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Machine learning algorithms are increasingly being utilized to identify brain connectivity biomarkers linked to behavioral and clinical outcomes. However, research often prioritizes prediction accuracy at the expense of biological interpretability, and inconsistent implementation of ML methods may hinder model accuracy. To address this, our paper introduces a network-level enrichment approach, which integrates brain system organization in the context of connectome-wide statistical analysis to reveal network-level links between brain connectivity and behavior. To demonstrate the efficacy of this approach, we used linear support vector regression (LSVR) models to examine the relationship between resting-state functional connectivity networks and chronological age. We compared network-level associations based on raw LSVR weights to those produced from the forward and inverse models. Results indicated that not accounting for shared family variance inflated prediction performance, the k-best feature selection via Pearson correlation reduced accuracy and reliability, and raw LSVR model weights produced network-level associations that deviated from the significant brain systems identified by forward and inverse models. Our findings offer crucial insights for applying machine learning to neuroimaging data, emphasizing the value of network enrichment for biological interpretation., Competing Interests: Competing Interests: The authors have declared that no competing interests exist., (© 2024 Massachusetts Institute of Technology.)

The cerebral cortex comprises discrete cortical areas that form during development. Accurate area parcellation in neuroimaging studies enhances statistical power and comparability across studies. The formation of cortical areas is influenced by intrinsic embryonic patterning as well as extrinsic inputs, particularly through postnatal exposure. Given the substantial changes in brain volume, microstructure, and functional connectivity during the first years of life, we hypothesized that cortical areas in 1-to-3-year-olds would exhibit major differences from those in neonates and progressively resemble adults as development progresses. Here, we parcellated the cerebral cortex into putative areas using local functional connectivity gradients in 92 toddlers at 2 years old. We demonstrated high reproducibility of these cortical regions across 1-to-3-year-olds in two independent datasets. The area boundaries in 1-to-3-year-olds were more similar to adults than neonates. While the age-specific group parcellation fitted better to the underlying functional connectivity in individuals during the first 3 years, adult area parcellations might still have some utility in developmental studies, especially in children older than 6 years. Additionally, we provided connectivity-based community assignments of the parcels, showing fragmented anterior and posterior components based on the strongest connectivity, yet alignment with adult systems when weaker connectivity was included., Competing Interests: Declaration of Competing Interests The authors declared no competing interests directly related to this manuscript.

Background: This study evaluated the long-term acoustic and subjective outcomes of Bonebridge bone conduction implant (BCI) 601 implantation in Taiwanese microtia patients with aural atresia (AA)., Methods: A total of 41 microtia patients (26 with bilateral AA and 15 with unilateral AA) who received Bonebridge BCI 601 implantation between December 2014 and March 2021 at Chang Gung Memorial Hospital, Linkou, Taiwan, were included in this retrospective study. Acoustic outcomes, including the functional hearing gain (FHG), speech reception threshold (SRT), and word recognition score (WRS), were assessed. Subjective outcomes were assessed using the Chinese versions of four questionnaires: the Abbreviated Profile of Hearing Aid Benefit (APHAB); the Speech, Spatial and Qualities of Hearing Scale; the International Outcome Inventory for Hearing Aids; and the Satisfaction with Amplification in Daily Living., Results: The mean follow-up duration was 6.3 years (range, 2.8-9.1). The mean unaided air conduction pure tone average (PTA4) was 65.3 ± 8.8 decibels (dB) hearing level (HL) and the mean aided sound field PTA4 was 31.1 ± 9.1 dB HL, resulting in a FHG of 34.2 ± 11.7 dB HL (p < 0.05). After Bonebridge implantation, the mean SRT in quiet, SRT in noise, WRS in quiet, and WRS in noise improved from 58.3 ± 7.4 dB HL to 29.4 ± 7.0 dB HL, from -1.4 ± 7.3 dB signal-to-noise ratio (SNR) to -9.6 ± 5.4 dB SNR, from 46.4 ± 26.9% to 93.8 ± 3.1%, and from 46.7 ± 21.8% to 72.7 ± 19.3%, respectively (p < 0.05). Additionally, the bilateral AA group exhibited greater SRT and WRS improvements compared to the unilateral AA group (p < 0.05). All mean subscale scores in the four questionnaires showed improvement after Bonebridge implantation, except for the mean aversiveness to sounds subscale score in the APHAB questionnaire., Conclusion: Bonebridge BCI 601 implantation provided long-term acoustic and subjective benefits to microtia patients with AA, particularly those with bilateral AA., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2024, the Chinese Medical Association.)

The human cerebral cortex contains groups of areas that support sensory, motor, cognitive, and affective functions, often categorized as functional networks. These areas show stronger internal and weaker external functional connectivity (FC) and exhibit similar FC profiles within rather than between networks. Previous studies have demonstrated the development of these networks from nascent forms present before birth to their mature, adult-like topography in childhood. However, analyses often still use definitions based on adult functional networks. We aim to assess how this might lead to the misidentification of functional networks and explore potential consequences and solutions. Our findings suggest that even though adult networks provide only a marginally better than-chance description of the infant FC organization, misidentification was largely driven by specific areas. By restricting functional networks to areas showing adult-like network clustering, we observed consistent within-network FC both within and across scans and throughout development. Additionally, these areas were spatially closer to locations with low variability in network identity among adults. Our analysis aids in understanding the potential consequences of using adult networks "as is" and provides guidance for future research on selecting and utilizing functional network models based on the research question and scenario., Competing Interests: Declaration of Competing Interests The authors declared that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background/purpose: Dental anxiety is prevalent and may result in the avoidance of periodontal therapy and maintenance. This study aimed to explore the impact of non-surgical periodontal treatment (NSPT) on dental anxiety among patients with periodontitis., Materials and Methods: In this study, 122 patients with periodontitis participated. The Chinese version of the Modified Dental Anxiety Scale (MDAS) gauged baseline dental anxiety during the initial appointment. Patients receiving non-surgical periodontal treatment (NSPT) in subsequent appointments formed the NSPT group, while those with a delayed NSPT of at least two months constituted the delayed group. In the NSPT group, the second termination questionnaire was administered one month post the last NSPT visit, just before the periodontal re-evaluation. In the delayed group, the second questionnaire was completed before the delayed NSPT initiation., Results: Baseline MDAS scores were comparable between the delay and NSPT groups. However, the NSPT group exhibited lower total scores and scores for each of the five MDAS items at termination compared with the delay group. At baseline, MDAS total scores were inversely associated with age and were lower in males. A reduction in MDAS total scores between observation points was correlated with NSPT, sex, and age after adjustment. Regarding MDAS item 4 (teeth scaled/polished), score reduction consistently correlated with NSPT and age., Conclusion: Participation in NSPT may alleviate dental anxiety, and consequently enhance the patients' conceptiveness to undergo periodontal maintenance or surgery., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2024 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Background: Secondary rhinoplasty in patients with bilateral cleft lip poses ongoing challenges and requires a reliable method for achieving optimal outcomes., Objectives: The purpose of this study was to establish a safe and effective method for secondary bilateral cleft rhinoplasty., Methods: A consecutive series of 92 skeletally matured patients with bilateral cleft lip and nasal deformity were included. All had undergone secondary open rhinoplasty, performed by a single surgeon with a bilateral reverse-U flap and septal extension graft, between 2013 and 2021. Medical records of these 92 patients were reviewed to assess the clinical course. A 3-dimensional (3D) anthropometric analysis and panel assessment of 32 patients were performed to evaluate the aesthetic improvement, with an age-, sex-, and ethnicity-matched normal control group for comparisons., Results: The methods showed statistically significant improvement in addressing a short columella (columellar height), short nasal bridge (nasal bridge length), de-projected nasal tip (nasal tip projection, nasal dorsum angle), poorly defined nasal tip (nasal tip angle, dome height, and panel assessment), and transversely oriented nostrils (columellar height, alar width, nostril type). Importantly, these improvements were accompanied by a low complication rate of 4%. However, upper lip deficiency over the upper lip angle and labial-columellar angle remained without significant improvement., Conclusions: In this study we described effective secondary rhinoplasty, which was composed of a bilateral reverse-U flap and septal extension graft, with acceptable outcome. The 3D anthropometric analysis and panel assessment clarified that our rhinoplasty procedure could bring the nasal morphology in these patients closer to the normal data., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Aesthetic Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer's disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer's disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer's disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer's disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer's disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The demand for health care has increased with the development of global technology and the rise of public health awareness, and smart service systems have also been introduced to medical care to relieve the pressure on hospital staff. However, the survey found that patients' willingness to use smart services at the time of consultation has not improved. The main research purpose of this study was to understand the willingness of patients from various groups to use smart medical service systems and to explore the influencing factors on patients' use of smart service systems in hospitals through the technology acceptance model. This study distributed questionnaires in the outpatient area of National Taiwan University Hospital Yunlin Branch, and a total of 202 valid questionnaires were obtained. After related research and regression analysis, it was found that patients paid more attention to the benefits and convenience brought by smart services. If patients believed that smart services were trustworthy and beneficial to themselves, their usage intention and attitude would be positive. The results of this study are summarized by the following four points: (1) Designed according to the cultural conditions of different regions; (2) think about design from the patient's perspective; (3) strengthen the explanation and promotion of smart services; and (4) add humanized care and design. This study could be used as a reference for hospitals to improve their service quality and systems in the future.

