Piperonylic Acid Promotes Hair Growth by Activation of EGFR and Wnt/ß-Catenin Pathway.

Dermal papilla cells (DPCs) are located at the bottom of the hair follicle and play a critical role in hair growth, shape, and cycle. Epidermal growth factor receptor (EGFR) and Wnt/ß-catenin signaling pathways are essential in promoting keratinocyte activation as well as hair follicle formation in DPCs. Piperonylic acid is a small molecule that induces EGFR activation in keratinocytes. However, the effects of piperonylic acid on DPCs in regard to the stimulation of hair growth have not been studied. In the present study, piperonylic acid was shown to activate the Wnt/ß-catenin signaling pathway in addition to the EGFR signaling pathway in DPCs. Piperonylic acid suppressed DKK1 expression, which presumably promoted the accumulation of ß-catenin in the nucleus. In addition, piperonylic acid promoted cyclin D upregulation and cell growth and increased the expression of alkaline phosphatase (ALP), a DPC marker. In a clinical study, the group that applied a formulation containing piperonylic acid had a significantly higher number of hairs per unit area than the placebo group. These results identify piperonylic acid as a promising new candidate for hair loss treatment.

The extent of harmful volatile organic compounds released when smoking after breaking the flavor capsules of heat-not-burn (HNB) cigarette products.

A number of flavored capsule heat-not-burn (FC-HNB) tobacco products such as IQOS, Lil, and Glo have been introduced as a new generation of cigarettes. As they can release various types of volatile organic compounds (VOCs), it is important to assess the harmfulness associated with their use. Thus, the composition of VOCs in HNB cigarette vapor was evaluated to investigate the interactive roles of key variables controlling the relationships between VOC composition and capsule breaking, particularly the compositional changes induced by capsule breaking and release of flavor from FC-HNB cigarettes relative to regular products. As the capsules of FC-HNB cigarettes were broken, the total VOC concentrations increased by as high as eight times from 60.3 ± 0.48 to 488 ± 21.8 µg cig-1. The key VOC components released after breaking the flavored capsules were identified as ethyl butyrate (157 ± 13.6 µg cig-1; Lil), isoamyl acetate (76.9 ± 1.98 µg cig-1; Lil), and limonene (52.3 ± 3.29 µg cig-1; Glo). If the primary health risks of FC-HNB cigarette vapor are assessed using National Institute for Occupational Safety & Health (NIOSH) guidelines, 2,3-butanedinone exceeds the maximum daily intake limit (i.e., 0.05 mg day-1). Our study is expected to offer valuable insights into the harmful effects of direct and indirect exposure to various VOCs in FC-HNB products.

An Indoor-Monitoring LiDAR Sensor for Patients with Alzheimer Disease Residing in Long-Term Care Facilities.

This paper introduces an indoor-monitoring LiDAR sensor for patients with Alzheimer disease residing in long-term care facilities (LTCFs), and this sensor exploits an optoelectronic analog front-end (AFE) to detect light signals from targets by utilizing on-chip avalanche photodiodes (APDs) realized in a 180 nm CMOS process and a neural processing unit (NPU) used for motion detection and decisions, especially for incidents of falls occurring in LTCFs. The AFE consists of an on-chip CMOS P+/N-well APD, a linear-mode transimpedance amplifier, a post-amplifier, and a time-to-digital converter, whereas the NPU exploits network sparsity and approximate processing elements for low-power operation. This work provides a potential solution of low-cost, low-power, indoor-monitoring LiDAR sensors for patients with Alzheimer disease in LTCFs.

A single mutation in the ACTR8 gene associated with lineage-specific expression in primates.

