A search for the natural host of Nipah virus has led to the isolation of a previously unknown member of the family Paramyxoviridae. Tioman virus (TiV) was isolated from the urine of fruit bats (Pteropus hypomelanus) found on the island of the same name off the eastern coast of peninsular Malaysia. An electron microscopic study of TiV-infected cells revealed spherical and pleomorphic-enveloped viral particles (100--500 nm in size) with a single fringe of embedded peplomers. Virus morphogenesis occurred at the plasma membrane of infected cells and morphological features of negative-stained ribonucleoprotein complexes were compatible with that of viruses in the family Paramyxoviridae. Serological studies revealed no cross-reactivity with antibodies against a number of known Paramyxoviridae members except for the newly described Menangle virus (MenV), isolated in Australia in 1997. Failure of PCR amplification using MenV-specific primers suggested that this new virus is related to but different from MenV. For molecular characterization of the virus, a cDNA subtraction strategy was employed to isolate virus-specific cDNA from virus-infected cells. Complete gene sequences for the nucleocapsid protein (N) and phosphoprotein (P/V) have been determined and recombinant N and V proteins produced in baculovirus. The recombinant N and V proteins reacted with porcine anti-MenV sera in Western blot, confirming the serological cross-reactivity observed during initial virus characterization. The lack of a C protein-coding region in the P/V gene, the creation of P mRNA by insertion of 2-G residues, and the results of phylogenetic analyses all indicated that TiV is a novel member of the genus Rubulavirus.
Deoxyribonucleic acid (DNA) emerges as building bricks for the fabrication of nanostructure with complete artificial architecture and geometry. The amazing ability of DNA in building two- and three-dimensional structures raises the possibility of developing smart nanomachines with versatile controllability for various applications. Here, we overviewed the recent progresses in engineering DNA machines for specific bioengineering and biomedical applications.
Objective: Esophageal squamous cell carcinoma (ESCC) is one of the most commonly diagnosed cancer types in China. Recent genomic sequencing analysis indicated the over-activation of Hippo/YAP signaling might play important roles for the carcinogenic process and progression for ESCC patients. However, little is known about the molecular mechanisms that controls Hippo signaling activity in ESCC. Our previous studies indicated that PLCE1-an important risk factor for ESCC-linked to ESCC progression through snail signaling, during this period, we found PARK2 was an important downstream target of PLCE1-snail axis. PARK2 was decreased in ESCC human samples, and correlated with good prognosis in ESCC patients. Further research showed that PARK2 could inhibit YAP, which functions as key downstream effectors of the Hippo pathway. Here, we aim to reveal the molecular mechanisms of PARK2 modulated Hippo pathway in ESCC. Methods: To evaluate the function of PARK2 in ESCC, we used a tissue microarray (TMA) of 223 human ESCC patients and immunohistochemistry to analyze the correlation between PARK2 expression and clinicopathologic variables. Depletion of endogenous PARK2 and YAP from ESCC cells using CRISPR/Cas9 technologies. Flow cytometry and EdU cell proliferation assay were used to detect proliferation of ESCC cells. Nude mice subcutaneous injection and Ki-67 staining were used to evaluate tumor growth in vivo. Migration and invasion assays were performed. In addition, lung metastasis models in mice were used to validate the function of PARK2 in vivo. Identification of PARK2 involved in hippo pathway was achieved by expression microarray screening, double immunofluorescence staining and co-immunoprecipitation assays. The RNA-seq analysis results were validated through quantitative real-time PCR (qRT-PCR) analysis. The protein half-life of YAP was analyzed by Cycloheximide assay, and the TEAD activity was detected by Luciferase reporter assays. Results: Clinical sample of ESCC revealed that low PARK2 expression correlated with late tumor stage (P < 0.001), poor differentiation (P < 0.04), lymph node (P < 0.001) and distant metastasis (P = 0.0087). Multivariate Cox proportional regression analysis further revealed that PARK2 expression (P = 0.032) is an independent prognostic factor for the overall survival of ESCC patients. Besides, the immunohistochemistry results showed that PARK2 negatively correlated with YAP protein level (P < 0.001). PARK2 depletion promotes ESCC progression both through Hippo/YAP axis, while PARK2 overexpression suppresses ESCC tumor progression by Hippo signaling. Co-IP and ubiquitination assays revealed that PARK2 could interact with YAP in the cytosol and promotes YAP K48-linked ubiquitination at K90 sites. Conclusion: Clinical sample analysis and mechanistic study have validated PARK2 as a tumor suppressor for ESCC. Multivariate Cox proportional regression analysis further revealed that PARK2 is an independent prognostic factor for the overall survival of ESCC patients. Cellular and molecular mechanisms in this study showed that PARK2 associated with YAP protein in the cytosol, promoted YAP ubiquitination and proteasome-dependent degradation in ESCC cells. Therefore, as a novel modulator for Hippo signaling, modulation of PARK2 activity or gene expression level could be an appealing strategy to treat esophageal.
