bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel tetrathiafulvalene based liquid crystalline organogelator: synthesis, self-assembly properties and potential utilization
Authors: Xu Chao , Wang Li , Xia Yan , Li Dongfeng , Yin Bingzhu , Hou Ruibin
Published: November 2022

Organogels with unique liquid crystalline properties are potential candidates for developing optical electronics.
A COF-coated polyamide membrane fabricated by vapor-assisted conversion for water-in-oil emulsion separation
Authors: Chen Ying , Chen Li , Lu Chenyang , Wang Linghao , Dong Lichun , Zhou Cailong , Huang Xiaowei
Published: November 2022

A PA@COF membrane prepared by vapor-assisted conversion at room temperature showed good separation ability for filtering various water-in-oil emulsions.
Determination of the optical constants of ligand-free organic lead halide perovskite quantum dots
Authors: Rubino Andrea , Lozano Gabriel , Calvo Mauricio E. , Míguez Hernán
Published: November 2022

We determine the complex refractive index of perovskite QDs, for which we take advantage of a ligand-free synthetic approach that facilitates discriminating the contribution of the nanocrystals to the effective optical constant of the ensemble.
Stereocontrolled total synthesis of Resolvin D4 and 17(R)-Resolvin D4
Authors: Nshimiyimana Robert , Glynn Stephen J. , Serhan Charles N. , Petasis Nicos A.
Published: November 2022

We describe the stereocontrolled synthesis of Resolvin D4 and 17(R)-Resolvin D4. These molecules possess protective activities in resolving inflammation.
Structural design strategies for superionic sodium halide solid electrolytes
Authors: Yu Seungho , Kim Kwangnam , Wood Brandon C. , Jung Hun-Gi , Chung Kyung Yoon
Published: November 2022

The material design principles in this study provide fundamental guidelines for the development of superionic sodium halide solid electrolytes for high-voltage sodium all-solid-state batteries.
A probabilistic approach for optimal operation of wind‐integrated power systems including UPFC
Authors: Rezaeian‐Marjani Saeed , Jalalat Sajjad Miralizadeh , Tousi Behrouz , Galvani Sadjad , Talavat Vahid
Published: November 2022

The optimal location and setting of the unified power flow controller (UPFC) along with power plant generators' output parameters to enhance power systems reliability in the presence of uncertain variables are determined in this paper. For this purpose, the expected power not served (EPNS) is used as a reliability index based on the total required load shedding at all buses in case of single contingencies such as the outage of lines or generators. The EPNS and components of system's normal operating conditions such as active power losses, voltage deviation index (VDI), as well as economic components, namely, the cost of power generation and UPFC allocation, are taken into consideration in the objective function. The particle swarm optimization (PSO) algorithm optimizes this objective function. Afterward, the firefly algorithm (FA) determines the minimum quantity of required load shedding based on all possible solutions obtained by PSO. Because of the probabilistic nature of loads and renewable generations like wind power generation (WPG), an accurate probabilistic assessment is essential. Therefore, the two‐point estimate method (2PEM) is used, and its performance is compared with the Latin hypercube sampling (LHS) method. The proposed solution method is evaluated on the IEEE 14‐bus and the IEEE 57‐bus test systems and results are discussed.
A real‐time fine echo generation method of extended false target with radially high‐speed moving
Authors: Lei Wei , Zhang Yue , Chen Zengping
Published: November 2022

The false‐target echo generation to Inverse Synthetic Aperture Radar (ISAR) is significant in jamming the enemy ISAR and promoting ISAR development. Generally, it requires false‐target echo coherent with the radar, real time and fine. However, conventional methods, such as digital image synthesizer (DIS), cannot meet those requirements. Moreover, existing methods do not consider the target's radial moving. To meet those demands, we propose an improved method in this study. We equivalently model echo formation as the synthesizer of two independent parts: (1) echo of remote target with radial moving and (2) echo of nearby extended target. In part one, accuracy is improved by utilising the Inner Pulse Motion (IPM) model and complexity is simplified by deducing it as a frequency offset modulation. In part two, the fine extended target echo is constructed by using convolution filtering whose resources consumption can be greatly reduced by separating it into an offline stage and a real‐time stage. Our method is verified by algorithm simulations and actual experiments. The results indicate that it can build the fine false‐target echo in real‐time and can adapt to the target's radial velocity, different resolution and size. Compared with the conventional DIS method, our method reduces the computational complexity significantly and has more comprehensive functions.
Industry 4.0 and healthcare: Context, applications, benefits and challenges
Authors: Kotzias Konstantinos , Bukhsh Faiza A. , Arachchige Jeewanie Jayasinghe , Daneva Maya , Abhishta Abhishta
Published: November 2022

