bluuebunny/crossref_metadata_2025 huggingface dataset:
Coupling of Estuarine Circulations in a Network of Fjords
Authors: Shan Shiliang , Hannah Charles G. , Wu Yongsheng
Published: September 2019

The Kitimat Fjord System in the northern British Columbia coast features a network of deep channels, islands, and shallow sills. In particular, the fresh water leaving Gardner Canal bifurcates at a triple junction: (1) north through a shallow sill (100‐m deep) to Devastation Channel and then out through Douglas Channel and (2) west along Verney Passage then passing over a shallow sill (35 m) to Wright Sound. The partitioning of the fresh water leaving Gardner Canal has substantial implications for interpreting estuarine circulation and water exchange of the system. In this study, the partitioning of the fresh water at the triple junction is quantified by using observations and a circulation model. The model is based on FVCOM with ~200‐m horizontal resolution in the narrow channels and forced by tides, winds, and river discharges. The remotely sensed freshwater plume, surface drifter trajectories, and temperature profiles suggest that the fresh water from Gardner Canal contributes to the estuarine circulation in the Douglas Channel. A passive tracer evolving with the advection and diffusion processes in the circulation model is used as a proxy to quantify the freshwater transport. The results show that the majority of low salinity water leaving Gardner Canal at the triple junction flows northward into the Douglas Channel through the Devastation Channel and the synoptic variability of the freshwater partition is modulated by strong wind events. A synthesis of various circulations in the abovementioned connecting channels around the Hawkesbury Island indicates a net anticyclonic circulation.
Attenuation of Ultraviolet Radiation in Rocks and Minerals: Implications for Mars Science
Authors: Carrier B. L. , Abbey W. J. , Beegle L. W. , Bhartia R. , Liu Y.
Published: September 2019

The effects of radiation on the survivability of key biosignatures are a driving factor in exploration strategies throughout the solar system. Ultraviolet (UV) radiation, especially shorter wavelength UVC radiation, is known to be damaging to organisms and to potential organic biosignatures; however, the interaction of UV radiation with minerals and rocks is not well understood. Constraining the survivability of organics and generation of habitable zones requires assessment of physical parameters such as penetration depth of UV photons. This type of information helps to identify to what extent rocks and minerals can provide effective shielding against UV radiation and is especially important on Mars, where the surface chemistry is more oxidizing, and the radiation environment is more extreme than on Earth. Using pressed pellets of natural gypsum, kaolinite, Mars simulant basalt, and welded tuff, we measured the spectral transmittance of each in the wavelength range of 220–400 nm. Although transmittance drops off quickly with depth, detectable levels of UV can penetrate >500 μm in each material. Each substrate allowed higher transmittance of UVC radiation than of longer wavelength UVA/B radiation, possibly as a result of surface reflectance and internal scattering properties. This could result in increased subsurface photolysis of organic compounds and biosignatures. We have used the transmittance data collected herein to constrain the lifetimes of several organic molecules in the Martian subsurface. These results will also have implications for organic analyses to be conducted by Mars 2020 and could be used to better constrain the SHERLOC/Mars 2020 interrogation volume.
Streamflow Generation From Catchments of Contrasting Lithologies: The Role of Soil Properties, Topography, and Catchment Size
Authors: Xiao Dacheng , Shi Yuning , Brantley Susan L. , Forsythe Brandon , DiBiase Roman , Davis Kenneth , Li Li
Published: September 2019

Understanding streamflow generation and its dependence on catchment characteristics requires large spatial data sets and is often limited by convoluted effects of multiple variables. Here we address this knowledge gap using data‐informed, physics‐based hydrologic modeling in two catchments with similar vegetation and climate but different lithology (Shale Hills [SH], shale, 0.08 km2, and Garner Run [GR], sandstone, 1.34 km2), which influences catchment topography and soil properties. The sandstone catchment, GR, is characterized by lower drainage density, extensive valley fill, and bouldery soils. We tested the hypothesis that the influence of topographic characteristics is more significant than that of soil properties and catchment size. Transferring calibration coefficients from the previously calibrated SH model to GR cannot reproduce monthly discharge until after incorporating measured boulder distribution at GR. Model calibration underscored the importance of soil properties (porosity, van Genuchten parameters, and boulder characteristics) in reproducing daily discharge. Virtual experiments were used to swap topography, soil properties, and catchment size one at a time to disentangle their influence. They showed that clayey SH soils led to high nonlinearity and threshold behavior. With the same soil and topography, changing from SH to GR size consistently increased dynamic water storage (Sd) from ~0.12 to ~0.17 m. All analyses accentuated the predominant control of soil properties, therefore rejecting the hypothesis. The results illustrate the use of physics‐based modeling for illuminating mechanisms and underscore the importance of subsurface characterization as we move toward hydrological prediction in ungauged basins.
Reward‐Based Participant Management for Crowdsourcing Rainfall Monitoring: An Agent‐Based Model Simulation
Authors: Yang Pan , Ng Tze Ling , Cai Ximing
Published: September 2019