Previously studied candidate genes have failed to account for inter-individual variability of docetaxel and doxorubicin disposition and effects. We genotyped the transcriptional regulators of CYP3A and ABCB1 in 101 breast cancer patients from 3 Asian ethnic groups, that is, Chinese, Malays and Indians, in correlation with the pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin. While there was no ethnic difference in docetaxel and doxorubicin pharmacokinetics, ethnic difference in docetaxel- (ANOVA, P=0.001) and doxorubicin-induced (ANOVA, P=0.003) leukocyte suppression was observed, with Chinese and Indians experiencing greater degree of docetaxel-induced myelosuppression than Malays (Bonferroni, P=0.002, P=0.042), and Chinese experiencing greater degree of doxorubicin-induced myelosuppression than Malays and Indians (post hoc Bonferroni, P=0.024 and 0.025). Genotyping revealed both PXR and CAR to be well conserved; only a PXR 5'-untranslated region polymorphism (-24381A>C) and a silent CAR variant (Pro180Pro) were found at allele frequencies of 26 and 53%, respectively. Two non-synonymous variants were identified in HNF4alpha (Met49Val and Thr130Ile) at allele frequencies of 55 and 1%, respectively, with the Met49Val variant associated with slower neutrophil recovery in docetaxel-treated patients (ANOVA, P=0.046). Interactions were observed between HNF4alpha Met49Val and CAR Pro180Pro, with patients who were wild type for both variants experiencing least docetaxel-induced neutropenia (ANOVA, P=0.030). No other significant genotypic associations with pharmacokinetics or pharmacodynamics of either drug were found. The PXR-24381A>C variants were significantly more common in Indians compared to Chinese or Malays (32/18/21%, P=0.035) Inter-individual and inter-ethnic variations of docetaxel and doxorubicin pharmacokinetics or pharmacodynamics exist, but genotypic variability of the transcriptional regulators PAR, CAR and HNF4alpha cannot account for this variability.
Fluorene-9-bisphenol (BHPF) is a bisphenol A substitute, which has been introduced for the production of so-called 'bisphenol A (BPA)-free' plastics. However, it has been reported that BHPF can enter living organisms through using commercial plastic bottles and cause adverse effects. To date, the majority of the toxicologic study of BHPF focused on investigating its doses above the toxicological threshold. Here, we studied the effects of BHPF on development, locomotion, neuron differentiation of the central nervous system (CNS), and the expression of genes in the hypothalamic-pituitary-thyroid (HPT) axis in zebrafish exposed to different doses of BHPF ranging from 1/5 of LD1 to LD50 (300, 500, 750, 1500, 3000, and 4500 nM). As a result, the possible hormetic effects of BHPF on regulating the HPT axis were revealed, in which low-dose BHPF positively affected the HPT axis while this regulation was inhibited as the dose increased. Underlying mechanism investigation suggested that BHPF disrupted myelination through affecting HPT axis including related genes expression and TH levels, thus causing neurotoxic characteristics. Collectively, this study provides the full understanding of the environmental impact of BHPF and its toxicity on living organisms, highlighting a substantial and generalized ongoing dose-response relationship with great implications for the usage and risk assessment of BHPF.