Industry 4.0 refers to the digital transformation in the manufacturing domain through new technology. Currently, it expands well beyond manufacturing, affecting many areas of life and posing implications for all types of business. This paper focuses on the relationships between Industry 4.0 and Healthcare which transitions to increased interconnectivity, automation and smart decision making. The integration context of Industry 4.0 into Healthcare is only partly understood. Little was done until now to consolidate what is known on the integration benefits and the challenges. This article reports results of a systematic mapping study that analysed 69 papers to extract knowledge about the concepts of Industry 4.0 and the emerging Healthcare 4.0., and the relationships between them. We found 10 different perspectives of Healthcare 4.0, ranging from strategic to tactical and operational levels. Next, our results show: (i) nine applications of Industry 4.0 in the Healthcare domain: Augmented Reality and Simulation, Autonomous Robotics, Cybersecurity, Big Data Analytics, Internet of Things, Cloud Computing, Additive Manufacturing and Systems Integration; and (ii) 10 benefits and nine challenges in Healthcare 4.0. The most frequently mentioned benefits are patients' diagnosis, monitoring, treatment, and financial benefits. The most researched challenges are data fragmentation, heterogeneity, complexity, and privacy.
First r-process enhanced star confirmed as a member of the Galactic bulge
Authors: Forsberg R. , Rich R. M. , Nieuwmunster N. , Jönsson H. , Schultheis M. , Ryde N. , Thorsbro B.
Published: November 2022

Aims. Stars with strong enhancements of r-process elements are rare and tend to be metal-poor, generally with [Fe/H] < −2 dex, and located in the halo. In this work, we aim to investigate a candidate r-process enriched bulge star with a relatively high metallicity of [Fe/H] ~ − 0.65 dex and to compare it with a previously published r-rich candidate star in the bulge.

Methods. We reconsidered the abundance analysis of a high-resolution optical spectrum of the red-giant star 2MASS J18082459-2548444 and determined its europium (Eu) and molybdenum (Mo) abundance, using stellar parameters from five different previous studies. Applying 2MASS photometry, Gaia astrometry, and kinematics, we estimated the distance, orbits, and population membership of 2MASS J18082459-2548444 and a previously reported r-enriched star 2MASS J18174532-3353235.

Results. We find that 2MASS J18082459-2548444 is a relatively metal-rich, enriched r-process star that is enhanced in Eu and Mo, but not substantially enhanced in s-process elements. There is a high probability that it has a Galactic bulge membership, based on its distance and orbit. We find that both stars show r-process enhancement with elevated [Eu/Fe]-values, even though 2MASS J18174532-3353235 is 1 dex lower in metallicity. Additionally, we find that the plausible origins of 2MASS J18174532-3353235 to be either that of the halo or the thick disc.

Conclusions. We conclude that 2MASS J18082459-2548444 represents the first example of a confirmed r-process enhanced star confined to the inner bulge. We assume it is possibly a relic from a period of enrichment associated with the formation of the bar.
HD 20329b: An ultra-short-period planet around a solar-type star found by TESS
Authors: Murgas F. , Nowak G. , Masseron T. , Parviainen H. , Luque R. , Pallé E. , Korth J. , Carleo I. , Csizmadia Sz. , Esparza-Borges E. , Alqasim A. , Cochran W. D. , Dai F. , Deeg H. J. , Gandolfi D. , Goffo E. , Kabáth P. , Lam K. W. F. , Livingston J. , Muresan A. , Osborne H. L. M. , Persson C. M. , Serrano L. M. , Smith A. M. S. , Van Eylen V. , Orell-Miquel J. , Hinkel N. R. , Galán D. , Puig-Subirà M. , Stangret M. , Fukui A. , Kagetani T. , Narita N. , Ciardi D. R. , Boyle A. W. , Ziegler C. , Briceño C. , Law N. , Mann A. W. , Jenkins J. M. , Latham D. W. , Quinn S. N. , Ricker G. , Seager S. , Shporer A. , Ting E. B. , Vanderspek R. , Winn J. N.
Published: November 2022

Context. Ultra-short-period (USP) planets are defined as planets with orbital periods shorter than one day. This type of planets is rare, highly irradiated, and interesting because their formation history is unknown.

Aims. We aim to obtain precise mass and radius measurements to confirm the planetary nature of a USP candidate found by the Transiting Exoplanet Survey Satellite (TESS). These parameters can provide insights into the bulk composition of the planet candidate and help to place constraints on its formation history.

Methods. We used TESS light curves and HARPS-N spectrograph radial velocity measurements to establish the physical properties of the transiting exoplanet candidate found around the star HD 20329 (TOI-4524). We performed a joint fit of the light curves and radial velocity time series to measure the mass, radius, and orbital parameters of the candidate.

Results. We confirm and characterize HD 20329b, a USP planet transiting a solar-type star. The host star (HD 20329, V = 8.74 mag, J = 7.5 mag) is characterized by its G5 spectral type with M* = 0.90 ± 0.05 M⊙, R* = 1.13 ± 0.02 R⊙, and Teff = 5596 ± 50 K; it is located at a distance d = 63.68 ± 0.29 pc. By jointly fitting the available TESS transit light curves and follow-up radial velocity measurements, we find an orbital period of 0.9261 ± (0.5 × 10−4) days, a planetary radius of 1.72 ± 0.07 R⊗, and a mass of 7.42 ± 1.09 M⊗, implying a mean density of ρp = 8.06 ± 1.53 g cm−3. HD 20329b joins the ~30 currently known USP planets with radius and Doppler mass measurements.
Reynolds stress modeling of supercritical narrow channel flows using OpenFOAM: Secondary currents and turbulent flow characteristics
Authors: Kadia Subhojit , Rüther Nils , Albayrak Ismail , Pummer Elena
Published: November 2022

