bluuebunny/crossref_metadata_2025 huggingface dataset:
Fast mode decomposition in few-mode fibers
Authors: Manuylovich Egor S. , Dvoyrin Vladislav V. , Turitsyn Sergei K.
Published: November 2020

Retrieval of the optical phase information from measurement of intensity is of a high interest because this would facilitate simple and cost-efficient techniques and devices. In scientific and industrial applications that exploit multi-mode fibers, a prior knowledge of spatial mode structure of the fiber, in principle, makes it possible to recover phases using measured intensity distribution. However, current mode decomposition algorithms based on the analysis of the intensity distribution at the output of a few-mode fiber, such as optimization methods or neural networks, still have high computational costs and high latency that is a serious impediment for applications, such as telecommunications. Speed of signal processing is one of the key challenges in this approach. We present a high-performance mode decomposition algorithm with a processing time of tens of microseconds. The proposed mathematical algorithm that does not use any machine learning techniques, is several orders of magnitude faster than the state-of-the-art deep-learning-based methods. We anticipate that our results can stimulate further research on algorithms beyond popular machine learning methods and they can lead to the development of low-cost phase retrieval receivers for various applications of few-mode fibers ranging from imaging to telecommunications.
Author Correction: Nuclei multiplexing with barcoded antibodies for single-nucleus genomics
Authors: Gaublomme Jellert T. , Li Bo , McCabe Cristin , Knecht Abigail , Yang Yiming , Drokhlyansky Eugene , Van Wittenberghe Nicholas , Waldman Julia , Dionne Danielle , Nguyen Lan , De Jager Philip L. , Yeung Bertrand , Zhao Xinfang , Habib Naomi , Rozenblatt-Rosen Orit , Regev Aviv
Published: November 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Parallel evolution in the emergence of highly pathogenic avian influenza A viruses
Authors: Escalera-Zamudio Marina , Golden Michael , Gutiérrez Bernardo , Thézé Julien , Keown Jeremy Russell , Carrique Loic , Bowden Thomas A. , Pybus Oliver G.
Published: November 2020

Parallel molecular evolution and adaptation are important phenomena commonly observed in viruses. Here, we exploit parallel molecular evolution to understand virulence evolution in avian influenza viruses (AIV). Highly-pathogenic AIVs evolve independently from low-pathogenic ancestors via acquisition of polybasic cleavage sites. Why some AIV lineages but not others evolve in this way is unknown. We hypothesise that the parallel emergence of highly-pathogenic AIV may be facilitated by permissive or compensatory mutations occurring across the viral genome. We combine phylogenetic, statistical and structural approaches to discover parallel mutations in AIV genomes associated with the highly-pathogenic phenotype. Parallel mutations were screened using a statistical test of mutation-phenotype association and further evaluated in the contexts of positive selection and protein structure. Our resulting mutational panel may help to reveal new links between virulence evolution and other traits, and raises the possibility of predicting aspects of AIV evolution.
Rapid and accurate determination of atomistic RNA dynamic ensemble models using NMR and structure prediction
Authors: Shi Honglue , Rangadurai Atul , Abou Assi Hala , Roy Rohit , Case David A. , Herschlag Daniel , Yesselman Joseph D. , Al-Hashimi Hashim M.
Published: November 2020

Biomolecules form dynamic ensembles of many inter-converting conformations which are key for understanding how they fold and function. However, determining ensembles is challenging because the information required to specify atomic structures for thousands of conformations far exceeds that of experimental measurements. We addressed this data gap and dramatically simplified and accelerated RNA ensemble determination by using structure prediction tools that leverage the growing database of RNA structures to generate a conformation library. Refinement of this library with NMR residual dipolar couplings provided an atomistic ensemble model for HIV-1 TAR, and the model accuracy was independently supported by comparisons to quantum-mechanical calculations of NMR chemical shifts, comparison to a crystal structure of a substate, and through designed ensemble redistribution via atomic mutagenesis. Applications to TAR bulge variants and more complex tertiary RNAs support the generality of this approach and the potential to make the determination of atomic-resolution RNA ensembles routine.
Measurement of genetic diseases as a cause of mortality in infants receiving whole genome sequencing
Authors: Kingsmore Stephen F. , Henderson Audrey , Owen Mallory J. , Clark Michelle M. , Hansen Christian , Dimmock David , Chambers Christina D. , Jeliffe-Pawlowski Laura L. , Hobbs Charlotte
Published: November 2020

Understanding causes of infant mortality shapes public health policy and prioritizes diseases for investments in surveillance, intervention and medical research. Rapid genomic sequencing has created a novel opportunity to decrease infant mortality associated with treatable genetic diseases. Herein, we sought to measure the contribution of genetic diseases to mortality among infants by secondary analysis of babies enrolled in two clinical studies and a systematic literature review. Among 312 infants who had been admitted to an ICU at Rady Children’s Hospital between November 2015 and September 2018 and received rapid genomic sequencing, 30 (10%) died in infancy. Ten (33%) of the infants who died were diagnosed with 11 genetic diseases. The San Diego Study of Outcomes in Mothers and Infants platform identified differences between in-hospital and out-of-hospital causes of infant death. Similarly, in six published studies, 195 (21%) of 918 infant deaths were associated with genetic diseases by genomic sequencing. In 195 infant deaths associated with genetic diseases, locus heterogeneity was 70%. Treatment guidelines existed for 70% of the genetic diseases diagnosed, suggesting that rapid genomic sequencing has substantial potential to decrease infant mortality among infants in ICUs. Further studies are needed in larger, comprehensive, unbiased patient sets to determine the generalizability of these findings.
Using a Bayesian modelling approach (INLA-SPDE) to predict the occurrence of the Spinetail Devil Ray (Mobular mobular)
Authors: Lezama-Ochoa Nerea , Pennino Maria Grazia , Hall Martin A. , Lopez Jon , Murua Hilario
Published: November 2020