Three-dimensional integrated circuit (3D IC) technologies have been receiving much attention recently due to the near-ending of Moore's law of minimization in 2D IC. However, the reliability of 3D IC, which is greatly influenced by voids and failure in interconnects during the fabrication processes, typically requires slow testing and relies on human's judgement. Thus, the growing demand for 3D IC has generated considerable attention on the importance of reliability analysis and failure prediction. This research conducts 3D X-ray tomographic images combining with AI deep learning based on a convolutional neural network (CNN) for non-destructive analysis of solder interconnects. By training the AI machine using a reliable database of collected images, the AI can quickly detect and predict the interconnect operational faults of solder joints with an accuracy of up to 89.9% based on non-destructive 3D X-ray tomographic images. The important features which determine the "Good" or "Failure" condition for a reflowed microbump, such as area loss percentage at the middle cross-section, are also revealed., (© 2022. The Author(s).)

With rapid technology developments and the convenient and fast pace of life in recent years, many people are using disposable products, which cause environmental and ecological damages. A variety of eco-friendly menstrual products have been launched on the market, and "menstrual pads" now have a large market share in Taiwan's menstrual product industry. This study interviewed experts and collected questionnaires for qualitative and quantitative investigation and analysis. The results show that women have positive and open concepts regarding sustainability, as well as a good understanding of their body and are very interested in the performance and usage efficiency of products. The results also indicate that consumers purchase based on their lifestyles; most women collected enough product information before purchasing while overcoming the difficulties in dealing with the environment and learning to adapt them, and the majority of consumers attach importance to comfort, volume, and duration of blood absorption. The results suggest that the government and private enterprises should increase and improve sanitation education and sanitary facilities and guide the approach and serve as an important reference index for the promotion of eco-friendly menstrual products for environmental benefits.

This study aimed to investigate whether orbital fracture increases the risk of dry eye syndrome (DES) and identified the profile of prognostic factors. We studied a cohort from the Taiwan National Health Insurance Research Database (NHIRD). Overall, 46,179 and 184,716 participants were enrolled in the study and control groups, respectively. Each patient in the case group was age- and gender-matched to four individuals without orbital fracture that served as the control group. Cox proportional hazards analysis regression was used to estimate the risks of incident DES. During the follow-up period, the case group was more likely to develop incident DES (0.17%) than the control group (0.11%) ( p = 0.001). Multivariate Cox regression analysis demonstrated that the case group had a 4.917-fold increased risk of DES compared to the controls. In the stratified age group, orbital fracture had the highest impact on patients aged 18-29 years. Furthermore, patients with orbital roof fracture have a greater risk of developing DES. Regardless of whether having received surgery or not, the patients with orbital fracture have higher risks of DES. Our study demonstrated that orbital fracture increases the risk of developing subsequent DES. Early recognition by thorough examinations with raised awareness in the clinical setting could preserve visual function and prevent further complications.

Successful pursuit and evasion require rapid and precise coordination of navigation with adaptive motor control. We hypothesize that the dorsal anterior cingulate cortex (dACC), which communicates bidirectionally with both the hippocampal complex and premotor/motor areas, would serve a mapping role in this process. We recorded responses of dACC ensembles in two macaques performing a joystick-controlled continuous pursuit/evasion task. We find that dACC carries two sets of signals, (1) world-centric variables that together form a representation of the position and velocity of all relevant agents (self, prey, and predator) in the virtual world, and (2) avatar-centric variables, i.e. self-prey distance and angle. Both sets of variables are multiplexed within an overlapping set of neurons. Our results suggest that dACC may contribute to pursuit and evasion by computing and continuously updating a multicentric representation of the unfolding task state, and support the hypothesis that it plays a high-level abstract role in the control of behavior.

We have the capacity to follow arbitrary stimulus-response rules, meaning simple policies that guide our behavior. Rule identity is broadly encoded across decision-making circuits, but there are less data on how rules shape the computations that lead to choices. One idea is that rules could simplify these computations. When we follow a rule, there is no need to encode or compute information that is irrelevant to the current rule, which could reduce the metabolic or energetic demands of decision-making. However, it is not clear if the brain can actually take advantage of this computational simplicity. To test this idea, we recorded from neurons in 3 regions linked to decision-making, the orbitofrontal cortex (OFC), ventral striatum (VS), and dorsal striatum (DS), while macaques performed a rule-based decision-making task. Rule-based decisions were identified via modeling rules as the latent causes of decisions. This left us with a set of physically identical choices that maximized reward and information, but could not be explained by simple stimulus-response rules. Contrasting rule-based choices with these residual choices revealed that following rules (1) decreased the energetic cost of decision-making; and (2) expanded rule-relevant coding dimensions and compressed rule-irrelevant ones. Together, these results suggest that we use rules, in part, because they reduce the costs of decision-making through a distributed representational warping in decision-making circuits., Competing Interests: The authors have declared that no competing interests exist.