In this study, the full Launder, Reece and Rodi pressure-strain model, and nonlinear boundary damping functions were incorporated in OpenFOAM® to simulate the turbulence-driven secondary currents in supercritical narrow channel flows, such as in sediment bypass tunnels. Five simulations were performed under uniform flow conditions covering Froude numbers from 1.69 to 2.56 and aspect ratios (channel width to flow depth) ar from 0.9 to 1.91 to investigate the formation of secondary currents and their impacts on longitudinal velocity, turbulence characteristics, and bed shear stress distribution. The numerical results of the maximum longitudinal velocity and the average shear velocity show marginal deviations, of less than 2.6%, from two-dimensional experimental results acquired under decelerating flow conditions. However, some differences are observed for the secondary currents and for the vertical turbulence intensity and Reynolds shear stress in the outer flow region, especially for cases with higher flow nonuniformity (that can influence the surface perturbation) whose influence is missing in the numerical model. No intermediate vortex is observed for ar = 1.91. However, it develops for lower ar and detaches from the free surface vortex when ar ≤ 1.05. Such vortex bulges the longitudinal velocity contour lines inward and the zone of higher longitudinal velocity narrows and deepens with a decrease in ar. The decrement reduces the magnitude of the normalized maximum secondary velocity. It also affects the bottom vortex which alters the bed shear stress distribution.
Study of flow and heat transfer characteristics of saturated flow film boiling over two inline cylinders
Authors: Thamil Kumaran S. M. , Premachandran B.
Published: November 2022

In this article, a numerical investigation carried out on saturated flow film boiling over two cylinders placed in an inline arrangement has been discussed. Water at near critical condition, p/pc = 0.99, is considered for all simulations, where pc is the critical pressure of water. In this study, buoyancy assisted flow is considered. The effects of different liquid Reynolds number ReD and wall superheat on heat transfer rates are studied for different spacings between the two cylinders. Interface structures and their modes of evolution greatly vary for different cases investigated. For some cases, especially for those with lower spacing between the cylinders, a steady vapor column connecting both cylinders in the gap region between them is formed. At higher flow rates, the vapor column in the gap region is unstable. At some cases where re-circulation zones are formed, the vapor column breaks off. The heat transfer rate from the rear cylinder is significantly affected by the modes of the phase-interface evolution and the types of flow structures formed in the gap region between the cylinders. It is found that the flow structures and the phase-interface evolution are strongly dependent on the distance between the two cylinders for a given Reynolds number and a non-dimensional wall superheat.
Experimental study of the influence of structural parameters on pressure fluctuations of cone–cylinder–hemisphere models
Authors: Li Yuhui , Miao Xuhong , Xiao Jingping , Pang Fuzhen , Wang Hongfu
Published: November 2022

When a viscous fluid flows over the surface of an object, different regions of the wall form different boundary layers. Fluctuating pressure in this boundary layer acts on the surface of the structure, causing it to vibrate and radiate noise; simultaneously, structural deformations will also have an impact on the flow field, and boundary layer pressure fluctuation is the most important component of flow noise. The characteristic parameters of a model, such as its wall thickness and the length of its parallel body section, will affect the pressure fluctuations it experiences. However, most studies treat the structure of the model as a rigid body. Therefore, this paper conducted experiments to examine the influences of the wall thickness and the parallel body length of a model on the pressure fluctuations it experiences. It was found that the fluctuating pressure at a given measuring position increases with decreasing wall thickness, and it decreases with increasing parallel body length. Then, this study demonstrated through comparative experiments that elastic and scale effects are important factors that cannot be ignored in calculations and experiments relating to pressure fluctuations. In addition, according to the characteristics of pressure fluctuation test values in different regions, the pressure-fluctuation prediction empirical formulas for different regions of the boundary layer were established or improved on the basis of previous research on pressure fluctuation in different regions of the boundary layer. Finally, by pasting a flow exciter at the transition position in the boundary layer of the model can keep its flow noise down, the experimental results show that rough particles can split the large vortex into smaller vortices and reduce flow noise by more than 5 dB. These results and empirical formulas provide references for numerical and experimental research examining pressure fluctuations.
Lying with deceptive implicatures? Solving a puzzle about conflicting results
Authors: Wiegmann Alex
Published: November 2022

Does lying require a speaker to explicitly express something (she believes to be) false, or is it also possible to lie with deceptive implicatures? Given that consistency with ordinary language is a desideratum of any philosophical definition of lying, several studies have addressed this question empirically in recent years. Their findings, however, seem to be in conflict. This paper reports an experiment with 222 participants that investigates the hypothesis that these conflicting results are due to variation regarding whether or not the speaker’s intention to deceive and the implicated content are made explicit. It is found that the presence versus the absence of such explicitness has a strong impact on people’s lie judgements, and can thus account for the conflicting results in the literature.
Perceptual odor qualities predict successful odor identification in old age
Authors: Lindroos Robert , Raj Rohan , Pierzchajlo Stephen , Hörberg Thomas , Herman Pawel , Challma Sandra , Hummel Thomas , Larsson Maria , Laukka Erika J , Olofsson Jonas K
Published: November 2022