Crowdsourcing incorporates common citizens as rich sources of data and is promising for environmental monitoring. In this paper, we propose and test the idea of incorporating incentives to crowdsourcing management for rainfall monitoring. Specifically, we model the allocation of incentives (quantitatively measurable and limited rewards) among crowdsourcing participants for a theoretical rainfall monitoring case. For this purpose, we develop an integrated model comprising a reward allocation component to represent the decision‐making process of a central manager, an agent‐based model to simulate the interactions between the manager and participants, and a rainfall simulation model to evaluate the effectiveness of various reward allocation policies. We simulate six reward allocation policies of varying levels of administrative cost, and consideration of participant and rainfall spatial heterogeneities. The results suggest the performance of each policy to improve with the reward budget and their spatial uniformity. Among the six policies tested, we find that the participant density weighted maximum participation policy yields the most accurate estimation of rainfall intensity due to its more explicit consideration of the spatial distribution of participants; however, this policy associates with a high administrative cost. This highlights the trade‐off between performance and cost in designing effective reward allocation policies. This paper provides a physical and behavior simulation modeling tool to study the feasibility and complexity of reward‐based participant management for crowdsourcing rainfall monitoring. The proposed crowdsourcing method is beneficial for a wide range of applications that require rainfall data with fine resolution, such as storm water management and water availability and biomass assessment for food and energy crops.
Internal Structure of a Seafloor Massive Sulfide Deposit by Electrical Resistivity Tomography, Okinawa Trough
Authors: Ishizu K. , Goto T. , Ohta Y. , Kasaya T. , Iwamoto H. , Vachiratienchai C. , Siripunvaraporn W. , Tsuji T. , Kumagai H. , Koike K.
Published: September 2019

Although seafloor massive sulfide (SMS) deposits are crucially important metal resources that contain high‐grade metals such as copper, lead, and zinc, their internal structures and generation mechanisms remain unclear. This study obtained detailed near‐seafloor images of electrical resistivity in a hydrothermal field off Okinawa, southwestern Japan, using deep‐towed marine electrical resistivity tomography. The image clarified a semi‐layered resistivity structure, interpreted as SMS deposits exposed on the seafloor, and another deep‐seated SMS layer at about 40‐m depth below the seafloor. The images reinforce our inference of a new mechanism of SMS evolution: Upwelling hydrothermal fluid is trapped under less‐permeable cap rock. The deeper embedded SMS accumulates there. Then hydrothermal fluids expelled on the seafloor form exposed SMS deposits.
Sensitivity of Tidewater Glaciers to Submarine Melting Governed by Plume Locations
Authors: Cowton Tom R. , Todd Joe A. , Benn Douglas I.
Published: September 2019

The response of tidewater glaciers to ocean warming remains a key uncertainty in sea level rise predictions. Here we use a 3‐D numerical model to examine the response of an idealized tidewater glacier to spatial variations in submarine melt rate. While melting toward the center of the terminus causes only a localized increase in mass loss, melting near the lateral margins triggers increased calving across the width of the glacier, causing the terminus to retreat at several times the width‐averaged melt rate. This occurs because melting near the margins has a greater disruptive impact on the compressive stress arch that transfers resistance from the side walls to the body of the glacier. We suggest that the rate of terminus advance or retreat may thus be governed by the difference between ice velocity and submarine melting in the slow‐flowing zones away from the glacier center.
Enhancing Tsunami Warning UsingPWave Coda
Authors: Lay Thorne , Liu Chengli , Kanamori Hiroo
Published: September 2019

Most large tsunamis are generated by earthquakes on offshore plate boundary megathrusts. The primary factors influencing tsunami excitation are the seismic moment, faulting geometry, and depth of the faulting. Efforts to provide rapid tsunami warning have emphasized seismic and geodetic methods for quickly determining the event size and faulting geometry. It remains difficult to evaluate the updip extent of rupture, which has significant impact on tsunami excitation. TeleseismicPwaves can constrain this issue; slip under deep water generates strongpwPwater reverberations that persist as ringingPcodaafter the directPphases from the faulting have arrived. Event‐averagedPcoda/Pamplitude measures at large epicentral distances (>80°), tuned to the dominant periods of deep waterpwP(~12–15 s), correlate well with independent models of whether slip extends to near the trench or not. Data at closer ranges (30° to 80°) reduce the time lag needed for inferring the updip extent of rupture to <15 min. Arrival ofPPandPPPphases contaminates closer distancePcodameasures, but this can be suppressed by azimuthal or distance binning of the measures. Narrowband spectral ratio measures and differential magnitude measures ofPcodaand directP(mB) perform comparably to broader band root‐mean‐square (RMS) measures.Pcoda/Plevels for large nonmegathrust events are also documented. Rapid measurement ofPcoda/Pmetrics after a large earthquake can supplement quick moment tensor determinations to enhance tsunami warnings; observation of largePcodalevels indicates that shallow submarine rupture occurred and larger than typical tsunami (for givenMW) can be expected.
Transport of Cobalt and Silver From the Ocean to a Reef Island by Seabirds in the South China Sea
Authors: Xu L. Q. , Wu L. B. , Zhang Y. H. , Zhao J. J.
Published: September 2019

Seabirds are typical biovectors, delivering both nutrients and metals across ecosystem boundaries. However, seabird transfer of Ag and Co has not been well documented. Using an ornithogenic sediment core collected from the remote Zhaoshu Island, South China Sea, we investigated potential impacts of seabirds on Ag and Co transportation. These two elements exhibited peak abundance in a guano layer in the sediment profile. Via statistical analyses, Ag, Co, and previously identified avian bio‐elements (Cn, Zn, Cd, P, As, and Se) had a common source, that is, guano. Guano input was also partly responsible for the distribution of Y, Ce, La, Sc, and U in the bulk sediments. The concentration‐versus‐depth profiles of Mn, Mo, Bi, Rb, and W were possibly associated with organic matter.
The latent structure of depressive symptoms across clinical high risk and chronic phases of psychotic illness
Authors: Vargas Teresa , Ahmed Anthony O. , Strauss Gregory P. , Brandes Cassandra M. , Walker Elaine F. , Buchanan Robert W. , Gold James M. , Mittal Vijay A.
Published: September 2019