Taiwan has actively promoted the concept of "successful aging" in recent years. The Executive Yuan drafted the White Paper for Aged Society , which set the primary goal to enable seniors to deal with daily life more independently. Although 'third places' enable seniors to live independently, the third places that Taiwanese seniors like are not well understood. Consequently, by investigating third places, this study will investigate the environment of achieving successful aging and happiness among seniors. This study uses the questionnaire survey, and the data of this study were collected from October to November 2018 in Taichung City Central District. A questionnaire survey was conducted in several administrative agencies and participants were selected by random sampling among the over-55-year-old citizens who were already retired. An estimate of 90% confidence limits with 5% marginal error gave us a sample size of 257. This study finally received 200 efficient samples. The women's top five choices of third places are the traditional market, supermarket, restaurant, daily necessities shop, and coffee shop. The men's top five choices of third places are the traditional market, supermarket, daily necessities shop, restaurant, and a friend's house. For seniors familiar with the concept of third places, the more often they go to third places, the higher happiness they achieve. This result investigates the importance of having awareness of third places for seniors. Therefore, we should encourage them to go to third places and engage in social activities frequently to achieve successful aging., Competing Interests: The authors declare no conflict of interest.

Longitudinal epidemiological studies are considered the gold standard for understanding craniofacial morphologic development, but participant recruitment and retention can be challenging. This study describes strategies used to recruit and maintain a high level of participation in a longitudinal study involving annual three-dimensional (3D) craniofacial soft-tissue imaging from healthy Taiwanese Chinese elementary school students aged 6 to 12 years. The key aspects for project delineation, implementation, and the initial three-year practical experiment are portrayed in an integrated multistep workflow: ethics- and grant-related issues; contact, approval, and engagement from partners of the project (school stakeholders and parents); a didactic approach to recruit the students; research staff composition with task design; three station-based data collection days with two educative activities (oral hygiene and psychosocial interaction stations) and one 3D craniofacial imaging activity; and reinforcement tactics to sustain the longitudinal annual participation after the first enrollment. Randomly selected students and teachers answered an experience satisfaction questionnaire (five-point Likert scale ranging from one to five) designed to assist in understanding what they think about the data collection day. Measures of frequency (percentage) and central tendency (mean) were adopted for descriptive analysis. Six of seven contacted schools accepted participation in the project. All parents who attended the explanatory meetings agreed to join the project. A cohort of 676 students (336 girls) participated at baseline enrollment, with a follow-up rate of 96% in the second data collection. The average questionnaire-related scores were 4.2 ± 0.7 and 4.4 ± 0.6 for teachers and students, respectively. These 3D craniofacial norms will benefit multidisciplinary teams managing cleft-craniofacial deformities in the globally distributed ethnic Chinese population, particularly useful for phenotypic variation characterization, conducting quantitative morphologic comparisons, and therapeutic planning and outcome assessment. The described pathway model will assist other groups to establish their own age-, sex-, and ethnic-specific normative databases., Competing Interests: The authors declare no conflicts of interest.

TGF-β1 is a main inducer of epithelial to mesenchymal transition (EMT). However, many breast cancer cells are not sensitive to the EMT induction by TGF-β1 alone. So far, the mechanisms underlying the induction of TGF-β1-insensitive breast cancer cells remains unclear. Here we report that TNF-α can induce EMT and invasiveness of breast cancer cells which are insensitive to TGF-β1. Intriguingly, TGF-β1 could cooperate with TNF-α to promote the EMT and invasiveness of breast cancer cells. The prolonged co-stimulation with TGF-β1 and TNF-α could enhance the sustained activation of Smad2/3, p38 MAPK, ERK, JNK and NF-κB pathways by enhancing the activation of TAK1, which was mediated by the gradually up-regulated TβRs. Except for JNK, all of these pathways were required for the effects of TGF-β1 and TNF-α. Importantly, the activation of p38 MAPK and ERK pathways resulted in a positive feed-back effect on TAK1 activation by up-regulating the expression of TβRs, favoring the activation of multiple signaling pathways. Moreover, SLUG was up-regulated and required for the TGF-β1/TNF-α-induced EMT and invasiveness. In addition, SLUG could also enhance the activation of signaling pathways by promoting TβRII expression. These findings suggest that the up-regulation of TβRs contributes to the sustained activation of TAK1 induced by TGF-β1/TNF-α and the following activation of multiple signaling pathways, resulting in EMT and invasiveness of breast cancer cells.

Aim: This study aimed to excavate the roles of BCYRN1 in hepatocellular carcinoma (HCC). Methods: A comprehensive strategy of microarray data mining, computational biology and experimental verification were adopted to assess the clinical significance of BCYRN1 and identify related pathways. Results: BCYRN1 was upregulated in HCC and its expression was positively associated with both tumor, node, metastasis and worse survival rate in patients with HCC. Through combing plasma BCYRN1 with alpha fetoprotein, the diagnosis of HCC was remarkably improved. BCYRN1 may regulate some cancer-related pathways to promote HCC initiation via an lncRNA-miRNA-mRNA network. Conclusion: Our results propose BCYRN1 as a potential diagnostic and prognostic biomarker and offer a novel perspective to explore the etiopathogenesis of HCC.

To make efficient foraging decisions, we must combine information about the values of available options with nonvalue information. Some accounts of ventromedial PFC (vmPFC) suggest that it has a narrow role limited to evaluating immediately available options. We examined responses of neurons in area 14 (a putative macaque homolog of human vmPFC) as 2 male macaques performed a novel foraging search task. Although many neurons encoded the values of immediately available offers, they also independently encoded several other variables that influence choice, but that are conceptually distinct from offer value. These variables include average reward rate, number of offers viewed per trial, previous offer values, previous outcome sizes, and the locations of the currently attended offer. We conclude that, rather than serving as specialized economic value center, vmPFC plays a broad role in integrating relevant environmental information to drive foraging decisions. SIGNIFICANCE STATEMENT Decision makers must often choose whether to take an immediately available option or continue to search for a better one. We hypothesized that this process, which is integral to foraging theory, leaves neural signatures in the brain region ventromedial PFC. Subjects performed a novel foraging task in which they searched through differently valued options and attempted to balance their reward threshold with various time costs. We found that neurons not only encode the values of immediately available offers, but multiplexed these with environmental variables, including reward rate, number of offers viewed, previous offer values, and spatial information. We conclude that vmPFC plays a rich role in encoding and integrating multiple foraging-related variables during economic decisions., (Copyright © 2019 the authors.)

Taking Type 2 diabetes as the research object, and through questionnaire interviews, this study sought to determine the degree of satisfaction of patients with different attributes with medical services according to the distribution of demographic variables. Finally, the statistical results were taken as the reference basis for medical personnel to provide care to patients. Regarding the questionnaire survey, the questionnaire items were designed through face-to-face interviews aiming at their medical treatment process, thus, patients could truly reflect their feelings. This study used the SPSS statistical software (IBM, Armonk, New York, NY, USA) for analysis, and the results show that: (1) Patients of different genders had different degrees of satisfaction with medical services. (2) The difference in age, monthly disposable income, occupational category, and education level had no significant effect on service satisfaction. (3) The research subjects were all on the high side regarding their satisfaction with the service provided by medical facilities. This study is a pilot study, and it is hoped it will be used as a guideline for improving patient care quality in the future, thus, reducing the occurrence of diabetic complications through better medical care. The long-term goal is to continuously improve care and medical service quality, thus, reducing the waste of medical resources., Competing Interests: The authors declare no conflict of interest.

