bluuebunny/crossref_metadata_2025 huggingface dataset:
A 3.4-Å cryo-electron microscopy structure of the human coronavirus spike trimer computationally derived from vitrified NL63 virus particles
Authors: Zhang Kaiming , Li Shanshan , Pintilie Grigore , Chmielewski David , Schmid Michael F. , Simmons Graham , Jin Jing , Chiu Wah
Published: November 2020

Human coronavirus NL63 (HCoV-NL63) is an enveloped pathogen of the family Coronaviridae that spreads worldwide and causes up to 10% of all annual respiratory diseases. HCoV-NL63 is typically associated with mild upper respiratory symptoms in children, elderly and immunocompromised individuals. It has also been shown to cause severe lower respiratory illness. NL63 shares ACE2 as a receptor for viral entry with SARS-CoV-1 and SARS-CoV-2. Here, we present the in situ structure of HCoV-NL63 spike (S) trimer at 3.4-Å resolution by single-particle cryo-EM imaging of vitrified virions without chemical fixative. It is structurally homologous to that obtained previously from the biochemically purified ectodomain of HCoV-NL63 S trimer, which displays a three-fold symmetric trimer in a single conformation. In addition to previously proposed and observed glycosylation sites, our map shows density at other sites, as well as different glycan structures. The domain arrangement within a protomer is strikingly different from that of the SARS-CoV-2 S and may explain their different requirements for activating binding to the receptor. This structure provides the basis for future studies of spike proteins with receptors, antibodies or drugs, in the native state of the coronavirus particles.
To Emerge? Breadwinning, Motherhood, and Women’s Decisions to Run for Office
Authors: BERNHARD RACHEL , SHAMES SHAUNA , TEELE DAWN LANGAN
Published: November 2020

Women’s underrepresentation in American politics is often attributed to relatively low levels of political ambition. Yet scholarship still grapples with a major leak in the pipeline to power: that many qualified and politically ambitious women decide against candidacy. Focusing on women with political ambition, we theorize that at the final stage of candidate emergence, household income, breadwinning responsibilities, and household composition are interlocking obstacles to women’s candidacies. We examine these dynamics through a multimethod design that includes an original survey of women most likely to run for office: alumnae of the largest Democratic campaign training organization in the United States. Although we do not find income effects, we provide evidence that breadwinning—responsibility for a majority of household income—negativelyaffects women’s ambition, especially for mothers. These findings have important implications for understanding how the political economy of the household affects candidate emergence and descriptive representation in the United States.
Effects of pistachios on anthropometric indices, inflammatory markers, endothelial function and blood pressure in adults: a systematic review and meta-analysis of randomised controlled trials
Authors: Asbaghi Omid , Hadi Amir , Campbell Marilyn S. , Venkatakrishnan Kamesh , Ghaedi Ehsan
Published: November 2020

Evidence suggests that eating nuts may reduce the risk of CVD. This study was intended to pool the data of all randomised controlled trials (RCT) available to determine if pistachios confer a beneficial effect on anthropometric indices, inflammatory markers, endothelial dysfunction and blood pressure. Without language restriction, PubMed, Scopus, Cochrane Library and Web of Science were searched for articles published from the earliest records to June 2019 investigating the effect of pistachio consumption on inflammation, endothelial dysfunction and hypertension. Mean difference (MD) was pooled using a random effects model. The Cochrane risk of bias tool was used to evaluate the quality of the studies. The meta-analysis of thirteen RCT with 563 participants indicated that pistachio consumption significantly decreased systolic blood pressure (SBP) (MD: −2·12 mmHg, 95 % CI −3·65, −0·59, P = 0·007), whereas changes in flow-mediated dilation (MD: 0·94 %, 95 % CI −0·99, 2·86, P = 0·813), diastolic blood pressure (MD: 0·32 mmHg, 95 % CI −1·37, 2·02, P = 0·707), C-reactive protein (MD: 0·00 mg/l, 95 % CI −0·21, 0·23, P = 0·942), TNF-α (MD: −0·09 pg/ml, 95 % CI −0·38, 0·20, P = 0·541), body weight (MD: 0·09 kg, 95 % CI −0·38, 0·69, P = 0·697), BMI (MD: 0·07 kg/m2, 95 % CI −0·16, 0·31, P = 0·553) and waist circumference (MD: 0·77 cm, 95 % CI −0·09, 1·64, P = 0·140) were not statistically significant. This systematic review and meta-analysis suggested the efficacy of pistachio consumption to reduce SBP levels. However, further large-scale studies are needed to confirm these results.
Patient satisfaction from ENT telephone consultations during the coronavirus disease 2019 pandemic
Authors: Zammit M , Siau R , Williams C , Hussein A
Published: November 2020

Background

Telephone consultations have rapidly increased in the out-patient setting because of the coronavirus pandemic. A quality improvement project was implemented to improve patient satisfaction of telephone consultations in our unit.

Methods

This was a prospective complete-cycle project. Patient satisfaction questionnaires were sent to patients following telephone consultations in ENT clinics. Based on a literature review and initial results, clinicians were encouraged to follow a structured consultation format. A second questionnaire survey was conducted following its implementation.

Results

One hundred patient questionnaires were collected during the survey (April and June 2020). There was significant improvement over the two surveys in terms of satisfaction scores (p = 0.026), along with a significantly increased preference for telephone consultations over face-to-face consultations (p = 0.021).

