Dowling-Degos disease (DDD), or reticular pigmented anomaly of the flexures, is a type of rare autosomal-dominant genodermatosis characterized by reticular hyperpigmentation and hypopigmentation of the flexures, such as the neck, axilla, and areas below the breasts and groin, and shows considerable heterogeneity. Loss-of-function mutations of keratin 5 (KRT5) have been identified in DDD individuals. In this study, we collected DNA samples from a large Chinese family affected by generalized DDD and found no mutation of KRT5. We performed a genome-wide linkage analysis of this family and mapped generalized DDD to a region between rs1293713 and rs244123 on chromosome 20 [corrected]. By exome sequencing, we identified nonsense mutation c.430G>T (p.Glu144(∗)) in POFUT1, which encodes protein O-fucosyltransferase 1, in the family. Study of an additional generalized DDD individual revealed the heterozygous deletion mutation c.482delA (p.Lys161Serfs(∗)42) in POFUT1. Knockdown of POFUT1 reduces the expression of NOTCH1, NOTCH2, HES1, and KRT5 in HaCaT cells. Using zebrafish, we showed that pofut1 is expressed in the skin and other organs. Morpholino knockdown of pofut1 in zebrafish produced a phenotype characteristic of hypopigmentation at 48 hr postfertilization (hpf) and abnormal melanin distribution at 72 hpf, replicating the clinical phenotype observed in our DDD individuals. At 48 and 72 hpf, tyrosinase activities decreased by 33% and 45%, respectively, and melanin protein contents decreased by 20% and 25%, respectively. Our findings demonstrate that POFUT1 mutations cause generalized DDD. These results strongly suggest that the protein product of POFUT1 plays a significant and conserved role in melanin synthesis and transport.
Purpose
The purpose of this paper is to investigate the influence of incorporating Chinese elements in global brands on consumer purchase likelihood.
Design/methodology/approach
Six global brand products from three categories that utilized Chinese elements are used to test hypotheses. The Total Effect Moderation Model is used to analyze by combining moderation and mediation under a general analytical framework.
Findings
The results show that cultural compatibility has direct positive effect, in addition to an indirect effect (through local iconness) on purchase likelihood. Meanwhile, consumer cultural identity is found to moderate the impact of brand local iconness on purchase likelihood.
Practical implications
Evaluation and improvement of cultural compatibility in a global brand that incorporates Chinese elements is recommended for multinational marketers entering Chinese consumer markets. Meanwhile, marketers should pay attention to consumer cultural identity in the market segmentation process.
Originality/value
This paper takes a unique perspective to investigate whether and how global brands can succeed when adding local cultural elements to the product design, packaging and promotion in emerging markets like China.
Macrophages play a crucial role in the control and elimination of invading Mycobacterium tuberculosis (Mtb), and also serve as the major residence for Mtb. However, the interaction between macrophages and Mtb remains to be clearly determined. Although long noncoding RNAs (lncRNAs) have emerged as key regulators in many biological processes, their roles in anti-mycobacterial responses of macrophages remain to be elucidated. Here, we applied microarray analysis to examine lncRNA and mRNA expression profiles in human primary macrophages after 72 h of infection with H37Ra or H37Rv. Our results revealed that many lncRNAs were differentially expressed in macrophages after H37Ra or H37Rv infection, indicating a possible role for lncRNAs in immune responses induced by Mtb infection and providing important cues for further functional studies. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathway analysis of the differentially expressed mRNAs showed the potential functions and pathways related to the pathogenesis of Mtb infection. Finally, two lncRNAs, MIR3945HG V1 and MIR3945HG V2, were identified as novel candidate diagnostic markers for tuberculosis. Our results provide novel insight into the mechanisms of the pivotal Mtb-macrophage interactions, and reveal potential targets for diagnostics and the treatment of tuberculosis.
Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants around the world. Because of large production volumes, widespread usage and persistence, PBDEs are now ubiquitous environmental pollutants detected in a wide variety of environment media and human samples and therefore pose a significant public health concern. Deca-PBDE (BDE-209) is the only commercial PBDE mixture still allowed for use at present, and has been recently detected at high levels in human samples. However, few studies explore its effect on development, reproduction or neurobehavior with animal models. In particular, studies with long-term chronic exposure at relatively low doses are lacking. In this study, we utilize the zebrafish model to explore the developmental, reproductive, and behavioral toxicities associated with long-term chronic exposure to deca-PBDE (BDE-209). Our findings revealed that long-term chronic exposure to low dose of deca-BDE (ranging from 0.001 to 1 μM) affected overall fitness (measured by condition factor), gonad development, male gamete quantity and quality in F0 parental fish. For F1 offspring without continuous exposure to BDE-209, parental BDE treatment led to delayed hatch and motor neuron development, loose muscle fiber, slow locomotion behavior in normal conditions, and hyperactivity when subjected to light-dark photoperiod stimulation. In conclusion, parental chronic low dose BDE-209 exposure not only affects F0 growth and reproduction, but also elicits neurobehavior alternations in F1 offspring.
Cardiovascular toxicity is a major challenge for the pharmaceutical industry and predictive screening models to identify and eliminate pharmaceuticals with the potential to cause cardiovascular toxicity in humans are urgently needed. In this study, taking advantage of the transparency of larval zebrafish, Danio rerio, we assessed cardiovascular toxicity of seven known human cardiotoxic drugs (aspirin, clomipramine hydrochloride, cyclophosphamide, nimodipine, quinidine, terfenadine and verapamil hydrochloride) and two non-cardiovascular toxicity drugs (gentamicin sulphate and tetracycline hydrochloride) in zebrafish using six specific phenotypic endpoints: heart rate, heart rhythm, pericardial edema, circulation, hemorrhage and thrombosis. All the tested drugs were delivered into zebrafish by direct soaking and yolk sac microinjection, respectively, and cardiovascular toxicity was quantitatively or qualitatively assessed at 4 and 24 h post drug treatment. The results showed that aspirin accelerated the zebrafish heart rate (tachycardia), whereas clomipramine hydrochloride, cyclophosphamide, nimodipine, quinidine, terfenadine and verapamil hydrochloride induced bradycardia. Quinidine and terfenadine also caused atrioventricular (AV) block. Nimodipine treatment resulted in atrial arrest with much slower but regular ventricular heart beating. All the tested human cardiotoxic drugs also induced pericardial edema and circulatory disturbance in zebrafish. There was no sign of cardiovascular toxicity in zebrafish treated with non-cardiotoxic drugs gentamicin sulphate and tetracycline hydrochloride. The overall prediction success rate for cardiotoxic drugs and non-cardiotoxic drugs in zebrafish were 100% (9/9) as compared with human results, suggesting that zebrafish is an excellent animal model for rapid in vivo cardiovascular toxicity screening. The procedures we developed in this report for assessing cardiovascular toxicity in zebrafish were suitable for drugs delivered by either soaking or microinjection.
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