGFR antibody, mAb 806, on the growth of intracranial xenografted gliomas in nude mice. Systemic treatment with mAb 806 significantly reduced the volume of tumors and increased the survival of mice bearing xenografts of U87 MG.DeltaEGFR, LN-Z308.DeltaEGFR, or A1207.DeltaEGFR gliomas, each of which expresses high levels of DeltaEGFR. In contrast, mAb 806 treatment was ineffective with mice bearing the parental U87 MG tumors, which expressed low levels of endogenous wild-type EGFR, or U87 MG.DK tumors, which expressed high levels of kinase-deficient DeltaEGFR. A slight increase of survival of mice xenografted with a wild-type EGFR-overexpressing U87 MG glioma (U87 MG.wtEGFR) was effected by mAb 806 concordant with its weak cross-reactivity with such cells. Treatment of U87 MG.DeltaEGFR tumors in mice with mAb 806 caused decreases in both tumor growth and angiogenesis, as well as increased apoptosis. Mechanistically, in vivo mAb 806 treatment resulted in reduced phosphorylation of the constitutively active DeltaEGFR and caused down-regulated expression of the apoptotic protector, Bcl-XL. These data provide preclinical evidence that mAb 806 treatment may be a useful biotherapeutic agent for those aggressive gliomas that express DeltaEGFR.

The s-Myc protein having the ability to induce apoptosis is selectively expressed in rat embryo chondrocytes.

Gene transfection experiments demonstrated that over-expression of the s-myc gene under the control of a human metallothionein promoter induced apoptosis in cells such as rat and human glioma cells. In contrast to c-Myc-mediated apoptosis requiring withdrawal of serum growth factors, s-myc expression induced apoptosis in glioma cells in the presence of 10% fetal calf serum. Whereas, s-Myc-mediated apoptosis was suppressed in proportion to the increase of bcl-2 expression as seen in c-Myc mediated apoptosis. The s-myc gene was expressed in rat embryo cells being committed to differentiate to hypertrophic chondrocytes which undergo programmed cell death. CAT assay demonstrated that in the NH2-terminal region, the s-Myc protein contains a domain structure required for expression of transactivation activity that is approximately six times higher than that of c-Myc. Therefore, these findings strongly suggest that s-Myc may play an important role in transcription regulation of a set of genes whose expression induces programmed cell death in vitro and in vivo.

Growth rate of myelin figures of egg-yolk phosphatidylcholine.

The growth length of myelin figures was measured in detail using a video tape recording system of optical microscopy. In the beginning stage of growth, the growth process was not adapted to the diffusion-limited process of lipid molecules, which has been recently proposed. Another interpretation for the growth mechanism was proposed, where the growth results from swelling. The initial growth rate measured was in good agreement with the estimated value in consideration with the water flux in the first approximation of the lipid concentration gradient.

Optical birefringence of phosphatidylcholine liposomes in gel phases.

A simple and rapid method for studying optical anisotropic properties of liposomes was proposed. Intensities of transmitted light through one spherical liposome of dipalmitoylphosphatidylcholine placed between two polarizers were measured at various wavelengths by a microscopic spectrophotometer. Large increases in the intensities were observed at the prephase-transition temperature, which were caused by an increase in the birefringence of the multilayer of the liposome. The birefringence values obtained from the intensity data were about 0.020 below the pretransition temperature and 0.028 above that temperature. These values are in good agreement with the results reported for the plane samples in which lipid bilayers are stacked. The obtained values of the birefringence were far lower than the values estimated from polarizabilities. This lower birefringence is attributed to disordering of the tilt direction in the multilayer. The degree of order of the liposome multilayers calculated from the birefringence increased by 38% at the pretransition. This simple method is applicable to the study of the multilayer structure of liposomes in water.

Double helix formation of phosphatidylcholine myelin figures.

Double helix formation of phosphatidylcholine myelin figures has been studied by use of optical microscopy. The winding of the double helices was looser than a geometrically possible one and the pitch was related proportionally to the outer radii of helical myelin figures. The regularity in the winding was explained in terms of the intermembrane binding energy and the bending elastic energy.