To protect the most vulnerable marine species it is essential to have an understanding of their spatiotemporal distributions. In recent decades, Bayesian statistics have been successfully used to quantify uncertainty surrounding identified areas of interest for bycatch species. However, conventional simulation-based approaches are often computationally intensive. To address this issue, in this study, an alternative Bayesian approach (Integrated Nested Laplace Approximation with Stochastic Partial Differential Equation, INLA-SPDE) is used to predict the occurrence of Mobula mobular species in the eastern Pacific Ocean (EPO). Specifically, a Generalized Additive Model is implemented to analyze data from the Inter-American Tropical Tuna Commission’s (IATTC) tropical tuna purse-seine fishery observer bycatch database (2005–2015). The INLA-SPDE approach had the potential to predict both the areas of importance in the EPO, that are already known for this species, and the more marginal hotspots, such as the Gulf of California and the Equatorial area which are not identified using other habitat models. Some drawbacks were identified with the INLA-SPDE database, including the difficulties of dealing with categorical variables and triangulating effectively to analyze spatial data. Despite these challenges, we conclude that INLA approach method is an useful complementary and/or alternative approach to traditional ones when modeling bycatch data to inform accurately management decisions.
Role of a schistosoma haematobium specific microRNA as a predictive and prognostic tool for bilharzial bladder cancer in Egypt
Authors: Gaber Dalia A. , Wassef Rita M. , El-Ayat Wael M. , El-Moazen Mohamed I. , Montasser Karim A. , Swar Sherif A. , Amin Hebat Allah A.
Published: November 2020

Urinary bladder cancer is a common malignancy in Egypt, thus reliable methodologies are required for screening and early detection. In this study, we analyzed the gene expression of a Schistosoma hematobium specific microRNA “Sha-miR-71a” and mitogen-associated protein kinase-3 (MAPK-3) in the urine samples of 50 bladder cancer patients and 50 patients with benign bilharzial cystitis. Fifty control subjects were also tested. Indirect hemagglutination test (IHA) diagnosed 70% of studied cancer cases as bilharzial associated bladder cancer (BBC), while histopathological examination detected only 18%. Urinary Sha-miR-71a & MAPK-3 revealed enhanced expression in BBC (p-value = 0.001) compared to non-bilharzial bladder cancer (NBBC) cases. Patients with chronic bilharzial cystitis exhibited a significant increase in gene expression compared to those with acute infection (p-value = 0.001). Sha-miR-71a and MAPK-3 showed good sensitivity and specificity in the diagnosis of BBC when analyzed by the receiver operating characteristic (ROC) curve. They were also prognostic regarding malignancy grade. Both biomarkers showed a positive correlation. Our results revealed that IHA is a reliable test in the diagnosis of bilharziasis associated with bladder cancer, and that Sha-miR-71a and MAPK-3 provide non-invasive specific biomarkers to diagnose BBC, as well as a potential role in testing bilharzial patients for risk to develop cancer.
Culicidae evolutionary history focusing on the Culicinae subfamily based on mitochondrial phylogenomics
Authors: da Silva Alexandre Freitas , Machado Laís Ceschini , de Paula Marcia Bicudo , da Silva Pessoa Vieira Carla Júlia , de Morais Bronzoni Roberta Vieira , de Melo Santos Maria Alice Varjal , Wallau Gabriel Luz
Published: November 2020

Mosquitoes are insects of medical importance due their role as vectors of different pathogens to humans. There is a lack of information about the evolutionary history and phylogenetic positioning of the majority of mosquito species. Here we characterized the mitogenomes of mosquito species through low-coverage whole genome sequencing and data mining. A total of 37 draft mitogenomes of different species were assembled from which 16 are newly-sequenced species. We datamined additional 49 mosquito mitogenomes, and together with our 37 mitogenomes, we reconstructed the evolutionary history of 86 species including representatives from 15 genera and 7 tribes. Our results showed that most of the species clustered in clades with other members of their own genus with exception of Aedes genus which was paraphyletic. We confirmed the monophyletic status of the Mansoniini tribe including both Coquillettidia and Mansonia genus. The Aedeomyiini and Uranotaeniini were consistently recovered as basal to other tribes in the subfamily Culicinae, although the exact relationships among these tribes differed between analyses. These results demonstrate that low-coverage sequencing is effective to recover mitogenomes, establish phylogenetic knowledge and hence generate basic fundamental information that will help in the understanding of the role of these species as pathogen vectors.
Potential and efficiency of statistical learning closely intertwined with individuals’ executive functions: a mathematical modeling study
Authors: Park Jungtak , Yoon Hee-Dong , Yoo Taehyun , Shin Minho , Jeon Hyeon-Ae
Published: November 2020