Conclusion

This study showed significant improvement in patient satisfaction and an increased telephone consultation preference through the use of a structured consultation model. The potential benefits in terms of infection control and impact on out-patient workload may see telephone consultations persist in the post-coronavirus era.
Multimodal input in second-language speech processing
Authors: Hardison Debra M.
Published: November 2020

This timeline provides an update on research since 2009 involving auditory-visual (AV) input in spoken language processing (see Hardison, 2010 for an earlier timeline on this topic). A brief background is presented here as a foundation for the more recent studies of speech as a multimodal phenomenon (e.g., Rosenblum, 2005).
Zeros of the Epstein zeta function to the right of the critical line
Authors: LAMZOURI YOUNESS
Published: November 2020

Let E(s, Q) be the Epstein zeta function attached to a positive definite quadratic form of discriminant D < 0, such that h(D) ≥ 2, where h(D) is the class number of the imaginary quadratic field ${\mathbb{Q}} (\sqrt D)$. We denote by ${N_E}({\sigma _1},{\sigma _2},T)$ the number of zeros of $[E(s,Q)$ in the rectangle ${\sigma _1} < {\mathop{\rm Re}\nolimits} (s) \le {\sigma _2}$ and $T \le {\mathop{\rm Im}\nolimits} (s) \le 2T$, where $1/2 < {\sigma _1} < {\sigma _2} < 1$ are fixed real numbers. In this paper, we improve the asymptotic formula of Gonek and Lee for ${N_E}({\sigma _1},{\sigma _2},T)$, obtaining a saving of a power of log T in the error term.
Randomized Controlled Trial of Point-of-Care Ultrasound Education for the Recognition of Tension Pneumothorax by Paramedics in Prehospital Simulation
Authors: Khalil Paul A. , Merelman Andrew , Riccio John , Peterson Jodi , Shelton Ryan , Meyers Jeff , Ketchmark Tim , Garneau Emily , Khalil Stephanie , Roosevelt Genie , Toney Amanda
Published: November 2020

Objective:

The primary goal of this study was to determine if ultrasound (US) use after brief point-of-care ultrasound (POCUS) training on cardiac and lung exams would result in more paramedics correctly identifying a tension pneumothorax (TPTX) during a simulation scenario.

Methods:

A randomized controlled, simulation-based trial of POCUS lung exam education investigating the ability of paramedics to correctly diagnose TPTX was performed. The US intervention group received a 30-minute cardiac and lung POCUS lecture followed by hands-on US training. The control group did not receive any POCUS training. Both groups participated in two scenarios: right unilateral TPTX and undifferentiated shock (no TPTX). In both scenarios, the patient continued to be hypoxemic after verified intubation with pulse oximetry of 86%-88% and hypotensive with a blood pressure of 70/50. Sirens were played at 65 decibels to mimic prehospital transport conditions. A simulation educator stated aloud the time diagnoses were made and procedures performed, which were recorded by the study investigator. Paramedics completed a pre-survey and post-survey.

Results:

Thirty paramedics were randomized to the control group; 30 paramedics were randomized to the US intervention group. Most paramedics had not received prior US training, had not previously performed a POCUS exam, and were uncomfortable with POCUS. Point-of-care US use was significantly higher in the US intervention group for both simulation cases (P <.001). A higher percentage of paramedics in the US intervention group arrived at the correct diagnosis (77%) for the TPTX case as compared to the control group (57%), although this difference was not significantly different (P = 0.1). There was no difference in the correct diagnosis between the control and US intervention groups for the undifferentiated shock case. On the post-survey, more paramedics in the US intervention group were comfortable with POCUS for evaluation of the lung and comfortable decompressing TPTX using POCUS (P <.001). Paramedics reported POCUS was within their scope of practice.

Conclusions:

Despite being novice POCUS users, the paramedics were more likely to correctly diagnose TPTX during simulation after a brief POCUS educational intervention. However, this difference was not statistically significant. Paramedics were comfortable using POCUS and felt its use improved their TPTX diagnostic skills.
“Certain Uncertainty: The Role of Internal Climate Variability in Projections of Regional Climate Change and Risk Management”
Authors: Deser Clara
Published: November 2020

Internal climate variability co‐exists with anthropogenic climate change and places limits on the accuracy of regional climate projections due to its inherent unpredictability. This “certain” uncertainty in regional projections introduced by internal variability contrasts with uncertainty resulting from structural differences amongst climate models, which is potentially reducible as climate models improve. Initial‐condition “Large Ensembles” of simulations with individual climate models provide a new perspective on the expected range of future climate change outcomes. Their value for climate risk assessment, adaptation management, and decision‐making has yet to be fully realized.
The Carbon Stock and Sequestration Rate in Tidal Flats From Coastal China
Authors: Chen Jie , Wang Dongqi , Li Yangjie , Yu Zhongjie , Chen Shu , Hou Xiyong , White John R. , Chen Zhenlou
Published: November 2020