Depressive symptoms are highly prevalent in psychotic populations and result in significant functional impairment. Limited knowledge of whether depressive symptoms are invariant across stages of illness curtails our ability to understand how these relate to illness progression. Clarifying the latent structure of depressive symptoms across stages of illness progression would aid etiological conceptualizations and preventive models. In the present study, one-factor (including all items) and two-factor (depression/hopelessness and guilt/self-depreciation) solutions were specified through confirmatory factor analysis (CFA). Measurement invariance analyses were undertaken across schizophrenia (SCZ; n = 312) and clinical high-risk (CHR; n = 175) groups to estimate whether the same construct is being measured across groups. Clinical correlates of the factors were examined. Results indicated that CHR individuals had a greater proportion of mood disorder diagnoses. Metric invariance held for the one-factor solution, and scalar invariance held for the two-factor solution. Notably, negative symptoms did not correlate with depressive symptoms in the SCZ group, though strong correlations were observed in CHR individuals. Positive symptoms were comparably associated with depressive symptoms in both groups. Results suggest depressive symptoms are more prevalent in CHR individuals. Targeting these symptoms may aid future efforts to identify risk of conversion. Further, some depressive symptoms may be systematically more endorsed in CHR individuals. Separating into depression/hopelessness and guilt/self-depreciation scores may aid comparability across stages of illness progression, though this issue deserves careful attention and future study.
Understanding of prognosis in non-metastatic prostate cancer: a randomised comparative study of clinician estimates measured against the PREDICT prostate prognostic model
Authors: Thurtle David R. , Jenkins Valerie , Pharoah Paul D. , Gnanapragasam Vincent J.
Published: September 2019

PREDICT Prostate is an individualised prognostic model that provides long-term survival estimates for men diagnosed with non-metastatic prostate cancer (www.prostate.predict.nhs.uk). In this study clinician estimates of survival were compared against model predictions and its potential value as a clinical tool was assessed. Prostate cancer (PCa) specialists were invited to participate in the study. 190 clinicians (63% urologists, 17% oncologists, 20% other) were randomised into two groups and shown 12 clinical vignettes through an online portal. Each group viewed opposing vignettes with clinical information alone, or alongside PREDICT Prostate estimates. 15-year clinician survival estimates were compared against model predictions and reported treatment recommendations with and without seeing PREDICT estimates were compared. 155 respondents (81.6%) reported counselling new PCa patients at least weekly. Clinician estimates of PCa-specific mortality exceeded PREDICT estimates in 10/12 vignettes. Their estimates for treatment survival benefit at 15 years were over-optimistic in every vignette, with mean clinician estimates more than 5-fold higher than PREDICT Prostate estimates. Concomitantly seeing PREDICT Prostate estimates led to significantly lower reported likelihoods of recommending radical treatment in 7/12 (58%) vignettes, particularly in older patients. These data suggest clinicians overestimate cancer-related mortality and radical treatment benefit. Using an individualised prognostic tool may help reduce overtreatment.
Prognosis and modulation mechanisms of COMMD6 in human tumours based on expression profiling and comprehensive bioinformatics analysis
Authors: Yang Mi , Huang Weiqiang , Sun Yaling , Liang Huazhen , Chen Min , Wu Xixi , Wang Xiaoqing , Zhang Longshan , Cheng Xiaoya , Fan Yao , Pan Hua , Chen Longhua , Guan Jian
Published: September 2019

Background

The Copper Metabolism MURR1 (COMM) domain family has been reported to play important roles in tumorigenesis. As a prototype for the COMMD family, the expression pattern and biological function of COMMD6 in human tumours remain unknown.

Methods

COMMD6 expression in BALB/c mice and human tissues was examined using real-time PCR and immunohistochemistry. Kaplan–Meier analysis was applied to evaluate the prognosis of COMMD6 in tumours. Competing endogenous RNA (ceRNA) and transcriptional regulation network were constructed based on differentially expressed mRNAs, microRNAs and long non-coding RNAs from the cancer genome atlas database. GO and KEGG enrichment analysis were used to explore the bioinformatics implication.

Results

COMMD6 expression was widely observed in BALB/c mice and human tissues, which predicted prognosis of cancer patients. Furthermore, we shed light on the underlying tumour promoting role and mechanism of COMMD6 by constructing a TEX41-miR-340-COMMD6 ceRNA network in head and neck squamous cell carcinoma and miR-218-CDX1-COMMD6 transcriptional network in cholangiocarcinoma. In addition, COMMD6 may modulate the ubiquitination and degradation of NF-κB subunits and regulate ribonucleoprotein and spliceosome complex biogenesis in tumours.

Conclusions

This study may help to elucidate the functions and mechanisms of COMMD6 in human tumours, providing a potential biomarker for tumour prevention and therapy.
Aberrations in Notch-Hedgehog signalling reveal cancer stem cells harbouring conserved oncogenic properties associated with hypoxia and immunoevasion
Authors: Chang Wai Hoong , Lai Alvina G.
Published: September 2019

Background

Cancer stem cells (CSCs) have innate abilities to resist even the harshest of therapies. To eradicate CSCs, parallels can be drawn from signalling modules that orchestrate pluripotency. Notch-Hedgehog hyperactivation are seen in CSCs, yet, not much is known about their conserved roles in tumour progression across cancers.

