bluuebunny/crossref_metadata_2025 huggingface dataset:
Coordinated activation of distinct Ca2+ sources and metabotropic glutamate receptors encodes Hebbian synaptic plasticity
Authors: Tigaret Cezar M. , Olivo Valeria , Sadowski Josef H.L.P. , Ashby Michael C. , Mellor Jack R.
Published: January 2016

At glutamatergic synapses, induction of associative synaptic plasticity requires time-correlated presynaptic and postsynaptic spikes to activate postsynaptic NMDA receptors (NMDARs). The magnitudes of the ensuing Ca2+ transients within dendritic spines are thought to determine the amplitude and direction of synaptic change. In contrast, we show that at mature hippocampal Schaffer collateral synapses the magnitudes of Ca2+ transients during plasticity induction do not match this rule. Indeed, LTP induced by time-correlated pre- and postsynaptic spikes instead requires the sequential activation of NMDARs followed by voltage-sensitive Ca2+ channels within dendritic spines. Furthermore, LTP requires inhibition of SK channels by mGluR1, which removes a negative feedback loop that constitutively regulates NMDARs. Therefore, rather than being controlled simply by the magnitude of the postsynaptic calcium rise, LTP induction requires the coordinated activation of distinct sources of Ca2+ and mGluR1-dependent facilitation of NMDAR function.
Crystal structure of the N-myristoylated lipopeptide-bound MHC class I complex
Authors: Morita Daisuke , Yamamoto Yukie , Mizutani Tatsuaki , Ishikawa Takeshi , Suzuki Juri , Igarashi Tatsuhiko , Mori Naoki , Shiina Takashi , Inoko Hidetoshi , Fujita Hiroaki , Iwai Kazuhiro , Tanaka Yoshimasa , Mikami Bunzo , Sugita Masahiko
Published: January 2016

The covalent conjugation of a 14-carbon saturated fatty acid (myristic acid) to the amino-terminal glycine residue is critical for some viral proteins to function. This protein lipidation modification, termed N-myristoylation, is targeted by host cytotoxic T lymphocytes (CTLs) that specifically recognize N-myristoylated short peptides; however, the molecular mechanisms underlying lipopeptide antigen (Ag) presentation remain elusive. Here we show that a primate major histocompatibility complex (MHC) class I-encoded protein is capable of binding N-myristoylated 5-mer peptides and presenting them to specific CTLs. A high-resolution X-ray crystallographic analysis of the MHC class I:lipopeptide complex reveals an Ag-binding groove that is elaborately constructed to bind N-myristoylated short peptides rather than prototypic 9-mer peptides. The identification of lipopeptide-specific, MHC class I-restricted CTLs indicates that the widely accepted concept of MHC class I-mediated presentation of long peptides to CTLs may need some modifications to incorporate a novel MHC class I function of lipopeptide Ag presentation.
Inherited breast cancer predisposition in Asians: multigene panel testing outcomes from Singapore
Authors: Wong Edward S Y , Shekar Sandhya , Met-Domestici Marie , Chan Claire , Sze Melody , Yap Yoon Sim , Rozen Steven G , Tan Min-Han , Ang Peter , Ngeow Joanne , Lee Ann S G
Published: January 2016

Genetic testing for germline mutations in breast cancer predisposition genes can potentially identify individuals at a high risk of developing breast and/or ovarian cancer. There is a paucity of such mutational information for Asians. Panel testing of 25 cancer susceptibility genes and BRCA1/2 deletion/duplication analysis was performed for 220 Asian breast cancer patients or their family members referred for genetics risk assessment. All 220 participants had at least one high-risk feature: having a family history of breast and/or ovarian cancer in first- and/or second-degree relatives; having breast and ovarian cancer in the same individual or bilateral breast cancer; having early-onset breast cancer or ovarian cancer (⩽40 years of age). We identified 67 pathogenic variants in 66 (30.0%) patients. Of these, 19 (28.3%) occurred in BRCA1, 16 (23.9%) in BRCA2, 7 (10.4%) in PALB2, 6 (9.0%) in TP53, 2 (3.0%) in PTEN, 2 (3.0%) in CDH1 and 15 (22.4%) in other predisposition genes. Notably, 47.8% of pathogenic variants were in non-BRCA1/2 genes. Of the 66 patients with pathogenic mutations, 63.6% (42/66) were under the age of 40 years. Family history of breast and/or ovarian cancer is enriched in patients with BRCA1/2 pathogenic variants but less predictive for non-BRCA1/2 related pathogenic variations. We detected a median of three variants of unknown significance (VUS) per gene (range 0–21). Custom gene panel testing is feasible and useful for the detection of pathogenic mutations and should be done in the setting of a formal clinical cancer genetics service given the rate of VUS.
Non-coding RNAs profiling in head and neck cancers
Authors: Salyakina Daria , Tsinoremas Nicholas F
Published: January 2016