Increasing trade cooperation under the Belt and Road (B&R) Initiative has promoted economic development and intensified the water scarcity risk transmission between China and countries along the route (B&R countries). Local water scarcity risk (LWSR, the potential direct production losses induced by local water scarcity) can transcend geographical boundaries through global supply chains and influence production activities in downstream economies. To understand the vulnerability of the Initiative to water scarcity, we investigated the impacts of LWSR in China and B&R countries on each other's economies during 2001-2013, using a global environmentally extended multi-regional input-output model. Results reveal that more than 80% of China's trade-related water scarcity risk imports (TWSR imports, the vulnerability to foreign water scarcity risk through imports) originates from B&R countries. The share of TWSR from China in total imports of B&R countries has steadily increased. In particular, India, Thailand, Iran, Pakistan and Kazakhstan have the largest TWSR exports (LWSR in each nation transmitted to other nations through its exports) to China, while South Korea, Thailand, Malaysia, Singapore and Indonesia have the largest imports from China. Water scarcity to their Agriculture sectors is responsible for TWSR transmission between them. Our study can contribute to the policy-making of governments and firms involved in mitigating the supply chain wide water scarcity risk. It also reveals the need for nations to collectively manage water resources to achieve sustainable development.
Tioman virus, a relatively new paramyxovirus, was isolated from fruit bats (Pteropus species) on Tioman Island, Malaysia, in 2001. The objective of this study was to determine the prevalence of antibodies to T. virus in island inhabitants, by use of comparative ELISA and serum neutralization assays. Of the 169 human sera analyzed, 5 (approximately 3.0%) were positive for T. virus, by comparative ELISA. Of these 5 sera, 3 (1.8% of the total) had neutralizing antibodies against T. virus, suggesting previous infection of this study population by this virus or a similar virus.
Hendra virus (HeV) and Nipah virus (NiV) are members of a new genus, Henipavirus, in the family paramyxoviridae. Each virus encodes a phosphoprotein (P) that is significantly larger than its counterparts in other known paramyxoviruses. The interaction of this unusually large P with its nucleocapsid protein (N) was investigated in this study by using recombinant full-length and truncated proteins expressed in bacteria and a modified protein-blotting protein-overlay assay. Results from our group demonstrated that the N and P of both viruses were able to form not only homologous, but also heterologous, N-P complexes, i.e. HeV N was able to interact with NiV P and vice versa. Deletion analysis of the N and P revealed that there were at least two independent N-binding sites on P and they resided at the N and C termini, respectively. Similarly, more than one P-binding site was present on N and one of these was mapped to a 29 amino acid (aa) C-terminal region, which on its own was sufficient to interact with the extreme C-terminal 165 aa region of P.
A search for supersymmetry is presented based on events with at least one photon, jets, and large missing transverse momentum produced in proton-proton collisions at a center-of-mass energy of 13
Te
. The data correspond to an integrated luminosity of 35.9
fb
- 1
and were recorded at the LHC with the CMS detector in 2016. The analysis characterizes signal-like events by categorizing the data into various signal regions based on the number of jets, the number of b -tagged jets, and the missing transverse momentum. No significant excess of events is observed with respect to the expectations from standard model processes. Limits are placed on the gluino and top squark pair production cross sections using several simplified models of supersymmetric particle production with gauge-mediated supersymmetry breaking. Depending on the model and the mass of the next-to-lightest supersymmetric particle, the production of gluinos with masses as large as 2120
Ge
and the production of top squarks with masses as large as 1230
A search is presented for the single production of vector-like quarks in proton-proton collisions at
s
= 13
TeV
. The data, corresponding to an integrated luminosity of 35.9
fb
- 1
, were recorded with the CMS experiment at the LHC. The analysis focuses on the vector-like quark decay into a top quark and a W boson, with one muon or electron in the final state. The mass of the vector-like quark candidate is reconstructed from hadronic jets, the lepton, and the missing transverse momentum. Methods for the identification of b quarks and of highly Lorentz boosted hadronically decaying top quarks and W bosons are exploited in this search. No significant deviation from the standard model background expectation is observed. Exclusion limits at 95% confidence level are set on the product of the production cross section and branching fraction as a function of the vector-like quark mass, which range from 0.3 to 0.03
pb
for vector-like quark masses of 700 to 2000
GeV
. Mass exclusion limits up to 1660
GeV
are obtained, depending on the vector-like quark type, coupling, and decay width. These represent the most stringent exclusion limits for the single production of vector-like quarks in this channel.