We aim to explore the correlation of TNFSF15 genetic polymorphisms with susceptibility to systemic lupus erythematosus (SLE). This study enrolled SLE patients and healthy individuals to detect three single nucleotide polymorphisms (SNPs) of TNFSF15 (rs3810936, rs6478108 and rs4979462) through using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to analyze the possible association of these three SNPs with the risk of SLE and the mRNA level of TNFSF15 was quantified by real-time PCR. The rs3810936 T allele carrier greatly decreased risk of SLE (OR = 0.620, 95% CI = 0.454-0.849, P = 0.003), while the risk of SLE for rs4979462 T allele carrier was significantly increased (OR = 1.66, 95% CI = 1.243-2.218, P < 0.001). The mRNA level of TNFSF15 was obviously higher in SLE patients, and specifically, the patients who carried the CC genotype of TNFSF15 rs3810936 had a higher TNFSF15 mRNA, but the rs4979462 CC genotype carriers appeared to be associated with the decreased TNFSF15 mRNA (all P < 0.05). Besides, the genotypes of rs3810936 and rs4979462 of TNFSF15 were significantly associated with butterfly rash, arthritis, serositis, renal nephritis, hematological disorder, immunological disorder and positive antinuclear antibody (ANA) of SLE patients (all P < 0.05). CCT and CTT haplotypes were risk factors of SLE, but CCC and TTT were protective factors of SLE (all P < 0.05). Logistic regression analysis showed that rs3810936 and rs4979462 of TNFSF15, histories of chilblain and wet living environment were independently associated with the risk of SLE (all P < 0.05).The current results suggested that TNFSF15 (rs3810936 and rs4979462) SNPs may confer susceptibility to SLE risk, which were significantly associated with the clinical phenotypes of SLE., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Noncoding RNAs are crucial regulators acting as either tumor suppressor genes or oncogenes in human cancer progression. The aberrant expression of noncoding RNAs has been confirmed in different kinds of cancers. Hepatocellular carcinoma is one of the most common malignant tumors worldwide, characterized by insidious onset, great malignancy, and high rates of recurrence and metastasis. Due to lack of early predictive markers, numerous patients are diagnosed in the late stages. As therapeutic options for advanced patients are quite limited, great efforts have been made to screen patients at early stages. A previous study reported that small nucleolar RNA host gene 18 played crucial role in glioma. However, its functions and roles in hepatocellular carcinoma are unknown., Purpose: To explore its functional role and diagnostic value in hepatocellular carcinoma, we investigated its expression level., Methods: We performed real-time quantitative polymerase chain reaction in tumor tissues and adjacent noncancerous tissues derived from patients with hepatocellular carcinoma as well as in plasma, including samples from the healthy control, patients with hepatitis B, cirrhosis, and hepatocellular carcinoma., Results: Small nucleolar RNA host gene 18 was downregulated in liver tissues compared to paired adjacent noncancerous tissues ( P < .0001). Meanwhile, plasma small nucleolar RNA host gene 18 showed a relatively high sensitivity and specificity (75.61% and 73.49%) for distinguishing patients with hepatocellular carcinoma whose α-fetoprotein levels were below 200 ng/mL from the healthy controls., Conclusion: Our study suggested that small nucleolar RNA host gene 18 might act as a tumor suppressor gene in hepatocellular carcinoma and potentially a diagnostic indicator to distinguish hepatocellular carcinoma from the healthy control and cirrhosis.

Ovarian cancer (OC) is the most deadly gynecological cancer and it is urgently needed to find a new marker for the progress of OC. Many long noncoding RNAs (lncRNAs) have been reported to be aberrantly expressed in ovarian carcinoma, and may serve as prognostic markers. Therefore, we conducted this meta-analysis to gain a better understanding of the prognostic value of lncRNAs in patients with varian carcinoma. We systematically searched PubMed, EMBASE, and Web of Science. A total of 13 eligible studies, including 10 on clinicopathological features, 13 on prognosis were identified. Pooled hazard ratios (HRs) or odds ratios (OR) and 95% confidence intervals (95% CIs) were calculated using random- or fixed-effects models. Our results revealed that the increased expressions of 8 lncRNAs were associated with poor prognosis and the decreased expressions of 5 lncRNAs were related to poor prognosis in ovarian carcinoma. High HOTAIR expression was associated with shorter overall survival in ovarian cancer (pooled HR: 2.05, 95% CI: 1.51-2.77, P < 0.001). In conclusion, our meta-analysis suggested that LncRNAs could function as potential prognostic markers for ovarian cancer patients and high expression HOTAIR was associated with shorter overall survival in ovarian cancer.

Relapse and metastasis are two key risk factors of hepatocellular carcinoma (HCC) prognosis; thus, it is emergent to develop an early and accurate detection method for prognostic evaluation of HCC after surgery. In this study, we sought to acquire oligonucleotide DNA aptamers that specifically bind to HCC cells with high metastatic potential. Two HCC cell lines derived from the same genetic background but with different metastatic potential were employed: MHCC97L (low metastatic properties) as subtractive targets and HCCLM9 (high metastatic properties) as screening targets. To mimic a fluid combining environment, initial DNA aptamers library was firstly labelled with magnetic nanoparticles using biotin-streptavidin system and then applied for aptamers selection. Through 10-round selection with subtractive Cell-SELEX, six aptamers, LY-1, LY-13, LY-46, LY-32, LY-27/45, and LY-7/43, display high affinity to HCCLM9 cells and do not bind to MHCC97L cells, as well as other tumor cell lines, including breast cancer, lung cancer, colon adenocarcinoma, gastric cancer, and cervical cancer, suggesting high specificity for HCCLM9 cells. Thus, the aptamers generated here will provide solid basis for identifying new diagnostic targets to detect HCC metastasis and also may provide valuable clues for developing new targeted therapeutics.

Recently, numerous studies indicate that H19 plays a key role in tumorigenesis, but the results have been disputed, especially in the aspects of tumor progression and metastasis. Therefore, we performed this meta-analysis to systematically summarize the relationship between H19 and cancers. We searched PubMed, the Cochrane Library, CNKI, and Chinese Wan Fang to identify eligible studies. Odds ratios and 95% confidence intervals were calculated to assess the effect size. A total of 13 studies were enrolled in this meta-analysis, which was performed by Revman5.3 and Stata11.0 software. Our meta-analysis showed that the expression of H19 was associated with distant metastasis in nongastrointestinal tumors (OR = 3.85, 95% CI = 1.31-11.36, P = 0.01) and, in gastrointestinal tumors (OR = 0.34, 95% CI = 0.15-0.78, P = 0.01), lymph node metastasis (OR = 2.04, 95% CI = 1.19-3.48, P = 0.009). Moreover, in gastric cancer, H19 expression was significantly related to histological grade (OR = 0.50, 95% CI = 0.29-0.86, P = 0.01), TNM stage (OR = 0.19, 95% CI = 0.11-0.33, P < 0.01), and tumor invasion depth (OR = 0.11, 95% CI = 0.04-0.27, P < 0.01). Therefore, H19 could serve as a potential marker for progression and metastasis evaluation of cancers.