BACKGROUND: Alternative splicing (AS) generates various transcripts from a single gene and thus plays a significant role in transcriptomic diversity and proteomic complexity. Alu elements are primate-specific transposable elements (TEs) and can provide a donor or acceptor site for AS. In a study on TE-mediated AS, we recently identified a novel AluSz6-exonized ACTR8 transcript of the crab-eating monkey (Macaca fascicularis). In the present study, we sought to determine the molecular mechanism of AluSz6 exonization of the ACTR8 gene and investigate its evolutionary and functional consequences in the crab-eating monkey. RESULTS: We performed RT-PCR and genomic PCR to analyze AluSz6 exonization in the ACTR8 gene and the expression of the AluSz6-exonized transcript in nine primate samples, including prosimians, New world monkeys, Old world monkeys, and hominoids. AluSz6 integration was estimated to have occurred before the divergence of simians and prosimians. The Alu-exonized transcript obtained by AS was lineage-specific and expressed only in Old world monkeys and apes, and humans. This lineage-specific expression was caused by a single G duplication in AluSz6, which provides a new canonical 5' splicing site. We further identified other alternative transcripts that were unaffected by the AluSz6 insertion. Finally, we observed that the alternative transcripts were transcribed into new isoforms with C-terminus deletion, and in silico analysis showed that these isoforms do not have a destructive function. CONCLUSIONS: The single G duplication in the TE sequence is the source of TE exonization and AS, and this mutation may suffer a different fate of ACTR8 gene expression during primate evolution.

Mitochondrial Cl--Selective Fluorescent Probe for Biological Applications.

Herein we describe the development of the first mitochondrial Cl--selective fluorescent probe, Mito-MQAE, and its applications in biological systems. Fluorescence of Mito-MQAE is insensitive to pH over the physiological pH range and is quenched by Cl- with a Stern-Volmer quenching constant of 201 M-1 at pH 7.0. The results of cell studies using Mito-MQAE show that substances with the ability to disrupt mitochondrial membranes cause increases in the mitochondrial Cl- concentration.

SPAM1/HYAL5 double deficiency in male mice leads to severe male subfertility caused by a cumulus-oocyte complex penetration defect.

The glycosylphosphatidylinositol-anchored sperm hyaluronidases (Hyals), sperm adhesion molecule 1 (SPAM1) and HYAL5, have long been believed to assist in sperm penetration through the cumulus-oocyte complex (COC), but their role in mammalian fertilization remains unclear. Previously, we have shown that mouse sperm devoid of either Spam1 or Hyal5 are still capable of penetrating the COC and that the loss of either Spam1 or Hyal5 alone does not cause male infertility in mice. In the present study, we found that Spam1/Hyal5 double knockout (dKO) mice produced significantly fewer offspring compared with wild-type (WT) mice, and this was due to defective COC dispersal. A comparative analysis between WT and Spam1/Hyal5 dKO epididymal sperm revealed that the absence of these 2 sperm Hyals resulted in a marked accumulation of sperm on the outside of the COC. This impaired sperm activity is likely due to the deficiency in the sperm Hyals, even though other somatic Hyals are expressed normally in the dKO mice. The fertilization ability of the Spam1/Hyal5 dKO sperm was restored by adding purified human sperm Hyal to the in vitro fertilization medium. Our results suggest that Hyal deficiency in sperm may be a significant risk factor for male sterility.-Park, S., Kim, Y.-H., Jeong, P.-S., Park, C., Lee, J.-W., Kim, J.-S., Wee, G., Song, B.-S., Park, B.-J., Kim, S.-H., Sim, B.-W., Kim, S.-U., Triggs-Raine, B., Baba, T., Lee, S.-R., Kim, E. SPAM1/HYAL5 double deficiency in male mice leads to severe male subfertility caused by a cumulus-oocyte complex penetration defect.

Idiopathic chronic diarrhea associated with dysbiosis in a captive cynomolgus macaque (Macaca fascicularis).

Chronic inflammatory enteric diseases occur commonly in humans and animals, especially in captive bred macaques. However, information about the etiology of idiopathic chronic inflammatory diarrhea in cynomolgus monkeys is limited. In this paper, we reported the unusual case of idiopathic chronic diarrhea in a captive cynomolgus monkey based on microbial, imaging, and microbiome examinations.

Energy-Efficient Cluster Management Using a Mobile Charger for Solar-Powered Wireless Sensor Networks.