Statistical learning (SL) is essential in enabling humans to extract probabilistic regularities from the world. The ability to accomplish ultimate learning performance with training (i.e., the potential of learning) has been known to be dissociated with performance improvement per amount of learning time (i.e., the efficiency of learning). Here, we quantified the potential and efficiency of SL separately through mathematical modeling and scrutinized how they were affected by various executive functions. Our results showed that a high potential of SL was associated with poor inhibition and good visuo-spatial working memory, whereas high efficiency of SL was closely related to good inhibition and good set-shifting. We unveiled the distinct characteristics of SL in relation to potential and efficiency and their interaction with executive functions.
High gene flow maintains genetic diversity following selection for high EPSPS copy number in the weed kochia (Amaranthaceae)
Authors: Martin Sara L. , Benedict Leshawn , Wei Wei , Sauder Connie A. , Beckie Hugh J. , Hall Linda M.
Published: November 2020

Kochia, a major weed species, has evolved resistance to four herbicide modes of action. Herbicide resistance appears to spread quickly, which could result in diminished standing genetic variation, reducing the ability of populations to adapt further. Here we used double digest restriction enzyme associated sequencing to determine the level of gene flow among kochia populations and whether selection for glyphosate resistance reduces genetic variation. Canadian Prairie populations show little to no genetic differentiation (FST = 0.01) and no correlation between genetic and geographic distance (r2 = − 0.02 p = 0.56), indicating high gene flow and no population structure. There is some evidence that kochia populations are genetically depauperate compared to other weed species, but genetic diversity did not differ between glyphosate susceptible and resistant populations or individuals. The inbreeding coefficients suggest there are 23% fewer heterozygotes in these populations than expected with random mating, and no variation was found within the chloroplast. These results indicate that any alleles for herbicide resistance can be expected to spread quickly through kochia populations, but there is little evidence this spread will reduce the species’ genetic variation or limit the species’ ability to respond to further selection pressure.
Proteomic identification of the proteins related to cigarette smoke-induced cardiac hypertrophy in spontaneously hypertensive rats
Authors: Kitamura Yuki , Mise Nathan , Mori Yurie , Suzuki Yuka , Ohashi Tomoki , Tada-Oikawa Saeko , Tokisu Masaki , Zong Cai , Oikawa Shinji , Ichihara Sahoko
Published: November 2020

Smoking increases the risk of cardiovascular diseases. The present study was designed to determine the effects of 2-month exposure to cigarette smoke (CS) on proteins in the left ventricles of spontaneously hypertensive rats (SHR) and to identify the molecular targets associated with the pathogenesis/progression of CS-induced cardiac hypertrophy. SHR and Wistar Kyoto rats (WKY) were exposed to CS at low (2 puffs/min for 40 min) or high dose (2 puffs/min for 120 min), 5 days a week for 2 months. Using the two-dimensional fluorescence difference gel electrophoresis combined with MALDI-TOF/TOF tandem mass spectrometry, we compared differences in the expression levels of proteins in the whole left ventricles induced by long-term smoking. High-dose CS mainly caused cardiac hypertrophy in SHR, but not WKY, but no change in blood pressure. Proteomic analysis identified 30 protein spots with significant alterations, with 14 up-regulated and 16 down-regulated proteins in the left ventricles of CS-exposed SHR, compared with control SHR. Among these proteins, two members of the heat shock proteins (HSP70 and HSP20) showed significant up-regulation in the left ventricles of CS high-dose SHR, and the results were confirmed by western blot analysis. Our findings suggested that HSPs play an important role in regulation of CS-induced cardiac hypertrophy.
Effects of high-fat diet and Apoe deficiency on retinal structure and function in mice
Authors: Cao Xiupeng , Guo Yatu , Wang Yuchuan , Wang Hao , Liu Dong , Gong Yibo , Wang Jue , Chen Xia , Zhang Wei
Published: November 2020

To investigate the effects of a high-fat diet (HFD) and apolipoprotein E (Apoe) deficiency on retinal structure and function in mice. Apoe KO mice and wild-type C57BL/6J mice were given a low-fat diet (LFD) or a HFD for 32 weeks. Blood glucose, serum lipids, body weight and visceral fat weight were evaluated. Retinal sterol quantification was carried out by isotope dilution gas chromatography-mass spectrometry. The cholesterol metabolism related genes SCAP-SREBP expressions were detected by qRT-PCR. Retinal function was recorded using an electroretinogram. The thickness of each layer of the retina was measured by optical coherence tomography. Fundus fluorescein angiography was performed to detect retinal vasculature changes. Immunohistochemical staining was used to determine the expression of NF-κB, TNF-α and VEGFR2 in the retina among HFD, HFD Apoe−/−, LFD Apoe−/− and WT mice retinas. HFD feeding caused the mice to gain weight and develop hypercholesterinemia, while Apoe−/− abnormalities also affected blood lipid metabolism. Both HFD and Apoe deficiency elevated retinal cholesterol, especially in the HFD Apoe−/− mice. No up-regulated expression of SCAP-SREBP was observed as a negative regulator. Impaired retinal functions, thinning retinas and abnormal retinal vasculature were observed in the peripheral retinas of the HFD and Apoe−/− mice compared with those in the normal chow group, particularly in the HFD Apoe−/− mice. Moreover, the expression of NF-κB in the retinas of the HFD and Apoe−/− mice was increased, together with upregulated TNF-α mRNA levels and TNF-α expression in the layer of retinal ganglion cells of the peripheral retina. At the same time, the expression level of VEGFR2 was elevated in the intervention groups, most notably in HFD Apoe−/− mice. HFD or Apoe gene deletion had certain adverse effects on retinal function and structure, which were far below the combined factors and induced harm to the retina. Furthermore, HFD caused retinal ischemia and hypoxia. Additionally, Apoe abnormality increased susceptibility to ischemia. These changes upregulated NF-κB expression in ganglion cells and activated downstream TNF-α. Simultaneously, they activated VEGFR2, accelerating angiogenesis and vascular permeability. All of the aforementioned outcomes initiated inflammatory responses to trigger ganglion cell apoptosis and aggravate retinal neovascularization.
Multi-mission satellite remote sensing data for improving land hydrological models via data assimilation
Authors: Khaki M. , Hendricks Franssen H.-J. , Han S. C.
Published: November 2020