Odor identification is a common assessment of olfaction, and it is affected in a large number of diseases. Identification abilities decline with age, but little is known about whether there are perceptual odor features that can be used to predict identification. Here, we analyzed data from a large, population-based sample of 2,479 adults, aged 60 years or above, from the Swedish National study on Aging and Care in Kungsholmen. Participants performed both free and cued odor identification tests. In a separate experiment, we assessed perceived pleasantness, familiarity, intensity, and edibility of all odors in the first sample, and examined how odor identification performance is associated with these variables. The analysis showed that high-intensity odors are easier to identify than low-intensity odors overall, but also that they are more susceptible to the negative repercussions of old age. This result indicates that sensory decline is a major aspect of age-dependent odor identification impairment, and suggests a framework where identification likelihood is proportional to the perceived intensity of the odor. Additional analyses further showed that high-performing individuals can discriminate target odors from distractors along the pleasantness and edibility dimensions and that unpleasant and inedible odors show smaller age-related differences in identification. Altogether, these results may guide further development and optimization of brief and efficient odor identification tests as well as influence the design of odorous products targeted toward older consumers.
Behavioral Response of Unmated Female Plodia interpunctella Hübner (Lepidoptera: Pyralidae) to Synthetic Sex Pheromone Lure
Authors: Gerken Alison R , Dryer Danielle , Abts Shelby R , Campbell James F
Published: November 2022

Indian meal moth, Plodia interpunctella Hübner, is an important pest of stored products in food facilities like processing plants, warehouses, and retail stores. Mating disruption, which uses synthetic pheromone to delay or prevent mating, is a relatively new management tactic for this pest but is becoming widely adopted. However, little is known about the mechanisms behind its efficacy, including how artificial pheromone impacts female behavior. Here we assay behavioral responses of two strains of unmated female P. interpunctella exposed to pheromone. Results show one strain increased the duration of calling behavior while the other decreased calling when exposed to pheromone lures. Time walking decreased, and time cleaning increased for both strains when exposed to pheromone. Time of first walking behavior was also delayed for one strain when exposed to pheromone. Females of both strains were less mobile when exposed to pheromone. These results show autodetection of pheromone by females, but also indicate that strains may vary in behavioral responses. Differing patterns of calling behavior between strains could be driven by either strain-specific genetic differences or laboratory induced effects. Decreasing calling behavior and overall movement during exposure to pheromone could enhance the effectiveness of a mating disruption program. However, increased calling by females in the presence of pheromone may be a competitive response and could increase mating success under certain scenarios. These findings suggest that artificial pheromone associated with monitoring and mating disruption programs has impacts on female behavior and warrants further study to determine the overall impacts on program effectiveness.
Early Postwar Accounts on Jewish Orphans from Transnistria
Authors: Mihăilescu Dana
Published: November 2022

This article focuses on the emotional and social challenges that Romanian Holocaust survivors, particularly children who became orphans, faced in the early postwar period. The author shows how the accounts of Jewish orphans from Transnistria did not initially come from experts, but from published booklets of Jewish survivors and journalists, and Jewish and non-Jewish Romanian press accounts, all of which had divergent agendas. Soon after the War, assessments by psychologists and physicians also appeared. The most important Jewish-Romanian figure to connect these diverse accounts to the psychological state of Romanian-Jewish orphans at the end of the Second World War was Dr. Theodor Loewenstein. In tracking and analyzing these narratives, the author seeks to understand the different representations of Jewish orphans from Transnistria in early postwar Romania.
On Resisting Art
Authors: Harold James
Published: November 2022

What responsibilities do audiences have in engaging with artworks? Certain audience responses seem quite clear: for example, audiences should not vandalize or destroy artworks; they should not disrupt performances. This paper examines other kinds of resisting responses that audiences sometimes engage in, including petitioning the artist to change their works, altering copies of artworks, and creating new artworks in another artist’s fictional world. I argue for five claims: (1) while these actions can sometimes infringe on the rights of artists, the rights of artists are not absolute; (2) the fact that such actions are based on mistaken interpretations of the artworks has no normative weight; (3) there can be reason to object to additions and alterations whose conception of the artwork is morally worse than the original (and so, there can be reason to support additions and alterations whose conception is morally better); (4) petitioning raises special moral problems; and, most important, (5) some of these actions are valuable because they involve creative and aesthetic activity. Those acts of audience resistance that are creative, morally improve on the original work, and that minimize the infringement of the artists’ rights are good, and should be encouraged.
The prediction accuracies of linear-type traits in Czech Holstein cattle when using ssGBLUP or wssGBLUP
Authors: Brzáková Michaela , Bauer Jiří , Steyn Yvette , Šplíchal Jiří , Fulínová Daniela
Published: November 2022

