bluuebunny/crossref_metadata_2025 huggingface dataset:
Inferring SARS-CoV-2 RNA shedding into wastewater relative to the time of infection
Authors: Cavany Sean , Bivins Aaron , Wu Zhenyu , North Devin , Bibby Kyle , Perkins T. Alex
Published: January 2022

Since the start of the coronavirus disease-2019 (COVID-19) pandemic, there has been interest in using wastewater monitoring as an approach for disease surveillance. A significant uncertainty that would improve the interpretation of wastewater monitoring data is the intensity and timing with which individuals shed RNA from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into wastewater. By combining wastewater and case surveillance data sets from a university campus during a period of heightened surveillance, we inferred that individual shedding of RNA into wastewater peaks on average 6 days (50% uncertainty interval (UI): 6–7; 95% UI: 4–8) following infection, and that wastewater measurements are highly overdispersed [negative binomial dispersion parameter,k= 0.39 (95% credible interval: 0.32–0.48)]. This limits the utility of wastewater surveillance as a leading indicator of secular trends in SARS-CoV-2 transmission during an epidemic, and implies that it could be most useful as an early warning of rising transmission in areas where transmission is low or clinical testing is delayed or of limited capacity.
Independent sets of a given size and structure in the hypercube
Authors: Jenssen Matthew , Perkins Will , Potukuchi Aditya
Published: January 2022

We determine the asymptotics of the number of independent sets of size
$\lfloor \beta 2^{d-1} \rfloor$
in the discrete hypercube
$Q_d = \{0,1\}^d$
for any fixed
$\beta \in (0,1)$
as
$d \to \infty$
, extending a result of Galvin for
$\beta \in (1-1/\sqrt{2},1)$
. Moreover, we prove a multivariate local central limit theorem for structural features of independent sets in
$Q_d$
drawn according to the hard-core model at any fixed fugacity
$\lambda>0$
. In proving these results we develop several general tools for performing combinatorial enumeration using polymer models and the cluster expansion from statistical physics along with local central limit theorems.
GENUS MINIMAL k-NOIDS AND SADDLE TOWERS IN
Authors: Castro-Infantes Jesús , Manzano José M.
Published: January 2022

For each
$k\geq 3$
, we construct a
$1$
-parameter family of complete properly Alexandrov-embedded minimal surfaces in the Riemannian product space
$\mathbb {H}^2\times \mathbb {R}$
with genus
$1$
and k embedded ends asymptotic to vertical planes. We also obtain complete minimal surfaces with genus
$1$
and
$2k$
ends in the quotient of
$\mathbb {H}^2\times \mathbb {R}$
by an arbitrary vertical translation. They all have dihedral symmetry with respect to k vertical planes, as well as finite total curvature
$-4k\pi $
. Finally, we provide examples of complete properly Alexandrov-embedded minimal surfaces with finite total curvature with genus
$1$
in quotients of
$\mathbb {H}^2\times \mathbb {R}$
by the action of a hyperbolic or parabolic translation.
Genetic combining, heterosis analysis for horticultural traits in tomato (Solanum lycopersicum L.) using ToLCV-resistant lines and molecular validation of Ty genes
Authors: Chandel Rahul , Sadashiva A. T. , Ravishankar Kundapura V. , Das Anjan , Rout Bichhinna Maitri , Singh Saurabh
Published: January 2022

Tomato is a pivotal vegetable crop worldwide concerning human nutrition, economy and in service to biotechnology. Tomato leaf curl virus (ToLCV) is a begomovirus transmitted through the whitefly (Bemisia tabaci) and is responsible for severe losses in tomato production. In this context, the current investigation was carried out to determine heterotic combiners with high yield, resistance to ToLCV and mode of gene action for economically important traits. For this, 11 prescreened inbred lines were crossed in a half diallel fashion to generate 55 F1 hybrids. The 55 crosses with 11 parents and commercial checks were evaluated for different horticultural traits and resistance to ToLCV. The molecular validation with SCAR markers TG0302 and SCAR1 confirmed the presence of ToLCV-resistant genes in parents and their crosses. The hybrid IIHR-2902 × IIHR-2852 showed the presence of both Ty-2 and Ty-3 alleles in the homozygous state. The estimation of σSCA2 and σGCA2 was significant. It also indicated that the genetic control of target traits was under additive and non-additive gene effects. The values of σA/D2 along with σGCA2/σSCA2 found to be less than unity indicates the preponderance of non-additive gene action in the expression of the studied traits except for percent disease incidence. The parental line IIHR-2919 was the best combiner for fruit and yield traits. The cross combinations IIHR-2913 × IIHR-2898 exhibited significantly higher economic heterosis for yield along with the presence of Ty-2 and Ty-3 genes. The study paves the way for breeding high yielding and ToLCV-resistant hybrids in tomato.
Reproductive fluids, added to the culture media, contribute to minimizing phenotypical differences between in vitro-derived and artificial insemination-derived piglets
Authors: París-Oller Evelyne , Soriano-Úbeda Cristina , Belda-Pérez Ramsés , Sarriás-Gil Lucía , Lopes Jordana S. , Canha-Gouveia Analuce , Gadea Joaquín , Vieira Luis Alberto , García-Vázquez Francisco Alberto , Romar Raquel , Cánovas Sebastian , Coy Pilar
Published: January 2022