Tidal flats form around the estuarine and coastal zone by continuous terrigenous sediment transport and deposition processes. Now a large body of published carbon research work frame within the vegetated area (mangrove forests, sea grass bed, and salt marshes). Nonvegetated tidal flats, which are characterized by predominantly silts and clays sediment, were generally impressed with low carbon stock due to their meager primary productivity. However, these regions may be a potentially important carbon sink, given their high burial rate, expanding areal coverage, and detrial organic carbon derived from watershed and adjacent vegetated area. Low carbon densities (<0.01 g cm−3) were found in Chinese tidal flat sediments by the study, but the carbon sequestration rates ranged from 35 to 361 g C m−2 yr−1, which were comparable to rates of worldwide vegetated coastal areas. The high rates can be ascribed to rapid sedimentation rates (1–2 cm yr−1) during the past several decades. The highest areal carbon stocks were located at tidal flat sites proximal to mangrove forests. The majority of carbon stocks (100 cm) was found in the unvegetated tidal flats instead of in the vegetated tidal flats. The former occupied 87% of the entire tidal area, 6.7 times larger than the latter. Tidal flats in coastal China store 78.07 Tg C (100 cm), accounting for nearly 80% of the C deposited in entire coastal tidal area. The future carbon sequestration rates of Chinese tidal flats are facing uncertainties under the pressures of reduced fluvial sediment loads from major rivers.
Body Wave Tomography of the Cascadia Subduction Zone and Juan de Fuca Plate System: Identifying Challenges and Solutions for Shore‐Crossing Data
Authors: Bodmer M. , Toomey D. R. , VanderBeek B. , Hooft E. E. , Byrnes J. S.
Published: November 2020

Recent seismic results from the Cascadia Initiative indicate that heterogeneity in the oceanic asthenosphere affects subduction dynamics. Accurate characterization of the oceanic upper mantle is thus necessary to fully understand subduction processes, including the behavioral segmentation of the megathrust. A key challenge is integrating onshore and offshore datasets, which span large variations in near‐surface features that teleseismic body wave tomography is ill‐posed to resolve. Here, we perform a series of P and S forward modeling predictions to better understand the relative contribution of elevation, crustal thickness, offshore sedimentation, and near‐surface velocity structure to teleseismic delay times. Crustal thickness and elevation variations dominate the signal, contributing ∼1 s of delay time difference for P‐waves (roughly double for S). We test several inversion strategies to account for near‐surface features, identifying potential artifacts and causes of imaging errors. Undamped station statics are found to absorb mantle structures and introduce low‐velocity artifacts beneath the forearc. Our preferred inversion strategy utilizes a three‐dimensional starting model (including elevation) of the upper 50 km and heavily damped station statics, which we find leads to better resolution of mantle structure, particularly at asthenospheric depths. These insights guide inversions of observed delay times from the Cascadia subduction zone and Juan de Fuca plate system. We present a new onshore‐offshore S model and an updated P model. Major features are common to both models, including localized subslab low‐velocity anomalies, along‐strike variations in slab structure, and offshore heterogeneity, while regional differences may reflect changes in Vp/Vs.
Well Log Generation via Ensemble Long Short‐Term Memory (EnLSTM) Network
Authors: Chen Yuntian , Zhang Dongxiao
Published: November 2020

In this study, we propose an ensemble long short‐term memory (EnLSTM) network, which can be trained on a small data set and process sequential data. The EnLSTM is built by combining the ensemble neural network and the cascaded LSTM network to leverage their complementary strengths. Two perturbation methods are applied to resolve the issues of overconvergence and disturbance compensation. The EnLSTM is compared with commonly used models on a published data set and proven to be the state‐of‐the‐art model in generating well logs. In the case study, 12 well logs that cannot be measured while drilling are generated based on the logs available in the drilling process. The EnLSTM is capable of reducing cost and saving time in practice.
Characterizing Tracer Transport Behavior in Two‐Phase Flow System: Implications for CO2 Geosequestration
Authors: Kim Minji , Kim Kue‐Young , Kim Chan Yeong , Chae Gi‐Tak , Han Weon Shik , Park Eungyu
Published: November 2020

Tracers are used to tag the injected carbon dioxide (CO2) for verification of the storage performance and containment in geosequestration. Yet the characterization of the transport behavior of a chemical tracer in two‐phase flow system has not been fully investigated. We present experimental observations together with numerical results for both homogeneous and heterogeneous media from core scale to field scale. The key features of the breakthrough curves (BTCs) that include the tracer arrival time, peak concentration, and tailing pattern were examined. We identify distinct differences in BTCs depending on whether the formation was previously swept by CO2. When the tracer is released before CO2 sweeps the formation, the tracer transports at the front of gas‐liquid interfaces with a narrow tracer plume distribution and the BTCs reflect the effect of local heterogeneity. Furthermore, a series of tracer pulse can be used to identify whether new pathways have been developed during CO2 injection.
Subsurface Evolution and Persistence of Marine Heatwaves in the Northeast Pacific
Authors: Scannell H. A. , Johnson G. C. , Thompson L. , Lyman J. M. , Riser S. C.
Published: November 2020

The reappearance of a northeast Pacific marine heatwave (MHW) sounded alarms in late summer 2019 for a warming event on par with the 2013–2016 MHW known as The Blob. Despite these two events having similar magnitudes in surface warming, differences in seasonality and salinity distinguish their evolutions. We compare and contrast the ocean's role in the evolution and persistence of the 2013–2016 and 2019–2020 MHWs using mapped temperature and salinity data from Argo floats. An unusual near‐surface freshwater anomaly in the Gulf of Alaska during 2019 increased the stability of the water column, preventing the MHW from penetrating deep as strongly as the 2013–2016 event. This freshwater anomaly likely contributed to the intensification of the MHW by increasing the near‐surface buoyancy. The gradual buildup of subsurface heat content throughout 2020 in the region suggests the potential for persistent ecological impacts.
Present‐Day Stress Field Influences Bedrock Fracture Openness Deep Into the Subsurface
Authors: Moon Seulgi , Perron J. Taylor , Martel Stephen J. , Goodfellow Bradley W. , Mas Ivars Diego , Hall Adrian , Heyman Jakob , Munier Raymond , Näslund Jens‐Ove , Simeonov Assen , Stroeven Arjen P.
Published: November 2020

