bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of SCATSat‐1 Retrieved Wind Vectors on Short‐Range WRF Model Predictions Over the South Asia Region
Authors: Kumar Prashant , Gairola R. M.
Published: November 2019

The Indian Space Research Organization launched SCATterometer Satellite‐1 (SCATSat­1) satellite by PSLV‐C35 on 26 September 2016 from Sriharikota. In this study, SCATSat‐1 retrieved winds are assimilated in the regional atmospheric model subsequent to preliminary evaluation of SCATSat‐1 retrieved winds against National Centers for Environmental Prediction final analyses. The Weather Research and Forecasting (WRF) model and its three‐ and four‐dimensional variational (3D‐Var and 4D‐Var) data assimilation system are used to demonstrate the importance of SCATSat‐1 retrieved winds on short‐range weather prediction. In the first set of experiments, two parallel runs are performed with and without assimilation of SCATSat‐1 retrieved winds using 6‐hourly cycling during entire month of December 2016. Results suggest that assimilation of SCATSat‐1 retrieved winds improved the WRF model analyses and subsequent forecasts of winds and moisture. In the second set of experiments, parallel assimilation experiments are performed with SCATSat‐1 retrieved winds using 3D‐Var and 4D‐Var method for the entire lifetime of tropical cyclone Ockhi as a case study. Results suggest that assimilation of SCATSat‐1 winds has positive impact on Ockhi tropical cyclone prediction with slightly better forecast skill for 4D‐Var technique. Moreover, assimilation of SCATSat‐1 retrieved winds improved predictions of surface convergence and accumulated rainfall. In the last set of experiments, forecast sensitivity to observations are performed for SCATSat‐1 retrieved different resolution winds using the WRF tangent linear and adjoint models for the entire lifetime of tropical cyclone Ockhi. Results suggest that SCATSat‐1 retrieved winds have positive impact on tropical cyclone simulation.
Advances in Quantifying Streamflow Variability Across Continental Scales: 1. Identifying Natural and Anthropogenic Controlling Factors in the USA Using a Spatially Explicit Modeling Method
Authors: Alexander Richard B. , Schwarz Gregory E. , Boyer Elizabeth W.
Published: November 2019

Despite considerable progress in hydrological modeling, challenges remain in the interpretation and accurate transfer of hydrological information across watersheds and scales. In the conterminous United States (CONUS), these limitations are related to spatial inconsistencies and constraints in hydrological model structures, including a lack of spatially explicit process components (streams, reservoirs, and watershed development) and restricted estimation of model parameters across watersheds. Collectively, such limitations can impede identification of the causes of streamflow variations across the diversity of watershed sizes and land uses in the CONUS and contribute to model imprecision and spatial inconsistencies in prediction uncertainties. We addressed these concerns with a new approach, the first hybrid (statistical‐mechanistic) SPARROW (SPAtially Referenced Regression On Watershed attributes) model of long‐term mean annual streamflow, applied across diverse environmental settings of the CONUS. The hybrid model coupled previous catchment‐scale (1 km) water balance predictions of “natural” unit area runoff, which are inclusive of major water cycling processes, with additional explanatory variables (e.g., soils, vegetation, land use, topography, water losses in streams, and reservoirs) that account for the effects of natural and cultural water supply and demand processes that operate over large spatial scales and explain streamflow variability across CONUS river basins. Accounting for these statistically unique effects, including a nonlinear surface area‐dependent scaling of water loss in river networks, significantly improved the accuracy of mean streamflow predictions in CONUS basins. Our hybrid modeling approach provides new methods for transferring hydrological information to ungauged locations in river networks, especially those in larger and more culturally diverse CONUS watersheds.
BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration
Authors: Loveridge Carolyn J. , Slater Sarah , Campbell Kirsteen J. , Nam Noor A. , Knight John , Ahmad Imran , Hedley Ann , Lilla Sergio , Repiscak Peter , Patel Rachana , Salji Mark , Fleming Janis , Mitchell Louise , Nixon Colin , Strathdee Douglas , Neilson Matthew , Ntala Chara , Bryson Sheila , Zanivan Sara , Edwards Joanne , Robson Craig N. , Goodyear Carl S. , Blyth Karen , Leung Hing Y.
Published: November 2019

BRF1 is a rate-limiting factor for RNA Polymerase III-mediated transcription and is elevated in numerous cancers. Here, we report that elevated levels of BRF1 associate with poor prognosis in human prostate cancer. In vitro studies in human prostate cancer cell lines demonstrated that transient overexpression of BRF1 increased cell proliferation whereas the transient downregulation of BRF1 reduced proliferation and mediated cell cycle arrest. Consistent with our clinical observations, BRF1 overexpression in a Pten-deficient mouse (PtenΔ/ΔBRF1Tg) prostate cancer model accelerated prostate carcinogenesis and shortened survival. In PtenΔ/ΔBRF1Tg tumours, immune and inflammatory processes were altered, with reduced tumoral infiltration of neutrophils and CD4 positive T cells, which can be explained by decreased levels of complement factor D (CFD) and C7 components of the complement cascade, an innate immune pathway that influences the adaptive immune response. We tested if the secretome was involved in BRF1-driven tumorigenesis. Unbiased proteomic analysis on BRF1-overexpresing PC3 cells confirmed reduced levels of CFD in the secretome, implicating the complement system in prostate carcinogenesis. We further identify that expression of C7 significantly correlates with expression of CD4 and has the potential to alter clinical outcome in human prostate cancer, where low levels of C7 associate with poorer prognosis.
TGF-β1 accelerates the hepatitis B virus X-induced malignant transformation of hepatic progenitor cells by upregulating miR-199a-3p
Authors: Dong Ke-shuai , Chen Yan , Yang Guang , Liao Zhi-bin , Zhang Hong-wei , Liang Hui-fang , Chen Xiao-ping , Dong Han-hua
Published: November 2019

