Primary familial brain calcification (PFBC) is a genetically heterogeneous disorder characterized by bilateral calcifications in the basal ganglia and other brain regions. The genetic basis of this disorder remains unknown in a significant portion of familial cases. Here, we reported a recessive causal gene, MYORG, for PFBC. Compound heterozygous or homozygous mutations of MYORG co-segregated completely with PFBC in six families, with logarithm of odds (LOD) score of 4.91 at the zero recombination fraction. In mice, Myorg mRNA was expressed specifically in S100β-positive astrocytes, and knockout of Myorg induced the formation of brain calcification at 9 months of age. Our findings provide strong evidence that loss-of-function mutations of MYORG cause brain calcification in humans and mice.

As retailers offer multiple channels in response to competitive pressures, switching costs incurred by both retailers and consumers will shape the evolution of retailing channels. In this paper we examine propositions regarding channel loyalty, channel switching, order size, and merchandise returns based on purchase data from a specific catalog retailer that has expanded its channels to include Internet shopping. The data for this retailer shows that all four groups of customers—those who entered the database as catalog buyers, as store buyers, as Internet buyers, and as non-buyers—used multiple channels. Switching solely to this established catalog retailer's new Internet channel appears to be more difficult for consumers than relying on two or more channels. The use of multiple channels is greatest among those who entered as Internet customers, reflecting their lower risk-aversion and lower learning costs. Since the database contained only transactional information, we can make limited inferences about customers’ underlying characteristics and motivations that influence their purchase behaviors. We draw case-specific inferences and eschew generalization. Other retailers’ experiences will be affected by their own past strategies and costs and not just by the general characteristics of the channels.

PurposeThe purpose of this paper is to identify website characteristics that affect customer evaluations and satisfaction with online stores at two interaction points – when the order is placed and after the order has been fulfilled.Design/methodology/approachUsing data collected by bizrate.com, data collected from customers of thousands of online stores, the analysis focuses on the changes in the relationships between website characteristics and customer ratings. Data for two‐time periods, 15 months apart, are used to determine the stability in the observed relationships.FindingsOrder fulfillment variables, particularly on‐time delivery, dominate the effects on overall customer evaluations and satisfaction. The statistical significance of other online store attributes, however, changes as differences are observed between 2003 and 2004.Research limitations/implicationsThe online environment is dynamic and the paper captures some of the changes in the relationships between website attributes and customer satisfaction. This requires continuous monitoring of the online environment. Since the paper relies on secondary data collected by bizrate.com, the research is limited by specific website attributes and measures of customer satisfaction adopted by a commercial enterprise.Practical implicationsOnline retailers must be strategic about fulfillment variables. When online stores compete with each other, it is easier to copy certain attributes like “shipping options” than other attributes such as “on‐time delivery.” This suggests that the most creative, interactive, and vivid online site will not compensate for weak fulfillment and customer support capabilities.Originality/valueNo other paper has looked at these data, collected from real customers making purchases at actual merchant sites, over two time periods. The results provide insights regarding stability of findings.

BackgroundHereditary spastic paraplegias (HSP) is a heterogeneous group of rare neurodegenerative disorders affecting the corticospinal tracts. To date, more than 78 HSP loci have been mapped to cause HSP. However, both the clinical and mutational spectrum of Chinese patients with HSP remained unclear. In this study, we aim to perform a comprehensive analysis of clinical phenotypes and genetic distributions in a large cohort of Chinese HSP patients, and to elucidate the primary pathogenesis in this population.MethodsWe firstly performed next-generation sequencing targeting 149 genes correlated with HSP in 99 index cases of our cohort. Multiplex ligation-dependent probe amplification testing was further carried out among those patients without known disease-causing gene mutations. We simultaneously performed a retrospective study on the reported patients exhibiting HSP in other Chinese cohorts. All clinical and molecular characterization from above two groups of Chinese HSP patients were analyzed and summarized. Eventually, we further validated the cellular changes in fibroblasts of two major spastic paraplegia (SPG) patients (SPG4 and SPG11) in vitro.ResultsMost patients of ADHSP (94%) are pure forms, whereas most patients of ARHSP (78%) tend to be complicated forms. In ADHSP, we found that SPG4 (79%) was the most prevalent, followed by SPG3A (11%), SPG6 (4%) and SPG33 (2%). Subtle mutations were the common genetic cause for SPG4 patients and most of them located in AAA cassette domain of spastin protein. In ARHSP, the most common subtype was SPG11 (53%), followed by SPG5 (32%), SPG35 (6%) and SPG46 (3%). Moreover, haplotype analysis showed a unique haplotype was shared in 14 families carrying c.334C > T (p.R112*) mutation in CYP7B1 gene, suggesting the founder effect. Functionally, we observed significantly different patterns of mitochondrial dynamics and network, decreased mitochondrial membrane potential (Δψm), increased reactive oxygen species and reduced ATP content in SPG4 fibroblasts. Moreover, we also found the enlargement of LAMP1-positive organelles and abnormal accumulation of autolysosomes in SPG11 fibroblasts.ConclusionsOur study present a comprehensive clinical spectrum and genetic landscape for HSP in China. We have also provided additional evidences for mitochondrial and autolysosomal-mediated pathways in the pathogenesis of HSP.Electronic supplementary materialThe online version of this article (10.1186/s13024-018-0269-1) contains supplementary material, which is available to authorized users.