Methods

Employing a comparative approach involving 21 cancers, we uncovered clinically-relevant, pan-cancer drivers of Notch and Hedgehog. GISTIC datasets were used to evaluate copy number alterations. Receiver operating characteristic and Cox regression were employed for survival analyses.

Results

We identified a Notch-Hedgehog signature of 13 genes exhibiting high frequencies of somatic amplifications leading to transcript overexpression. The signature successfully predicted patients at risk of death in five cancers (n = 2278): glioma (P < 0.0001), clear cell renal cell (P = 0.0022), papillary renal cell (P = 0.00099), liver (P = 0.014) and stomach (P = 0.011). The signature was independent of other clinicopathological parameters and offered an additional resolution to stratify similarly-staged tumours. High-risk patients exhibited features of stemness and had more hypoxic tumours, suggesting that hypoxia may influence CSC behaviour. Notch-Hedgehog+ CSCs had an immune privileged phenotype associated with increased regulatory T cell function.

Conclusion

This study will set the stage for exploring adjuvant therapy targeting the Notch-Hedgehog axis to help optimise therapeutic regimes leading to successful CSC elimination.
Apatinib in patients with extensive-stage small-cell lung cancer after second-line or third-line chemotherapy: a phase II, single-arm, multicentre, prospective study
Authors: Xu Yanjun , Huang Zhiyu , Lu Hongyang , Yu Xinming , Li Yuping , Li Wenfeng , Chen Jun , Chen Ming , Gong Lei , Chen Kaiyan , Qin Jin , Xu Xiaoling , Jin Ying , Zhao Jun , Shi Xun , Han Na , Xie Fajun , Zhang Peng , Xu Weizhen , Fan Yun
Published: September 2019

Background

Small-cell lung cancer (SCLC) remains an aggressive cancer with short-term survival due to limited therapeutic options. Apatinib is a small-molecule tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor-2. This study aimed to investigate the efficacy and safety of apatinib in patients with extensive-stage (EC) SCLC who had progressed after two or three previous therapies.

Methods

Eligible patients were histologically confirmed ES-SCLC after two or three previous treatments, including a platinum-based regimen. Patients received apatinib at an initial dose of 500 mg once daily. The primary endpoint was the objective response rate.

Results

Forty patients were enrolled. At the data cut-off time (November 15, 2018), the median follow-up was 7.4 months; no patients remained on treatment, and five were still in follow-up. An objective response was achieved in 7 of 40 patients (17.5%) in the intention-to-treat population, and 7 of 38 patients (18.4%) in the per-protocol population. The median progression-free survival and overall survival were 3.0 months and 5·8 months, respectively. The most commonly observed grade 3 or greater treatment-related adverse events were hypertension, hand–foot syndrome, increased L-gamma-glutamyltransferase.

Conclusions

Apatinib exhibited efficacy and an acceptable safety profile in previously heavily-treated ES-SCLC patients. Further exploration of apatinib in phase III trials is warranted.

Trial registration

NCT02945852.
A FBN1 variant manifesting as non-syndromic ectopia lentis with retinal detachment: clinical and genetic characteristics
Authors: Stephenson Kirk A. J. , Dockery Adrian , O’Keefe Michael , Green Andrew , Farrar G. Jane , Keegan David J.
Published: September 2019

Background/objectives

Fibrillin-1 (FBN1) mutations cause connective tissue dysgenesis the main ocular manifestation being ectopia lentis (EL), which may be syndromic or non-syndromic. We describe a pedigree with a FBN1 mutation causing non-syndromic EL with retinal detachment (RRD) and their management.

Subjects/methods

Patients with familial EL with RRD were invited to participate (vitreoretinopathy branch of Target 5000, the Irish inherited retinal degeneration study). All patients signed full informed consent. The study was approved by the Institutional Review Board of the Mater Hospital, Dublin and abided by the Declaration of Helsinki.

Results

Seven adults were affected with bilateral EL. All subjects had RRD with bilateral non-synchronous RRD in 57%.

Conclusions

The FBN1 variant described herein confers an increased risk of both EL and RRD and can now be upgraded to ‘pathogenic’ ACMG status.
Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma
Authors: Li Zhaoming , Zhang Xudong , Xue Weili , Zhang Yanjie , Li Chaoping , Song Yue , Mei Mei , Lu Lisha , Wang Yingjun , Zhou Zhiyuan , Jin Mengyuan , Bian Yangyang , Zhang Lei , Wang Xinhua , Li Ling , Li Xin , Fu Xiaorui , Sun Zhenchang , Wu Jingjing , Nan Feifei , Chang Yu , Yan Jiaqin , Yu Hui , Feng Xiaoyan , Wang Guannan , Zhang Dandan , Fu Xuefei , Zhang Yuan , Young Ken H. , Li Wencai , Zhang Mingzhi
Published: September 2019