Increasing evidence has suggested that liver cancer arises partially from transformed hepatic progenitor cells (HPCs). However, the detailed mechanisms underlying HPC transformation are poorly understood. In this study, we provide evidence linking the coexistence of hepatitis B virus X protein (HBx) and transforming growth factor beta 1 (TGF-β1) with miR-199a-3p in the malignant transformation of HPCs. The examination of liver cancer specimens demonstrated that HBx and TGF-β1 expression was positively correlated with epithelial cell adhesion molecule (EpCAM) and cluster of differentiation 90 (CD90). Importantly, EpCAM and CD90 expression was much higher in the specimens expressing both high HBx and high TGF-β1 than in those with high HBx or high TGF-β1 and the double-low-expression group. HBx and TGF-β1 double-high expression was significantly associated with poor prognosis in primary liver cancer. We also found that HBx and TGF-β1 induced the transformation of HPCs into hepatic cancer stem cells and promoted epithelial–mesenchymal transformation, which was further enhanced by concomitant HBx and TGF-β1 exposure. Moreover, activation of the c-Jun N-terminal kinase (JNK)/c-Jun pathway was involved in the malignant transformation of HPCs. miR-199a-3p was identified as a significantly upregulated microRNA in HPCs upon HBx and TGF-β1 exposure, which were shown to promote miR-199a-3p expression via c-Jun-mediated activation. Finally, we found that miR-199a-3p was responsible for the malignant transformation of HPCs. In conclusion, our results provide evidence that TGF-β1 cooperates with HBx to promote the malignant transformation of HPCs through a JNK/c-Jun/miR-199a-3p-dependent pathway. This may open new avenues for therapeutic interventions targeting the malignant transformation of HPCs in treating liver cancer.
Water vapor thermal therapy to alleviate catheter-dependent urinary retention secondary to benign prostatic hyperplasia
Authors: McVary Kevin T. , Holland Bradley , Beahrs J. Randolf
Published: November 2019

Background

Water vapor thermal therapy utilizes convectively delivered thermal energy to target ablation of obstructive prostatic tissue. We report results of this thermal therapy for relief of nonneurogenic complete urinary retention associated with BPH.

Patients and methods

We conducted a retrospective analysis of 38 catheter-dependent men with complete urinary retention consecutively enrolled in a registry in two centers: median age 75.5 years and multiple comorbidities, median prostate volume 58.5 cc (23–153), median 2 failed trials without catheter (TWOCs), and median catheter dependency 3 months (0.3–35). The Rezūm™ System thermal therapy procedure was performed in an ambulatory surgery center with conscious sedation or an office procedure room with a modified periprostatic block. Water vapor injections were customized to the configuration of the hyperplastic gland, including median lobe and/or enlarged central zone.

Results

Of the 38 treated patients, one was lost to follow-up and 26 of 37 (70.3%) voided spontaneously (mean of 1.6 ± 0.8 TWOCs) and were catheter free a median of 26 days (range 4–65) after the procedure; 18 of these 26 (69%) patients discontinued BPH medications. No significant differences in age, prostate volume, number of water vapor injections, or presence of the median lobe were associated with predicting a successful treatment outcome. Duration of follow-up for 20 catheter-free patients was a median of 475 days or 15.8 months (140–804 days); six patients were followed a median of 31.5 days (0–60). Adverse events were infrequent, mild, and resolved quickly including dysuria in five patients (13%), gross hematuria in four (10.5%), and UTIs in two (2.6%) with indwelling catheters.

Conclusions

Water vapor thermal therapy may provide an effective and safe alternative to surgical treatment in this group of catheter-dependent patients in complete urinary retention.
Breast milk-derived human milk oligosaccharides promote Bifidobacterium interactions within a single ecosystem
Authors: Lawson Melissa A E , O’Neill Ian J , Kujawska Magdalena , Gowrinadh Javvadi Sree , Wijeyesekera Anisha , Flegg Zak , Chalklen Lisa , Hall Lindsay J
Published: November 2019

Diet-microbe interactions play an important role in modulating the early-life microbiota, with Bifidobacterium strains and species dominating the gut of breast-fed infants. Here, we sought to explore how infant diet drives distinct bifidobacterial community composition and dynamics within individual infant ecosystems. Genomic characterisation of 19 strains isolated from breast-fed infants revealed a diverse genomic architecture enriched in carbohydrate metabolism genes, which was distinct to each strain, but collectively formed a pangenome across infants. Presence of gene clusters implicated in digestion of human milk oligosaccharides (HMOs) varied between species, with growth studies indicating that within single infants there were differences in the ability to utilise 2′FL and LNnT HMOs between strains. Cross-feeding experiments were performed with HMO degraders and non-HMO users (using spent or ‘conditioned’ media and direct co-culture). Further 1H-NMR analysis identified fucose, galactose, acetate, and N-acetylglucosamine as key by-products of HMO metabolism; as demonstrated by modest growth of non-HMO users on spend media from HMO metabolism. These experiments indicate how HMO metabolism permits the sharing of resources to maximise nutrient consumption from the diet and highlights the cooperative nature of bifidobacterial strains and their role as ‘foundation’ species in the infant ecosystem. The intra- and inter-infant bifidobacterial community behaviour may contribute to the diversity and dominance of Bifidobacterium in early life and suggests avenues for future development of new diet and microbiota-based therapies to promote infant health.
Integrative proteomics and pharmacogenomics analysis of methylphenidate treatment response
Authors: da Silva Bruna S. , Leffa Douglas T. , Beys-da-Silva Walter O. , Torres Iraci L. S. , Rovaris Diego L. , Victor Marcelo M. , Rohde Luis A. , Mota Nina R. , Oliveira Carla de , Berger Markus , Yates John R. , Sabnis Renuka , Peña Ramón Díaz , Campos Alexandre Rosa , Grevet Eugenio H. , Santi Lucelia , Bau Claiton H. D. , Contini Verônica
Published: November 2019