Background: Human infection with avian influenza A H7N9 virus is an acute respiratory infectious disease, which usually causes severe pneumonia with a high mortality. Chest radiographs and Computed Tomography (CT) are principal radiological modalities to assess the lung abnormalities., Objectives: The goal of this study was to investigate the chest images characteristic of H7N9 subtype of human avian influenza., Materials and Methods: The clinical and imaging data of 11 cases diagnosed as H7N9 subtype of human avian influenza were collected from 4 cities in the southern region of the Yangtze River, China. The chest imaging manifestations were analyzed by the assigned expert group. The analyzed cases include 7 males and 4 females aged from 20 to 84 years, with a mean of 55.6 years. The clinical symptoms were mainly fever (100%, 11/11) and cough (72.7%, 8/11)., Results: Segmental or lobar ground-glass opacity (GGO) or consolidation was shown in 8 cases (72.7% or 8/11). Air bronchogram was found in 7 cases (63.6% or 7/11). The lesions developed into multiple or diffuse in both lungs rapidly at the progressive stage. The reticulation shadows were shown after some lesions absorbed at the stable stage., Conclusions: The characteristic imaging demonstrations of H7N9 subtype of human avian influenza are segmental or lobar exudative lesions at lungs at the initial stage, which rapidly progress into bilateral distribution at lungs at the progressive stage., (Copyright © 2015 Beijing You&apos;an Hospital affiliated to Capital Medical University. Production and hosting by Elsevier B.V.)

Increasing evidences suggest that inflammation plays an important role in the pathogenesis of coronary artery disease (CAD). Numerous inflammatory cytokines and related genes mediate adverse cardiovascular events in patients with CAD, such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and Homer in the present study. The study was carried out on 163 CAD patients at different stages and 68 controls. The gene expression of Homer1, Homer2, Homer3, IL-1β, and TNF-α in the peripheral blood leukocytes were measured by real-time polymerase chain reaction. The mRNA levels of Homer1, IL-1β, and TNF-α in CAD patients were significantly higher than those in the control group, but not Homer2 and Homer3. However, there was no considerable difference in the mRNA levels of Homer1, IL-1β, and TNF-α among AMI, UAP, and SAP three subgroups of CAD. The receiver operating characteristic (ROC) curves showed that Homer1 had a better diagnostic value for UAP patients compared with IL-1β and TNF-α. Like IL-1β and TNF-α, Homer1 may also be an important participant of atherosclerotic plaque development and eventually rupture. The results of the present study may provide an important basis for diagnosing CAD patients, and provide new therapeutic targets for CAD.

Background: Free fatty acids (FFAs) play importance roles in the development of diabetes and cardiovascular diseases. We measured serum FFA levels from type 2 diabetes mellitus (T2DM) and acute myocardial infarction (AMI) patients and assay the correlation between serum FFA levels and related factors. The present study was undertaken to investigate a possible relation between the changes in serum free fatty acid concentration with acute myocardial infarction and type 2 diabetes mellitus., Methods: The study population consisted of 540 healthy individuals and 103 patients with T2DM, 59 patients with AMI and 21 volunteers. Serum FFAs were measured with high pressure liquid chromatography. Blood urea nitrogen and uric acid were measured in clinical laboratory, as were glycemic, lipid and blood routine parameters. We selected 242 individuals with age over 60 years, 143 healthy individuals and 52 patients with T2DM, 47 patients with AMI were incorporated into three groups as control group, T2DM group and AMI group. Associations were analyzed with stepwise regression analysis with adjusted for age, sex, body mass index., Results: Serum FFA levels were significantly higher in the age over 60 years individuals compared to 20 ~ 50 years (logFFA μmmol/L:2.60 ± 0.16 vs. 2.73 ± 0.18, P < .001) in the healthy group. We found lower FFA levels in the AMI compared to the T2DM and control group (2.64 ± 0.22 vs. 2.72 ± 0.13&2.72 ± 0.16, respectively, P < .05&P < 0.01) in the age over 60, fasting blood glucose level higher in the AMI and T2DM (5.78 ± 1.32&7.75 ± 2.93 mmol/L vs. 4.90 ± 0.47 mmol/L, P < .01&P < .001) compared with the normal group, HDL level (1.01 ± 0.22&0.98 ± 0.18 mmol/L vs.1.30 ± 0.22 mmol/L, P < .001&P < .001). With stepwise regression analysis, the serum FFA levels was positively associated with the HDL in the control group (YlogFFA = 2.32 + 0.33XHDL, R = 0.26, P < .01) and T2MD (YlogFFA = 2.46 + 0.27XHDL, R = 0.36, P < .05), AST in AMI (YlogFFA =2.24 + 0. 015XAST, R = 0.49, P < .01)., Conclusions: Compared to control group, serum FFA levels were decreased only in AMI group, while HDL level was increased in both AMI and T2DM group. The serum FFA levels were positive association with the HDL level in both T2DM and control group, FFA levels were positive association with AST in AMI.

Background: The aim of the present study was to analyze whether Homer1 is a potential prognostic marker for intrahepatic cholangiocarcinoma (ICC)., Materials and Methods: The expression of Homer1 in ICC tissue was detected with immunohistochemistry and levels of protein in ICC and paratumor tissues were evaluated by Western blotting. Survival analysis by the Kaplan-Meier method was performed to assess prognostic significance., Results: Homer1 expression was high in 67.4% (58/86) of ICC samples, and there was significant difference between ICC and adjacent noncancerous tissues (p<0.001); high expression was associated with poor histologic differentiation (p=0.019), TNM stage (p=0.014), lymph node metastasis (p=0.040), and lymphatic invasion (p=0.025). On Kaplan-Meier analysis, a comparison of survival curves of low versus high expressors of Homer1 revealed a highly significant difference in OS (p=0.001) and DFS (p=0.006), indicating that high expression of Homer1 was linked with a worse prognosis. Multivariate analyses showed that Homer1 expression was an independent risk factor predicting overall survival[Hazard ratio(HR), 7.52; 95% confidence interval (CI), 2.63- 21.47; p=0.002] and disease-free survival (HR, 11.56; 95%CI, 5.17-25.96; p<0.001) in ICC., Conclusions: Homer1 promotes lymphatic invasion and associates with lymph node metastasis and poor prognosis of ICC. The current study shows that Homer1 may be an independent prognostic factor for ICC patients after curative resection, and it provides an important basis for screening/treating high-risk patients.

Background: Recent studies have indicated that microRNA-15a (miR-15a) is dysregulated in breast cancer (BC). We aimed to evaluate the expression of miR-15a in BC tissues and corresponding para-carcinoma tissues. We also focused on effects of miR-15a on cellular behavior of MDA-MB-231 and expression of its target gene synuclein-γ (SNCG)., Materials and Methods: The expression levels of miR-15a were analysed in BC formalin fixed paraffin embedded (FFPE) tissues by microarray and quantitative real-time PCR. CCK-8 assays, cell cycle and apoptosis assays were used to explore the potential functions of miR-15a in MDA-MB-231 human BC cells. A luciferase reporter assay confirmed direct targets., Results: Downregulation of miR-15a was detected in most primary BCs. Ectopic expression of miR-15a promoted proliferation and suppressed apoptosis in vivo. Further studies indicated that miR-15a may directly interact with the 3'-untranslated region (3'-UTR) of SNCG mRNA, downregulating its mRNA and protein expression levels. SNCG expression was negatively correlated with miR-15a expression., Conclusions: MiR-15a has a critical role in mediating cell cycle arrest and promoting cell apoptosis of BC, probably by directly targeting SNCG. Thus, it may be involved in development and progression of BC.