Fracturing of bedrock promotes water‐rock interactions and influences the formation of the life‐sustaining layer of soil at Earth's surface. Models predict that present‐day stress fields should influence bedrock fracture openness, but testing this prediction has proven difficult because comprehensive fracture data sets are rarely available. We model the three‐dimensional present‐day stress field beneath the deglaciated, low‐relief landscape of Forsmark, Sweden. We account for ambient regional stresses, pore pressure, topography, sediment weight, and seawater loading. We then compare the modeled stresses to a data set of ~50,000 fractures reaching depths of 600 m at Forsmark. We show that modeled failure proxies correlate strongly with the fraction of observed open fractures to depths of ~500 m. This result implies that the present‐day regional stress field, affected by surface conditions and pore pressure, influences fracture openness in bedrock hundreds of meters beneath the surface, thereby preparing the rock for further weathering.
Analysis and Attribution of Climate Change in the Upper Atmosphere From 1950 to 2015 Simulated by WACCM‐X
Authors: Cnossen I.
Published: November 2020

Monitoring climatic changes in the thermosphere and ionosphere and understanding their causes is important for practical purposes. To support this effort and facilitate comparisons between observations and model results, a long transient simulation with the Whole Atmosphere Community Climate Model eXtension (WACCM‐X) from 1950 to 2015 was conducted. This simulation used realistic variations in solar and geomagnetic activity, main magnetic field changes, and trace gas emissions, including CO2, thereby including all known drivers of upper atmosphere climate change. Analysis of the full 1950–2015 interval with a standard multilinear regression approach demonstrated difficulties in removing solar cycle effects sufficiently to obtain reliable trends. Results improved when an (F10.7a)2 was included in the regression model, in addition to terms for F10.7a, KP, and the trend itself. Comparisons with previous studies and analysis of spatial variations in trend estimates confirmed that the increase in CO2 concentration is the main driver of trends in thermosphere temperature and density, but at high (magnetic) latitudes effects of main magnetic field changes play a role as well, especially in the Northern Hemisphere. Spatial patterns of trends in hmF2, NmF2, and total electron content indicate a superposition of CO2 and geomagnetic field effects, with the latter dominating trends in the region of ∼50–20°N, ∼60°W to 20°E. Additional model experiments to investigate the indirect dynamical effects of climate change in the lower atmosphere (<50 km) on the upper atmosphere (>100 km) suggested that these effects are small and insignificant. However, current model limitations could mean that these effects are underestimated.
Three‐Dimensional P Wave Velocity Structure of the Northern Hikurangi Margin From the NZ3D Experiment: Evidence for Fault‐Bound Anisotropy
Authors: Arai Ryuta , Kodaira Shuichi , Henrys Stuart , Bangs Nathan , Obana Koichiro , Fujie Gou , Miura Seiichi , Barker Daniel , Bassett Dan , Bell Rebecca , Mochizuki Kimihiro , Kellett Richard , Stucker Valerie , Fry Bill ,   NZ3D Team
Published: November 2020

We present a high‐resolution three‐dimensional (3‐D) anisotropic P wave velocity (Vp) model in the northern Hikurangi margin offshore Gisborne, New Zealand, constructed by tomographic inversion of over 430,000 first arrivals recorded by a dense grid of ocean bottom seismometers. Since the study area covers a region where shallow slow slip events (SSEs) occur repeatedly and the subduction of a seamount is proposed, it offers an ideal location to link our understanding of structural and hydrogeologic properties at megathrust faults to slip behavior. The Vp model reveals an ~30‐km‐wide, low‐velocity accretionary wedge at the toe of the overriding plate, where previous seismic reflection studies show a series of active thrust faults branching from the plate interface. We find some locations with significant Vp azimuthal anisotropy >5% near the branching faults and the deformation front. This finding suggests that the anisotropy is not ubiquitous and homogeneous within the overriding plate, but more localized in the vicinity of active thrust faults. The fast axes of Vp within the accretionary wedge are mostly oriented to the plate convergence direction, which is interpreted as preferentially oriented cracks in a compressional stress regime associated with plate subduction. We find that the magnitudes of anisotropy are roughly equivalent to values found at oceanic spreading centers, where the extensional stress regime is dominant and the crack density is expected to be higher than subduction zones. This consideration may indicate that additional effects such as fault foliation and clay mineral alignment also contribute to upper plate anisotropy along subduction margins.
Understanding the Asymmetry of Annual Streamflow Responses to Seasonal Warming in the Western United States
Authors: Ban Zhaoxin , Das Tapash , Cayan Dan , Xiao Mu , Lettenmaier Dennis P.
Published: November 2020