The majority of studies on human cancers published to date focus on coding genes. More recently, however, non-coding RNAs (ncRNAs) are gaining growing recognition as important regulatory components. Here we characterise the ncRNA landscape in 442 head and neck squamous cell carcinomas (HNSCs) from the cancer genome atlas (TCGA). HNSCs represent an intriguing case to study the potential role of ncRNA as a function of viral presence, especially as HPV is potentially oncogenic. Thus, we identify HPV16-positive (HPV16+) and HPV-negative (HPV−) tumours and study the expression of ncRNAs on both groups. Overall, the ncRNAs comprise 36% of all differentially expressed genes, with antisense RNAs being the most represented ncRNA type (12.6%). Protein-coding genes appear to be more frequently downregulated in tumours compared with controls, whereas ncRNAs show significant upregulation in tumours, especially in HPV16+ tumours. Overall, expression of pseudogenes, antisense and short RNAs is elevated in HPV16+ tumours, while the remaining long non-coding RNA types are more active in all HNSC tumours independent of HPV status. In addition, we identify putative regulatory targets of differentially expressed ncRNAs. Among these ‘targets’ we find several well-established oncogenes, tumour suppressors, cytokines, growth factors and cell differentiation genes, which indicates the potential involvement of ncRNA in the control of these key regulators as a direct consequence of HPV oncogenic activity. In conclusion, our findings establish the ncRNAs as crucial transcriptional components in HNSCs. Our results display the great potential for the study of ncRNAs and the role they have in human cancers.
Genomic medicine in the military
Authors: De Castro Mauricio , Biesecker Leslie G , Turner Clesson , Brenner Ruth , Witkop Catherine , Mehlman Maxwell , Bradburne Chris , Green Robert C
Published: January 2016

The announcement of the Precision Medicine Initiative was an important step towards establishing the use of genomic information as part of the wider practice of medicine. The US military has been exploring the role that genomic information will have in health care for service members (SMs) and its integration into the continuum of military medicine. An important part of the process is establishing robust protections to protect SMs from genetic discrimination in the era of exome/genome sequencing.
Genome-wide methylation analysis identifies genes silenced in non-seminoma cell lines
Authors: Noor Dzul Azri Mohamed , Jeyapalan Jennie N , Alhazmi Safiah , Carr Matthew , Squibb Benjamin , Wallace Claire , Tan Christopher , Cusack Martin , Hughes Jaime , Reader Tom , Shipley Janet , Sheer Denise , Scotting Paul J
Published: January 2016

Silencing of genes by DNA methylation is a common phenomenon in many types of cancer. However, the genome-wide effect of DNA methylation on gene expression has been analysed in relatively few cancers. Germ cell tumours (GCTs) are a complex group of malignancies. They are unique in developing from a pluripotent progenitor cell. Previous analyses have suggested that non-seminomas exhibit much higher levels of DNA methylation than seminomas. The genomic targets that are methylated, the extent to which this results in gene silencing and the identity of the silenced genes most likely to play a role in the tumours’ biology have not yet been established. In this study, genome-wide methylation and expression analysis of GCT cell lines was combined with gene expression data from primary tumours to address this question. Genome methylation was analysed using the Illumina infinium HumanMethylome450 bead chip system and gene expression was analysed using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Regulation by methylation was confirmed by demethylation using 5-aza-2-deoxycytidine and reverse transcription–quantitative PCR. Large differences in the level of methylation of the CpG islands of individual genes between tumour cell lines correlated well with differential gene expression. Treatment of non-seminoma cells with 5-aza-2-deoxycytidine verified that methylation of all genes tested played a role in their silencing in yolk sac tumour cells and many of these genes were also differentially expressed in primary tumours. Genes silenced by methylation in the various GCT cell lines were identified. Several pluripotency-associated genes were identified as a major functional group of silenced genes.
Fatigue in Parkinson’s disease: report from a multidisciplinary symposium
Authors: Friedman Joseph H , Beck James C , Chou Kelvin L , Clark Gracia , Fagundes Christopher P , Goetz Christopher G , Herlofson Karen , Kluger Benzi , Krupp Lauren B , Lang Anthony E , Lou Jao-Shin , Marsh Laura , Newbould Anne , Weintraub Daniel
Published: January 2016

Fatigue is a severe problem for many people living with Parkinson’s disease (PD). Best estimates suggest that more than 50% of patients experience this debilitating symptom. Little is known about its etiology or treatment, making the understanding of fatigue a true unmet need. As part of the Parkinson’s Disease Foundation Community Choice Research Program, patients, caregivers, and scientists attended a symposium on fatigue on 16 and 17 October 2014. We present a summary of that meeting, reviewing what is known about the diagnosis and treatment of fatigue, its physiology, and what we might learn from multiple sclerosis (MS), depression, and cancer—disorders in which fatigue figures prominently too. We conclude with focused recommendations to enhance our understanding and treatment of this prominent problem in PD.
Different PD-MCI criteria and risk of dementia in Parkinson’s disease: 4-year longitudinal study
Authors: Wood Kyla-Louise , Myall Daniel J , Livingston Leslie , Melzer Tracy R , Pitcher Toni L , MacAskill Michael R , Geurtsen Gert J , Anderson Tim J , Dalrymple-Alford John C
Published: January 2016