In solar-powered wireless sensor networks (SP-WSNs), sensor nodes can continuously harvest energy to relieve the energy constraint problem in battery-powered WSNs. With the advent of wireless power transmission (WPT) technology, the nodes can be charged remotely if the energy harvested is insufficient. However, even in SP-WSNs with WPT, an energy imbalance problem is observed, in which the energy consumption of the nodes around a sink node increases abnormally if the sink node is stationary. To solve this problem, recent studies have been conducted using a mobile sink node instead of a stationary one. Generally, a clustering scheme is used for the efficient utilization of a mobile sink. However, even in the case of mobile sinks, it is still necessary to minimize the energy burden of the cluster heads and their surrounding nodes. In this study, we propose a scheme that mitigates the energy imbalance problem of SP-WSNs by using a WPT-capable mobile sink and an efficient clustering scheme. In the proposed scheme, the energy imbalance is minimized by electing the cluster heads effectively after considering the energy state of the nodes, and by enabling the sink node to charge the energy of the cluster heads while collecting data from them. Consequently, this scheme allows the sink node to collect more data with fewer blackouts of the sensor nodes.

Transport Studies of Epi-Al/InAs Two-Dimensional Electron Gas Systems for Required Building-Blocks in Topological Superconductor Networks.

One-dimensional (1D) electronic transport and induced superconductivity in semiconductor nanostructures are crucial ingredients to realize topological superconductivity. Our approach for topological superconductivity employs a two-dimensional electron gas (2DEG) formed by an InAs quantum well, cleanly interfaced with an epitaxial superconductor (epi-Al). This epi-Al/InAs quantum well heterostructure is advantageous for fabricating large-scale nanostructures consisting of multiple Majorana zero modes. Here, we demonstrate transport studies of building-blocks using a high-quality epi-Al/InAs 2DEG heterostructure, which could be put together to realize various proposed 1D nanowire-based nanostructures and 2DEG-based networks that could host multiple Majorana zero modes. The studies include (1) gate-defined quasi-1D channels in the InAs 2DEG and (2) quantum point contacts for tunneling spectroscopy, as well as induced superconductivity in (3) a ballistic Al-InAs 2DEG-Al Josephson junction. From 1D transport, systematic evolution of conductance plateaus in half-integer conductance quanta is observed with Landé g-factor of 17, indicating the strong spin-orbit coupling and high quality of the InAs 2DEG. The improved 2DEG quality leads to ballistic Josephson junctions with enhanced characteristic parameters such as Ic Rn and Iexc Rn, the product of superconducting critical current Ic (and excess current Iexc) and normal resistance Rn. Our results of electronic transport studies based on the 2D approach suggest that the epitaxial superconductor/2D semiconductor system with improved 2DEG quality is suitable for realizing large-scale nanostructures for quantum computing applications.

Cooperative evolution of two different TEs results in lineage-specific novel transcripts in the BLOC1S2 gene.

BACKGROUND: The BLOC1S2 gene encodes the multifunctional protein BLOS2, a shared subunit of two lysosomal trafficking complexes: i) biogenesis of lysosome-related organelles complex-1 and i) BLOC-1-related complex. In our previous study, we identified an intriguing unreported transcript of the BLOC1S2 gene that has a novel exon derived from two transposable elements (TEs), MIR and AluSp. To investigate the evolutionary footprint and molecular mechanism of action of this transcript, we performed PCR and RT-PCR experiments and sequencing analyses using genomic DNA and RNA samples from humans and various non-human primates. RESULTS: The results showed that the MIR element had integrated into the genome of our common ancestor, specifically in the BLOC1S2 gene region, before the radiation of all primate lineages and that the AluSp element had integrated into the genome of our common ancestor, fortunately in the middle of the MIR sequences, after the divergence of Old World monkeys and New World monkeys. The combined MIR and AluSp sequences provide a 3' splice site (AG) and 5' splice site (GT), respectively, and generate the Old World monkey-specific transcripts. Moreover, branch point sequences for the intron removal process are provided by the MIR and AluSp combination. CONCLUSIONS: We show for the first time that sequential integration into the same location and sequence divergence events of two different TEs generated lineage-specific transcripts through sequence collaboration during primate evolution.

nc886, a non-coding RNA, inhibits UVB-induced MMP-9 and COX-2 expression via the PKR pathway in human keratinocytes.