Transcriptomics and candidate gene/protein expression studies have indicated several biological processes modulated by methylphenidate (MPH), widely used in attention-deficit/hyperactivity disorder (ADHD) treatment. However, the lack of a differential proteomic profiling of MPH treatment limits the understanding of the most relevant mechanisms by which MPH exerts its pharmacological effects at the molecular level. Therefore, our aim is to investigate the MPH-induced proteomic alterations using an experimental design integrated with a pharmacogenomic analysis in a translational perspective. Proteomic analysis was performed using the cortices of Wistar-Kyoto rats, which were treated by gavage with MPH (2 mg/kg) or saline for two weeks (n = 6/group). After functional enrichment analysis of the differentially expressed proteins (DEP) in rats, the significant biological pathways were tested for association with MPH response in adults with ADHD (n = 189) using genome-wide data. Following MPH treatment in rats, 98 DEPs were found (P < 0.05 and FC < −1.0 or > 1.0). The functional enrichment analysis of the DEPs revealed 18 significant biological pathways (gene-sets) modulated by MPH, including some with recognized biological plausibility, such as those related to synaptic transmission. The pharmacogenomic analysis in the clinical sample evaluating these pathways revealed nominal associations for gene-sets related to neurotransmitter release and GABA transmission. Our results, which integrate proteomics and pharmacogenomics, revealed putative molecular effects of MPH on several biological processes, including oxidative stress, cellular respiration, and metabolism, and extended the results involving synaptic transmission pathways to a clinical sample. These findings shed light on the molecular signatures of MPH effects and possible biological sources of treatment response variability.
Maternal embryonic leucine zipper kinase is a novel target for diffuse large B cell lymphoma and mantle cell lymphoma
Authors: Maes Anke , Maes Ken , Vlummens Philip , De Raeve Hendrik , Devin Julie , Szablewski Vanessa , De Veirman Kim , Menu Eline , Moreaux Jerome , Vanderkerken Karin , De Bruyne Elke
Published: November 2019

Diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) are among the most aggressive B cell non-Hodgkin lymphomas. Maternal embryonic leucine zipper kinase (MELK) plays a role in cancer cell cycle progression and is associated with poor prognosis in several cancer cell types. In this study, the role of MELK in DLBCL and MCL and the therapeutic potential of MELK targeting is evaluated. MELK is highly expressed in DLBCL and MCL patient samples, correlating with a worse clinical outcome in DLBCL. Targeting MELK, using the small molecule OTSSP167, impaired cell growth and survival and induced caspase-mediated apoptosis in the lymphoma cells. Western blot analysis revealed that MELK targeting decreased the phosphorylation of FOXM1 and the protein levels of EZH2 and several mitotic regulators, such as Cdc25B, cyclin B1, Plk-1, and Aurora kinases. In addition, OTSSP167 also sensitized the lymphoma cells to the clinically relevant Bcl-2 inhibitor venetoclax by strongly reducing Mcl1 levels. Finally, OTSSP167 treatment of A20-inoculated mice resulted in a significant prolonged survival. In conclusion, targeting MELK with OTSSP167 induced strong anti-lymphoma activity both in vitro and in vivo. These findings suggest that MELK could be a potential new target in these aggressive B cell malignancies.
Tumor suppressor ZHX2 inhibits NAFLD–HCC progression via blocking LPL-mediated lipid uptake
Authors: Wu Zhuanchang , Ma Hongxin , Wang Liyuan , Song Xiaojia , Zhang Jie , Liu Wen , Ge Yutong , Sun Yang , Yu Xiangguo , Wang Zehua , Wang Jianping , Zhang Yankun , Li Chunyang , Li Nailin , Gao Lifen , Liang Xiaohong , Yue Xuetian , Ma Chunhong
Published: November 2019

Non-alcoholic fatty liver disease (NAFLD) leads to hepatocellular carcinoma (HCC). However, the underlying mechanism remains largely unclear. Here, we investigated the role of the tumor suppressor Zinc fingers and homeoboxes 2 (ZHX2) in the progression of NAFLD to HCC. ZHX2 expression was significantly decreased in fatty liver tissues, especially in the liver with NAFLD–HCC. ZHX2 overexpression disturbed lipid homeostasis of cultured HCC cells, and inhibited lipid deposition in hepatocytes both in vitro and in vivo. Moreover, ZHX2 inhibited uptake of exogenous lipids through transcriptional suppression of lipid lipase (LPL), leading to retarded proliferation of HCC cells. Importantly, LPL overexpression significantly reversed ZHX2-mediated inhibition of HCC cell proliferation, xenograft tumor growth, lipid deposition, and spontaneous liver tumor formation. Consistently, IHC staining demonstrated a negative correlation of ZHX2 with LPL in an HCC cohort. Collectively, ZHX2 protects hepatocytes from abnormal lipid deposition in NAFLD through transcriptional repression of LPL, which subsequently retards cell growth and NAFLD–HCC progression. These findings illustrate a novel mechanism of NAFLD progression into HCC.
FGF21 augments autophagy in random-pattern skin flaps via AMPK signaling pathways and improves tissue survival
Authors: Zhou Kailiang , Chen Huanwen , Lin Jinti , Xu Hui , Wu Hongqiang , Bao Guodong , Li Jiafeng , Deng Xiangyang , Shui Xiaolong , Gao Weiyang , Ding Jian , Xiao Jian , Xu Huazi
Published: November 2019