Natural killer/T cell lymphoma (NKTCL) is a rare and aggressive malignancy with a higher prevalence in Asia and South America. However, the molecular genetic mechanisms underlying NKTCL remain unclear. Here, we identify somatic mutations ofGNAQ(encoding the T96S alteration of Gαq protein) in 8.7% (11/127) of NKTCL patients, through whole-exome/targeted deep sequencing. Using conditional knockout mice (Ncr1-Cre-Gnaqfl/fl), we demonstrate that Gαq deficiency leads to enhanced NK cell survival. We also find that Gαq suppresses tumor growth of NKTCL via inhibition of the AKT and MAPK signaling pathways. Moreover, the Gαq T96S mutant may act in a dominant negative manner to promote tumor growth in NKTCL. Clinically, patients withGNAQT96S mutations have inferior survival. Taken together, we identify recurrent somaticGNAQT96S mutations that may contribute to the pathogenesis of NKTCL. Our work thus has implications for refining our understanding of the genetic mechanisms of NKTCL and for the development of therapies.
A phyB-PIF1-SPA1 kinase regulatory complex promotes photomorphogenesis in Arabidopsis
Authors: Paik Inyup , Chen Fulu , Ngoc Pham Vinh , Zhu Ling , Kim Jeong-Il , Huq Enamul
Published: September 2019

CONSTITUTIVELY PHOTOMORPHOGENIC1 (COP1) is a highly conserved E3 ubiquitin ligase from plants to animals and acts as a central repressor of photomorphogenesis in plants. SUPPRESSOR OF PHYA-105 1 family members (SPA1-SPA4) directly interact with COP1 and enhance COP1 activity. Despite the presence of a kinase domain at the N-terminus, no COP1-independent role of SPA proteins has been reported. Here we show that SPA1 acts as a serine/threonine kinase and directly phosphorylates PIF1 in vitro and in vivo. SPAs are necessary for the light-induced phosphorylation, ubiquitination and subsequent degradation of PIF1. Moreover, the red/far-red light photoreceptor phyB interacts with SPA1 through its C-terminus and enhances the recruitment of PIF1 for phosphorylation. These data provide a mechanistic view on how the COP1-SPA complexes serve as an example of a cognate kinase-E3 ligase complex that selectively triggers rapid phosphorylation and removal of its substrates, and how phyB modulates this process to promote photomorphogenesis.
Learning the pattern of epistasis linking genotype and phenotype in a protein
Authors: Poelwijk Frank J. , Socolich Michael , Ranganathan Rama
Published: September 2019

Understanding the pattern of epistasis—the non-independence of mutations—is critical for relating genotype and phenotype. However, the combinatorial complexity of potential epistatic interactions has severely limited the analysis of this problem. Using new mutational approaches, we report a comprehensive experimental study of all 213 mutants that link two phenotypically distinct variants of the Entacmaea quadricolor fluorescent protein—an opportunity to examine epistasis up to the 13th order. The data show the existence of many high-order epistatic interactions between mutations, but also reveal extraordinary sparsity, enabling novel experimental and computational strategies for learning the relevant epistasis. We demonstrate that such information, in turn, can be used to accurately predict phenotypes in practical situations where the number of measurements is limited. Finally, we show how the observed epistasis shapes the solution space of single-mutation trajectories between the parental fluorescent proteins, informative about the protein’s evolutionary potential. This work provides conceptual and experimental strategies to profoundly characterize epistasis in a protein, relevant to both natural and laboratory evolution.
Immunoinformatics approaches to explore Helicobacter Pylori proteome (Virulence Factors) to design B and T cell multi-epitope subunit vaccine
Authors: Khan Mazhar , Khan Shahzeb , Ali Asim , Akbar Hameed , Sayaf Abrar Mohammad , Khan Abbas , Wei Dong-Qing
Published: September 2019

Helicobacter Pyloriis a known causal agent of gastric malignancies and peptic ulcers. The extremophile nature of this bacterium is protecting it from designing a potent drug against it. Therefore, the use of computational approaches to design antigenic, stable and safe vaccine against this pathogen could help to control the infections associated with it. Therefore, in this study, we used multiple immunoinformatics approaches along with other computational approaches to design a multi-epitopes subunit vaccine againstH.Pylori. A total of 7 CTL and 12 HTL antigenic epitopes based on c-terminal cleavage and MHC binding scores were predicted from the four selected proteins (CagA, OipA, GroEL and cagA). The predicted epitopes were joined by AYY and GPGPG linkers. Β-defensins adjuvant was added to the N-terminus of the vaccine. For validation, immunogenicity, allergenicity and physiochemical analysis were conducted. The designed vaccine is likely antigenic in nature and produced robust and substantial interactions with Toll-like receptors (TLR-2, 4, 5, and 9). The vaccine developed was also subjected to anin silicocloning and immune response prediction model, which verified its efficiency of expression and the immune system provoking response. These analyses indicate that the suggested vaccine may produce particular immune responses againstH. pylori, but laboratory validation is needed to verify the safety and immunogenicity status of the suggested vaccine design.
Clearance of hepatitis C virus is associated with early and potent but narrowly-directed, Envelope-specific antibodies
Authors: Walker Melanie R. , Leung Preston , Eltahla Auda A. , Underwood Alexander , Abayasingam Arunasingam , Brasher Nicholas A. , Li Hui , Wu Bing-Ru , Maher Lisa , Luciani Fabio , Lloyd Andrew R. , Bull Rowena A.
Published: September 2019