The aim of this study was to assess the contribution of the weighted single-step genomic best linear unbiased prediction (wssGBLUP) method compared to the single-step genomic best linear unbiased prediction (ssGBLUP) method for genomic evaluation of 25 linear-type traits in the Czech Holstein cattle population. The nationwide database of linear-type traits with 6,99,681 records combined with deregressed proofs from Interbull (MACE method) was used as the input data. Genomic breeding values (GEBVs) were predicted based on these phenotypes using ssGBLUP and wssGBLUP methods using the BLUPF90 software. The bull validation test was employed which was based on comparing GEBVs of young bulls (N = 334) with no progeny in 2016. A minimum of 50 daughters with their own performance in 2020 was chosen to verify the contribution to the GEBV prediction, GEBV reliability, validation reliabilities (R2), and regression coefficients (b1). The results showed that the differences between the two methods were negligible. The low benefit of wssGBLUP may be due to the inclusion of a small number of SNPs; therefore, most predictions rely on polygenic relationships between animals. Nevertheless, the benefits of wssGBLUP analysis should be assessed with respect to specific population structures and given traits.
Habitat Diversity, Stability, and Productivity of Malaria Vectors in Irrigated and Nonirrigated Ecosystems in Western Kenya
Authors: Orondo Pauline Winnie , Wang Xiaoming , Lee Ming-Chieh , Nyanjom Steven G , Atieli Harrysone , Ondeto Benyl M , Ochwedo Kevin O , Omondi Collince J , Otambo Wilfred Ouma , Zhou Guofa , Zhong Daibin , Githeko Andrew K , Kazura James W , Yan Guiyun
Published: November 2022

Several sub-Saharan African countries rely on irrigation for food production. This study examined the impact of environmental modifications resulting from irrigation on the ecology of aquatic stages of malaria vectors in a semi-arid region of western Kenya. Mosquito larvae were collected from irrigated and non-irrigated ecosystems during seasonal cross-sectional and monthly longitudinal studies to assess habitat availability, stability, and productivity of anophelines in temporary, semipermanent, and permanent habitats during the dry and wet seasons. The duration of habitat stability was also compared between selected habitats. Emergence traps were used to determine the daily production of female adult mosquitoes from different habitat types. Malaria vectors were morphologically identified and sibling species subjected to molecular analysis. Data was statistically compared between the two ecosystems. After aggregating the data, the overall malaria vector productivity for habitats in the two ecosystems was estimated. Immatures of the malaria vector (Anopheles arabiensis) Patton (Diptera: Culicidae) comprised 98.3% of the Anopheles in both the irrigated and non-irrigated habitats. The irrigated ecosystem had the most habitats, higher larval densities, and produced 85.8% of emerged adult females. These results showed that irrigation provided conditions that increased habitat availability, stability, and diversity, consequently increasing the An. arabiensis production and potential risk of malaria transmission throughout the year. The irrigated ecosystems increased the number of habitats suitable for Anopheles breeding by about 3-fold compared to non-irrigated ecosystems. These results suggest that water management in the irrigation systems of western Kenya would serve as an effective method for malaria vector control.
The Dynamics of Adaptation to Stress from Standing Genetic Variation and de novo Mutations
Authors: Ament-Velásquez Sandra Lorena , Gilchrist Ciaran , Rêgo Alexandre , Bendixsen Devin P , Brice Claire , Grosse-Sommer Julie Michelle , Rafati Nima , Stelkens Rike
Published: November 2022

Adaptation from standing genetic variation is an important process underlying evolution in natural populations, but we rarely get the opportunity to observe the dynamics of fitness and genomic changes in real time. Here, we used experimental evolution and Pool-Seq to track the phenotypic and genomic changes of genetically diverse asexual populations of the yeast Saccharomyces cerevisiae in four environments with different fitness costs. We found that populations rapidly and in parallel increased in fitness in stressful environments. In contrast, allele frequencies showed a range of trajectories, with some populations fixing all their ancestral variation in <30 generations and others maintaining diversity across hundreds of generations. We detected parallelism at the genomic level (involving genes, pathways, and aneuploidies) within and between environments, with idiosyncratic changes recurring in the environments with higher stress. In particular, we observed a tendency of becoming haploid-like in one environment, whereas the populations of another environment showed low overall parallelism driven by standing genetic variation despite high selective pressure. This work highlights the interplay between standing genetic variation and the influx of de novo mutations in populations adapting to a range of selective pressures with different underlying trait architectures, advancing our understanding of the constraints and drivers of adaptation.
Crystal structure of monkeypox H1 phosphatase, an antiviral drug target
Authors: Cui Wen , Huang Haojun , Duan Yinkai , Luo Zhi , Wang Haofeng , Zhang Tenan , Nguyen Henry C , Shen Wei , Su Dan , Li Xi , Ji Xiaoyun , Yang Haitao , Wang Wei
Published: November 2022

The current monkeypox outbreak has caused over 73,000 global cases, but the effective treatments are very limited. The dual specific phosphatase (H1) from monkeypox antagonizes the immune response and is crucial for viral replication, making it an attractive antiviral target. Here we determined a 1.8-Å crystal structure of H1, which forms a domain swapped dimer resembling a butterfly. Each active site, which consists of a Cys-Arg-Asp triad, captures a phosphate ion. The observed conformation mimics the final step of catalysis prior to product release. The crystal structure provides a strong foundation for the discovery of new antivirals against this emerging worldwide pathogen.
Auditory Hallucinations and Self-Injurious Behavior in General Population Adolescents: Modeling Within-Person Effects in the Tokyo Teen Cohort
Authors: Stanyon Daniel , DeVylder Jordan , Yamasaki Syudo , Yamaguchi Satoshi , Ando Shuntaro , Usami Satoshi , Endo Kaori , Miyashita Mitsuhiro , Kanata Sho , Morimoto Yuko , Hosozawa Mariko , Baba Kaori , Nakajima Naomi , Niimura Junko , Nakanishi Miharu , Hiraiwa-Hasegawa Mariko , Kasai Kiyoto , Nishida Atsushi
Published: November 2022

Background and Hypotheses

A wealth of evidence suggests that adolescent psychotic experiences (PEs), and especially auditory hallucinations (AHs), are associated with an increased risk for self-injurious behavior (SIB). However, the directionality and specificity of this association are not well understood, and there are no published studies investigating within-person effects over time. The present study aimed to test whether AHs and SIB prospectively increase reciprocal risk at the individual level during early-to-middle adolescence.