The response of annual runoff volume to sub‐annual climate warming is highly uncertain, and the governing mechanisms remain poorly understood, challenging adaptive water management. A typical exemplar is the Western United States, where climate models project substantially stronger warming in the warm season (April to September) than in the cool season (October to March). We investigate the asymmetrical responses of annual and seasonal streamflow changes to warm season and cool season warming for four regionally important basins in the Western United States using an ensemble of four land surface (hydrological) models. Our results show that (i) the general features of seasonal and annual streamflow responses to asymmetrical warming are consistent across models, although the magnitudes vary. The multi‐model mean shows annual runoff declining from 2.0% up to 7.5% under 3°C warm season warming, and from 2.2% up to 4.7% under 3°C cool season warming across the four basins. (ii) The asymmetry of the seasonal evapotranspiration sensitivity to temperature constrains the asymmetry of annual streamflow responses to seasonal warming; and (iii) basins with characteristics such as high ratios of warm to cool season gross incoming water, cooler summers, and colder winters have the strongest relative annual streamflow decreases for warm season warming relative to cool season warming. The pattern in (iii) is explained by the variation of evapotranspiration‐temperature sensitivity in response to a compound set of processes, including the enhanced rate of water holding capacity increase with warmer temperatures, temperature‐related snowmelt‐albedo feedback, and enhanced surface resistance with warmer temperatures.
Modeling the Unfrozen Water Content of Frozen Soil Based on the Absorption Effects of Clay Surfaces
Authors: Jin Xiao , Yang Wen , Gao Xiaoqing , Zhao Jian‐Qi , Li Zhenchao , Jiang Junxia
Published: November 2020

Unfrozen water content significantly affects the thermal‐hydro‐mechanical characteristics of frozen soil. Currently, theoretical explanations for the presence of unfrozen water include capillary action, surface effects, adsorption forces, and the electrical double layer. However, the relationships between unfrozen water and these actions are not well explained, except for capillary forces. In addition, although frost heave experiments indicate that the electrical double‐layer solution on a clay particle contains the main portion of unfrozen water, the electrical double‐layer theory which produces a cation solution has not previously been used to calculate unfrozen water content. In this paper, it is assumed that the residual unfrozen water at very low temperatures (below −18°C) is held within the adsorption‐layer solution and that the remaining unfrozen water within the influence of surface effects is the cationic solution in the diffuse layer. Based on these assumptions, a theoretical model of unfrozen water is established with independent variables of temperature, specific surface area, and electrical double‐layer parameters. While the input parameters of the theoretical model are numerous and difficult to obtain, the theoretical model is simplified as a parametric model. Results of the parametric model are strongly consistent with experimental data within a certain temperature range, supporting the hypothetical conditions. The similarity in the underlying mathematical structure of the derived theoretical and parametric models to current semi‐empirical models further suggests that the surface effects of clay are the main causes of unfrozen water in frozen soil.
Hollow silica reinforced magnesium nanocomposites with enhanced mechanical and biological properties with computational modeling analysis for mandibular reconstruction
Authors: Prasadh Somasundaram , Manakari Vyasaraj , Parande Gururaj , Wong Raymond Chung Wen , Gupta Manoj
Published: November 2020

The present study investigates Mg-SiO2 nanocomposites as biodegradable implants for orthopedic and maxillofacial applications. The effect of presence and progressive addition of hollow silica nanoparticles (0.5, 1, and 1.5) vol.% on the microstructural, mechanical, degradation, and biocompatibility response of pure Mg were investigated. Results suggest that the increased addition of hollow silica nanoparticles resulted in a progressive increase in yield strength and ultimate compressive strength with Mg-1.5 vol.% SiO2 exhibiting superior enhancement. The response of Mg-SiO2 nanocomposites under the influence of Hanks’ balanced salt solution revealed that the synthesized composites revealed lower corrosion rates, indicating rapid dynamic passivation when compared with pure Mg. Furthermore, cell adhesion and proliferation of osteoblast cells were noticeably higher than pure Mg with the addition of 1 vol.% SiO2 nanoparticle. The biocompatibility and the in vitro biodegradation of the Mg-SiO2 nanocomposites were influenced by the SiO2 content in pure Mg with Mg-0.5 vol.% SiO2 nanocomposite exhibiting the best corrosion resistance and biocompatibility when compared with other nanocomposites. Enhancement in mechanical, corrosion, and biocompatibility characteristics of Mg-SiO2 nanocomposites developed in this study are also compared with properties of other metallic biomaterials used in alloplastic mandibular reconstruction in a computational model.
Correction: Identifying and validating subtypes within major psychiatric disorders based on frontal–posterior functional imbalance via deep learning
Authors: Chang Miao , Womer Fay Y. , Gong Xiaohong , Chen Xi , Tang Lili , Feng Ruiqi , Dong Shuai , Duan Jia , Chen Yifan , Zhang Ran , Wang Yang , Ren Sihua , Wang Yi , Kang Jujiao , Yin Zhiyang , Wei Yange , Wei Shengnan , Jiang Xiaowei , Xu Ke , Cao Bo , Zhang Yanbo , Zhang Weixiong , Tang Yanqing , Zhang Xizhe , Wang Fei
Published: November 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Phase 1 randomized study on the safety, tolerability, and pharmacodynamic cognitive and electrophysiological effects of a dopamine D1 receptor positive allosteric modulator in patients with schizophrenia
Authors: Desai Amit , Benner Lauren , Wu Ruishan , Gertsik Lev , Maruff Paul , Light Gregory A. , Uz Tolga , Marek Gerard J. , Zhu Tong
Published: November 2020