Pkd2L1 (also called TRPP3) is a non-selective cation channel permeable to Ca(2+), Na(+), and K(+) and is activated by Ca(2+). It is also part of an acid-triggered off-response cation channel complex. We previously reported roles of the Pkd2L1 C-terminal fragments in its channel function, but the role of the N terminus remains unclear. Using a yeast two-hybrid screening, we found that the Pkd2L1 N terminus interacts with the receptor for activated C kinase 1 (RACK1), a scaffolding/anchoring protein implicated in various cellular functions. This interaction requires the last two Trp-Asp (WD) motifs of RACK1 and fragment Ala(19)-Pro(45) of Pkd2L1. The interaction was confirmed by GST pulldown, blot overlay, and co-immunoprecipitation assays. By (45)Ca tracer uptake and two-microelectrode voltage clamp electrophysiology, we found that in Xenopus oocytes with RACK1 overexpression Pkd2L1 channel activity is abolished or substantially reduced. Combining with oocyte surface biotinylation experiments, we demonstrated that RACK1 inhibits the function of Pkd2L1 channel on the plasma membrane in addition to reducing its total and plasma membrane expression. Overexpressing Pkd2L1 N- or C-terminal fragments as potential blocking peptides for the Pkd2L1-RACK1 interaction, we found that Pkd2L1 N-terminal fragment Met(1)-Pro(45), but not Ile(40)-Ile(97) or C-terminal fragments, abolishes the inhibition of Pkd2L1 channel by overexpressed and oocyte-native RACK1 likely through disrupting the Pkd2L1-RACK1 association. Taken together, our study demonstrated that RACK1 inhibits Pkd2L1 channel function through binding to domain Met(1)-Pro(45) of Pkd2L1. Thus, Pkd2L1 is a novel target channel whose function is regulated by the versatile scaffolding protein RACK1.

Filamins are important actin cross-linking proteins implicated in scaffolding, membrane stabilization and signal transduction, through interaction with ion channels, receptors and signaling proteins. Here we report the physical and functional interaction between filamins and polycystin-2, a TRP-type cation channel mutated in 10-15% patients with autosomal dominant polycystic kidney disease. Yeast two-hybrid and GST pull-down experiments demonstrated that the C-termini of filamin isoforms A, B and C directly bind to both the intracellular N- and C-termini of polycystin-2. Reciprocal co-immunoprecipitation experiments showed that endogenous polycystin-2 and filamins are in the same complexes in renal epithelial cells and human melanoma A7 cells. We then examined the effect of filamin on polycystin-2 channel function by electrophysiology studies with a lipid bilayer reconstitution system and found that filamin-A substantially inhibits polycystin-2 channel activity. Our study indicates that filamins are important regulators of polycystin-2 channel function, and further links actin cytoskeletal dynamics to the regulation of this channel protein.

We have created a mouse genetic model that mimics a human mutation of Shank3 that deletes the C terminus and is associated with autism. Expressed as a single copy [Shank3(+/ΔC) mice], Shank3ΔC protein interacts with the wild-type (WT) gene product and results in >90% reduction of Shank3 at synapses. This "gain-of-function" phenotype is linked to increased polyubiquitination of WT Shank3 and its redistribution into proteasomes. Similarly, the NR1 subunit of the NMDA receptor is reduced at synapses with increased polyubiquitination. Assays of postsynaptic density proteins, spine morphology, and synapse number are unchanged in Shank3(+/ΔC) mice, but the amplitude of NMDAR responses is reduced together with reduced NMDAR-dependent LTP and LTD. Reciprocally, mGluR-dependent LTD is markedly enhanced. Shank3(+/ΔC) mice show behavioral deficits suggestive of autism and reduced NMDA receptor function. These studies reveal a mechanism distinct from haploinsufficiency by which mutations of Shank3 can evoke an autism-like disorder., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: The prevalence of prostate cancer (PCa) is high and PCa is the most common cutaneous cancer in men worldwide. Despite extensive research efforts, very few biomarkers of PCa have been introduced to date in clinical practice. A meta-analysis was performed on the most recently reported CTC to assess its prognostic effect and to elucidate whether its detection in the peripheral blood of patients diagnosed with metastatic, castration-resistant prostate cancer (CPRC) and Hormone Refractory Prostate Cancer (HRPC) can be used as a prognostic factor for survival., Methods: We searched Science Direct, EMBASE, PubMed, and Cell Research databases for studies that assessed the prognostic relevance of the presence number of circulating tumor cells (CTC) detection in the peripheral blood (PB). A fixed effects model with relative risk (RR) and 95% confidence interval (95% CI) is used for analysis., Results: A total of 4 studies, including 486 patients, were eligible for final analysis. Pooled analysis indicated the presence number of CTC per 7.5 ml peripheral blood is associated with a poor survival rate (RR=2.51, 95% CI 1.96-3.21)., Conclusion: The unfavorable count (presence of 5 or more CTCs per 7.5 ml peripheral blood) was associated with poor overall survival in patients with PCa. CTC counts can be used as an accurate and independent predictor of survival rate in patients with PCa.

In the present study, joint-control training was applied when teaching manded selection responses to children with autism. Four vocal children with autism participated in the first experiment, two males (ages seven and eight) and two females (ages seven and nine). The results showed that it was only after object-word naming was trained under joint control that the symmetrical performance of manded selection responses appeared with no additional training. Four non-vocal children with autism participated in the second experiment, two males (ages six and seven), and two females (ages twelve and thirteen). These results also showed that it was only after the joint tact/self-mimetic/sequelic control training that the symmetrical performance of manded selection responses appeared with no additional training.

Shank proteins assemble glutamate receptors with their intracellular signaling apparatus and cytoskeleton at the postsynaptic density. Whether Shank plays a role in spinogenesis and synaptogenesis remained unclear. Here, we report that knock-down of Shank3/prolinerich synapse-associated protein-2 by RNA interference reduces spine density in hippocampal neurons. Moreover, transgene expression of Shank 3 is sufficient to induce functional dendritic spines in aspiny cerebellar neurons. Transfected Shank protein recruits functional glutamate receptors, increases the number and size of synaptic contacts, and increases amplitude, frequency, and the AMPA component of miniature EPSCs, similar to what is observed during synapse developmental maturation. Mutation/deletion approaches indicate that these effects require interactions of Shank3 with the glutamate receptor complex. Consistent with this observation, chronic treatment with glutamate receptor antagonists alters maturation of the Shank3-induced spines. These results strongly suggest that Shank proteins and the associated glutamate receptors participate in a concerted manner to form spines and functional synapses.