Study Design

Three waves (12y, 14y, and 16y) of self-reported AHs and SIB data from a large Tokyo-based adolescent birth cohort (N = 2825) were used. Random Intercept Cross-Lagged Panel Model (RI-CLPM) analysis was conducted to test the within-person prospective associations between AHs and SIB.

Study Results

At the within-person level, AHs were associated with subsequent SIB over the observation period (12y–14y: β = .118, P < .001; 14–16y: β = .086, P = .012). The reverse SIB->AHs relationship was non-significant at 12–14y (β = .047, P = .112) but emerged from 14y to 16y as the primary direction of influence (β = .243, P < .001). Incorporating depression as a time-varying covariate did not meaningfully alter model estimates.

Conclusions

A complex bi-directional pattern of relationships was observed between AHs and SIB over the measurement period, and these relationships were independent of depressive symptoms. Adolescent AHs may be both a predictor of later SIB and also a manifestation of SIB-induced psychological distress.
Evolution of a globally unique SARS-CoV-2 Spike E484T monoclonal antibody escape mutation in a persistently infected, immunocompromised individual
Authors: Halfmann Peter J , Minor Nicholas R , Haddock III Luis A , Maddox Robert , Moreno Gage K , Braun Katarina M , Baker David A , Riemersa Kasen K , Prasad Ankur , Alman Kirsten J , Lambert Matthew C , Florek Kelsey , Bateman Allen , Westergaard Ryan , Safdar Nasia , Andes David R , Kawaoka Yoshihiro , Fida Madiha , Yao Joseph D , Friedrich Thomas C , O’Connor David H
Published: November 2022

Prolonged infections in immunocompromised individuals may be a source for novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants, particularly when both the immune system and antiviral therapy fail to clear the infection and enable within-host evolution. Here we describe a 486-day case of SARS-CoV-2 infection in an immunocompromised individual. Following monotherapy with the monoclonal antibody Bamlanivimab, the individual’s virus acquired resistance, likely via the earliest known occurrence of Spike amino acid variant E484T. Recently, E484T has arisen again as a derivative of E484A in the Omicron Variant of Concern, supporting the hypothesis that prolonged infections can give rise to novel variants long before they become prevalent in the human population.
Tuning the potency and therapeutic window of ImmTAC molecules by affinity modulation
Authors: Robertson Ian B , Mulvaney Rachel , Dieckmann Nele , Vantellini Alessio , Canestraro Martina , Amicarella Francesca , O’Dwyer Ronan , Cole David K. , Harper Stephen , Dushek Omer , Kirk Peter
Published: November 2022

T cell engaging bispecifics have great clinical potential for the treatment of cancer and infectious diseases. The binding affinity and kinetics of a bispecific molecule for both target and T cell CD3 have substantial effects on potency and specificity, but the rules governing these relationships are not fully understood. Using ImmTAC (Immune mobilizing monoclonal TCRs Against Cancer) molecules as a model, we explored the impact of altering affinity for target and CD3 on the potency and specificity of the re-directed T cell response. This class of bispecifics, exemplified by tebentafusp which has recently shown survival benefit in a randomized phase 3 clinical trial1, bind specific target peptides presented by human leukocyte antigen (HLA) on the cell surfaceviaan affinity-enhanced T cell receptor and can redirect T cell activation with an anti-CD3 effector moiety. The data reveal that combining a strong affinity TCR with an intermediate affinity anti-CD3 results in optimal T cell activation, while strong affinity of both targeting and effector domains significantly reduces efficacy. Moreover, by optimising the affinity of both parts of the molecule, it is possible to improve the therapeutic window. These results could be effectively modelled based on kinetic proof-reading with limited signalling. This model explained the experimental observation that strong binding at both ends of the molecules leads to reduced activity, through very stable target-bispecific-effector complexes leading to CD3 entering a non-signalling dark-state. These findings have important implications for the design of anti-CD3 based bispecifics with optimal biophysical parameters for both activity and specificity.

Graphical abstract
TCR_Explore: a novel webtool for T cell receptor repertoire analysis
Authors: Mullan Kerry A. , Zhang Justin B. , Jones Claerwen M. , Goh Shawn J. R. , Revote Jerico , Illing Patricia T. , Purcell Anthony W. , Gruta Nicole L. La , Li Chen , Mifsud Nicole A.
Published: November 2022

T cells expressing either alpha-beta or gamma-delta T cell receptors (TCR) are critical sentinels of the adaptive immune system, with receptor diversity being essential for protective immunity against a broad array of pathogens and agents. Programs available to profile TCR clonotypic signatures can be limiting for users with no coding expertise. Current analytical pipelines can be inefficient due to manual processing steps, open to data transcription errors and have multiple analytical tools with unique inputs that require coding expertise. Here we present a bespoke webtool designed for users irrespective of coding expertise, coined ‘TCR_Explore’, incorporating automated quality control steps that generates a single output file for creation of flexible and publication ready figures. TCR_Explore will elevate a user’s capacity to undertake in-depth TCR repertoire analysis of both new and pre-existing datasets for identification of T cell clonotypes associated with health and disease. The web application is located athttps://tcr-explore.erc.monash.edufor users to interactively explore TCR repertoire datasets.