Measurements are presented of the triple-differential cross section for inclusive isolated-photon+jet events in
p p
collisions at
s
= 8
TeV as a function of photon transverse momentum (
p
T
γ
), photon pseudorapidity (
η
γ
), and jet pseudorapidity (
η jet
). The data correspond to an integrated luminosity of
19.7
fb
- 1
that probe a broad range of the available phase space, for
|
η
γ
| < 1.44
and
1.57 < |
η
γ
| < 2.50
,
|
η jet
| < 2.5
,
40 <
p
T
γ
< 1000
GeV
, and jet transverse momentum,
p
T
jet
, > 25
GeV
. The measurements are compared to next-to-leading order perturbative quantum chromodynamics calculations, which reproduce the data within uncertainties.
This paper presents new sets of parameters ("tunes") for the underlying-event model of the H E R W I G 7 event generator. These parameters control the description of multiple-parton interactions (MPI) and colour reconnection in H E R W I G 7 , and are obtained from a fit to minimum-bias data collected by the CMS experiment at s = 0.9 , 7, and 13 Te . The tunes are based on the NNPDF 3.1 next-to-next-to-leading-order parton distribution function (PDF) set for the parton shower, and either a leading-order or next-to-next-to-leading-order PDF set for the simulation of MPI and the beam remnants. Predictions utilizing the tunes are produced for event shape observables in electron-positron collisions, and for minimum-bias, inclusive jet, top quark pair, and Z and W boson events in proton-proton collisions, and are compared with data. Each of the new tunes describes the data at a reasonable level, and the tunes using a leading-order PDF for the simulation of MPI provide the best description of the data.
Results of the Model Unspecific Search in CMS (MUSiC), using proton-proton collision data recorded at the LHC at a centre-of-mass energy of 13 TeV , corresponding to an integrated luminosity of 35.9 fb - 1 , are presented. The MUSiC analysis searches for anomalies that could be signatures of physics beyond the standard model. The analysis is based on the comparison of observed data with the standard model prediction, as determined from simulation, in several hundred final states and multiple kinematic distributions. Events containing at least one electron or muon are classified based on their final state topology, and an automated search algorithm surveys the observed data for deviations from the prediction. The sensitivity of the search is validated using multiple methods. No significant deviations from the predictions have been observed. For a wide range of final state topologies, agreement is found between the data and the standard model simulation. This analysis complements dedicated search analyses by significantly expanding the range of final states covered using a model independent approach with the largest data set to date to probe phase space regions beyond the reach of previous general searches.
A combination of searches for top squark pair production using proton-proton collision data at a center-of-mass energy of 13 Te at the CERN LHC, corresponding to an integrated luminosity of 137 fb - 1 collected by the CMS experiment, is presented. Signatures with at least 2 jets and large missing transverse momentum are categorized into events with 0, 1, or 2 leptons. New results for regions of parameter space where the kinematical properties of top squark pair production and top quark pair production are very similar are presented. Depending on the model, the combined result excludes a top squark mass up to 1325 Ge for a massless neutralino, and a neutralino mass up to 700 Ge for a top squark mass of 1150 Ge . Top squarks with masses from 145 to 295 Ge , for neutralino masses from 0 to 100 Ge , with a mass difference between the top squark and the neutralino in a window of 30 Ge around the mass of the top quark, are excluded for the first time with CMS data. The results of theses searches are also interpreted in an alternative signal model of dark matter production via a spin-0 mediator in association with a top quark pair. Upper limits are set on the cross section for mediator particle masses of up to 420 Ge .
The measurement of the luminosity recorded by the CMS detector installed at LHC interaction point 5, using proton-proton collisions at s = 13 TeV in 2015 and 2016, is reported. The absolute luminosity scale is measured for individual bunch crossings using beam-separation scans (the van der Meer method), with a relative precision of 1.3 and 1.0% in 2015 and 2016, respectively. The dominant sources of uncertainty are related to residual differences between the measured beam positions and the ones provided by the operational settings of the LHC magnets, the factorizability of the proton bunch spatial density functions in the coordinates transverse to the beam direction, and the modeling of the effect of electromagnetic interactions among protons in the colliding bunches. When applying the van der Meer calibration to the entire run periods, the integrated luminosities when CMS was fully operational are 2.27 and 36.3 fb - 1 in 2015 and 2016, with a relative precision of 1.6 and 1.2%, respectively. These are among the most precise luminosity measurements at bunched-beam hadron colliders.