The Movement Disorder Society Task Force (MDS-TF) has proposed diagnostic criteria for mild cognitive impairment in Parkinson’s disease (PD-MCI). We hypothesized that the risk of dementia (PDD) varies across the different cutoff schemes allowed. A longitudinal study followed 121 non-demented PD patients for up to 4.5 years. In Part One, unique groups of patients were identified as PD-MCI at baseline using the MDS-TF requirement of two impaired cognitive test scores, with both scores classified as impaired at either (i) 2 s.d., (ii) 1.5 s.d. or (iii) 1 s.d. below normative data; relative risk (RR) of PDD was assessed at each criterion. In Part Two, the whole sample was reassessed and (i) RR of PDD determined when two impairments at 1.5 s.d. existed within a single cognitive domain, followed by (ii) RR of PDD in the unique group whose two impairments at 1.5 s.d. did not exist within a single domain (i.e., only across two domains). Twenty-one percent of patients converted to PDD. Part One showed that the 1.5 s.d. criterion at baseline is optimal to maximize progression to PDD over 4 years. Part Two, however, showed that the 1.5 s.d. cutoff produced a high RR of PDD only when two impairments were identified within a single cognitive domain (7.2, 95% confidence interval (CI)=3.4–16.6, P<0.0001; 51% converted). The RR when the 1.5 s.d. impairments occurred only across two different domains, was nonsignificant (1.7, CI=0.5–7.4, P=0.13; 11% converted) and similar to using a 1 s.d. criterion (1.9, CI=0.3–4.3, P=0.13; 8% converted). If the intent of a PD-MCI diagnosis is to detect increased risk of PDD in the next 4 years, optimal criteria should identify at least two impairments at 1.5 s.d. within a single cognitive domain.
The Mesoscopic Electrochemistry of Molecular Junctions
Authors: Bueno Paulo R. , Benites Tiago A. , Davis Jason J.
Published: January 2016

Within the context of an electron dynamic (time-dependent) perspective and a voltage driving force acting to redistribute electrons between metallic and addressable molecular states, we define here the associated electron admittance and conductance. We specifically present a mesoscopic approach to resolving the electron transfer rate associated with the electrochemistry of a redox active film tethered to metallic leads and immersed in electrolyte. The methodology is centred on aligning the lifetime of the process of electron exchange with associated resistance and capacitance quantities. Notably, however, these are no longer those empirically known as charge transfer resistance and pseudo-capacitance, but are those derived instead from a consideration of the quantum states contained in molecular films and their accessibility through a scattering region existing between them and the metallic probe. The averaged lifetime (τr) associated with the redox site occupancy is specifically dependent on scattering associated with the quantum channels linking them to the underlying metallic continuum and associated with both a quantum resistance (Rq) and an electrochemical (redox) capacitance (Cr). These are related to electron transfer rate throughk = 1/τr = (RqCr)−1. The proposed mesoscopic approach is consistent with Marcus’s (electron transfer rate) theory and experimental measurements obtained by capacitance spectroscopy.
Prevalence and care index of early childhood caries in mainland China: evidence from epidemiological surveys during 1987–2013
Authors: Zhang Xiaonan , Yang Sheng , Liao Zhaoying , Xu Ling , Li Conghua , Zeng Huan , Song Jinlin , Zhang Lei
Published: January 2016

Early childhood caries (ECC) is the most common chronic disease in young children. Its reported prevalence varies greatly across China. This systematic review aimed to explore the epidemiological characteristics of ECC in mainland China from 1987 to 2013. In total, 102 articles were included. The pooled national prevalence and care index (ft/dmft%) for ECC were 65.5% and 3.6%, respectively. The overall ECC prevalence declined from 77.9% during 1987–1994 to 56.4% during 2010–2013. The pooled ECC prevalence for children aged 1–6 years was 0.3%, 17.3%, 40.2%, 54.4%, 66.1% and 70.7%, respectively. There was no significant difference in prevalence between boys (59.1%) and girls (58.9%); and the care index was also similar (8.1% versus 7.7%). Slightly higher ECC prevalence was observed in rural areas (63.5%) compared with urban areas (59.5%) (RR = 1.08, 95% CI: 1.02–1.14); but a much higher care index was reported in urban children (6.0%) than their rural counterparts (1.6%) (RR = 3.68, 95% CI: 2.54–5.35). The 2006–2013 map of ECC prevalence among 5-year-olds showed wide geographic variations across China. Four adjacent provinces, including Sichuan, Chongqing, Hubei and Shaanxi, constituted the areas with the lowest ECC prevalence in mainland China.
Scalable topographies to support proliferation and Oct4 expression by human induced pluripotent stem cells
Authors: Reimer Andreas , Vasilevich Aliaksei , Hulshof Frits , Viswanathan Priyalakshmi , van Blitterswijk Clemens A. , de Boer Jan , Watt Fiona M.
Published: January 2016

It is well established that topographical features modulate cell behaviour, including cell morphology, proliferation and differentiation. To define the effects of topography on human induced pluripotent stem cells (iPSC), we plated cells on a topographical library containing over 1000 different features in medium lacking animal products (xeno-free). Using high content imaging, we determined the effect of each topography on cell proliferation and expression of the pluripotency marker Oct4 24 h after seeding. Features that maintained Oct4 expression also supported proliferation and cell-cell adhesion at 24 h and by 4 days colonies of Oct4-positive, Sox2-positive cells had formed. Computational analysis revealed that small feature size was the most important determinant of pluripotency, followed by high wave number and high feature density. Using this information we correctly predicted whether any given topography within our library would support the pluripotent state at 24 h. This approach not only facilitates the design of substrates for optimal human iPSC expansion, but also, potentially, identification of topographies with other desirable characteristics, such as promoting differentiation.
Vitamin D status predicts reproductive fitness in a wild sheep population
Authors: Handel Ian , Watt Kathryn A. , Pilkington Jill G. , Pemberton Josephine M. , Macrae Alastair , Scott Philip , McNeilly Tom N. , Berry Jacqueline L. , Clements Dylan N. , Nussey Daniel H. , Mellanby Richard J.
Published: January 2016