Random-pattern skin flap is commonly used for surgical tissue reconstruction due to its ease and lack of axial vascular limitation. However, ischemic necrosis is a common complication, especially in distal parts of skin flaps. Previous studies have shown that FGF21 can promote angiogenesis and protect against ischemic cardiovascular disease, but little is known about the effect of FGF21 on flap survival. In this study, using a rat model of random skin flaps, we found that the expression of FGF21 is significantly increased after establishment skin flaps, suggesting that FGF21 may exert a pivotal effect on flap survival. We conducted experiments to elucidate the role of FGF21 in this model. Our results showed that FGF21 directly increased the survival area of skin flaps, blood flow intensity, and mean blood vessel density through enhancing angiogenesis, inhibiting apoptosis, and reducing oxidative stress. Our studies also revealed that FGF21 administration leads to an upregulation of autophagy, and the beneficial effects of FGF21 were reversed by 3-methyladenine (3MA), which is a well-known inhibitor of autophagy, suggesting that autophagy plays a central role in FGF21’s therapeutic benefit on skin flap survival. In our mechanistic investigation, we found that FGF21-induced autophagy enhancement is mediated by the dephosphorylation and nuclear translocation of TFEB; this effect was due to activation of AMPK-FoxO3a-SPK2-CARM1 and AMPK-mTOR signaling pathways. Together, our data provides novel evidence that FGF21 is a potent modulator of autophagy capable of significantly increasing random skin flap viability, and thus may serve as a promising therapy for clinical use.
Becker muscular dystrophy caused by exon 2-truncating mutation of DMD
Authors: Ikeda Tetsuhiko , Fujinaka Hidehiko , Goto Kiyoe , Nakajima Takashi , Ozawa Tetsuo
Published: November 2019

Nonsense and frameshift mutations of the dystrophin (DMD) gene usually cause severe Duchenne muscular dystrophy (DMD). Interestingly, however, premature stop codons in exons 1 and 2 result in relatively mild Becker muscular dystrophy (BMD). Herein, we report the clinical course of a patient with a very mild phenotype of BMD caused by a frameshift mutation, NM_004006.2: c.40_41del GA/p.(Glu14ArgfsX17), in exon 2 of the DMD gene.
Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome
Authors: Aguado Julio , Sola-Carvajal Agustin , Cancila Valeria , Revêchon Gwladys , Ong Peh Fern , Jones-Weinert Corey Winston , Wallén Arzt Emelie , Lattanzi Giovanna , Dreesen Oliver , Tripodo Claudio , Rossiello Francesca , Eriksson Maria , d’Adda di Fagagna Fabrizio
Published: November 2019

Hutchinson–Gilford progeria syndrome (HGPS) is a genetic disorder characterized by premature aging features. Cells from HGPS patients express progerin, a truncated form of Lamin A, which perturbs cellular homeostasis leading to nuclear shape alterations, genome instability, heterochromatin loss, telomere dysfunction and premature entry into cellular senescence. Recently, we reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) which control the DNA damage response (DDR) at dysfunctional telomeres. Here we show that progerin-induced telomere dysfunction induces the transcription of tncRNAs. Their functional inhibition by sequence-specific telomeric antisense oligonucleotides (tASOs) prevents full DDR activation and premature cellular senescence in various HGPS cell systems, including HGPS patient fibroblasts. We also show in vivo that tASO treatment significantly enhances skin homeostasis and lifespan in a transgenic HGPS mouse model. In summary, our results demonstrate an important role for telomeric DDR activation in HGPS progeroid detrimental phenotypes in vitro and in vivo.
Microbial reduction of metal-organic frameworks enables synergistic chromium removal
Authors: Springthorpe Sarah K. , Dundas Christopher M. , Keitz Benjamin K.
Published: November 2019

Redox interactions between electroactive bacteria and inorganic materials underpin many emerging technologies, but commonly used materials (e.g., metal oxides) suffer from limited tunability and can be challenging to characterize. In contrast, metal-organic frameworks exhibit well-defined structures, large surface areas, and extensive chemical tunability, but their utility as microbial substrates has not been examined. Here, we report that metal-organic frameworks can support the growth of the metal-respiring bacteriumShewanella oneidensis, specifically through the reduction of Fe(III). In a practical application, we show that cultures containingS. oneidensisand reduced metal-organic frameworks can remediate lethal concentrations of Cr(VI) over multiple cycles, and that pollutant removal exceeds the performance of either component in isolation or bio-reduced iron oxides. Our results demonstrate that frameworks can serve as growth substrates and suggest that they may offer an alternative to metal oxides in applications seeking to combine the advantages of bacterial metabolism and synthetic materials.
Fast, accurate, and transferable many-body interatomic potentials by symbolic regression
Authors: Hernandez Alberto , Balasubramanian Adarsh , Yuan Fenglin , Mason Simon A. M. , Mueller Tim
Published: November 2019