nc886, a long non-coding RNA (ncRNA) of 101 nucleotides in length, is known as a vault RNA or microRNA precursor. Despite the recent discovery that ncRNAs in the nucleus play a crucial role in regulating chromosomal transformation and transcription, only a few studies have focused on the function of ncRNAs in the cytoplasm, such as nc886. Several studies have investigated the function of nc886 as a suppressor of carcinogenesis and inflammation in different cancer cell types; however, its role in the skin has yet to be clearly elucidated. The two RNA binding sites for protein kinase RNA-activated (PKR) are located in the central region of the stable structure of nc886, which competes with other double-stranded RNA species. Successful binding results in decreased PKR activity. Among changes in skin cells induced by ultraviolet B (UVB) radiation, nc886 expression decreases, whereas PKR phosphorylation via mitogen-activated protein kinases (MAPKs) increases. Reduced nc886 expression leads to uncontrolled PKR activity and increases in the expression of inflammatory cytokines, matrix metalloproteinase-9 (MMP-9), type IV collagenase, and cyclooxygenase (COX-2), which ultimately accelerate inflammatory responses and skin aging. The present study investigated the regulatory mechanism associated with PKR activity and nc886-PKR binding in skin cell aging and inflammation. These results suggest a role for nc886 in controlling photoaging and inflammation in skin cells.

Transient meiotic arrest maintained by DON (6-diazo-5-oxo-l-norleucine) enhances nuclear/cytoplasmic maturation of porcine oocytes.

The developmental competence of in vitro-matured oocytes is still lower than that of the in vivo-matured oocytes due to precocious meiotic resumption and inappropriate cytoplasmic maturation. Although numerous efforts have been attempted to accomplish better in vitro maturation (IVM) condition, only limited progress has been achieved. Thus, a current study was conducted to examine the effects of 6-diazo-5-oxo-l-norleucine (DON, an inhibitor of hyaluronan synthesis) during the first half period of IVM on nuclear/cytoplasmic maturation of porcine oocytes and subsequent embryonic development. Based on the observation of the nucleus pattern, metaphase II (MII) oocyte production rate in 1 µM DON group was significantly higher than other groups at 44 h of IVM. The 1 µM of DON was suggested to be optimal for porcine IVM and was therefore used for further investigation. Meiotic arrest effect of DON was maximal at 6 h of IVM, which was supported by the maintenance of significantly higher intra-oocyte cAMP level. In addition, increased pERK1/2 levels and clear rearrangement of cortical granules in membrane of MII oocytes matured with DON provided the evidence for balanced meiosis progression between nuclear and cytoplasmic maturation. Subsequently, DON significantly improved blastocyst formation rate, total cell numbers, and cellular survival in blastocysts after parthenogenetic activation, in vitro fertilization, and somatic cell nuclear transfer. Altogether, our results showed for the first time that 1 µM DON can be used to increase the yield of developmentally competent MII oocytes by synchronizing nuclear/cytoplasmic maturation, and it subsequently improves embryo developmental competence.

Successful application of human-based methyl capture sequencing for methylome analysis in non-human primate models.

BACKGROUND: The characterization of genomic or epigenomic variation in human and animal models could provide important insight into pathophysiological mechanisms of various diseases, and lead to new developments in disease diagnosis and clinical intervention. The African green monkey (AGM; Chlorocebus aethiops) and cynomolgus monkey (CM; Macaca fascicularis) have long been considered important animal models in biomedical research. However, non-human primate-specific methods applicable to epigenomic analyses in AGM and CM are lacking. The recent development of methyl-capture sequencing (MC-seq) has an unprecedented advantage of cost-effectiveness, and further allows for extending the methylome coverage compared to conventional sequencing approaches. RESULTS: Here, we used a human probe-designed MC-seq method to assay DNA methylation in DNA obtained from 13 CM and three AGM blood samples. To effectively adapt the human probe-designed target region for methylome analysis in non-human primates, we redefined the target regions, focusing on regulatory regions and intragenic regions with consideration of interspecific sequence homology and promoter region variation. Methyl-capture efficiency was controlled by the sequence identity between the captured probes based on the human reference genome and the AGM and CM genome sequences, respectively. Using reasonable guidelines, 56 and 62% of the human-based capture probes could be effectively mapped for DNA methylome profiling in the AGM and CM genome, respectively, according to numeric global statistics. In particular, our method could cover up to 89 and 87% of the regulatory regions of the AGM and CM genome, respectively. CONCLUSIONS: Use of human-based MC-seq methods provides an attractive, cost-effective approach for the methylome profiling of non-human primates at the single-base resolution level.