Satellite remote sensing offers valuable tools to study Earth and hydrological processes and improve land surface models. This is essential to improve the quality of model predictions, which are affected by various factors such as erroneous input data, the uncertainty of model forcings, and parameter uncertainties. Abundant datasets from multi-mission satellite remote sensing during recent years have provided an opportunity to improve not only the model estimates but also model parameters through a parameter estimation process. This study utilises multiple datasets from satellite remote sensing including soil moisture from Soil Moisture and Ocean Salinity Mission and Advanced Microwave Scanning Radiometer Earth Observing System, terrestrial water storage from the Gravity Recovery And Climate Experiment, and leaf area index from Advanced Very-High-Resolution Radiometer to estimate model parameters. This is done using the recently proposed assimilation method, unsupervised weak constrained ensemble Kalman filter (UWCEnKF). UWCEnKF applies a dual scheme to separately update the state and parameters using two interactive EnKF filters followed by a water balance constraint enforcement. The performance of multivariate data assimilation is evaluated against various independent data over different time periods over two different basins including the Murray–Darling and Mississippi basins. Results indicate that simultaneous assimilation of multiple satellite products combined with parameter estimation strongly improves model predictions compared with single satellite products and/or state estimation alone. This improvement is achieved not only during the parameter estimation period ($$\sim $$
∼
 32% groundwater RMSE reduction and soil moisture correlation increase from $$\sim $$
∼
 0.66 to $$\sim $$
∼
 0.85) but also during the forecast period ($$\sim $$
∼
 14% groundwater RMSE reduction and soil moisture correlation increase from $$\sim $$
∼
 0.69 to $$\sim $$
∼
 0.78) due to the effective impacts of the approach on both state and parameters.
Bioactive potential of endophytic fungus Chaetomium globosum and GC–MS analysis of its responsible components
Authors: Kaur Navdeep , Arora Daljit Singh , Kalia Namarta , Kaur Manpreet
Published: November 2020

The recent exploration of various medicinal plants for bioactive potential has led to the growing interest to explore their endophytes for such bioactive potential which may turn out to be better option than the plants. In the present study, Chaetomium globosum, an endophytic fungus isolated from Moringa oleifera Lam has been explored for its various biological activities. The chloroformic extract of C. globosum showed good antimutagenicity against the reactive carcinogenic mutagen, 2-aminofluorene (2-AF) in Ames test. The antiproliferative activity against various cell lines such as HCT-15, HeLa and U87-MG was found to be dose dependent and the viability reduced to 9.26%, 15.7% and 16.3%, respectively. Further, the chloroformic fungal extract was investigated for free radical scavenging activity using 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethyl-benzthiazolin-6-sulfonic acid) assay which showed the IC50 value of 45.16 µg/ml and 50.55 µg/ml, respectively. The fungal extract also showed good ferric reducing power. Total phenolic and flavonoid content was found to be in linear relationship with the antioxidant potential of the fungal extract. High performance liquid chromatography showed the presence of phenolics which may help to combat the free radicals. The presence of various bioactive compounds was analysed by GC–MS which endorsed Chaetomium globosum to be a promising candidate for drug development.
Assessment of nanoindentation in stiffness measurement of soft biomaterials: kidney, liver, spleen and uterus
Authors: Wu Guanlin , Gotthardt Michael , Gollasch Maik
Published: November 2020

Nanoindentation technology with high spatial resolution and force sensitivity is widely used to measure the mechanical properties of hard biomaterials and tissues. However, its reliability to analyze soft biomaterials and organs has not been tested. Here, we evaluated the utility of nanoindentation to measure the passive mechanical properties of soft biological specimen. Kidney, liver, spleen and uterus samples were harvested from C57BL/6 N mice. We assessed test–retest repeatability in biological specimen and hydrogel controls using Bland–Altman diagrams, intraclass correlation coefficients (ICCs) and the within-subject coefficients of variation (COVs). The results were calculated using Hertzian, JKR and Oliver & Pharr models. Similar to hydrogels, Bland–Altman plots of all biological specimen showed good reliability in stiffness test and retest examinations. In gels, ICCs were larger than 0.8 and COVs were smaller than 15% in all three models. In kidney, liver, spleen and uterus, ICCs were consistently larger than 0.8 only in the Hertzian model but not in the JKR and Oliver & Pharr models. Similarly, COVs were consistently smaller than 15% in kidney, liver, spleen and uterus only in the Hertzian model but not in the other models. We conclude that nanoindentation technology is feasible in detecting the stiffness of kidney, liver, spleen and uterus. The Hertzian model is the preferred method to provide reliable results on ex vivo organ stiffness of the biological specimen under study.
Controllable deposition of organic metal halide perovskite films with wafer-scale uniformity by single source flash evaporation
Authors: Lee Woocheol , Lee Jonghoon , Lee Hyeon-Dong , Kim Junwoo , Ahn Heebeom , Kim Youngrok , Yoo Daekyoung , Lee Jeongjae , Lee Tae-Woo , Kang Keehoon , Lee Takhee
Published: November 2020