Vitamin D deficiency has been associated with the development of many human diseases and with poor reproductive performance in laboratory rodents. We currently have no idea how natural selection directly acts on variation in vitamin D metabolism due to a total lack of studies in wild animals. Here, we measured serum 25 hydroxyvitamin D (25(OH)D) concentrations in female Soay sheep that were part of a long-term field study on St Kilda. We found that total 25(OH)D was strongly influenced by age and that light coloured sheep had higher 25(OH)D3 (but not 25(OH)D2) concentrations than dark sheep. The coat colour polymorphism in Soay sheep is controlled by a single locus, suggesting vitamin D status is heritable in this population. We also observed a very strong relationship between total 25(OH)D concentrations in summer and a ewe’s fecundity the following spring. This resulted in a positive association between total 25(OH)D and the number of lambs produced that survived their first year of life, an important component of female reproductive fitness. Our study provides the first insight into naturally-occurring variation in vitamin D metabolites and offers the first evidence that vitamin D status is both heritable and under natural selection in the wild.
Large molecular systems landscape uncovers T cell trapping in human skin cancer
Authors: Hillert Reyk , Gieseler Anne , Krusche Andreas , Humme Daniel , Röwert-Huber Hans-Joachim , Sterry Wolfram , Walden Peter , Schubert Walter
Published: January 2016

Immune surveillance of tumour cells is an important function of CD8 T lymphocytes, which has failed in cancer for reasons still unknown in many respect but mainly related to cellular processes in the tumour microenvironment. Applying imaging cycler microscopy to analyse the immune contexture in a human skin cancer we could identify and map 7,000 distinct cell surface-associated multi-protein assemblies. The resulting combinatorial geometry-based high-functional resolution led to discovery of a mechanism of T cell trapping in the epidermis, which involves SPIKE, a network of suprabasal keratinocyte projections piercing and interconnecting CD8 T cells. It appears initiated by clusters of infrabasal T and dendritic cells connected via cell projections across a fractured basal lamina to suprabasal keratinocytes and T lymphocytes.
Temperature based Restricted Boltzmann Machines
Authors: Li Guoqi , Deng Lei , Xu Yi , Wen Changyun , Wang Wei , Pei Jing , Shi Luping
Published: January 2016

Restricted Boltzmann machines (RBMs), which apply graphical models to learning probability distribution over a set of inputs, have attracted much attention recently since being proposed as building blocks of multi-layer learning systems called deep belief networks (DBNs). Note that temperature is a key factor of the Boltzmann distribution that RBMs originate from. However, none of existing schemes have considered the impact of temperature in the graphical model of DBNs. In this work, we propose temperature based restricted Boltzmann machines (TRBMs) which reveals that temperature is an essential parameter controlling the selectivity of the firing neurons in the hidden layers. We theoretically prove that the effect of temperature can be adjusted by setting the parameter of the sharpness of the logistic function in the proposed TRBMs. The performance of RBMs can be improved by adjusting the temperature parameter of TRBMs. This work provides a comprehensive insights into the deep belief networks and deep learning architectures from a physical point of view.
Parathyroidectomy Associates with Reduced Mortality in Taiwanese Dialysis Patients with Hyperparathyroidism: Evidence for the Controversy of Current Guidelines
Authors: Ho Li-Chun , Hung Shih-Yuan , Wang Hsi-Hao , Kuo Te-Hui , Chang Yu-Tzu , Tseng Chin-Chung , Wu Jia-Ling , Li Chung-Yi , Wang Jung-Der , Tsai Yau-Sheng , Sung Junne-Ming ,   Tainan RENal Disease Study (TRENDS) group, Sung Junne-Ming , Wang Jung-Der , Li Chung-Yi , Tseng Chin-Chung , Chang Yu-Tzu , Kuo Te-Hui , Wang Hsi-Hao , Ho Li-Chun , Wu Jia-Ling , Hsieh Chih-Cheng , Yen Miao-Fen , Wu Hung-Lien , Chen Ping-Yu , Li Wen-Huang , Chang Wei-Ting
Published: January 2016

Parathyroidectomy is recommended by the clinical guidelines for dialysis patients with unremitting secondary hyperparathyroidism (SHPT). However, the survival advantage of parathyroidectomy is debated because of the selection bias in previous studies. To minimize potential bias in the present nationwide cohort study, we enrolled only dialysis patients who had undergone radionuclide parathyroid scanning to ensure all patients had severe SHPT. The parathyroidectomized patients were matched with the controls based on propensity score for parathyroidectomy. Mortality hazard was estimated using multivariate Cox proportional hazard models adjusting for comorbidities before scanning (model 1) or over the whole study period (model 2). Our results showed that among the 2786 enrolled patients, 1707 underwent parathyroidectomy and the other 1079 were controls. The crude mortality rates were lower in the parathyroidectomized patients than in the controls. In adjusted analyses for the population matched on propensity score, parathyroidectomy was associated with a significant 20% to 25% lower risk for all-cause mortality (model 1: hazard ratio 0.76, 95% confidence interval 0.61 to 0.94; model 2: hazard ratio 0.80, 95% confidence internal 0.64 to 0.98). We concluded that parathyroidectomy was associated with a reduced long-term mortality risk in dialysis patients with severe SHPT.
Genetic affinities of the Jewish populations of India
Authors: Chaubey Gyaneshwer , Singh Manvendra , Rai Niraj , Kariappa Mini , Singh Kamayani , Singh Ashish , Pratap Singh Deepankar , Tamang Rakesh , Selvi Rani Deepa , Reddy Alla G. , Kumar Singh Vijay , Singh Lalji , Thangaraj Kumarasamy
Published: January 2016