Key Points

Bespoke program for non-specialists in computerised methodologies for deep exploration of TCR repertoire analysis

Automated QC and analysis pipelines for Sanger based TCR sequencing coupled with immunophenotyping, with the capacity for integration of other sequencing platform outputs

Automated summary processes to aid data visualisation and generation of publication-ready graphical displays
A cellular and spatial map of salivary glands at single cell resolution reveals the functional basis of tertiary lymphoid structure formation in Sjogren’s syndrome
Authors: Nayar Saba , Turner Jason D. , Asam Saba , Fennell Eanna , Pugh Matthew , Colfrancesco Serena , Berardicurti Onorina , Smith Charlotte G. , Flint Joe , Teodosio Ana , Iannizzotto Valentina , Gardner David H. , van Roon Joel , Korsunsky Ilya ,   Roche Fibroblast Network Consortium, Bowman Simon J. , Ng Wan-Fai , Croft Adam P , Filer Andrew , Fisher Benjamin A. , Buckley Christopher D. , Barone Francesca
Published: November 2022

The key role of tertiary lymphoid structures in autoimmune and non-autoimmune conditions has been recently appreciated. While many of the molecular mechanisms involved in tertiary lymphoid structure (TLS) formation have been identified, their cellular sources and their temporal and spatial relationship to each other during the development of TLS remain unknown. Here we have constructed a cellular and functional map of key components involved in the formation of TLS in the minor salivary glands (SG) in humans. We have confirmed the presence of an immunofibroblast cell state and identified an undescribed immunopericyte cell state with potential immunological functions within TLS. The identification of TLS cellular and functional properties and their relevant modulators provided by this analysis provides key therapeutic cues for TLS associated conditions in autoimmunity and cancer.
Acetylation of fission yeast tropomyosin does not promote differential association with cognate formins
Authors: Tang Qing , Pollard Luther W. , Homa Kaitlin E. , Kovar David R. , Trybus Kathleen M.
Published: November 2022

It was proposed from cellular studies thatS. pombetropomyosin Cdc8 (Tpm) segregates into two populations due to the presence or absence of an amino-terminal acetylation that specifies which formin-mediated F-actin networks it binds, but with no supporting biochemistry. To address this mechanismin vitro, we developed methods forS. pombeactin expression in Sf9 cells. We then employed 3-color TIRF microscopy using all recombinantS. pombeproteins to probein vitromulticomponent mechanisms involving actin, acetylated and unacetylated Tpm, formins, and myosins. Acetyl-Tpm exhibits tight binding to actin in contrast to weaker binding by unacetylated Tpm. In disagreement with the differential recruitment model, Tpm showed no preferential binding to filaments assembled by the FH1-FH2-domains of twoS. pombeformins, nor did Tpm binding have any bias towards the growing formin-bound actin filament barbed end. Although ourin vitrofindings do not support a direct formin-tropomyosin interaction, it is possible that formins bias differential tropomyosin isoform recruitment through undiscovered mechanisms. Importantly, despite a 12% sequence divergence between skeletal andS. pombeactin,S. pombemyosins Myo2 and Myo51 exhibited similar motile behavior with these two actins, validating key prior findings with these myosins that used skeletal actin.
ASCARIS: Positional Feature Annotation and Protein Structure-Based Representation of Single Amino Acid Variations
Authors: Cankara Fatma , Doğan Tunca
Published: November 2022

Motivation

Genomic variations may cause deleterious effects on protein functionality and perturb biological processes. Elucidating the effects of variations is critical for developing novel treatment strategies for diseases of genetic origin. Computational approaches have been aiding the work in this field by modeling and analyzing the mutational landscape. However, new approaches are required, especially for accurate and comprehensive representation and data-centric analysis of sequence variations.

Results

In this study, we propose ASCARIS (Annotation and StruCture-bAsed RepresentatIon of Single amino acid variations - SAVs), a method for the featurization (i.e., quantitative representation) of SAVs, which could be used for a variety of purposes, such as predicting their functional effects or building multi-omics-based integrative models. In ASCARIS representations, we incorporated the correspondence between the location of the SAV on the sequence and 30 different types of positional feature annotations (e.g., active/lipidation/glycosylation sites; calcium/metal/DNA binding, inter/transmembrane regions, etc.) from UniProt, along with structural features such as protein domains, the location of variation (e.g., core/interface/surface), and the change in physico-chemical properties using models from PDB and AlphaFold-DB. We also mapped the mutated and annotated residues to the 3-D plane and calculated the spatial distances between them in order to account for the functional changes caused by variations in positions close to the functionally essential ones. Finally, we constructed a 74-dimensional feature set to represent each SAV in a dataset composed of ∼100,000 data points.