Conventional solution-processing techniques such as the spin-coating method have been used successfully to reveal excellent properties of organic–inorganic halide perovskites (OHPs) for optoelectronic devices such as solar cell and light-emitting diode, but it is essential to explore other deposition techniques compatible with large-scale production. Single-source flash evaporation technique, in which a single source of materials of interest is rapidly heated to be deposited in a few seconds, is one of the candidate techniques for large-scale thin film deposition of OHPs. In this work, we investigated the reliability and controllability of the single-source flash evaporation technique for methylammonium lead iodide (MAPbI3) perovskite. In-depth statistical analysis was employed to demonstrate that the MAPbI3 films prepared via the flash evaporation have an ultrasmooth surface and uniform thickness throughout the 4-inch wafer scale. We also show that the thickness and grain size of the MAPbI3 film can be controlled by adjusting the amount of the source and number of deposition steps. Finally, the excellent large-area uniformity of the physical properties of the deposited thin films can be transferred to the uniformity in the device performance of MAPbI3 photodetectors prepared by flash evaporation which exhibited the responsivity of 51 mA/W and detectivity of 9.55 × 1010 Jones.
Asymmetric dynamic coupling promotes alternative evolutionary pathways in an enzyme dimer
Authors: Ambrus V. , Hoffka Gy. , Fuxreiter M.
Published: November 2020

The importance of dynamic factors in enzyme evolution is gaining recognition. Here we study how the evolution of a new enzymatic activity exploits conformational tinkering and demonstrate that conversion of a dimeric phosphotriesterase to an arylesterase in Pseudomonas diminuta is accompanied by structural divergence between the two subunits. Deviations in loop conformations increase with promiscuity, leading to functionally distinct states, while they decrease during specialisation for the new function. We show that opposite loop movements in the two subunits are due to a dynamic coupling with the dimer interface, the importance of which is also corroborated by the co-evolution of the loop and interface residues. These results illuminate how protein dynamics promotes conformational heterogeneity in a dimeric enzyme, leading to alternative evolutionary pathways for the emergence of a new function.
Optical coherence tomography-based deep-learning model for detecting central serous chorioretinopathy
Authors: Yoon Jeewoo , Han Jinyoung , Park Ji In , Hwang Joon Seo , Han Jeong Mo , Sohn Joonhong , Park Kyu Hyung , Hwang Daniel Duck-Jin
Published: November 2020

Central serous chorioretinopathy (CSC) is a common condition characterized by serous detachment of the neurosensory retina at the posterior pole. We built a deep learning system model to diagnose CSC, and distinguish chronic from acute CSC using spectral domain optical coherence tomography (SD-OCT) images. Data from SD-OCT images of patients with CSC and a control group were analyzed with a convolutional neural network. Sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve (AUROC) were used to evaluate the model. For CSC diagnosis, our model showed an accuracy, sensitivity, and specificity of 93.8%, 90.0%, and 99.1%, respectively; AUROC was 98.9% (95% CI, 0.983–0.995); and its diagnostic performance was comparable with VGG-16, Resnet-50, and the diagnoses of five different ophthalmologists. For distinguishing chronic from acute cases, the accuracy, sensitivity, and specificity were 97.6%, 100.0%, and 92.6%, respectively; AUROC was 99.4% (95% CI, 0.985–1.000); performance was better than VGG-16 and Resnet-50, and was as good as the ophthalmologists. Our model performed well when diagnosing CSC and yielded highly accurate results when distinguishing between acute and chronic cases. Thus, automated deep learning system algorithms could play a role independent of human experts in the diagnosis of CSC.
Active maintenance of eligibility trace in rodent prefrontal cortex
Authors: Lim Dong-Hyun , Yoon Young Ju , Her Eunsil , Huh Suehee , Jung Min Whan
Published: November 2020

Even though persistent neural activity has been proposed as a mechanism for maintaining eligibility trace, direct empirical evidence for active maintenance of eligibility trace has been lacking. We recorded neuronal activity in the medial prefrontal cortex (mPFC) in rats performing a dynamic foraging task in which a choice must be remembered until its outcome on the timescale of seconds for correct credit assignment. We found that mPFC neurons maintain significant choice signals during the time period between action selection and choice outcome. We also found that neural signals for choice, outcome, and action value converge in the mPFC when choice outcome was revealed. Our results indicate that the mPFC maintains choice signals necessary for temporal credit assignment in the form of persistent neural activity in our task. They also suggest that the mPFC might update action value by combining actively maintained eligibility trace with action value and outcome signals.
Field-free molecular orientation by delay- and polarization-optimized two fs pulses
Authors: Mun Je Hoi , Kim Dong Eon
Published: November 2020