Due to the lack of written records or inscription, the origin and affiliation of Indian Jewish populations with other world populations remain contentious. Previous genetic studies have found evidence for a minor shared ancestry of Indian Jewish with Middle Eastern (Jewish) populations. However, these studies (relied on limited individuals), haven’t explored the detailed temporal and spatial admixture process of Indian Jewish populations with the local Indian populations. Here, using large sample size with combination of high resolution biparental (autosomal) and uniparental markers (Y chromosome and mitochondrial DNA), we reconstructed genetic history of Indian Jewish by investigating the patterns of genetic diversity. Consistent with the previous observations, we detected minor Middle Eastern specific ancestry component among Indian Jewish communities, but virtually negligible in their local neighbouring Indian populations. The temporal test of admixture suggested that the first admixture of migrant Jewish populations from Middle East to South India (Cochin) occurred during fifth century. Overall, we concluded that the Jewish migration and admixture in India left a record in their genomes, which can link them to the ‘Jewish Diaspora’.
Support for the Microgenderome: Associations in a Human Clinical Population
Authors: Wallis Amy , Butt Henry , Ball Michelle , Lewis Donald P. , Bruck Dorothy
Published: January 2016

The ‘microgenderome’ provides a paradigm shift that highlights the role of sex differences in the host-microbiota interaction relevant for autoimmune and neuro-immune conditions. Analysis of cross-sectional self-report and faecal microbial data from 274 patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) suggests that commensal gut microorganisms may play both protective and deleterious roles in symptom expression. Results revealed significant sex-specific interactions between Firmicutes (Clostridium, Streptococcus, Lactobacillus and Enterococcus) and ME/CFS symptoms (including neurological, immune and mood symptoms), regardless of compositional similarity in microbial levels across the sexes. Extending animal studies, we provide support for the microgenderome in a human clinical population. Applied and mechanistic research needs to consider sex-interactions when examining the composition and function of human microbiota.
α-Synuclein and huntingtin exon 1 amyloid fibrils bind laterally to the cellular membrane
Authors: Monsellier Elodie , Bousset Luc , Melki Ronald
Published: January 2016

Fibrillar aggregates involved in neurodegenerative diseases have the ability to spread from one cell to another in a prion-like manner. The underlying molecular mechanisms, in particular the binding mode of the fibrils to cell membranes, are poorly understood. In this work we decipher the modality by which aggregates bind to the cellular membrane, one of the obligatory steps of the propagation cycle. By characterizing the binding properties of aggregates made of α-synuclein or huntingtin exon 1 protein displaying similar composition and structure but different lengths to mammalian cells we demonstrate that in both cases aggregates bind laterally to the cellular membrane, with aggregates extremities displaying little or no role in membrane binding. Lateral binding to artificial liposomes was also observed by transmission electron microscopy. In addition we show that although α-synuclein and huntingtin exon 1 fibrils bind both laterally to the cellular membrane, their mechanisms of interaction differ. Our findings have important implications for the development of future therapeutic tools that aim to block protein aggregates propagation in the brain.
Long-distance continuous-variable quantum key distribution by controlling excess noise
Authors: Huang Duan , Huang Peng , Lin Dakai , Zeng Guihua
Published: January 2016

Quantum cryptography founded on the laws of physics could revolutionize the way in which communication information is protected. Significant progresses in long-distance quantum key distribution based on discrete variables have led to the secure quantum communication in real-world conditions being available. However, the alternative approach implemented with continuous variables has not yet reached the secure distance beyond 100 km. Here, we overcome the previous range limitation by controlling system excess noise and report such a long distance continuous-variable quantum key distribution experiment. Our result paves the road to the large-scale secure quantum communication with continuous variables and serves as a stepping stone in the quest for quantum network.
Evaluating and excluding swap errors in analogue tests of working memory
Authors: Bays Paul M
Published: January 2016

When observers retrieve simple visual features from working memory, two kinds of error are typically confounded in their recall. First, responses reflect noise or variability within the feature dimension they were asked to report. Second, responses are corrupted by “swap errors”, in which a different item from the memory set is reported in place of the one that was probed. Independent evaluation of these error sources is vital for understanding the structure of internal representations and their binding. However, previous methods for disentangling these errors have been critically dependent on assumptions about the noise distribution, which is a priori unknown. Here I address this question with novel non-parametric (NP) methods, which estimate swap frequency and feature variability with fewer prior assumptions and without a fitting procedure. The results suggest that swap errors are considerably more prevalent than previously appreciated (accounting for more than a third of responses at set size 8). These methods also identify which items are swapped in for targets: when the target item is cued by location, the items in closest spatial proximity are most likely to be incorrectly reported, thus implicating noise in the probe feature dimension as a source of swap errors.
Polysaccharide-based Noncovalent Assembly for Targeted Delivery of Taxol
Authors: Yang Yang , Zhang Ying-Ming , Chen Yong , Chen Jia-Tong , Liu Yu
Published: January 2016

The construction of synthetic straightforward, biocompatible and biodegradable targeted drug delivery system with fluorescent tracking abilities, high anticancer activities and low side effects is still a challenge in the field of biochemistry and material chemistry. In this work, we constructed targeted paclitaxel (Taxol) delivery nanoparticles composed of permethyl-β-cyclodextrin modified hyaluronic acid (HApCD) and porphyrin modified paclitaxel prodrug (PorTaxol), through host-guest and amphiphilic interactions. The obtained nanoparticles (HATXP) were biocompatible and enzymatic biodegradable due to their hydrophilic hyaluronic acid (HA) shell and hydrophobic Taxol core and exhibited specific targeting internalization into cancer cells via HA receptor mediated endocytosis effects. The cytotoxicity experiments showed that the HATXP exhibited similar anticancer activities to, but much lower side effects than commercial anticancer drug Taxol. The present work would provide a platform for targeted paclitaxel drug delivery and a general protocol for the design of advanced multifunctional nanoscale biomaterials for targeted drug/gene delivery.
FAS rs2234767 and rs1800682 polymorphisms jointly contributed to risk of colorectal cancer by affecting SP1/STAT1 complex recruitment to chromatin
Authors: Wang Shizhi , Wu Shenshen , Meng Qingtao , Li Xiaobo , Zhang Jinchun , Chen Rui , Wang Meilin
Published: January 2016