Hepatitis C virus (HCV) is one of very few viruses that are either naturally cleared, or alternatively persist to cause chronic disease. Viral diversity and escape, as well as host adaptive immune factors, are believed to control the outcome. To date, there is limited understanding of the critical, early host-pathogen interactions. The asymptomatic nature of early HCV infection generally prevents identification of the transmitted/founder (T/F) virus, and thus the study of host responses directed against the autologous T/F strain. In this study, 14 rare subjects identified from very early in infection (4–45 days) with varied disease outcomes (n = 7 clearers) were examined in regard to the timing, breadth, and magnitude of the neutralizing antibody (nAb) response, as well as evolution of the T/F strain. Clearance was associated with earlier onset and more potent nAb responses appearing at a mean of 71 days post-infection (DPI), but these responses were narrowly directed against the autologous T/F virus or closely related variants. In contrast, a delayed onset of nAbs (mean 425 DPI) was observed in chronic progressors that appear to have targeted longitudinal variants rather than the T/F strain. The nAb responses in the chronic progressors mapped to known CD81 binding epitopes, and were associated with rapid emergence of new viral variants with reduced CD81 binding. We propose that the prolonged period of viremia in the absence of nAbs in these subjects was associated with an increase in viral diversity, affording the virus greater options to escape nAb pressure once it emerged. These findings indicate that timing of the nAb response is essential for clearance. Further investigation of the specificities of the early nAbs and the factors regulating early induction of protective nAbs is needed.
Fatty Acid Inhibition Sensitizes Androgen-Dependent and -Independent Prostate Cancer to Radiotherapy via FASN/NF-κB Pathway
Authors: Chuang Hui-Yen , Lee Yen-Po , Lin Wei-Chan , Lin Yi-Hsien , Hwang Jeng-Jong
Published: September 2019

Elevated fatty acid synthase (FASN) has been reported in both androgen-dependent and -independent prostate cancers. Conventional treatment for prostate cancer is radiotherapy (RT); however, the following radiation-induced radioresistance often causes treatment failure. Upstream proteins of FASN such as Akt and NF-κB are found increased in the radioresistant prostate cancer cells. Nevertheless, whether inhibition of FASN could improve RT outcomes and reverse radiosensitivity of prostate cancer cells is still unknown. Here, we hypothesised that orlistat, a FASN inhibitor, could improve RT outcomes in prostate cancer. Orlistat treatment significantly reduced the S phase population in both androgen-dependent and -independent prostate cancer cells. Combination of orlistat and RT significantly decreased NF-κB activity and related downstream proteins in both prostate cancer cells. Combination effect of orlistat and RT was further investigated in both LNCaP and PC3 tumour-bearing mice. Combination treatment showed the best tumour inhibition compared to that of orlistat alone or RT alone. These results suggest that prostate cancer treated by conventional RT could be improved by orlistat via inhibition of FASN.
Nanomechanics of tip-link cadherins
Authors: Oroz Javier , Galera-Prat Albert , Hervás Rubén , Valbuena Alejandro , Fernández-Bravo Débora , Carrión-Vázquez Mariano
Published: September 2019

Hearing and balance rely on the transduction of mechanical stimuli arising from sound waves or head movements into electrochemical signals. This archetypal mechanoelectrical transduction process occurs in the hair-cell stereocilia of the inner ear, which experience continuous oscillations driven by undulations in the endolymph in which they are immersed. The filamentous structures called tip links, formed by an intertwined thread composed of an heterotypic complex of cadherin 23 and protocadherin 15 ectodomain dimers, connect each stereocilium to the tip of the lower sterocilium, and must maintain their integrity against continuous stimulatory deflections. By using single molecule force spectroscopy, here we demonstrate that in contrast to the case of classical cadherins, tip-link cadherins are mechanoresilient structures even at the exceptionally low Ca2+ concentration of the endolymph. We also show that the D101G deafness point mutation in cadherin 23, which affects a Ca2+ coordination site, exhibits an altered mechanical phenotype at the physiological Ca2+ concentration. Our results show a remarkable case of functional adaptation of a protein’s nanomechanics to extremely low Ca2+ concentrations and pave the way to a full understanding of the mechanotransduction mechanism mediated by auditory cadherins.
Identification of telomerase RNAs in species of the Yarrowia clade provides insights into the co-evolution of telomerase, telomeric repeats and telomere-binding proteins
Authors: Červenák Filip , Juríková Katarína , Devillers Hugo , Kaffe Binyamin , Khatib Areej , Bonnell Erin , Sopkovičová Martina , Wellinger Raymund J. , Nosek Jozef , Tzfati Yehuda , Neuvéglise Cécile , Tomáška Ľubomír
Published: September 2019

Telomeric repeats in fungi of the subphylum Saccharomycotina exhibit great inter- and intra-species variability in length and sequence. Such variations challenged telomeric DNA-binding proteins that co-evolved to maintain their functions at telomeres. Here, we compare the extent of co-variations in telomeric repeats, encoded in the telomerase RNAs (TERs), and the repeat-binding proteins from 13 species belonging to the Yarrowia clade. We identified putative TER loci, analyzed their sequence and secondary structure conservation, and predicted functional elements. Moreover, in vivo complementation assays with mutant TERs showed the functional importance of four novel TER substructures. The TER-derived telomeric repeat unit of all species, except for one, is 10 bp long and can be represented as 5′-TTNNNNAGGG-3′, with repeat sequence variations occuring primarily outside the vertebrate telomeric motif 5′-TTAGGG-3′. All species possess a homologue of the Yarrowia lipolytica Tay1 protein, YlTay1p. In vitro, YlTay1p displays comparable DNA-binding affinity to all repeat variants, suggesting a conserved role among these species. Taken together, these results add significant insights into the co-evolution of TERs, telomeric repeats and telomere-binding proteins in yeasts.
Audio-Tactile Skinny Buttons for Touch User Interfaces
Authors: Van Duong Quang , Nguyen Vinh Phu , Luu Anh Tuan , Choi Seung Tae
Published: September 2019