Unless the molecular axis is fixed in the laboratory frame, intrinsic structural information of molecules can be averaged out over the various rotational states. The macroscopic directional properties of polar molecules have been controlled by two fs pulses with an optimized delay. In the method, the first one-color laser pulse provokes molecular alignment. Subsequently, the molecular sample is irradiated with the second two-color laser pulse, when the initial even—J states are aligned, and the odd—J states are anti-aligned in the thermal ensemble. The second pulse selectively orients only the aligned even—J states in the same direction, which results in significant enhancement of the net degree of orientation. This paper reports the results of simulations showing that the two-pulse technique can be even more powerful when the second pulse is cross-polarized. This study shows that the alignment and orientation can be very well synchronized temporally because the crossed field does not disturb the preformed alignment modulation significantly, suggesting that the molecules are very well confined in the laboratory frame. This cross-polarization method will serve as a promising technique for studying ultrafast molecular spectroscopy in a molecule-fixed frame.
Stopping targeted therapy for complete responders in advanced BRAF mutant melanoma
Authors: Warburton L. , Meniawy T. M. , Calapre L. , Pereira M. , McEvoy A. , Ziman M. , Gray E. S. , Millward M.
Published: November 2020

BRAF inhibitors revolutionised the management of melanoma patients and although resistance occurs, there is a subgroup of patients who maintain durable disease control. For those cases with durable complete response (CR) it is not clear whether it is safe to cease therapy. Here we identified 13 patients treated with BRAF +/− MEK inhibitors, who cease therapy after prolonged CR (median = 34 months, range 20–74). Recurrence was observed in 3/13 (23%) patients. In the remaining 10 patients with sustained CR off therapy, the median follow up after discontinuation was 19 months (range 8–36). We retrospectively measured ctDNA levels using droplet digital PCR (ddPCR) in longitudinal plasma samples. CtDNA levels were undetectable in 11/13 cases after cessation and remained undetectable in patients in CR (10/13). CtDNA eventually became detectable in 2/3 cases with disease recurrence, but remained undetectable in 1 patient with brain only progression. Our study suggests that consideration could be given to ceasing targeted therapy in the context of prolonged treatment, durable response and no evidence of residual disease as measured by ctDNA.
ESCRT-III controls nuclear envelope deformation induced by progerin
Authors: Arii Jun , Maeda Fumio , Maruzuru Yuhei , Koyanagi Naoto , Kato Akihisa , Mori Yasuko , Kawaguchi Yasushi
Published: November 2020

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder, caused by mutation in the gene encoding lamin A/C, which produces a truncated protein called progerin. In cells from HGPS patients, progerin accumulates at the nuclear membrane (NM), where it causes NM deformations. In this study, we investigated whether progerin-induced NM deformation involved ESCRT-III, a protein complex that remodels nuclear and cytoplasmic membranes. The ESCRT-III protein CHMP4B was recruited to sites of aberrant NM proliferation in human cells ectopically expressing progerin and in patient-derived HGPS fibroblasts. Derepression of NM deformation in these cells was observed following depletion of CHMP4B or an ESCRT-III adaptor, ALIX. Treatment with rapamycin (which induce autophagic clearance of progerin and reverse progerin-induced cellular phenotypes) down-regulated progerin-induced NM deformation, whereas treatment with bafilomycin A1 (an inhibitor of autophagy and lysosome-based degradation) or CHMP4B depletion antagonized the effects of rapamycin. These results indicate that the ALIX-mediated ESCRT-III pathway plays a suppressive role in progerin-induced NM deformation and suggest that autophagy down-regulates progerin-induced NM deformation in a manner dependent on ESCRT-III machinery.
Hepatobiliary malignancies have distinct peripheral myeloid-derived suppressor cell signatures and tumor myeloid cell profiles
Authors: Bayik Defne , Lauko Adam J. , Roversi Gustavo A. , Serbinowski Emily , Acevedo-Moreno Lou-Anne , Lanigan Christopher , Orujov Mushfig , Lo Alice , Alban Tyler J. , Kim Adam , Silver Daniel J. , Nagy Laura E. , Brown J. Mark , Allende Daniela S. , Aucejo Federico N. , Lathia Justin D.
Published: November 2020

Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells that are increased in patients with numerous malignancies including viral-derived hepatocellular carcinoma (HCC). Here, we report an elevation of MDSCs in the peripheral blood of patients with other hepatobiliary malignancies including non-viral HCC, neuroendocrine tumors (NET), and colorectal carcinoma with liver metastases (CRLM), but not cholangiocarcinoma (CCA). The investigation of myeloid cell infiltration in HCC, NET and intrahepatic CCA tumors further established that the frequency of antigen-presenting cells was limited compared to benign lesions, suggesting that primary and metastatic hepatobiliary cancers have distinct peripheral and tumoral myeloid signatures. Bioinformatics analysis of The Cancer Genome Atlas dataset demonstrated that a high MDSC score in HCC patients is associated with poor disease outcome. Given our observation that MDSCs are increased in non-CCA malignant liver cancers, these cells may represent suitable targets for effective immunotherapy approaches.
Identification of HMGA2 inhibitors by AlphaScreen-based ultra-high-throughput screening assays
Authors: Su Linjia , Bryan Nadezda , Battista Sabrina , Freitas Juliano , Garabedian Alyssa , D’Alessio Federica , Romano Miriam , Falanga Fabiana , Fusco Alfredo , Kos Lidia , Chambers Jeremy , Fernandez-Lima Francisco , Chapagain Prem P. , Vasile Stefan , Smith Layton , Leng Fenfei
Published: November 2020