The addition of reproductive fluids (RF) to the culture media has shown benefits in different embryonic traits but its long-term effects on the offspring phenotype are still unknown. We aimed to describe such effects in pigs. Blood samples and growth parameters were collected from piglets derived from in vitro-produced embryos (IVP) with or without RF added in the culture media versus those artificially inseminated (AI), from day 0 to month 6 of life. An oral glucose tolerance test was performed on day 45 of life. We show here the first comparative data of the growth of animals produced through different assisted reproductive techniques, demonstrating differences between groups. Overall, there was a tendency to have a larger size at birth and faster growth in animals derived from in vitro fertilization and embryo culture versus AI, although this trend was diminished by the addition of RFs to the culture media. Similarly, small differences in hematological indices and glucose tolerance between animals derived from AI and those derived from IVP, with a sex-dependent effect, tended to fade in the presence of RF. The addition of RF to the culture media could contribute to minimizing the phenotypical differences between the in vitro-derived and AI offspring, particularly in males.
Curved Trajectory Effect on Charge‐Exchange Collision at Ionospheric Temperatures
Authors: Ieda A.
Published: January 2022

Collision between ions and neutral particles is an essential characteristic of Earth's ionosphere. This ion‐neutral collision is usually caused by the polarization of neutral particles. This collision can also be caused by charge exchange, if the particle pair is parental, such as atomic oxygen and its ion. The total collision frequency is not the sum of the polarization and charge‐exchange components, but is essentially equal to the dominant component. The total is enhanced only around the classic transition temperature, which is near the ionospheric temperature range (typically 200–2000 K). However, the magnitude of this enhancement has differed among previous studies; the maximum enhancement has been reported as 41% and 11% without physical explanation. In the present study, the contribution of the polarization force to the charge‐exchange collision is expressed as a simple curved particle trajectory effect. As a result, the maximum enhancement is found to be 22%. It is discussed that the enhancement has been neglected in classic ionospheric studies partly due to confusion with the glancing particle contribution, which adds 10.5% to the polarization component. The enhancement has been neglected presumably also because there has been no functional form to express it. Such an expression is derived in this study.
Transpolar Arcs: Seasonal Dependence Identified by an Automated Detection Algorithm
Authors: Bower G. E. , Milan S. E. , Paxton L. J. , Imber S. M.
Published: January 2022

Transpolar arcs (TPAs) are auroral features that occur polewards of the main auroral oval suggesting that the magnetosphere has acquired a complicated magnetic topology. They are primarily a northward interplanetary magnetic field (IMF) auroral phenomenon, and their formation and evolution have no single explanation that is unanimously agreed upon. An automated detection algorithm has been developed to detect the occurrence of TPAs in UV images captured from the Special Sensor Ultraviolet Spectrographic Imager (SSUSI) instrument onboard the Defense Meteorological Satellite Program (DMSP) spacecraft, in order to further study their occurrence. Via this detection algorithm TPAs are identified as a peak in the average radiance intensity poleward of 12.5° colatitude, in two or more of the wavelengths/bands sensed by SSUSI. Using the detection algorithm for the years 2010 to 2016, over 5000 images containing TPAs are identified. The occurrence of these TPAs shows a seasonal dependence, with more arcs being visible in the winter hemisphere. The orbital plane of DMSP has been investigated as a possible explanation of the dependences in the results of the detection algorithm. For the spacecraft of interest this leads to a preferential observation of the northern hemisphere with the detection algorithm missing TPAs in the southern hemisphere around 01–06 UT. No seasonal bias has been found for these spacecraft. We discuss the ramifications of these findings in terms of proposed TPA generation mechanisms and suggest reasons for the seasonal dependence including it being a reflection of probability of seeing TPAs due to visibility.
Energetic Ions Downtail of the Reconnection Site
Authors: Birn Joachim , Hesse Michael , Runov Andrei , Turner Drew L. , Cohen Ian , Slavin James A.
Published: January 2022