Hindpaw inflammation induces tyrosine phosphorylation (tyr-P) of the NMDA receptor (NMDAR) 2B (NR2B) subunit in the rat spinal dorsal horn that is closely related to the initiation and development of hyperalgesia. Here, we show that in rats with Freund's adjuvant-induced inflammation, the increased dorsal horn NR2B tyr-P is blocked by group I metabotropic glutamate receptor (mGluR) antagonists [7-(hydroxyimino)cyclopropa[b] chromen-1a-carboxylate ethyl ester (CPCCOEt) and 2-methyl-6-(phenylethynyl)-pyridine (MPEP), by the Src inhibitor CGP 77675, but not by the MAP kinase inhibitor 2'-amino-3'-methoxyflavone. Analysis of the calcium pathways shows that the in vivo NR2B tyr-P is blocked by an IP3 receptor antagonist 2-aminoethoxydiphenylborate (2APB) but not by antagonists of ionotropic glutamate receptors and voltage-dependent calcium channels, suggesting that the NR2B tyr-P is dependent on intracellular calcium release. In a dorsal horn slice preparation, the group I (dihydroxyphenylglycine), but not group II [(2R,4R)-4-aminopyrrolidine-2,3-dicarboxylate] and III [L-AP 4 (L-(+)-2-amino-4-phosphonobutyric acid)], mGluR agonists, an IP3 receptor (D-IP3) agonist, and a PKC (PMA) activator, induces NR2B tyr-P similar to that seen in vivo after inflammation. Coimmunoprecipitation indicates that Shank, a postsynaptic density protein associated with mGluRs, formed a complex involving PSD-95 (postsynaptic density-95), NR2B, and Src in the spinal dorsal horn. Double immunofluorescence studies indicated that NR1 is colocalized with mGluR5 in dorsal horn neurons. mGluR5 also coimmunoprecipitates with NR2B. Finally, intrathecal pretreatment of CPCCOEt, MPEP, and 2APB attenuates inflammatory hyperalgesia. Thus, inflammation and mGluR-induced NR2B tyr-P share similar mechanisms. The group ImGluR-NMDAR coupling cascade leads to phosphorylation of the NMDAR and appears necessary for the initiation of spinal dorsal horn sensitization and behavioral hyperalgesia after inflammation.

Drug addiction involves complex interactions between pharmacology and learning in genetically susceptible individuals. Members of the Homer gene family are regulated by acute and chronic cocaine administration. Here, we report that deletion of Homer1 or Homer2 in mice caused the same increase in sensitivity to cocaine-induced locomotion, conditioned reward, and augmented extracellular glutamate in nucleus accumbens as that elicited by withdrawal from repeated cocaine administration. Moreover, adeno-associated virus-mediated restoration of Homer2 in the accumbens of Homer2 KO mice reversed the cocaine-sensitized phenotype. Further analysis of Homer2 KO mice revealed extensive additional behavioral and neurochemical similarities to cocaine-sensitized animals, including accelerated acquisition of cocaine self-administration and altered regulation of glutamate by metabotropic glutamate receptors and cystine/glutamate exchange. These data show that Homer deletion mimics the behavioral and neurochemical phenotype produced by repeated cocaine administration and implicate Homer in regulating addiction to cocaine., (Copyright 2004 Cell Press)

In 2001, soybean fields were surveyed to determine the incidence of viruses because soybean aphids (Aphis glycines Matsamura), known to transmit Soybean mosaic virus (SMV) (2), were found in Ontario. In addition, bean leaf beetle (Cerotoma trifurcata Forster) was found during 2000 to be contaminated with Bean pod mottle virus (BPMV), although soybean plants, on which the beetles were feeding, tested negative (3). In the current survey, young soybean leaves were selected at random in July and August from 20 plants per site at growth stages R4 to R5 (1) from 415 sites representing the entire soybean-producing area in Ontario. Samples were maintained under cool conditions until received at the laboratory, where they were promptly processed. A combined sub-sample was obtained from the 20 plants per site. The 415 sub-samples were tested for SMV, BPMV, Tobacco ringspot virus (TRSV), and Tobacco streak virus (TSV) using polyclonal antibody kits for double-antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA) (Agdia Inc., Elkart, IN). The ELISA plates were read with a plate reader (MRX, Dynex Technologies Inc., Chantilly, VA), and results were analyzed using ELISA software (Leading Edge Research, Merrickville, Ontario) and compared positive and negative controls (Agdia). TRSV was detected in one sample from Essex County and another sample from Middlesex County. SMV, BPMV, and TSV were not found in commercial soybean fields. However, SMV and BPMV were found in samples originating from two soybean breeding nurseries, one in Essex County and one in Kent County. Seedlings of soybean cv. Williams 82 were inoculated in the greenhouse with sap from leaf samples that tested positive for BPMV. Leaves of plants that developed mosaic symptoms were retested using ELISA and confirmed to be positive for BPMV. SMV and TRSV have been found previously in commercial soybean fields in Ontario (4). To our knowledge, this is the first report of BPMV on soybean plants in Canada. References: (1) W. R. Fehr et al. Merr. Crop. Sci. 11:929, 1971. (2) J. H. Hill et al. Plant Dis. 85:561, 2001. (3) A. U. Tenuta. Crop Pest. 5 (11):8, 2000. (4) J. C. Tu. Can. J. Plant Sci. 66:491, 1986.

G-protein-coupled receptors (GPCRs) transduce signals from extracellular transmitters to the inside of the cell by activating G proteins. Mutation and overexpression of these receptors have revealed that they can reach their active state even in the absence of agonist, as a result of a natural shift in the equilibrium between their inactive and active conformations. Such agonist-independent (constitutive) activity has been observed for the glutamate GPCRs (the metabotropic glutamate receptors mGluR1a and mGluR5) when they are overexpressed in heterologous cells. Here we show that in neurons, the constitutive activity of these receptors is controlled by Homer proteins, which bind directly to the receptors' carboxy-terminal intracellular domains. Disruption of this interaction by mutagenesis or antisense strategies, or expression of endogenous Homer1a (H1a), induces constitutive activity in mGluR1a or mGluR5. Our results show that these glutamate GPCRs can be directly activated by intracellular proteins as well as by agonists.

The physiological actions of neurotransmitter receptors are intimately linked to their proper neuronal compartment localization. Here we studied the effect of the metabotropic glutamate receptor (mGluR)-interacting proteins, Homer1a, b, and c, in the targeting of mGluR5 in neurons. We found that mGluR5 was exclusively localized in cell bodies when transfected alone in cultured cerebellar granule cells. In contrast, mGluR5 was found also in dendrites when coexpressed with Homer1b or Homer1c, and in both dendrites and axons when cotransfected with Homer1a. In dendrites, cotransfected mGluR5 and Homer1b/c formed clusters that colocalized with the synaptic marker synaptophysin. Interestingly when transfected alone, the Homer proteins were also translocated to neurites but did not form such clusters. Depolarization of the neurons with a mixture of ionotropic glutamate receptor agonists, NMDA and kainate, or potassium channel blockers, tetraethylammonium and 4-aminopyridine, induced transient expression of endogenous Homer1a and persistent neuritic localization of transfected mGluR5 even long after degradation of Homer1a. These results suggest that Homer1a/b/c proteins are involved in the targeting of mGluR5 to dendritic synaptic sites and/or axons and that this effect can be regulated by neuronal activity. Because the activity-dependent effect of endogenous Homer1a was also long-lasting, the axonal targeting of mGluR5 by this protein is likely to play an important role in synaptic plasticity.