The mammalian high mobility group protein AT-hook 2 (HMGA2) is a multi-functional DNA-binding protein that plays important roles in tumorigenesis and adipogenesis. Previous results showed that HMGA2 is a potential therapeutic target of anticancer and anti-obesity drugs by inhibiting its DNA-binding activities. Here we report the development of a miniaturized, automated AlphaScreen ultra-high-throughput screening assay to identify inhibitors targeting HMGA2-DNA interactions. After screening the LOPAC1280 compound library, we identified several compounds that strongly inhibit HMGA2-DNA interactions including suramin, a century-old, negatively charged antiparasitic drug. Our results show that the inhibition is likely through suramin binding to the “AT-hook” DNA-binding motifs and therefore preventing HMGA2 from binding to the minor groove of AT-rich DNA sequences. Since HMGA1 proteins also carry multiple “AT-hook” DNA-binding motifs, suramin is expected to inhibit HMGA1-DNA interactions as well. Biochemical and biophysical studies show that charge-charge interactions and hydrogen bonding between the suramin sulfonated groups and Arg/Lys residues play critical roles in the binding of suramin to the “AT-hook” DNA-binding motifs. Furthermore, our results suggest that HMGA2 may be one of suramin’s cellular targets.
A biodegradable microneedle sheet for intracorporeal topical hemostasis
Authors: Yokoyama Mao , Chihara Namie , Tanaka Atsushi , Katayama Yosuke , Taruya Akira , Ishida Yuko , Yuzaki Mitsuru , Honda Kentaro , Nishimura Yoshiharu , Kondo Toshikazu , Akasaka Takashi , Kato Nobuhiro
Published: November 2020

Management of bleeding is critical for improving patient outcomes. While various hemostatic products are used in daily practice, technical improvement is still needed. To addresses this problem, we newly developed a microneedle hemostatic sheet based on microneedle technology. We demonstrated the unique features of this microneedle hemostatic sheet, including reduced hemostatic time, biodegradable polymer composition that allows intracorporeal use without increasing infectious risk incorporation of microneedles to fix the sheet to the wound even on the left ventricular wall of a swine while beating, and a mesh structure with flexibility comparable to that of bonding surgical tape and sufficient rigidity to penetrate human aorta tissue and swine left ventricular wall. One potential application of the microneedle hemostatic sheet is intracorporeal topical hemostasis for parenchymatous organs, large vessels, and heart wall during trauma or surgery, in addition to new, widespread applications.
Greater hippocampal gray matter volume in subjective hyperosmia: a voxel-based morphometry study
Authors: Han Pengfei , Stiller-Stut Franz Paul , Fjaeldstad Alexander , Hummel Thomas
Published: November 2020

Subjective hyperosmia refers to a self-reported olfactory ability that is superior to a normal, intact sense of smell (normosmia), and is associated with olfactory emotional experience. The current study used voxel-based morphometry to investigate the gray matter volume (GMV) in people with self-rated hyperosmia (subjective hyperosmia, SH, N = 18) in comparison to people with self-rated normal olfaction (subjective normosmia, SN, N = 14). Participants’ olfactory function were assessed by the extensive olfactory test battery, the “Sniffin’ Sticks” test. Within the predicted brain regions (regions-of-interest analyses), the SH participants showed larger GMV of the left hippocampus as compared to SN participants (FWE corrected p < 0.05). Further, the whole-brain search indicated that SH had larger GMV of the bilateral hippocampus, the right hypothalamus, the left precuneus, and the left superior frontal gyrus as compared to the SN group. ROI analyses showed positive correlations between the left hippocampal GMV and odor threshold or discrimination scores across all participants. In addition, the whole-brain analysis suggested that the self-rated olfactory ability was positively associated with GMV in the cerebellum, superior frontal gyrus and the precentral gyrus among SH participants. In conclusion, the current results suggest that SH was associated with increased GMV in several brain regions that were previously shown to be involved in the processing of cognitive aspects of odors.
Diverse and abundant resistome in terrestrial and aquatic vertebrates revealed by transcriptional analysis
Authors: Chen Yan-Mei , Holmes Edward C. , Chen Xiao , Tian Jun-Hua , Lin Xian-Dan , Qin Xin-Cheng , Gao Wen-Hua , Liu Jing , Wu Zhong-Dao , Zhang Yong-Zhen
Published: November 2020

Despite increasing evidence that antibiotic resistant pathogens are shared among humans and animals, the diversity, abundance and patterns of spread of antibiotic resistance genes (ARGs) in wildlife remains unclear. We identified 194 ARGs associated with phenotypic resistance to 13 types of antibiotic in meta-transcriptomic data generated from a broad range of lower vertebrates residing in both terrestrial and aquatic habitats. These ARGs, confirmed by PCR, included those that shared high sequence similarity to clinical isolates of public health concern. Notably, the lower vertebrate resistome varied by ecological niche of the host sampled. The resistomes in marine fish shared high similarity and were characterized by very high abundance, distinct from that observed in other habitats. An assessment of ARG mobility found that ARGs in marine fish were frequently co-localized with mobile elements, indicating that they were likely spread by horizontal gene transfer. Together, these data reveal the remarkable diversity and transcriptional levels of ARGs in lower vertebrates, and suggest that these wildlife species might play an important role in the global spread of ARGs.
Novel glucose-responsive of the transparent nanofiber hydrogel patches as a wearable biosensor via electrospinning
Authors: Kim Gun Jin , Kim Kyu Oh
Published: November 2020