We statistically analyzed the relationship between each of these features and the consequences of variations, and found that each of them carries information in this regard. To investigate potential applications of ASCARIS, we trained variant effect predictor models that utilize our SAV representations as input. We carried out both an ablation study and a comparison against the state-of-the-art methods over well-known benchmark datasets. We observed that our method displays a competing performance against widely-used predictors. Also, our predictions were complementary to these methods which is probably due to fact that ASCARIS has a rather unique focus in modeling variations. ASCARIS can be used either alone or in combination with other approaches, to universally represent SAVs from a functional perspective.

Availability and implementation

The source code, datasets, results, and user instructions of ASCARIS are available athttps://github.com/HUBioDataLab/ASCARIS.
BCL6 regulates the endothelial pro-immunogenic phenotype relevant to organ transplant rejection
Authors: Acevedo Adriana Franco , Valenzuela Nicole M
Published: November 2022

Background

IFNγ induces an endothelial cell pro-immunogenic phenotype through the JAK/STAT1 pathway, which can influence alloreactive leukocytes in transplant rejection. Numerous endogenous suppressors of JAK and STAT activation have been described, but regulation of STAT1 at the level of transcription is not well-understood. In immune cells, the DNA binding protein BCL6 controls transcription of lineage and inflammatory genes, including STAT-dependent responses. The goal of this study was to determine if BCL6 also modulates the IFNγ-induced immunogenic phenotype in endothelium.

Methods

BCL6 binding to target genes and similarity to STAT1 motifs was analyzedin silicousing public datasets.In vitro, primary human aortic endothelial cells were tested for expression of IFNγ-inducible costimulatory molecules, HLA and cytokines, under BCL6 overexpression, depletion and pharmacological targeting. Gene expression was measured by RNA-Seq and protein expression was confirmed by flow cytometry, Luminex and ELISA. Paired biopsies from stable and rejecting human cardiac allografts were compared for expression of BCL6, PD ligands, CXCL chemokines and HLA-DR in the vasculature.

Results

BCL6 expression is increased within human cardiac transplants during rejection, which is positively correlated with expression of interferon response gene HLA-DR in donor blood vessels. Further, BCL6 is IFNγ-inducible via JAK1/2 in endothelium. Next, the consensus DNA binding motif of BCL6 is highly similar to that of STAT1, and numerous interferon response genes harbor BCL6 DNA binding motifs. Depletion of BCL6 in endothelium results in augmentation, while overexpression causes suppression, of MHC class II, chemokine, and PD ligand expression. Unexpectedly, pharmacological targeting of the corepressor domain BTB domain of BCL6 also repressed many interferon response genes, particularly HLA class II, CXCR3 chemokines and PD-L2. On the other hand, BCL6 targeting did not impact inducible expression of any HLA class I genes, PD-L1 or CD40; and the effect is correlated with the presence of BCL6 binding motifs in or near affected genes.

Conclusion

Our results show for the first time that the transcriptional repressor BCL6 selectively controls the endothelial response to IFNγ. A better understanding of the endogenous mechanisms that regulate donor endothelial activation has the potential to discover new avenues to dampen transplant rejection, with broader relevance to other vascular inflammatory diseases.
RNA m6A and 5hmC regulate monocyte and macrophage gene expression programs
Authors: Pinello Natalia , Song Renhua , Lee Quintin , Calonne Emilie , Duan Kun-Long , Wong Emilie , Tieng Jessica , Mehravar Majid , Rong Bowen , Lan Fei , Roediger Ben , Ma Cheng-Jie , Yuan Bi-Feng , Rasko John E J , Larance Mark , Ye Dan , Fuks François , Wong Justin J. -L.
Published: November 2022

Background

RNA modifications are essential for the establishment of cellular identity. Although increasing evidence indicates that RNA modifications regulate the innate immune response, their role in monocyte-to-macrophage differentiation and polarisation is unclear. To date, most studies have focused on m6A, while other RNA modifications, including 5hmC, remain poorly characterised. The interplay between different RNA modifications that may occur in specific cellular contexts remains similarly unexplored.

Results

We profiled m6A and 5hmC epitranscriptomes, transcriptomes, translatomes and proteomes of monocytes and macrophages at rest and pro- and anti-inflammatory states. We observed that decreased expression of m6A and 5hmC writers, METTL3 and TET-enzymes respectively, facilitated monocyte-to-macrophage differentiation. Despite a global trend of m6A and 5hmC loss during macrophage differentiation, enrichment of m6A and/or 5hmC on specific categories of transcripts essential for macrophage differentiation positively correlated with their expression and translation. m6A and 5hmC mark and are associated with the expression of transcripts with critical functions in pro- and anti-inflammatory macrophages. Notably, we also discovered the coexistence of m6A and 5hmC marking alternatively-spliced isoforms and/or opposing ends of the untranslated regions (UTR) of transcripts with key roles in macrophage biology. In specific examples, RNA 5hmC controls the decay of transcripts independently of m6A.

Conclusions

This study: i) uncovers m6A, 5hmC and their writer enzymes as regulators of monocyte and macrophage gene expression programs and ii) provides a comprehensive dataset to interrogate the role of RNA modifications in a plastic system. Altogether, this work sheds light on the role of RNA modifications as central regulators of effector cells in innate immunity.