：Background: The frequency of take-out food consumption has increased rapidly among Chinese college students, which has contributed to high obesity prevalence. However, the relationships between take-out food consumption, body mass index (BMI), and other individual factors influencing eating behavior among college students are still unclear. This study explored the association of take-out food consumption with gender, BMI, physical activity, preference for high-fat and high-sugar (HFHS) food, major category, and degree level among Chinese college students. Methods: Cross-sectional data were collected from 1220 college students in Beijing, China, regarding information about take-out food consumption, physical activity, and preference for HFHS food using a self-reported questionnaire. The logistic linear regression model was used to analyze the association between take-out food consumption and personal and lifestyle characteristics. Results: Out of 1220 college students, 11.6% of college students were overweight or obese. Among the personal and lifestyle characteristics, high frequency of take-out food consumption was significantly associated with a non-medical major, high preference for HFHS food, degree level, and higher BMI, but not physical activity. Conclusion: Among Chinese college students, consumption of take-out food may be affected by major category, preference for HFHS food, degree level, and BMI. This could provide guidance on restrictions of high take-out food consumption, which contributes to high obesity prevalence and high risk for metabolic diseases.

Sensorimotor transformation, a process that converts sensory stimuli into motor actions, is critical for the brain to initiate behaviors. Although the circuitry involved in sensorimotor transformation has been well delineated, the molecular logic behind this process remains poorly understood. Here, we performed high-throughput and circuit-specific single-cell transcriptomic analyses of neurons in the superior colliculus (SC), a midbrain structure implicated in early sensorimotor transformation. We found that SC neurons in distinct laminae express discrete marker genes. Of particular interest, Cbln2 and Pitx2 are key markers that define glutamatergic projection neurons in the optic nerve (Op) and intermediate gray (InG) layers, respectively. The Cbln2+ neurons responded to visual stimuli mimicking cruising predators, while the Pitx2+ neurons encoded prey-derived vibrissal tactile cues. By forming distinct input and output connections with other brain areas, these neuronal subtypes independently mediate behaviors of predator avoidance and prey capture. Our results reveal that, in the midbrain, sensorimotor transformation for different behaviors may be performed by separate circuit modules that are molecularly defined by distinct transcriptomic codes.

PurposeThe purpose of this paper is to address the following questions in the context of a transactional web site. How do web site attributes influence customer satisfaction? Will an increase in the performance of a specific attribute lead to increased satisfaction?Design/methodology/approachSince interactivity is considered a distinguishing characteristic of the new media and a web site is composed of multiple attributes, the paper empirically examines the interactivity‐satisfaction relationship at the individual attribute level using the Kano methodology. Changes in the interactivity‐satisfaction relationships over time and with user experience are also analyzed.FindingsThe paper identifies several relationships between interactive web site attributes and customer satisfaction. At this stage of web development, no attribute emerges as a “must‐be” attribute; one‐dimensional or linear attributes are common but not the only category of interactive attributes. In addition, mixed and attractive attributes were also found. Moreover, the paper confirms that Kano categories shift over time and with usage experience.Practical implicationsDifferent web site design strategies should be used depending on users' online experience and the various relationships between interactive web site attributes and customer satisfaction.Originality/valueNo previous research has yet examined interactivity at the attribute level. Web site designers and managers have to make decisions regarding each attribute. Adopting the Kano methodology, widely used in other areas of research, this paper examines the relationships between attribute‐level interactivity and customer satisfaction with a retail web site.

Parkinson's disease (PD) is a chronic neurodegenerative disorder that is characterized by motor symptoms as a result of a loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), accompanied by chronic neuroinflammation, oxidative stress, formation of α-synuclein aggregates. Celastrol, a potent anti-inflammatory and anti-oxidative pentacyclic triterpene, has emerged as a neuroprotective agent. However, the mechanisms by which celastrol is neuroprotective in PD remain elusive. Here we show that celastrol protects against dopamine neuron loss, mitigates neuroinflammation, and relieves motor deficits in MPTP-induced PD mouse model and AAV-mediated human α-synuclein overexpression PD model. Whole-genome deep sequencing analysis revealed that Nrf2, NLRP3 and caspase-1 in SNc may be associated with the neuroprotective actions of celastrol in PD. By using multiple genetically modified mice (Nrf2-KO, NLRP3-KO and Caspase-1-KO), we identified that celastrol inhibits NLRP3 inflammasome activation, relieves motor deficits and nigrostriatal dopaminergic degeneration through Nrf2-NLRP3-caspase-1 pathway. Taken together, these findings suggest that Nrf2-NLRP3-caspase-1 axis may serve as a key target of celastrol in PD treatment, and highlight the favorable properties of celastrol for neuroprotection, making celastrol as a promising disease-modifying agent for PD.