The length and time scales of atomistic simulations are limited by the computational cost of the methods used to predict material properties. In recent years there has been great progress in the use of machine-learning algorithms to develop fast and accurate interatomic potential models, but it remains a challenge to develop models that generalize well and are fast enough to be used at extreme time and length scales. To address this challenge, we have developed a machine-learning algorithm based on symbolic regression in the form of genetic programming that is capable of discovering accurate, computationally efficient many-body potential models. The key to our approach is to explore a hypothesis space of models based on fundamental physical principles and select models within this hypothesis space based on their accuracy, speed, and simplicity. The focus on simplicity reduces the risk of overfitting the training data and increases the chances of discovering a model that generalizes well. Our algorithm was validated by rediscovering an exact Lennard-Jones potential and a Sutton-Chen embedded-atom method potential from training data generated using these models. By using training data generated from density functional theory calculations, we found potential models for elemental copper that are simple, as fast as embedded-atom models, and capable of accurately predicting properties outside of their training set. Our approach requires relatively small sets of training data, making it possible to generate training data using highly accurate methods at a reasonable computational cost. We present our approach, the forms of the discovered models, and assessments of their transferability, accuracy and speed.
Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein Protect Against Diverse α-Synuclein Mediated Dysfunctions
Authors: Tóth Gergely , Neumann Thomas , Berthet Amandine , Masliah Eliezer , Spencer Brian , Tao Jiahui , Jobling Michael F. , Gardai Shyra J. , Bertoncini Carlos W. , Cremades Nunilo , Bova Michael , Ballaron Stephen , Chen Xiao-Hua , Mao Wenxian , Nguyen Phuong , Tabios Mariano C. , Tambe Mitali A. , Rochet Jean-Christophe , Junker Hans-Dieter , Schwizer Daniel , Sekul Renate , Ott Inge , Anderson John P. , Szoke Balazs , Hoffman Wherly , Christodoulou John , Yednock Ted , Agard David A. , Schenk Dale , McConlogue Lisa
Published: November 2019

The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson’s disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson’s disease.
Coincidence of photic zone euxinia and impoverishment of arthropods in the aftermath of the Frasnian-Famennian biotic crisis
Authors: Broda Krzysztof , Marynowski Leszek , Rakociński Michał , Zatoń Michał
Published: November 2019

The lowermost Famennian deposits of the Kowala quarry (Holy Cross Mountains, Poland) are becoming famous for their rich fossil content such as their abundant phosphatized arthropod remains (mostly thylacocephalans). Here, for the first time, palaeontological and geochemical data were integrated to document abundance and diversity patterns in the context of palaeoenvironmental changes. During deposition, the generally oxic to suboxic conditions were interrupted at least twice by the onset of photic zone euxinia (PZE). Previously, PZE was considered as essential in preserving phosphatised fossils from, e.g., the famous Gogo Formation, Australia. Here, we show, however, that during PZE, the abundance of arthropods drastically dropped. The phosphorous content during PZE was also very low in comparison to that from oxic-suboxic intervals where arthropods are the most abundant. As phosphorous is essential for phosphatisation but also tends to flux off the sediment during bottom water anoxia, we propose that the PZE in such a case does not promote the fossilisation of the arthropods but instead leads to their impoverishment and non-preservation. Thus, the PZE conditions with anoxic bottom waters cannot be presumed as universal for exceptional fossil preservation by phosphatisation, and caution must be paid when interpreting the fossil abundance on the background of redox conditions.
The impact of Climate Change on the Western Pacific Subtropical High and the related ozone pollution in Shanghai, China
Authors: Chang Luyu , Xu Jianming , Tie Xuexi , Gao Wei
Published: November 2019

Severe ozone (O3) episodes occur frequently in Shanghai during late-summers. We define geopotential height averaged over the key area region (122.5°E-135°E, 27.5°N -35°N) at 500 hPa as a WPSH_SHO3 index which has high positive correlation with surface O3 concentration in Shanghai. In addition, the index has a significant long-term increasing trend during the recent 60 years. Analysis shows the meteorological conditions under the strong WPSH_SHO3 climate background (compared to the weak background) have several important anomalies: (1) A strong WPSH center occurs over the key area region. (2) The cloud cover is less, resulting in high solar radiation and low humidity, enhancing the photochemical reactions of O3. (3) The near-surface southwesterly winds are more frequent, enhancing the transport of upwind pollutants and O3 precursors from polluted regions to Shanghai and producing higher O3 chemical productions. This study suggests that the global climate change could lead to a stronger WPSH in the key region, enhancing ozone pollution in Shanghai. A global chemical/transport model (MOZART-4) is applied to show that the O3 concentrations can be 30 ppbv higher under a strong WPSH_SHO3 condition than a weak condition, indicating the important effect of the global climate change on local air pollution in Shanghai.
Different lasers reveal different skin microcirculatory flowmotion - data from the wavelet transform analysis of human hindlimb perfusion
Authors: Rodrigues L. Monteiro , Rocha Clemente , Ferreira Hugo , Silva Henrique
Published: November 2019