Collinear (small-angle) and large-angle, as well as soft and hard radiations are investigated in three-jet and Z + two-jet events collected in proton-proton collisions at the LHC. The normalized production cross sections are measured as a function of the ratio of transverse momenta of two jets and their angular separation. The measurements in the three-jet and Z + two-jet events are based on data collected at a center-of-mass energy of 8 TeV , corresponding to an integrated luminosity of 19.8 fb - 1 . The Z + two-jet events are reconstructed in the dimuon decay channel of the Z boson. The three-jet measurement is extended to include s = 13 TeV data corresponding to an integrated luminosity of 2.3 fb - 1 . The results are compared to predictions from event generators that include parton showers, multiple parton interactions, and hadronization. The collinear and soft regions are in general well described by parton showers, whereas the regions of large angular separation are often best described by calculations using higher-order matrix elements.
A measurement for inclusive 2- and 3-jet events of the azimuthal correlation between the two jets with the largest transverse momenta, Δ ϕ 12 , is presented. The measurement considers events where the two leading jets are nearly collinear ("back-to-back") in the transverse plane and is performed for several ranges of the leading jet transverse momentum. Proton-proton collision data collected with the CMS experiment at a center-of-mass energy of 13 Te and corresponding to an integrated luminosity of 35.9 fb - 1 are used. Predictions based on calculations using matrix elements at leading-order and next-to-leading-order accuracy in perturbative quantum chromodynamics supplemented with leading-log parton showers and hadronization are generally in agreement with the measurements. Discrepancies between the measurement and theoretical predictions are as large as 15%, mainly in the region 177 ∘ < Δ ϕ 12 < 180 ∘ . The 2- and 3-jet measurements are not simultaneously described by any of models.
A search is presented for a heavy pseudoscalar boson A decaying to a Z boson and a Higgs boson with mass of 125 GeV . In the final state considered, the Higgs boson decays to a bottom quark and antiquark, and the Z boson decays either into a pair of electrons, muons, or neutrinos. The analysis is performed using a data sample corresponding to an integrated luminosity of 35.9 fb - 1 collected in 2016 by the CMS experiment at the LHC from proton-proton collisions at a center-of-mass energy of 13 Te . The data are found to be consistent with the background expectations. Exclusion limits are set in the context of two-Higgs-doublet models in the A boson mass range between 225 and 1000 GeV .
A search for the pair production of heavy vector-like partners T and B of the top and bottom quarks has been performed by the CMS experiment at the CERN LHC using proton-proton collisions at s = 13 Te . The data sample was collected in 2016 and corresponds to an integrated luminosity of 35.9 fb - 1 . Final states studied for T T ¯ production include those where one of the T quarks decays via T → t Z and the other via T → b W , t Z , or t H , where H is a Higgs boson. For the B B ¯ case, final states include those where one of the B quarks decays via B → b Z and the other B → t W , b Z , or b H . Events with two oppositely charged electrons or muons, consistent with coming from the decay of a Z boson, and jets are investigated. The number of observed events is consistent with standard model background estimations. Lower limits at 95% confidence level are placed on the masses of the T and B quarks for a range of branching fractions. Assuming 100% branching fractions for T → t Z , and B → b Z , T and B quark mass values below 1280 and 1130 Ge , respectively, are excluded.
A top quark mass measurement is performed using 35.9 fb - 1 of LHC proton-proton collision data collected with the CMS detector at s = 13 TeV . The measurement uses the t t ¯ all-jets final state. A kinematic fit is performed to reconstruct the decay of the t t ¯ system and suppress the multijet background. Using the ideogram method, the top quark mass ( m t ) is determined, simultaneously constraining an additional jet energy scale factor ( JSF ). The resulting value of m t = 172.34 ± 0.20 (stat+JSF) ± 0.70 (syst) GeV is in good agreement with previous measurements. In addition, a combined measurement that uses the t t ¯ lepton+jets and all-jets final states is presented, using the same mass extraction method, and provides an m t measurement of 172.26 ± 0.07 (stat+JSF) ± 0.61 (syst) GeV . This is the first combined m t extraction from the lepton+jets and all-jets channels through a single likelihood function.