Group I metabotropic glutamate receptors (mGluR1 and 5) couple to intracellular calcium pools by a family of proteins, termed Homer, that cross-link the receptor to inositol trisphosphate receptors. mGluRs also couple to membrane ion channels via G-proteins. The role of Homer proteins in channel modulation was investigated by expressing mGluRs and various forms of Homer in rat superior cervical ganglion (SCG) sympathetic neurons by intranuclear cDNA injection. Expression of cross-linking-capable forms of Homer (Homer 1b, 1c, 2, and 3, termed long forms) occluded group I mGluR-mediated N-type calcium and M-type potassium current modulation. This effect was specific for group I mGluRs. mGluR2 (group II)-mediated inhibition of N-channels was unaltered. Long forms of Homer decreased modulation of N- and M-type currents but did not selectively block distinct G-protein pathways. Short forms of Homer, which cannot self-multimerize (Homer 1a and a Homer 2 C-terminal deletion), did not alter mGluR-ion channel coupling. When coexpressed with long forms of Homer, short forms restored the mGluR1a-mediated calcium current modulation in an apparent dose-dependent manner. Homer 2b induced cell surface clusters of mGluR5 in SCG neurons. Conversely, a uniform distribution was observed when mGluR5 was expressed alone or with Homer short forms. These studies indicate that long and short forms of Homer compete for binding to mGluRs and regulate their coupling to ion channels. In vivo, the immediate early Homer 1a is anticipated to enhance ion channel modulation and to disrupt coupling to releasable intracellular calcium pools. Thus, Homer may regulate the magnitude and predominate signaling output of group I mGluRs.

Homer EVH1 (Ena/VASP Homology 1) domains interact with proline-rich motifs in the cytoplasmic regions of group 1 metabotropic glutamate receptors (mGluRs), inositol-1,4,5-trisphosphate receptors (IP3Rs), and Shank proteins. We have determined the crystal structure of the Homer EVH1 domain complexed with a peptide from mGluR (TPPSPF). In contrast to other EVH1 domains, the bound mGluR ligand assumes an unusual conformation in which the side chains of the Ser-Pro tandem are oriented away from the Homer surface, and the Phe forms a unique contact. This unusual binding mode rationalizes conserved features of both Homer and Homer ligands that are not shared by other EVH1 domains. Site-directed mutagenesis confirms the importance of specific Homer residues for ligand binding. These results establish a molecular basis for understanding the biological properties of Homer-ligand complexes.

The molecular basis for glutamate receptor trafficking to the plasma membrane is not understood. In the present study, we demonstrate that Homer 1b (H1b), a constitutively expressed splice form of the immediate early gene product Homer (now termed Homer 1a) regulates the trafficking and surface expression of group I metabotropic glutamate receptors. H1b inhibits surface expression of the metabotropic glutamate receptor mGluR5 in heterologous cells, causing mGluR5 to be retained in the endoplasmic reticulum (ER). In contrast, mGluR5 alone or mGluR5 coexpressed with Homer 1a successfully travels through the secretory pathway to the plasma membrane. In addition, point mutations that disrupt mGluR5 binding to H1b eliminate ER retention of mGluR5, demonstrating that H1b affects metabotropic receptor localization via a direct protein-protein interaction. Electron microscopic analysis reveals that the group I metabotropic receptor mGluR1alpha is significantly enriched in the ER of Purkinje cells, suggesting that a similar mechanism may exist in vivo. Because H1b is found in dendritic spines of neurons, local retention of metabotropic receptors within dendritic ER provides a potential mechanism for regulating synapse-specific expression of group I metabotropic glutamate receptors.

NMDA receptors are linked to intracellular cytoskeletal and signaling molecules via the PSD-95 protein complex. We report a novel family of postsynaptic density (PSD) proteins, termed Shank, that binds via its PDZ domain to the C terminus of PSD-95-associated protein GKAP. A ternary complex of Shank/GKAP/PSD-95 assembles in heterologous cells and can be coimmunoprecipitated from rat brain. Synaptic localization of Shank in neurons is inhibited by a GKAP splice variant that lacks the Shank-binding C terminus. In addition to its PDZ domain, Shank contains a proline-rich region that binds to cortactin and a SAM domain that mediates multimerization. Shank may function as a scaffold protein in the PSD, potentially cross-linking NMDA receptor/PSD-95 complexes and coupling them to regulators of the actin cytoskeleton.

Shank is a recently described family of postsynaptic proteins that function as part of the NMDA receptor-associated PSD-95 complex (Naisbitt et al., 1999 [this issue of Neuron]). Here, we report that Shank proteins also bind to Homer. Homer proteins form multivalent complexes that bind proline-rich motifs in group 1 metabotropic glutamate receptors and inositol trisphosphate receptors, thereby coupling these receptors in a signaling complex. A single Homer-binding site is identified in Shank, and Shank and Homer coimmunoprecipitate from brain and colocalize at postsynaptic densities. Moreover, Shank clusters mGluR5 in heterologous cells in the presence of Homer and mediates the coclustering of Homer with PSD-95/GKAP. Thus, Shank may cross-link Homer and PSD-95 complexes in the PSD and play a role in the signaling mechanisms of both mGluRs and NMDA receptors.

Homer is a neuronal immediate early gene (IEG) that is enriched at excitatory synapses and binds group 1 metabotropic glutamate receptors (mGluRs). Here, we characterize a family of Homer-related proteins derived from three distinct genes. Like Homer IEG (now termed Homer 1a), all new members bind group 1 mGluRs. In contrast to Homer 1a, new members are constitutively expressed and encode a C-terminal coiled-coil (CC) domain that mediates self-multimerization. CC-Homers form natural complexes that cross-link mGluRs and are enriched at the postsynaptic density. Homer 1a does not multimerize and blocks the association of mGluRs with CC-Homer complexes. These observations support a model in which the dynamic expression of Homer 1a competes with constitutively expressed CC-Homers to modify synaptic mGluR properties.

Group I metabotropic glutamate receptors (mGluRs) activate PI turnover and thereby trigger intracellular calcium release. Previously, we demonstrated that mGluRs form natural complexes with members of a family of Homer-related synaptic proteins. Here, we present evidence that Homer proteins form a physical tether linking mGluRs with the inositol trisphosphate receptors (IP3R). A novel proline-rich "Homer ligand" (PPXXFr) is identified in group 1 mGluRs and IP3R, and these receptors coimmunoprecipitate as a complex with Homer from brain. Expression of the IEG form of Homer, which lacks the ability to cross-link, modulates mGluR-induced intracellular calcium release. These studies identify a novel mechanism in calcium signaling and provide evidence that an IEG, whose expression is driven by synaptic activity, can directly modify a specific synaptic function.

By using adenyl cyclase as a marker enzyme, the relationship between the membrane envelope of the bacteroids of rhizobia and the plasma membrane of the host cell was demonstrated histochemically. Electron-dense deposits were found on the outer surface of the plasma membrane of the host cell and on the inner surface of the membrane envelopes of the bacteroids, but not in vacuole membranes, endoplasmic reticula, Golgi apparatus, and mitochondrial membranes. The results suggest that the membrane envelopes of the bacteroids are closely related to the host plasma membrane, and that entry of the bacteroids into the cytoplasm is in a manner similar to endocytosis.