Laser Doppler flowmetry (LDF) and reflection photoplethysmography (PPG) are standard technologies to access microcirculatory function in vivo. However, different light frequencies mean different interaction with tissues, such that LDF and PPG flowmotion curves might have distinct meanings, particularly during adaptative (homeostatic) processes. Therefore, we analyzed LDF and PPG perfusion signals obtained in response to opposite challenges. Young healthy volunteers, both sexes, were assigned to Group 1 (n = 29), submitted to a normalized Swedish massage procedure in one lower limb, increasing perfusion, or Group 2 (n = 14), submitted to a hyperoxia challenge test, decreasing perfusion. LDF (Periflux 5000) and PPG (PLUX-Biosignals) green light sensors applied distally on both lower limbs recorded perfusion changes for each experimental protocol. Both techniques detected the perfusion increase with massage, and the perfusion decrease with hyperoxia, in both limbs. Further analysis with the wavelet transform (WT) revealed better depth-related discriminative ability for PPG (more superficial, less blood sampling) compared with LDF in both challenges. Spectral amplitude profiles consistently demonstrated better sensitivity for LDF, especially regarding the lowest frequency components. Strong correlations between components were not found. Therefore, LDF and PPG flowmotion curves are not equivalent, a relevant finding to better study microcirculatory physiology.
Genomic Patterns of Homozygosity in Chinese Local Cattle
Authors: Xu Lingyang , Zhao Guoyao , Yang Liu , Zhu Bo , Chen Yan , Zhang Lupei , Gao Xue , Gao Huijiang , Liu George E. , Li Junya
Published: November 2019

Genome-wide single nucleotide polymorphism (SNP) arrays can be used to explore homozygosity segments, where two haplotypes inherited from the parents are identical. In this study, we identified a total of 27,358 runs of homozygosity (ROH) with an average of 153 ROH events per animal in Chinese local cattle. The sizes of ROH events varied considerably ranging from 0.5 to 66 Mb, with an average length of 1.22 Mb. The highest average proportion of the genome covered by ROH (~11.54% of the cattle genome) was found in Nanda cattle (NDC) from South China, whereas the lowest average proportion (~3.1%) was observed in Yanhuang cattle (YHC). The average estimated FROH ranged from 0.03 in YHC to 0.12 in NDC. For each of three ROH classes with different sizes (Small 0.5–1 Mb, Medium 1–5 Mb and Large >5 Mb), the numbers and total lengths of ROH per individual showed considerable differences across breeds. Moreover, we obtained 993 to 3603 ROH hotspots (which were defined where ROH frequency at a SNP within each breed exceeded the 1% threshold) among eight cattle breeds. Our results also revealed several candidate genes embedded with ROH hotspots which may be related to environmental conditions and local adaptation. In conclusion, we generated baselines for homozygosity patterns in diverse Chinese cattle breeds. Our results suggested that selection has, at least partially, played a role with other factors in shaping the genomic patterns of ROH in Chinese local cattle and might provide valuable insights for understanding the genetic basis of economic and adaptive traits.
Relativistic quantum heat engine from uncertainty relation standpoint
Authors: Chattopadhyay Pritam , Paul Goutam
Published: November 2019

Established heat engines in quantum regime can be modeled with various quantum systems as working substances. For example, in the non-relativistic case, we can model the heat engine using infinite potential well as a working substance to evaluate the efficiency and work done of the engine. Here, we propose quantum heat engine with a relativistic particle confined in the one-dimensional potential well as working substance. The cycle comprises of two isothermal processes and two potential well processes of equal width, which forms the quantum counterpart of the known isochoric process in classical nature. For a concrete interpretation about the relation between the quantum observables with the physically measurable parameters (like the efficiency and work done), we develop a link between the thermodynamic variables and the uncertainty relation. We have used this model to explore the work extraction and the efficiency of the heat engine for a relativistic case from the standpoint of uncertainty relation, where the incompatible observables are the position and the momentum operators. We are able to determine the bounds (the upper and the lower bounds) of the efficiency of the heat engine through the thermal uncertainty relation.
VAR2CSA binding phenotype has ancient origin and arose before Plasmodium falciparum crossed to humans: implications in placental malaria vaccine design
Authors: Gangnard Stéphane , Chêne Arnaud , Dechavanne Sébastien , Srivastava Anand , Avril Marion , Smith Joseph D. , Gamain Benoît
Published: November 2019

VAR2CSA is a leading candidate for developing a placental malaria (PM) vaccine that would protect pregnant women living in malaria endemic areas against placental infections and improve birth outcomes. Two VAR2CSA-based PM vaccines are currently under clinical trials, but it is still unclear if the use of a single VAR2CSA variant will be sufficient to induce a broad enough humoral response in humans to cross-react with genetically diverse parasite populations. Additional immuno-focusing vaccine strategies may therefore be required to identify functionally conserved antibody epitopes in VAR2CSA. We explored the possibility that conserved epitopes could exist between VAR2CSA from the chimpanzee parasite Plasmodium reichenowi and Plasmodium falciparum sequences. Making use of VAR2CSA recombinant proteins originating from both species, we showed that VAR2CSA from P. reichenowi (Pr-VAR2CSA) binds to the placental receptor CSA with high specificity and affinity. Antibodies raised against Pr-VAR2CSA were able to recognize native VAR2CSA from different P. falciparum genotypes and to inhibit the interaction between CSA and P. falciparum-infected erythrocytes expressing different VAR2CSA variants. Our work revealed the existence of cross-species inhibitory epitopes in VAR2CSA and calls for pre-clinical studies assessing the efficacy of novel VAR2CSA-based cross-species boosting regimens.
Functional tunability from a distance: Rheostat positions influence allosteric coupling between two distant binding sites
Authors: Wu Tiffany , Swint-Kruse Liskin , Fenton Aron W.
Published: November 2019