Using combined MHD/test particle simulations, we explore characteristics of ion (proton) acceleration tailward of a near‐Earth reconnection site. We present spatial distributions and explore acceleration mechanisms and sources of accelerated ions. Acceleration is due primarily due simple crossings of the enhanced electric field near the x‐line or in the departing plasmoid. The energetic particle distributions show the expected energy dispersed tailward streaming at the plasma sheet boundary, while equatorial distributions are more complicated, resulting from different acceleration sites within the moving plasmoid. Sources are mostly inside the central plasma sheet dawnward of the plasmoid.
An Experimental Study of the Breakthrough‐Phase and Return‐Stroke Processes in Long Sparks
Authors: Bogatov N. A. , Syssoev V. S. , Sukharevsky D. I. , Orlov A. I. , Rakov V. A. , Mareev E. A.
Published: January 2022

The dynamics of the brightness of a long‐spark channel during the breakthrough and the return‐stroke phases of discharge development were experimentally studied using streak‐camera images synchronized with current recordings at the high‐voltage electrode. The velocities of primary positive leader developing from the high‐voltage electrode and connecting negative leader extending from the grounded electrode during the breakthrough phase were measured as a function of the discharge current and the distance between leader tips. The velocities of the return‐stroke waves propagating upward and downward along the positive and negative leader channels, respectively, were also measured. The connection region exhibited channel splitting and reduced brightness relative to the channels above and below it.
Global Simulation of Snow Algal Blooming by Coupling a Land Surface and Newly Developed Snow Algae Models
Authors: Onuma Y. , Yoshimura K. , Takeuchi N.
Published: January 2022

Snow algae are found from spring to summer on snowfields and glaciers throughout the world. Their blooming darkens snow surfaces, reducing snow surface albedo and accelerating melting. Uncertainties remain, however, regarding the blooming season and global distribution of these algae. To reproduce snow algal bloom temporal and geographical variability, we improved an existing snow algae model using a land surface model calibrated with a reanalysis dataset of the global atmosphere. Snowfall and daylight length data for selected model locations were also incorporated. To evaluate its performance, we used in situ observational data from 15 polar to alpine area sites. The improvements made in this study allowed the reconstruction of detailed snow algal blooming reports from various locations worldwide, and the results suggested that the major factors affecting the appearance of snow algal blooming were the snow melting period duration and algal growth interruption by new snow cover. We then incorporated the updated snow algae model into a land surface model and performed a global simulation. In this case, our simulation suggested that red snow could appear on snowfields during the melting season but only in the absence of frequent new snowfalls, and if the snow cover persists long enough to allow prolonged algal growth. This simulation has the potential to be used for global prediction of future red snow phenomena, which are likely to synchronize with global climate change.
High-performance photodetector based on an interface engineering-assisted graphene/silicon Schottky junction
Authors: Ji Peirui , Yang Shuming , Wang Yu , Li Kaili , Wang Yiming , Suo Hao , Woldu Yonas Tesfaye , Wang Xiaomin , Wang Fei , Zhang Liangliang , Jiang Zhuangde
Published: January 2022

Graphene/silicon Schottky junctions have been proven efficient for photodetection, but the existing high dark current seriously restricts applications such as weak signal detection. In this paper, a thin layer of gadolinium iron garnet (Gd3Fe5O12, GdIG) film is introduced to engineer the interface of a graphene/silicon Schottky photodetector. The novel structure shows a significant decrease in dark current by 54 times at a −2 V bias. It also exhibits high performance in a self-powered mode in terms of an Ilight/Idark ratio up to 8.2 × 106 and a specific detectivity of 1.35 × 1013 Jones at 633 nm, showing appealing potential for weak-light detection. Practical suitability characterizations reveal a broadband absorption covering ultraviolet to near-infrared light and a large linear response with a wide range of light intensities. The device holds an operation speed of 0.15 ms, a stable response for 500 continuous working cycles, and long-term environmental stability after several months. Theoretical analysis shows that the interlayer increases the barrier height and passivates the contact surface so that the dark current is suppressed. This work demonstrates the good capacity of GdIG thin films as interlayer materials and provides a new solution for high-performance photodetectors.
Neonatal sepsis: a systematic review of core outcomes from randomised clinical trials
Authors: Henry Cían J. , Semova Gergana , Barnes Ellen , Cotter Isabel , Devers Tara , Rafaee Aisyah , Slavescu Andreea , Cathain Niamh O. , McCollum Danielle , Roche Edna , Mockler David , Allen John , Meehan Judith , Klingenberg Claus , Latour Jos M. , van den Hoogen Agnes , Strunk Tobias , Giannoni Eric , Schlapbach Luregn J. , Degtyareva Marina , Plötz Frans B. , de Boode Willem P. , Naver Lars , Wynn James L. , Küster Helmut , Janota Jan , Keij Fleur M. , Reiss Irwin K. M. , Bliss Joseph M. , Polin Richard , Koenig Joyce M. , Turner Mark A. , Gale Christopher , Molloy Eleanor J. ,   On behalf of the Infection, Inflammation, Immunology and Immunisation (I4) section of the European Society for Paediatric Research (ESPR)
Published: January 2022

Background

The lack of a consensus definition of neonatal sepsis and a core outcome set (COS) proves a substantial impediment to research that influences policy and practice relevant to key stakeholders, patients and parents.