FAS rs2234767 (−1377 G>A), rs1800682 (−670 A>G) and FASLG rs763110 (−844 C>T) promoter polymorphisms can influence transcriptional activities of the genes and thus multiple tumors susceptibility. To investigate their association with risk of colorectal cancer (CRC), the three SNPs were genotyped in 878 cases and 884 controls and the results showed that the FAS rs2234767 and rs1800682 were in a high linkage disequilibrium (LD) with each other (D’ = 0.994) and jointly contributed to an increased risk of CRC (without vs. with rs2234767 GG/rs1800682 AA genotypes, adjusted OR = 1.30, 95% CI = 1.05 − 1.61). In vivo ChIP assays evaluated the effect of rs2234767 and rs1800682 on recruitment of SP1 and STAT1, respectively, to chromatin. The results showed SP1 interacting specifically with STAT1 recruited to their respective motifs for transcriptional activation. The mutant alleles rs2234767 A and rs1800682 G jointly affected coupled SP1 and STAT1 recruitment to chromatin. The interplay between SP1 and STAT1 was critical for the functional outcome of rs2234767 and rs1800682 in view of their high LD. In conclusion, the FAS rs2234767 and rs1800682 polymorphisms were in high LD with each other and they jointly contributed to an increased risk of CRC by altering recruitment of SP1/STAT1 complex to the FAS promoter for transcriptional activation.
Interaction of RNA with a C-terminal fragment of the amyotrophic lateral sclerosis-associated TDP43 reduces cytotoxicity
Authors: Kitamura Akira , Nakayama Yusaku , Shibasaki Ai , Taki Ayami , Yuno Sachiko , Takeda Kayo , Yahara Masao , Tanabe Naoki , Kinjo Masataka
Published: January 2016

A hallmark of amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, is formation of inclusion bodies (IBs) from misfolded proteins in neuronal cells. TAR RNA/DNA-binding protein 43 kDa (TDP43) is an ALS-causative protein forming IBs in ALS patients. The relation between localization of the IBs and neurotoxicity remains largely unknown. We characterized aggregation of fluorescently tagged TDP43 and its carboxyl-terminal fragments (CTFs) by analytical fluorescence imaging techniques. Quantitative time-lapse analysis in individual live cells showed that fluorescent-protein-tagged TDP43 was cleaved and a 35 kDa TDP43 CTF (TDP35) formed ubiquitin (Ub)-negative cytoplasmic IBs. Although TDP35 formed mildly toxic Ub-negative IBs in the cytoplasm, TDP25, another type of a TDP43 CTF, efficiently formed sufficiently toxic Ub-positive IBs. One- or two-color fluorescence correlation spectroscopy (FCS/FCCS) revealed that coaggregation of TDP25 with TDP43 was initiated by depletion of the RNA that binds to TDP25. Moreover, nuclear localization tagging TDP25 reduced the rate of neuronal cell death. These observations point to the need to elucidate the novel sequestration mechanism and details of the toxicity of the misfolded and aggregation-prone TDP43 CTFs (as well as the RNA binding and nuclear retention) in order to identify possible preventive interventions against ALS.
Pterisolic Acid B is a Nrf2 Activator by Targeting C171 within Keap1-BTB Domain
Authors: Dong Ting , Liu Weilong , Shen Zhirong , Li Lin , Chen She , Lei Xiaoguang
Published: January 2016

The use of chemoprotective agents to minimize the side effects of the chemotherapy, primarily via activation of the Nrf2 pathway, is an emerging research field, which has attracted broad attention from both academia and pharmaceutical industry. Through high-throughput chemical screens we have disclosed that pterisolic acid B (J19), a naturally occuring diterpenoid, is an effective Nrf2 activator. We have also identified a more potent natural product analogue J19-1 by semisynthesis and the subsequent biochemical evaluations revealed that J19-1 activates the Nrf2 pathway by covalently modifying Cys171 of keap1, which inhibits Nrf2 degradation mediated by Keap1-Cul3 complexes. Ultimately, we have demonstrated that J19-1 shows significant cytoprotective effect against cisplatin-induced cytotoxicity in HKC cells.
Single-crystalline ZnO sheet Source-Gated Transistors
Authors: Dahiya A. S. , Opoku C. , Sporea R. A. , Sarvankumar B. , Poulin-Vittrant G. , Cayrel F. , Camara N. , Alquier D.
Published: January 2016