This study proposes a novel skinny button with multimodal audio and haptic feedback to enhance the touch user interface of electronic devices. The active material in the film-type actuator is relaxor ferroelectric polymer (RFP) poly(vinylidene fluoride-trifluoroethylene-chlorofluoroethylene) [P(VDF-TrFE-CFE)] blended with poly(vinylidene fluoride-trifluoroethylene) [P(VDF-TrFE)], which produces mechanical vibrations via the fretting vibration phenomenon. Normal pressure applied by a human fingertip on the film-type skinny button mechanically activates the locally concentrated electric field under the contact area, thereby producing a large electrostrictive strain in the blended RFP film. Multimodal audio and haptic feedback is obtained by simultaneously applying various electric signals to the pairs of ribbon-shaped top and bottom electrodes. The fretting vibration provides tactile feedback at frequencies of 50–300 Hz and audible sounds at higher frequencies of 500 Hz to 1 kHz through a simple on-off mechanism. The advantage of the proposed audio-tactile skinny button is that it restores the “click” sensation to the popular virtual touch buttons employed in contemporary electronic devices.
Cryopreserved embryo replacement is associated with higher birthweight compared with fresh embryo: multicentric sibling embryo cohort study
Authors: Anav Margaux , Phillips Simon , Ferrieres-Hoa Alice , Gala Anna , Fournier Alice , Vincens Claire , Vintejoux Emmanuelle , Maris Elsa , Grysole Camille , Bissonnette François , Brouillet Sophie , Kadoch Isaac Jacques , Hamamah Samir
Published: September 2019

Birth weight (BW) is higher after frozen embryo transfer (FET) than after fresh embryo replacement. No study has compared the BW of siblings conceived using the same oocyte/embryo cohort. The aim of this study was to determine whether the freezing-thawing procedure is involved in such difference. Multicenter study at Montpellier University Hospital, Clinique Ovo, Canada and Grenoble-Alpes University Hospital. The first cohort (Fresh/FET) included in vitro fertilization (IVF) cycles where the older was born after fresh embryo transfer (n = 158) and the younger after transfer of frozen supernumerary embryos (n = 158). The second cohort (FET/FET) included IVF cycles where older and younger were born after FET of embryos from the same cohort. The mean adjusted BW of the FET group was higher than that of the fresh group (3508.9 ± 452.4 g vs 3237.7 ± 463.3 g; p < 0.01). In the FET/FET cohort, the mean adjusted BW was higher for the younger by 93.1 g but this difference is not significant (3430.2 ± 347.6 g vs 3337.1 ± 391.9 g; p = 0.3789). Our results strongly suggest that cryopreservation is directly involved in the BW variation. Comparing BW difference between Fresh/FET cohort and FET/FET one, it suggests that parity is not the only responsible, increasing the role of cryopreservation step in BW variation.
A Novel Digital Score for Abundance of Tumour Infiltrating Lymphocytes Predicts Disease Free Survival in Oral Squamous Cell Carcinoma
Authors: Shaban Muhammad , Khurram Syed Ali , Fraz Muhammad Moazam , Alsubaie Najah , Masood Iqra , Mushtaq Sajid , Hassan Mariam , Loya Asif , Rajpoot Nasir M.
Published: September 2019

Oral squamous cell carcinoma (OSCC) is the most common type of head and neck (H&N) cancers with an increasing worldwide incidence and a worsening prognosis. The abundance of tumour infiltrating lymphocytes (TILs) has been shown to be a key prognostic indicator in a range of cancers with emerging evidence of its role in OSCC progression and treatment response. However, the current methods of TIL analysis are subjective and open to variability in interpretation. An automated method for quantification of TIL abundance has the potential to facilitate better stratification and prognostication of oral cancer patients. We propose a novel method for objective quantification of TIL abundance in OSCC histology images. The proposed TIL abundance (TILAb) score is calculated by first segmenting the whole slide images (WSIs) into underlying tissue types (tumour, lymphocytes, etc.) and then quantifying the co-localization of lymphocytes and tumour areas in a novel fashion. We investigate the prognostic significance of TILAb score on digitized WSIs of Hematoxylin and Eosin (H&E) stained slides of OSCC patients. Our deep learning based tissue segmentation achieves high accuracy of 96.31%, which paves the way for reliable downstream analysis. We show that the TILAb score is a strong prognostic indicator (p = 0.0006) of disease free survival (DFS) on our OSCC test cohort. The automated TILAb score has a significantly higher prognostic value than the manual TIL score (p = 0.0024). In summary, the proposed TILAb score is a digital biomarker which is based on more accurate classification of tumour and lymphocytic regions, is motivated by the biological definition of TILs as tumour infiltrating lymphocytes, with the added advantages of objective and reproducible quantification.
A method for the reconstruction of multifocal structured illumination microscopy data with high efficiency
Authors: Feng Liang , Zhou Langfeng , Sun Xinlei , Xu Qiang , Chen Ping , Wang Xiaolei , Liu Weiwei
Published: September 2019