ASP4345, a novel dopamine D1 receptor positive allosteric modulator, is being evaluated for the treatment of cognitive impairment associated with schizophrenia (CIAS). This phase 1 multiple ascending-dose study (NCT02720263) assessed the safety, tolerability, and pharmacodynamics of ASP4345 in patients with schizophrenia/schizoaffective disorder. Pharmacodynamic assessments were Cogstate cognitive tests and electrophysiological biomarkers, including gamma-band power and phase synchronization in response to 40-Hz auditory steady-state stimulation, as well as mismatch negativity (MMN) and P3a event-related potentials. The sample size determination was based on standard practice in assessing safety and tolerability of a new chemical entity. Data were summarized by conversion of this data into effect sizes using descriptive and inferential statistics. A total of 36 randomized patients received ASP4345 (3, 15, 50, and 150 mg; n = 9 each dose) and 12 patients received placebo. Patients in the ASP4345 group experienced 73 treatment-emergent adverse events (TEAEs) and 34 TEAEs were reported for the placebo group. The most common TEAEs were headache and somnolence and nearly all TEAEs were mild in severity. No changes in mood or self-reports of suicidal ideation/behavior were observed. Improvements in performance on cognitive tests were noted, which suggests a potential improvement in psychomotor function and visual attention. Furthermore, positive changes in neurophysiological biomarkers (auditory steady-state response [ASSR] and MMN) suggest improvement in information processing. The findings need to be confirmed in studies with a larger patient population. Nonetheless, the trends in safety and pharmacodynamic data support further clinical development of ASP4345 for the treatment of CIAS.
Mechanical suppression of breast cancer cell invasion and paracrine signaling to osteoclasts requires nucleo-cytoskeletal connectivity
Authors: Yi Xin , Wright Laura E. , Pagnotti Gabriel M. , Uzer Gunes , Powell Katherine M. , Wallace Joseph M. , Sankar Uma , Rubin Clinton T. , Mohammad Khalid , Guise Theresa A. , Thompson William R.
Published: November 2020

Exercise benefits the musculoskeletal system and reduces the effects of cancer. The effects of exercise are multifactorial, where metabolic changes and tissue adaptation influence outcomes. Mechanical signals, a principal component of exercise, are anabolic to the musculoskeletal system and restrict cancer progression. We examined the mechanisms through which cancer cells sense and respond to low-magnitude mechanical signals introduced in the form of vibration. Low-magnitude, high-frequency vibration was applied to human breast cancer cells in the form of low-intensity vibration (LIV). LIV decreased matrix invasion and impaired secretion of osteolytic factors PTHLH, IL-11, and RANKL. Furthermore, paracrine signals from mechanically stimulated cancer cells, reduced osteoclast differentiation and resorptive capacity. Disconnecting the nucleus by knockdown of SUN1 and SUN2 impaired LIV-mediated suppression of invasion and osteolytic factor secretion. LIV increased cell stiffness; an effect dependent on the LINC complex. These data show that mechanical vibration reduces the metastatic potential of human breast cancer cells, where the nucleus serves as a mechanosensory apparatus to alter cell structure and intercellular signaling.
Pathological features of 11,337 patients with primary ductal carcinoma in situ (DCIS) and subsequent events: results from the UK Sloane Project
Authors:   on behalf of the Sloane Project Steering Committee, Shaaban Abeer M. , Hilton Bridget , Clements Karen , Provenzano Elena , Cheung Shan , Wallis Matthew G. , Sawyer Elinor , Thomas Jeremy S. , Hanby Andrew M. , Pinder Sarah E. , Thompson Alastair M.
Published: November 2020

Background

The Sloane audit compares screen-detected ductal carcinoma in situ (DCIS) pathology with subsequent management and outcomes.

Methods

This was a national, prospective cohort study of DCIS diagnosed during 2003–2012.

Results

Among 11,337 patients, 7204 (64%) had high-grade DCIS. Over time, the proportion of high-grade disease increased (from 60 to 65%), low-grade DCIS decreased (from 10 to 6%) and mean size increased (from 21.4 to 24.1 mm). Mastectomy was more common for high-grade (36%) than for low-grade DCIS (15%). Few (6%) patients treated with breast-conserving surgery (BCS) had a surgical margin <1 mm. Of the 9191 women diagnosed in England (median follow-up 9.4 years), 7% developed DCIS or invasive malignancy in the ipsilateral and 5% in the contralateral breast. The commonest ipsilateral event was invasive carcinoma (n = 413), median time 62 months, followed by DCIS (n = 225), at median 37 months. Radiotherapy (RT) was most protective against recurrence for high-grade DCIS (3.2% for high-grade DCIS with RT compared to 6.9% without, compared with 2.3 and 3.0%, respectively, for low/intermediate-grade DCIS). Ipsilateral DCIS events lessened after 5 years, while the risk of ipsilateral invasive cancer remained consistent to beyond 10 years.

Conclusion

DCIS pathology informs patient management and highlights the need for prolonged follow-up of screen-detected DCIS.
Migrant birds and mammals live faster than residents
Authors: Soriano-Redondo Andrea , Gutiérrez Jorge S. , Hodgson Dave , Bearhop Stuart
Published: November 2020

Billions of vertebrates migrate to and from their breeding grounds annually, exhibiting astonishing feats of endurance. Many such movements are energetically costly yet there is little consensus on whether or how such costs might influence schedules of survival and reproduction in migratory animals. Here we provide a global analysis of associations between migratory behaviour and vertebrate life histories. After controlling for latitudinal and evolutionary patterns, we find that migratory birds and mammals have faster paces of life than their non-migratory relatives. Among swimming and walking species, migrants tend to have larger body size, while among flying species, migrants are smaller. We discuss whether pace of life is a determinant, consequence, or adaptive outcome, of migration. Our findings have important implications for the understanding of the migratory phenomenon and will help predict the responses of bird and mammal species to environmental change.
Young adult-born neurons improve odor coding by mitral cells
Authors: Shani-Narkiss H. , Vinograd A. , Landau I. D. , Tasaka G. , Yayon N. , Terletsky S. , Groysman M. , Maor I. , Sompolinsky H. , Mizrahi A.
Published: November 2020