For protein mutagenesis, a common expectation is that important positions will behave like on/off “toggle” switches (i.e., a few substitutions act like wildtype, most abolish function). However, there exists another class of important positions that manifests a wide range of functional outcomes upon substitution: “rheostat” positions. Previously, we evaluated rheostat positions located near the allosteric binding sites for inhibitor alanine (Ala) and activator fructose-1,6-bisphosphate (Fru-1,6-BP) in human liver pyruvate kinase. When substituted with multiple amino acids, many positions demonstrated moderate rheostatic effects on allosteric coupling between effector binding and phosphoenolpyruvate (PEP) binding in the active site. Nonetheless, the combined outcomes of all positions sampled the full range of possible allosteric coupling (full tunability). However, that study only evaluated allosteric tunability of “local” positions, i.e., positions were located near the binding sites of the allosteric ligand being assessed. Here, we evaluated tunability of allosteric coupling when mutated sites were distant from the allosterically-coupled binding sites. Positions near the Ala binding site had rheostatic outcomes on allosteric coupling between Fru-1,6-BP and PEP binding. In contrast, positions in the Fru-1,6-BP site exhibited modest effects on coupling between Ala and PEP binding. Analyzed in aggregate, both PEP/Ala and PEP/Fru-1,6-BP coupling were again fully tunable by amino acid substitutions at this limited set of distant positions. Furthermore, some positions exhibited rheostatic control over multiple parameters and others exhibited rheostatic effects on one parameter and toggle control over a second. These findings highlight challenges in efforts to both predict/interpret mutational outcomes and engineer functions into proteins.
Comparison of pressure- and volume-controlled ventilation during laparoscopic colectomy in patients with colorectal cancer
Authors: Choi Sangbong , Yang So Young , Choi Geun Joo , Kim Beom Gyu , Kang Hyun
Published: November 2019

This study investigated the differences in airway mechanics and postoperative respiratory complications using two mechanical ventilation modalities and the relationship between biomarkers and postoperative respiratory complications in patients with colorectal cancer who underwent laparoscopic colectomy. Forty-six patients with colorectal cancer scheduled for laparoscopic colectomy were randomly allocated to receive mechanical ventilation using either volume-controlled ventilation (VCV) (n = 23) or pressure-controlled ventilation (PCV) (n = 23). Respiratory parameters were measured and plasma sRAGE and S100A12 were collected 20 minutes after the induction of anesthesia in the supine position without pneumoperitoneum (T1), 40 minutes after 30° Trendelenburg position with pneumoperitoneum (T2), at skin closure in the supine position (T3), and 24 hours after the operation (T4). The peak airway pressure (Ppeak) at T2 was lower in the PCV group than in the VCV group. The plateau airway pressures (Pplat) at T2 and T3 were higher in the VCV group than in the PCV group. Plasma levels of sRAGE at T2 and T3 were 1.6- and 1.4-fold higher in the VCV group than in the PCV group, while plasma S100A12 levels were 2.6- and 2.2-fold higher in the VCV group than in the PCV group, respectively. There were significant correlations between Ppeak and sRAGE, and between Ppeak and S100A12. There were also correlations between Pplat and sRAGE, and between Pplat and S100A12. sRAGE and S100A12 levels at T2 and T3 showed high sensitivity and specificity for postoperative respiratory complications. Postoperative respiratory complications were 3-fold higher in the VCV group than in the PCV group. In conclusion, during laparoscopic colectomy in patients with colorectal cancer, the peak airway pressure, the incidence of postoperative respiratory complications, and plasma sRAGE and S100A12 levels were lower in the PCV group than in the VCV group. Intra- and postoperative plasma sRAGE and S100A12 were useful for predicting the development of postoperative respiratory complications.
Association of longitudinal risk profile trajectory clusters with adipose tissue depots measured by magnetic resonance imaging
Authors: Rospleszcz Susanne , Lorbeer Roberto , Storz Corinna , Schlett Christopher L. , Meisinger Christa , Thorand Barbara , Rathmann Wolfgang , Bamberg Fabian , Lieb Wolfgang , Peters Annette
Published: November 2019

The objective of the study was to identify associations of longitudinal trajectories of traditional cardiometabolic risk factors with abdominal and ectopic adipose tissue depots measured by magnetic resonance imaging (MRI). We measured total abdominal, visceral, and subcutaneous adipose tissue in liter and intrahepatic, intrapancreatic and renal sinus fat as fat fractions by MRI in 325 individuals free of cardiovascular disease at Exam 3 of a population-based cohort. We related these MRI measurements at Exam 3 to longitudinal risk profile trajectory clusters, based on risk factor measurements from Exam 3, Exam 2 (seven years prior to MRI) and Exam 1 (14 years prior to MRI). Based on the levels and longitudinal trajectories of several risk factors (blood pressure, lipid profile, anthropometric measurements, HbA1c), we identified three different trajectory clusters. These clusters displayed a graded association with all adipose tissue traits after adjustment for potential confounders (e.g. visceral adipose tissue: βClusterII = 1.30 l, 95%-CI:[0.84 l;1.75 l], βClusterIII = 3.32 l[2.74 l;3.90 l]; intrahepatic: EstimateClusterII = 1.54[1.27,1.86], EstimateClusterIII = 2.48[1.93,3.16]. Associations remained statistically significant after additional adjustment for the risk factor levels at Exam 1 or Exam 3, respectively. Trajectory clusters provided additional information in explaining variation in the different fat compartments beyond risk factor profiles obtained at individual exams. In conclusion, sustained high risk factor levels and unfavorable trajectories are associated with high levels of adipose tissue; however, the association with cardiometabolic risk factors varies substantially between different ectopic adipose tissues. Trajectory clusters, covering longitudinal risk profiles, provide additional information beyond single-point risk profiles. This emphasizes the need to incorporate longitudinal information in cardiometabolic risk estimation.
Surface effects on the self equilibrium, self bending and symmetry lowering of nanofilms
Authors: Li Jiangang , Han Meiqin , Li Lingfang , Gao Zhixiang , Zhang Huili
Published: November 2019