Iloprost supports early development of in vitro-produced porcine embryos through activation of the phosphatidylinositol 3-kinase/AKT signalling pathway.

Despite evidence of the presence of prostaglandin (PG) I2 in mammalian oviducts, its role in early development of in vitro-produced (IVP) embryos is largely unknown. Thus, in the present study we examined the effects of iloprost, a PGI2 analogue, on the in vitro developmental competence of early porcine embryos and the underlying mechanism(s). To examine the effects of iloprost on the development rate of IVF embryos, iloprost was added to the in vitro culture (IVC) medium and cultured for 6 days. Supplementation of the IVC medium with iloprost significantly improved developmental parameters, such as blastocyst formation rate, the trophectoderm:inner cell mass ratio and cell survival in IVF and parthenogenetically activated (PA) embryos. In addition, post-blastulation development into the expanded blastocyst stage was improved in iloprost-treated groups compared with controls. Interestingly, the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway was significantly activated by iloprost supplementation in a concentration-dependent manner (10-1000nM), and the beneficial effects of iloprost on the early development of porcine IVF and PA embryos was completely ablated by treatment with 2.5µM wortmannin, a PI3K/AKT signalling inhibitor. Importantly, expression of the PI3K/AKT signalling pathway was significantly reduced in somatic cell nuclear transfer (SCNT) compared with IVF embryos, and iloprost supported the early development of SCNT embryos, as was the case for IVF and PA embryos, suggesting a consistent effect of iloprost on the IVC of IVP porcine embryos. Together, these results indicate that iloprost can be a useful IVC supplement for production of IVP early porcine embryos with high developmental competence.

First demonstration of SiGe-based carrier-injection Mach-Zehnder modulator with enhanced plasma dispersion effect.

We demonstrate a strained Si0.91Ge0.09-based carrier-injection Mach-Zehnder (MZ) optical modulator using the enhanced plasma dispersion effect in strained SiGe through mass modulation for the first time. The SiGe modulator has an injection current of 1.47 mA for a phase shift of π which is lower than that for a Si modulator. Also, it is expected that the injection current can be further reduced by increasing the strain and Ge fraction, enabling operation at an injection current of less than 1 mA. As an example of the dynamic characteristics, 10 Gbps modulation with clear eye opening was obtained by the pre-emphasis method.

The immediate upstream region of the 5'-UTR from the AUG start codon has a pronounced effect on the translational efficiency in Arabidopsis thaliana.

The nucleotide sequence around the translational initiation site is an important cis-acting element for post-transcriptional regulation. However, it has not been fully understood how the sequence context at the 5'-untranslated region (5'-UTR) affects the translational efficiency of individual mRNAs. In this study, we provide evidence that the 5'-UTRs of Arabidopsis genes showing a great difference in the nucleotide sequence vary greatly in translational efficiency with more than a 200-fold difference. Of the four types of nucleotides, the A residue was the most favourable nucleotide from positions -1 to -21 of the 5'-UTRs in Arabidopsis genes. In particular, the A residue in the 5'-UTR from positions -1 to -5 was required for a high-level translational efficiency. In contrast, the T residue in the 5'-UTR from positions -1 to -5 was the least favourable nucleotide in translational efficiency. Furthermore, the effect of the sequence context in the -1 to -21 region of the 5'-UTR was conserved in different plant species. Based on these observations, we propose that the sequence context immediately upstream of the AUG initiation codon plays a crucial role in determining the translational efficiency of plant genes.

Demonstration of record-low injection-current variable optical attenuator based on strained SiGe with optimized lateral pin junction.