New neurons are continuously generated in the adult brain through a process called adult neurogenesis. This form of plasticity has been correlated with numerous behavioral and cognitive phenomena, but it remains unclear if and how adult-born neurons (abNs) contribute to mature neural circuits. We established a highly specific and efficient experimental system to target abNs for causal manipulations. Using this system with chemogenetics and imaging, we found that abNs effectively sharpen mitral cells (MCs) tuning and improve their power to discriminate among odors. The effects on MCs responses peaked when abNs were young and decreased as they matured. To explain the mechanism of our observations, we simulated the olfactory bulb circuit by modelling the incorporation of abNs into the circuit. We show that higher excitability and broad input connectivity, two well-characterized features of young neurons, underlie their unique ability to boost circuit computation.
PrimPol-dependent single-stranded gap formation mediates homologous recombination at bulky DNA adducts
Authors: Piberger Ann Liza , Bowry Akhil , Kelly Richard D. W. , Walker Alexandra K. , González-Acosta Daniel , Bailey Laura J. , Doherty Aidan J. , Méndez Juan , Morris Joanna R. , Bryant Helen E. , Petermann Eva
Published: November 2020

Stalled replication forks can be restarted and repaired by RAD51-mediated homologous recombination (HR), but HR can also perform post-replicative repair after bypass of the obstacle. Bulky DNA adducts are important replication-blocking lesions, but it is unknown whether they activate HR at stalled forks or behind ongoing forks. Using mainly BPDE-DNA adducts as model lesions, we show that HR induced by bulky adducts in mammalian cells predominantly occurs at post-replicative gaps formed by the DNA/RNA primase PrimPol. RAD51 recruitment under these conditions does not result from fork stalling, but rather occurs at gaps formed by PrimPol re-priming and resection by MRE11 and EXO1. In contrast, RAD51 loading at double-strand breaks does not require PrimPol. At bulky adducts, PrimPol promotes sister chromatid exchange and genetic recombination. Our data support that HR at bulky adducts in mammalian cells involves post-replicative gap repair and define a role for PrimPol in HR-mediated DNA damage tolerance.
Polycarbonate-based ultra-pH sensitive nanoparticles improve therapeutic window
Authors: Wang Xu , Wilhelm Jonathan , Li Wei , Li Suxin , Wang Zhaohui , Huang Gang , Wang Jian , Tang Houliang , Khorsandi Sina , Sun Zhichen , Evers Bret , Gao Jinming
Published: November 2020

Stimuli-sensitive nanomaterials with cooperative response are capable of converting subtle and gradual biological variations into robust outputs to improve the precision of diagnostic or therapeutic outcomes. In this study, we report the design, synthesis and characterization of a series of degradable ultra-pH sensitive (dUPS) polymers that amplify small acidic pH changes to efficacious therapeutic outputs. A hydrolytically active polycarbonate backbone is used to construct the polymer with pH-dependent degradation kinetics. One dUPS polymer, PSC7A, can achieve activation of the stimulator of interferon genes and antigen delivery upon endosomal pH activation, leading to T cell-mediated antitumor immunity. While a non-degradable UPS polymer induces granulomatous inflammation that persists over months at the injection site, degradable PSC7A primes a transient acute inflammatory response followed by polymer degradation and complete tissue healing. The improved therapeutic window of the dUPS polymers opens up opportunities in pH-targeted drug and protein therapy.
Microcephalin 1/BRIT1-TRF2 interaction promotes telomere replication and repair, linking telomere dysfunction to primary microcephaly
Authors: Cicconi Alessandro , Rai Rekha , Xiong Xuexue , Broton Cayla , Al-Hiyasat Amer , Hu Chunyi , Dong Siying , Sun Wenqi , Garbarino Jennifer , Bindra Ranjit S. , Schildkraut Carl , Chen Yong , Chang Sandy
Published: November 2020

Telomeres protect chromosome ends from inappropriately activating the DNA damage and repair responses. Primary microcephaly is a key clinical feature of several human telomere disorder syndromes, but how microcephaly is linked to dysfunctional telomeres is not known. Here, we show that the microcephalin 1/BRCT-repeats inhibitor of hTERT (MCPH1/BRIT1) protein, mutated in primary microcephaly, specifically interacts with the TRFH domain of the telomere binding protein TRF2. The crystal structure of the MCPH1–TRF2 complex reveals that this interaction is mediated by the MCPH1 330YRLSP334 motif. TRF2-dependent recruitment of MCPH1 promotes localization of DNA damage factors and homology directed repair of dysfunctional telomeres lacking POT1-TPP1. Additionally, MCPH1 is involved in the replication stress response, promoting telomere replication fork progression and restart of stalled telomere replication forks. Our work uncovers a previously unrecognized role for MCPH1 in promoting telomere replication, providing evidence that telomere replication defects may contribute to the onset of microcephaly.
Docking sites inside Cas9 for adenine base editing diversification and RNA off-target elimination
Authors: Li Shuo , Yuan Bo , Cao Jixin , Chen Jingqi , Chen Jinlong , Qiu Jiayi , Zhao Xing-Ming , Wang Xiaolin , Qiu Zilong , Cheng Tian-Lin
Published: November 2020