We present and demonstrate an efficient method for the reconstruction of profiles acquired by multifocal structured illumination microscopy (MSIM) utilizing few raw images. Firstly, we propose a method to produce nine raw multifocal images with enhanced modulation depth to accomplish the uniform illumination of the sample. Then, combing with the parameter of the arrays, we perform the standard construct reconstruction procedure of structured illumination microscopy (SIM) row by row and column by column. Finally, we combine these restored images together to obtain the final image with enhanced resolution and good contrast. Based on theoretical analysis and numerical simulations, this method shows great potential in the field of the image reconstruction of MSIM data.
NeuRiPP: Neural network identification of RiPP precursor peptides
Authors: de los Santos Emmanuel L. C.
Published: September 2019

Significant progress has been made in the past few years on the computational identification of biosynthetic gene clusters (BGCs) that encode ribosomally synthesized and post-translationally modified peptides (RiPPs). This is done by identifying both RiPP tailoring enzymes (RTEs) and RiPP precursor peptides (PPs). However, identification of PPs, particularly for novel RiPP classes remains challenging. To address this, machine learning has been used to accurately identify PP sequences. Current machine learning tools have limitations, since they are specific to the RiPPclass they are trained for and are context-dependent, requiring information about the surrounding genetic environment of the putative PP sequences. NeuRiPP overcomes these limitations. It does this by leveraging the rich data set of high-confidence putative PP sequences from existing programs, along with experimentally verified PPs from RiPP databases. NeuRiPP uses neural network archictectures that are suitable for peptide classification with weights trained on PP datasets. It is able to identify known PP sequences, and sequences that are likely PPs. When tested on existing RiPP BGC datasets, NeuRiPP was able to identify PP sequences in significantly more putative RiPP clusters than current tools while maintaining the same HMM hit accuracy. Finally, NeuRiPP was able to successfully identify PP sequences from novel RiPP classes that were recently characterized experimentally, highlighting its utility in complementing existing bioinformatics tools.
Neuronal avalanches and time-frequency representations in stimulus-evoked activity
Authors: Arviv Oshrit , Goldstein Abraham , Shriki Oren
Published: September 2019

Neuronal avalanches are a hallmark feature of critical dynamics in the brain. While the theoretical framework of a critical branching processes is generally accepted for describing avalanches during ongoing brain activity, there is a current debate about the corresponding dynamical description during stimulus-evoked activity. As the brain activity evoked by external stimuli considerably varies in magnitude across time, it is not clear whether the parameters that govern the neuronal avalanche analysis (a threshold or a temporal scale) should be adaptively altered to accommodate these changes. Here, the relationship between neuronal avalanches and time-frequency representations of stimulus-evoked activity is explored. We show that neuronal avalanche metrics, calculated under a fixed threshold and temporal scale, reflect genuine changes in the underlying dynamics. In particular, event-related synchronization and de-synchronization are shown to align with variations in the power-law exponents of avalanche size distributions and the branching parameter (neural gain), as well as in the spatio-temporal spreading of avalanches. Nonetheless, the scale-invariant behavior associated with avalanches is shown to be a robust feature of healthy brain dynamics, preserved across various periods of stimulus-evoked activity and frequency bands. Taken together, the combined results suggest that throughout stimulus-evoked responses the operating point of the dynamics may drift within an extended-critical-like region.
Tracking a mass mortality outbreak of pen shell Pinna nobilis populations: A collaborative effort of scientists and citizens
Authors: Cabanellas-Reboredo Miguel , Vázquez-Luis Maite , Mourre Baptiste , Álvarez Elvira , Deudero Salud , Amores Ángel , Addis Piero , Ballesteros Enric , Barrajón Agustín , Coppa Stefania , García-March José Rafael , Giacobbe Salvatore , Casalduero Francisca Giménez , Hadjioannou Louis , Jiménez-Gutiérrez Santiago V. , Katsanevakis Stelios , Kersting Diego , Mačić Vesna , Mavrič Borut , Patti Francesco Paolo , Planes Serge , Prado Patricia , Sánchez Jordi , Tena-Medialdea José , de Vaugelas Jean , Vicente Nardo , Belkhamssa Fatima Zohra , Zupan Ivan , Hendriks Iris E.
Published: September 2019

A mass mortality event is devastating the populations of the endemic bivalve Pinna nobilis in the Mediterranean Sea from early autumn 2016. A newly described Haplosporidian endoparasite (Haplosporidium pinnae) is the most probable cause of this ecological catastrophe placing one of the largest bivalves of the world on the brink of extinction. As a pivotal step towards Pinna nobilis conservation, this contribution combines scientists and citizens’ data to address the fast- and vast-dispersion and prevalence outbreaks of the pathogen. Therefore, the potential role of currents on parasite expansion was addressed by means of drift simulations of virtual particles in a high-resolution regional currents model. A generalized additive model was implemented to test if environmental factors could modulate the infection of Pinna nobilis populations. The results strongly suggest that the parasite has probably dispersed regionally by surface currents, and that the disease expression seems to be closely related to temperatures above 13.5 °C and to a salinity range between 36.5–39.7 psu. The most likely spread of the disease along the Mediterranean basin associated with scattered survival spots and very few survivors (potentially resistant individuals), point to a challenging scenario for conservation of the emblematic Pinna nobilis, which will require fast and strategic management measures and should make use of the essential role citizen science projects can play.