Micro- and nanofiber (NF) hydrogels fabricated by electrospinning to typically exhibit outstanding high porosity and specific surface area under hydrated conditions. However, the high crystallinity of NFs limits the achievement of transparency via electrospinning. Transparent poly(vinyl alcohol)/β-cyclodextrin polymer NF hydrogels contacted with reverse iontophoresis electrodes were prepared for the development of a non-invasive continuous monitoring biosensor platform of interstitial fluid glucose levels reaching ~ 1 mM. We designed the PVA/BTCA/β-CD/GOx/AuNPs NF hydrogels, which exhibit flexibility, biocompatibility, excellent absorptivity (DI water: 21.9 ± 1.9, PBS: 41.91 ± 3.4), good mechanical properties (dried: 12.1 MPa, wetted: 5.33 MPa), and high enzyme activity of 76.3%. Owing to the unique features of PVA/β-CD/GOx containing AuNPs NF hydrogels, such as high permeability to bio-substrates and rapid electron transfer, our biosensors demonstrate excellent sensing performance with a wide linear range, high sensitivity(47.2 μA mM−1), low sensing limit (0.01 mM), and rapid response time (< 15 s). The results indicate that the PVA/BTCA/β-CD/GOx/AuNPs NF hydrogel patch sensor can measure the glucose concentration in human serum and holds massive potential for future clinical applications.
Numerical investigation of dynamic responses and mooring forces of submerged floating tunnel driven by surface waves
Authors: Chen Xuebin , Chen Zhiwu , Cai Shuqun , Xu Wei , Zhuo Xianrong , Lv Jiangen , Zhao Jiajian
Published: November 2020

Based on Navier–Stokes equations, a numerical model for studying the dynamic responses and mooring forces of the moored Submerged Floating Tunnel (SFT) driven by surface waves is presented in this paper. The mechanics models of the vertically and inclinedly moored floating body under wave forces are built, and the overset meshing method is employed to dynamically configure the computational meshes. Two laboratory experiments are used for validating the numerical model in terms of motion responses and mooring forces of the SFT, indicating the proposed model is capable of accurately simulating the instantaneous position of the body under the wave action. This hydrodynamic model is then utilized to simulate the wave–structure interaction of the prototype SFT designed for Qiongzhou Strait located between Mainland China and Hainan Island. The effects of the fundamental structure parameter, or the inclined mooring angle (IMA), on the dynamic responses of SFT are analyzed. The numerical experiments not only shed light on the mooring forces, as well as pitch, sway and heave responses of the SFT with various values of IMA, but also provide guidance for the choice of IMA in engineering design. The range of IMA is separated into five zones, and Zone 2 is regarded as the best choice for the design of IMA for both motion displacements and mooring forces are relatively small in this zone. Zone 3 is considered to be the worst choice as not only are motion responses of SFT severe in this zone, but also the mooring chains are at the risk of going slack under severe wave conditions.
Social hierarchy and the choice of metal recycling at Anyang, the last capital of Bronze Age Shang China
Authors: Liu Ruiliang , Pollard A. Mark , Cao Qin , Liu Cheng , Sainsbury Victoria , Howarth Philly , Bray Peter , Huan Limin , Yao Bohao , Fu Yuting , Tang Jigen
Published: November 2020

Anyang, the last capital of the Chinese Shang dynasty, became one of the largest metal consumers in Eurasia during the second millennium BCE. However, it remains unclear how Anyang people managed to sustain such a large supply of metal. By considering the chemical analysis of bronze objects within archaeological contexts, this paper shows that the casting and circulation of metal at Anyang was effectively governed by social hierarchy. Objects belonging to the high elites such as Fuhao, particularly the bronze ritual vessels, were made by carefully controlled alloying practice (primary) using very pure copper, whereas the lower elites only had access to bronzes made by secondary alloying practice and copper with more impurities. Such contrasts allow scholars to identify those objects which are less likely to have been made by mixing and recycling, which has very important implications for the chemical and isotopic determination of provenance for future studies.
Primary efficacy of percutaneous microwave ablation of malignant liver tumors: comparison of stereotactic and conventional manual guidance
Authors: Schaible Jan , Lürken Lukas , Wiggermann Philipp , Verloh Niklas , Einspieler Ingo , Zeman Florian , Schreyer Andreas G. , Bale Reto , Stroszczynski Christian , Beyer Lukas
Published: November 2020

In this study, we compare the primary efficacy of computed tomography-navigated stereotactic guidance to that of manual guidance for percutaneous microwave ablation of liver malignancies. In total, 221 patients (140, 17, and 64 with hepatocellular carcinoma, cholangiocellular carcinoma, and liver metastases, respectively) with 423 treated liver lesions underwent microwave ablation (MWA). Manual guidance (M) and stereotactic guidance (S) were used for 136 and 287 lesions, respectively. The primary endpoint was the primary efficacy and the secondary endpoint was the radiation dose. A generalised estimating equation was applied to analyse the correlation between the primary efficacy (lesion basis) and the type of guidance, size and location of lesion. The primary efficacy rate was significantly higher in the S-group (84.3%) than in the M-group (75.0%, p = 0.03). Lesion size > 30 mm was negatively correlated with the efficacy rate (odds ratio 0.38; 95% confidence interval 0.20–0.74). Stereotactic guidance was associated with a significantly lower dose length product (p < 0.01). In this retrospective study, percutaneous microwave ablation under stereotactic guidance exhibited significantly greater primary efficacy than conventional manual guidance.