Base editing tools with diversified editing scopes and minimized RNA off-target activities are required for broad applications. Nevertheless, current Streptococcus pyogenes Cas9 (SpCas9)-based adenine base editors (ABEs) with minimized RNA off-target activities display constrained editing scopes with efficient editing activities at positions 4-8. Here, functional ABE variants with diversified editing scopes and reduced RNA off-target activities are identified using domain insertion profiling inside SpCas9 and with different combinations of TadA variants. Engineered ABE variants in this study display narrowed, expanded or shifted editing scopes with efficient editing activities across protospacer positions 2-16. And when combined with deaminase engineering, the RNA off-target activities of engineered ABE variants are further minimized. Thus, domain insertion profiling provides a framework to improve and expand ABE toolkits, and its combination with other strategies for ABE engineering deserves comprehensive explorations in the future.
Understanding complex dynamics of behavioral, neurochemical and transcriptomic changes induced by prolonged chronic unpredictable stress in zebrafish
Authors: Demin Konstantin A. , Lakstygal Anton M. , Krotova Nataliya A. , Masharsky Alexey , Tagawa Natsuki , Chernysh Maria V. , Ilyin Nikita P. , Taranov Alexander S. , Galstyan David S. , Derzhavina Ksenia A. , Levchenko Nataliia A. , Kolesnikova Tatiana O. , Mor Mikael S. , Vasyutina Marina L. , Efimova Evgeniya V. , Katolikova Nataliia , Prjibelski Andrey D. , Gainetdinov Raul R. , de Abreu Murilo S. , Amstislavskaya Tamara G. , Strekalova Tatyana , Kalueff Allan V.
Published: November 2020

Stress-related neuropsychiatric disorders are widespread, debilitating and often treatment-resistant illnesses that represent an urgent unmet biomedical problem. Animal models of these disorders are widely used to study stress pathogenesis. A more recent and historically less utilized model organism, the zebrafish (Danio rerio), is a valuable tool in stress neuroscience research. Utilizing the 5-week chronic unpredictable stress (CUS) model, here we examined brain transcriptomic profiles and complex dynamic behavioral stress responses, as well as neurochemical alterations in adult zebrafish and their correction by chronic antidepressant, fluoxetine, treatment. Overall, CUS induced complex neurochemical and behavioral alterations in zebrafish, including stable anxiety-like behaviors and serotonin metabolism deficits. Chronic fluoxetine (0.1 mg/L for 11 days) rescued most of the observed behavioral and neurochemical responses. Finally, whole-genome brain transcriptomic analyses revealed altered expression of various CNS genes (partially rescued by chronic fluoxetine), including inflammation-, ubiquitin- and arrestin-related genes. Collectively, this supports zebrafish as a valuable translational tool to study stress-related pathogenesis, whose anxiety and serotonergic deficits parallel rodent and clinical studies, and genomic analyses implicate neuroinflammation, structural neuronal remodeling and arrestin/ubiquitin pathways in both stress pathogenesis and its potential therapy.
Epstein–Barr virus peptides derived from latent cycle proteins alter NKG2A + NK cell effector function
Authors: Mbiribindi Berenice , Pena Josselyn K. , Arvedson Matthew P. , Moreno Romero Claudia , McCarthy Sarah R. , Hatton Olivia L. , Esquivel Carlos O. , Martinez Olivia M. , Krams Sheri M.
Published: November 2020

Natural killer (NK) cells control viral infection through the interaction between inhibitory receptors and human leukocyte antigen (HLA) ligands and bound peptide. NK cells expressing the inhibitory receptor NKG2A/CD94 recognize and respond to autologous B cells latently infected with Epstein–Barr virus (EBV). The mechanism is not yet understood, thus we investigated peptides derived from seven latent proteins of EBV in the interaction of NKG2A and its ligand HLA-E. Functional analysis demonstrated that EBV peptides can bind to HLA-E and block inhibition of NK cell effector function. Moreover, analysis of DNA from 79 subjects showed sequence variations in the latent protein, LMP1, which alters NK responses to EBV. We provide evidence that peptides derived from EBV latent cycle proteins can impair the recognition of NKG2A despite being presented by HLA-E, resulting in NK cell activation.
Biosynthesis of zinc oxide nanoparticles by cell-biomass and supernatant of Lactobacillus plantarum TA4 and its antibacterial and biocompatibility properties
Authors: Mohd Yusof Hidayat , Abdul Rahman Nor’Aini , Mohamad Rosfarizan , Zaidan Uswatun Hasanah , Samsudin Anjas Asmara
Published: November 2020

This study aims to utilize the cell-biomass (CB) and supernatant (CFS) of zinc-tolerant Lactobacillus plantarum TA4 as a prospective nanofactory to synthesize ZnO NPs. The surface plasmon resonance for the biosynthesized ZnO NPs-CFS and ZnO NPs-CB was 349 nm and 351 nm, respectively, thereby confirming the formation of ZnO NPs. The FTIR analysis revealed the presence of proteins, carboxyl, and hydroxyl groups on the surfaces of both the biosynthesized ZnO NPs that act as reducing and stabilizing agents. The DLS analysis revealed that the poly-dispersity indexes was less than 0.4 for both ZnO NPs. In addition, the HR-TEM micrographs of the biosynthesized ZnO NPs revealed a flower-like pattern for ZnO NPs-CFS and an irregular shape for ZnO NPs-CB with particles size of 291.1 and 191.8 nm, respectively. In this study, the biosynthesized ZnO NPs exhibited antibacterial activity against pathogenic bacteria in a concentration-dependent manner and showed biocompatibility with the Vero cell line at specific concentrations. Overall, CFS and CB of L. plantarum TA4 can potentially be used as a nanofactory for the biological synthesis of ZnO NPs.