We demonstrate a strained SiGe variable optical attenuator (VOA) with a lateral pin junction which exhibits record-low injection-current for 20-dB attenuation. We optimize the distance between the highly doped p + and n + regions in the lateral pin junction to effectively inject electrons and holes, taking into account the propagation loss. In conjunction with the enhanced free-carrier absorption in strained SiGe, the SiGe VOA with the optimized lateral pin junction exhibits 20-dB attenuation by 20-mA/mm injection current, which is 1.5 times lower current density than that of the Si VOA. The SiGe VOA also shows better RF response than the Si VOA due to the short carrier lifetime in SiGe, allowing us to achieve efficient and fast attenuation modulation simultaneously. Furthermore, 2-GHz switching and error-free transmission of 4 × 12.5 Gbps WDM signal have been also achieved.

Impurity-Induced Bound States in Superconductors with Spin-Orbit Coupling.

We study the effect of strong spin-orbit coupling (SOC) on bound states induced by impurities in superconductors. The presence of SOC breaks the SU(2)-spin symmetry and causes the superconducting order parameter to have generically both singlet (s-wave) and triplet (p-wave) components. We find that in the presence of SOC the spectrum of Yu-Shiba-Rusinov (YSR) states is qualitatively different in s-wave and p-wave superconductors, a fact that can be used to identify the superconducting pairing symmetry of the host system. We also predict that, in the presence of SOC, the spectrum of the impurity-induced bound states depends on the orientation of the magnetic moment S of the impurity and, in particular, that by changing the orientation of S, the fermion-parity of the lowest energy bound state can be tuned. We then study the case of a dimer of magnetic impurities and show that, in this case, the YSR spectrum for a p-wave superconductor is qualitatively very different from the one for an s-wave superconductor even in the limit of vanishing SOC.

Acute and subchronic (28 days) oral toxicity studies of Codonopsis lanceolata extract in Sprague-Dawley rats.

Codonopsis lanceolata is a perennial plant that has been used as a food and in traditional medicine for the treatment of cough, bronchitis, and inflammation in East Asia including Korea, Japan, and China. However, information regarding its toxicity is limited. Therefore, we performed a safety evaluation of aqueous C. lanceolata root extract (CLE) in Sprague-Dawley rats. Assessment of acute toxicity revealed that CLE did not influence mortality, clinical appearance, body weight gain, or necropsy findings at a dose of 5000 mg/kg body weight. In the subchronic oral toxicity, data revealed that several significant alteration in food consumption, water consumption, protein excretion, WBCs levels, TGs, BUN levels, and the absolute and relative weights in the liver, spleen and lungs. However, these changes were transient and were not considered treatment related because they showed no apparent dose dependent. These results suggest that CLE (1250, 2500, and 5000 mg/kg body weight/day) administered orally does not cause acute or subchronic toxicity to male or female rats. The 50% lethal dose (LD50) of CLE was determined to be greater than 5000 mg/kg.

Quantitative expression analysis of APP pathway and tau phosphorylation-related genes in the ICV STZ-induced non-human primate model of sporadic Alzheimer's disease.

The accumulation and aggregation of misfolded proteins in the brain, such as amyloid-ß (Aß) and hyperphosphorylated tau, is a neuropathological hallmark of Alzheimer's disease (AD). Previously, we developed and validated a novel non-human primate model for sporadic AD (sAD) research using intracerebroventricular administration of streptozotocin (icv STZ). To date, no characterization of AD-related genes in different brain regions has been performed. Therefore, in the current study, the expression of seven amyloid precursor protein (APP) pathway-related and five tau phosphorylation-related genes was investigated by quantitative real-time PCR experiments, using two matched-pair brain samples from control and icv STZ-treated cynomolgus monkeys. The genes showed similar expression patterns within the control and icv STZ-treated groups; however, marked differences in gene expression patterns were observed between the control and icv STZ-treated groups. Remarkably, other than ß-secretase (BACE1) and cyclin-dependent kinase 5 (CDK5), all the genes tested showed similar expression patterns in AD models compared to controls, with increased levels in the precuneus and occipital cortex. However, significant changes in gene expression patterns were not detected in the frontal cortex, hippocampus, or posterior cingulate. Based on these results, we conclude that APP may be cleaved via the general metabolic mechanisms of increased α- and γ-secretase levels, and that hyperphosphorylation of tau could be mediated by elevated levels of tau protein kinase, specifically in the precuneus and occipital cortex.