A continuum theoretical scheme for self equilibrium, self bending and symmetry lowering of nanofilms was obtained by considering surface elasticity, surface stress and the corresponding surface slice thickness. When surface stress and surface elasticity are both balance, the nanofilm is simply compressed (or expanded). When the surface stress or surface elasticity is imbalance, the nanofilm will bend. On the other hand, surface stress and surface elasticity imbalances induce a nanofilm to curl into a nanotube when the nanofilm is very thin. The surface stress and surface elasticity balances induce uniform in-plane strain (the overall film relaxation), while the vertical direction of the nanofilm relaxes reversely due to Poisson’s effect. And then, the crystal lattice constants of in-plane and vertical directions are different from each other, the ratio of these two lattice constants decrease with film thickness increase. Hence, the symmetry of the nanofilm is lowered by the overall film relaxation.
Determination of residual phenylhydrazines in drug substances by high-performance liquid chromatography with pre-column derivatization
Authors: Li Jiaxin , Nadine Joelle Eyoro Noah , Yang Qian , Zheng Feng , Liu Wenyuan , Liu Jing
Published: November 2019

A selective, sensitive and general HPLC method with pre-column derivatization was developed for the determination of residual phenylhydrazines (known as genotoxic impurities) in drug substances.
Hierarchy of interfacial passivation in inverted perovskite solar cells
Authors: Wang Tun , Abbasi Sadeq , Wang Xin , Wang Yangrunqian , Cheng Zhendong , Wang Jiayuan , Liu Hong , Shen Wenzhong
Published: November 2019

The crucial hierarchy of the interfacial passivation at different positions of perovskite solar cells together with the corresponding mechanism has been studied despite the selection of passivation mediums in this work.
Cell-penetrating peptide-modified quantum dots as a ratiometric nanobiosensor for the simultaneous sensing and imaging of lysosomes and extracellular pH
Authors: Yang Yan , Xia Mengchan , Zhang Sichun , Zhang Xinrong
Published: November 2019

A ratiometric QD-peptide nanobiosensor is developed for the simultaneous sensing and imaging of lysosomes and extracellular pH.
The terahertz dynamics interfaces to ion–lipid interaction confined in phospholipid reverse micelles
Authors: Yang Jing , Tang Chao , Wang Yadi , Chang Chao , Zhang Jianbing , Hu Jun , Lü Junhong
Published: November 2019

The terahertz dynamics of water nanodroplets confined in phospholipid reverse micelles are studied as a probe for metal ion–membrane interface interactions.
Rational engineering of amide synthetase enables bioconversion to diverse xiamenmycin derivatives
Authors: Weng Jing-Yi , Bu Xu-Liang , He Bei-Bei , Cheng Zhuo , Xu Jun , Da Lin-Tai , Xu Min-Juan
Published: November 2019

To improve the enzyme promiscuity, we engineered XimA by site-directed mutagenesis at a specific position based on our theoretical model.
Metal organic frameworks as solid catalysts for liquid-phase continuous flow reactions
Authors: Dhakshinamoorthy Amarajothi , Navalon Sergio , Asiri Abdullah M. , Garcia Hermenegildo
Published: November 2019

This Feature Article describes the recent developments in the use of MOFs as catalysts under continuous flow conditions illustrating that these materials can meet the required stability.
A non-luminescent Eu-MOF-based “turn-on” sensor towards an anthrax biomarker through single-crystal to single-crystal phase transition
Authors: Wu Dai , Zhang Zhe , Chen Xiwen , Meng Lingkun , Li Chunguang , Li Guanghua , Chen Xiaobo , Shi Zhan , Feng Shouhua
Published: November 2019

A non-luminescent NH2-MOF-76(Eu) exhibits selective fluorescence recovery for sensing anthrax biomarker DPA through a single-crystal to single-crystal phase transition.
Kinetic investigation of a chemical process in single-molecule junction
Authors: Hasegawa Yusuke , Harashima Takanori , Jono Yuki , Seki Takumi , Kiguchi Manabu , Nishino Tomoaki
Published: November 2019

Herein, we report on the kinetic investigation for the breakdown of single-molecule junctions.
Completely regioselective insertion of unsymmetrical alkynes into electron-deficient alkenes for the synthesis of new pentacyclic indoles
Authors: Chen Ke , Xu Ting , Liang Jian , Zhou Meng , Zhang Jie , Hao Wen-Juan , Wang Jianyi , Tu Shu-Jiang , Jiang Bo
Published: November 2019

A Lewis acid catalyzed insertion of unsymmetrical alkynes into electron-deficient alkenes has been reported for the first time, leading to 34 examples of hitherto unreported pentacyclic benzo[5,6]chromeno[2,3-b]indoles.