Due to their fabrication simplicity, fully compatible with low-cost large-area device assembly strategies, source-gated transistors (SGTs) have received significant research attention in the area of high-performance electronics over large area low-cost substrates. While usually based on either amorphous or polycrystalline silicon (α-Si and poly-Si, respectively) thin-film technologies, the present work demonstrate the assembly of SGTs based on single-crystalline ZnO sheet (ZS) with asymmetric ohmic drain and Schottky source contacts. Electrical transport studies of the fabricated devices show excellent field-effect transport behaviour with abrupt drain current saturation (IDSSAT) at low drain voltages well below 2 V, even at very large gate voltages. The performance of a ZS based SGT is compared with a similar device with ohmic source contacts. The ZS SGT is found to exhibit much higher intrinsic gain, comparable on/off ratio and low off currents in the sub-picoamp range. This approach of device assembly may form the technological basis for highly efficient low-power analog and digital electronics using ZnO and/or other semiconducting nanomaterial.
Analysis of a four generation family reveals the widespread sequence-dependent maintenance of allelic DNA methylation in somatic and germ cells
Authors: Tang Aifa , Huang Yi , Li Zesong , Wan Shengqing , Mou Lisha , Yin Guangliang , Li Ning , Xie Jun , Xia Yudong , Li Xianxin , Luo Liya , Zhang Junwen , Chen Shen , Wu Song , Sun Jihua , Sun Xiaojuan , Jiang Zhimao , Chen Jing , Li Yingrui , Wang Jian , Wang Jun , Cai Zhiming , Gui Yaoting
Published: January 2016

Differential methylation of the homologous chromosomes, a well-known mechanism leading to genomic imprinting and X-chromosome inactivation, is widely reported at the non-imprinted regions on autosomes. To evaluate the transgenerational DNA methylation patterns in human, we analyzed the DNA methylomes of somatic and germ cells in a four-generation family. We found that allelic asymmetry of DNA methylation was pervasive at the non-imprinted loci and was likely regulated by cis-acting genetic variants. We also observed that the allelic methylation patterns for the vast majority of the cis-regulated loci were shared between the somatic and germ cells from the same individual. These results demonstrated the interaction between genetic and epigenetic variations and suggested the possibility of widespread sequence-dependent transmission of DNA methylation during spermatogenesis.
Psmir: a database of potential associations between small molecules and miRNAs
Authors: Meng Fanlin , Wang Jing , Dai Enyu , Yang Feng , Chen Xiaowen , Wang Shuyuan , Yu Xuexin , Liu Dianming , Jiang Wei
Published: January 2016

miRNAs are key post-transcriptional regulators of many essential biological processes and their dysregulation has been validated in almost all human cancers. Restoring aberrantly expressed miRNAs might be a novel therapeutics. Recently, many studies have demonstrated that small molecular compounds can affect miRNA expression. Thus, prediction of associations between small molecules and miRNAs is important for investigation of miRNA-targeted drugs. Here, we analyzed 39 miRNA-perturbed gene expression profiles and then calculated the similarity of transcription responses between miRNA perturbation and drug treatment to predict drug-miRNA associations. At the significance level of 0.05, we obtained 6501 candidate associations between 1295 small molecules and 25 miRNAs, which included 624 FDA approved drugs. Finally, we constructed the Psmir database to store all potential associations and the related materials. In a word, Psmir served as a valuable resource for dissecting the biological significance in small molecules’ effects on miRNA expression, which will facilitate developing novel potential therapeutic targets or treatments for human cancers. Psmir is supported by all major browsers and is freely available at http://www.bio-bigdata.com/Psmir/.
A True Metasurface Antenna
Authors: Badawe Mohamed El , Almoneef Thamer S. , Ramahi Omar M.
Published: January 2016

We present a true metasurface antenna based on electrically-small resonators. The resonators are placed on a flat surface and connected to one feed point using corporate feed. Unlike conventional array antennas where the distance between adjacent antennas is half wavelength to reduce mutual coupling between adjacent antennas, here the distance between the radiating elements is electrically very small to affect good impedance matching of each resonator to its feed. A metasurface antenna measuring 1.2λ × 1.2λ and designed to operate at 3 GHz achieved a gain of 12 dBi. A prototype was fabricated and tested showing good agreement between numerical simulations and experimental results. Through numerical simulation, we show that the metasurface antenna has the ability to provide beam steering by phasing all the resonators appropriately.
Uncoupling shear and uniaxial elastic moduli of semiflexible biopolymer networks: compression-softening and stretch-stiffening
Authors: van Oosten Anne S. G. , Vahabi Mahsa , Licup Albert J. , Sharma Abhinav , Galie Peter A. , MacKintosh Fred C. , Janmey Paul A.
Published: January 2016

Gels formed by semiflexible filaments such as most biopolymers exhibit non-linear behavior in their response to shear deformation, e.g., with a pronounced strain stiffening and negative normal stress. These negative normal stresses suggest that networks would collapse axially when subject to shear stress. This coupling of axial and shear deformations can have particularly important consequences for extracellular matrices and collagenous tissues. Although measurements of uniaxial moduli have been made on biopolymer gels, these have not directly been related to the shear response. Here, we report measurements and simulations of axial and shear stresses exerted by a range of hydrogels subjected to simultaneous uniaxial and shear strains. These studies show that, in contrast to volume-conserving linearly elastic hydrogels, the Young’s moduli of networks formed by the biopolymers are not proportional to their shear moduli and both shear and uniaxial moduli are strongly affected by even modest degrees of uniaxial strain.
Synthesis, optical properties and helical self-assembly of a bivaline-containing tetraphenylethene
Authors: Li Hongkun , Zheng Xiaoyan , Su Huimin , Lam Jacky W. Y. , Sing Wong Kam , Xue Shan , Huang Xuejiao , Huang Xuhui , Li Bing Shi , Tang Ben Zhong
Published: January 2016

A chiral tetraphenylethene derivative with two valine-containing attachments (TPE-DVAL), was synthesized by Cu(I)-catalyzed azide-alkyne “click” reaction. The optical properties and self-assembling behaviours of TPE-DVAL were investigated. The molecule is non-emissive and circular dichroism (CD)-silent in solution, but shows strong fluorescence and Cotton effects in the aggregation state, demonstrating aggregation-induced emission (AIE) and CD (AICD) characteristics. TPE-DVAL exhibits good circularly polarized luminescence (CPL) when depositing on the surface of quartz to allow the evaporation of its 1,2-dichloroethane solution. SEM and TEM images of the molecule show that the molecule readily self-assembles into right-handed helical nanofibers upon the evaporation of its solvent of DCE. The molecular alignments and interactions in assembling process are further explored through XRD analysis and computational simulation. The driving forces for the formation of the helical fibers were from the cooperative effects of intermolecular hydrogen bonding, π-π interactions and steric effect.
Direct comparison of shot-to-shot noise performance of all normal dispersion and anomalous dispersion supercontinuum pumped with sub-picosecond pulse fiber-based laser
Authors: Klimczak Mariusz , Soboń Grzegorz , Kasztelanic Rafał , Abramski Krzysztof M. , Buczyński Ryszard
Published: January 2016

Coherence of supercontinuum sources is critical for applications involving characterization of ultrafast or rarely occurring phenomena. With the demonstrated spectral coverage of supercontinuum extending from near-infrared to over 10 μm in a single nonlinear fiber, there has been a clear push for the bandwidth rather than for attempting to optimize the dynamic properties of the generated spectrum. In this work we provide an experimental assessment of the shot-to-shot noise performance of supercontinuum generation in two types of soft glass photonic crystal fibers. Phase coherence and intensity fluctuations are compared for the cases of an anomalous dispersion-pumped fiber and an all-normal dispersion fiber. With the use of the dispersive Fourier transformation method, we demonstrate that a factor of 100 improvement in signal-to-noise ratio is achieved in the normal-dispersion over anomalous dispersion-pumped fiber for 390 fs long pump pulses. A double-clad design of the photonic lattice of the fiber is further postulated to enable a pump-related seeding mechanism of normal-dispersion supercontinuum broadening under sub-picosecond pumping, which is otherwise known for similar noise characteristics as modulation instability driven, soliton-based spectra.
Remote and reversible inhibition of neurons and circuits by small molecule induced potassium channel stabilization
Authors: Auffenberg Eva , Jurik Angela , Mattusch Corinna , Stoffel Rainer , Genewsky Andreas , Namendorf Christian , Schmid Roland M. , Rammes Gerhard , Biel Martin , Uhr Manfred , Moosmang Sven , Michalakis Stylianos , Wotjak Carsten T. , Thoeringer Christoph K.
Published: January 2016

Manipulating the function of neurons and circuits that translate electrical and chemical signals into behavior represents a major challenges in neuroscience. In addition to optogenetic methods using light-activatable channels, pharmacogenetic methods with ligand induced modulation of cell signaling and excitability have been developed. However, they are largely based on ectopic expression of exogenous or chimera proteins. Now, we describe the remote and reversible expression of a Kir2.1 type potassium channel using the chemogenetic technique of small molecule induced protein stabilization. Based on shield1-mediated shedding of a destabilizing domain fused to a protein of interest and inhibition of protein degradation, this principle has been adopted for biomedicine, but not in neuroscience so far. Here, we apply this chemogenetic approach in brain research for the first time in order to control a potassium channel in a remote and reversible manner. We could show that shield1-mediated ectopic Kir2.1 stabilization induces neuronal silencing in vitro and in vivo in the mouse brain. We also validated this novel pharmacogenetic method in different neurobehavioral paradigms.The DD-Kir2.1 may complement the existing portfolio of pharmaco- and optogenetic techniques for specific neuron manipulation, but it may also provide an example for future applications of this principle in neuroscience research.
Productive Entry of Foot-and-Mouth Disease Virus via Macropinocytosis Independent of Phosphatidylinositol 3-Kinase
Authors: Han Shi-Chong , Guo Hui-Chen , Sun Shi-Qi , Jin Ye , Wei Yan-Quan , Feng Xia , Yao Xue-Ping , Cao Sui-Zhong , Xiang Liu Ding , Liu Xiang-Tao
Published: January 2016

Virus entry is an attractive target for therapeutic intervention. Here, using a combination of electron microscopy, immunofluorescence assay, siRNA interference, specific pharmacological inhibitors and dominant negative mutation, we demonstrated that the entry of foot-and-mouth disease virus (FMDV) triggered a substantial amount of plasma membrane ruffling. We also found that the internalization of FMDV induced a robust increase in fluid-phase uptake and virions internalized within macropinosomes colocalized with phase uptake marker dextran. During this stage, the Rac1-Pak1 signaling pathway was activated. After specific inhibition on actin, Na+/H+ exchanger, receptor tyrosine kinase, Rac1, Pak1, myosin II and protein kinase C, the entry and infection of FMDV significantly decreased. However, inhibition of phosphatidylinositol 3-kinase (PI3K) did not reduce FMDV internalization but increased the viral entry and infection to a certain extent, implying that FMDV entry did not require PI3K activity. Results showed that internalization of FMDV exhibited the main hallmarks of macropinocytosis. Moreover, intracellular trafficking of FMDV involves EEA1/Rab5-positive vesicles. The present study demonstrated macropinocytosis as another endocytic pathway apart from the clathrin-mediated pathway. The findings greatly expand our understanding of the molecular mechanisms of FMDV entry into cells, as well as provide potential insights into the entry mechanisms of other picornaviruses.