Methods

A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. In the included studies, the described outcomes were extracted in accordance with the provisions of the Core Outcome Measures in Effectiveness Trials (COMET) handbook and registered.

Results

Among 884 abstracts identified, 90 randomised controlled trials (RCTs) were included in this review. Only 30 manuscripts explicitly stated the primary and/or secondary outcomes. A total of 88 distinct outcomes were recorded across all 90 studies included. These were then assigned to seven different domains in line with the taxonomy for classification proposed by the COMET initiative. The most frequently reported outcome was survival with 74% (n = 67) of the studies reporting an outcome within this domain.

Conclusions

This systematic review constitutes one of the initial phases in the protocol for developing a COS in neonatal sepsis. The paucity of standardised outcome reporting in neonatal sepsis hinders comparison and synthesis of data. The final phase will involve a Delphi Survey to generate a COS in neonatal sepsis by consensus recommendation.

Impact

This systematic review identified a wide variation of outcomes reported among published RCTs on the management of neonatal sepsis.

The paucity of standardised outcome reporting hinders comparison and synthesis of data and future meta-analyses with conclusive recommendations on the management of neonatal sepsis are unlikely.

The final phase will involve a Delphi Survey to determine a COS by consensus recommendation with input from all relevant stakeholders.
Toxic potency-adjusted control of air pollution for solid fuel combustion
Authors: Wu Di , Zheng Haotian , Li Qing , Jin Ling , Lyu Rui , Ding Xiang , Huo Yaoqiang , Zhao Bin , Jiang Jingkun , Chen Jianmin , Li Xiangdong , Wang Shuxiao
Published: January 2022

The combustion of solid fuels, including coal and biomass, is a main anthropogenic source of atmospheric particulate matter (PM). The hidden costs have been underestimated due to lack of consideration of the toxicity of PM. Here we report the unequal toxicity of inhalable PM emitted from energy use in the residential sector and coal-fired power plants (CFPPs). The incomplete burning of solid fuels in household stoves generates much higher concentrations of carbonaceous matter, resulting in more than one order of magnitude greater toxicity than that from CFPPs. When compared with CFPPs, the residential sector consumed only a tenth of solid fuels in mainland China in 2017, but it contributed about 200-fold higher of the population-weighted toxic potency-adjusted PM2.5 exposure risk. We suggest that PM2.5-related toxicity should be considered when making air pollution emission control strategies, and incomplete combustion sources should receive more policy attention to reduce exposure risks.
Optically reconfigurable quasi-phase-matching in silicon nitride microresonators
Authors: Nitiss Edgars , Hu Jianqi , Stroganov Anton , Brès Camille-Sophie
Published: January 2022

Quasi-phase-matching has long been a widely used approach in nonlinear photonics, enabling efficient parametric frequency conversions such as second-harmonic generation. However, in silicon photonics the task remains challenging, as materials best suited for photonic integration lack second-order susceptibility (χ(2)), and means for achieving momentum conservation are limited. Here we present optically reconfigurable quasi-phase-matching in large-radius silicon nitride microresonators, resulting in up to 12.5-mW on-chip second-harmonic generated power and a conversion efficiency of 47.6% W−1. Most importantly, we show that such all-optical poling can occur unconstrained from intermodal phase-matching, leading to broadly tunable second-harmonic generation. We confirm the phenomenon by two-photon imaging of the inscribed χ(2) grating structures within the microresonators as well as by in situ tracking of both the pump and second-harmonic mode resonances during all-optical poling. These results unambiguously establish that the photogalvanic effect, responsible for all-optical poling, can overcome phase mismatch constraints, even in resonant systems.
Clinical features of invasive fungal disease in children with no underlying disease
Authors: Huang Juan , Liu Chentao , Zheng Xiangrong
Published: January 2022

There is limited research into Invasive fungal disease (IFD) in children with no underlying disease. We undertook a retrospective study of children with IFD who did not suffer from another underlying disease, from June 2010 to March 2018 in Changsha, China. Nine children were identified. Eosinophil counts were elevated in six cases. The level of procalcitonin (PCT) was elevated in six cases. Fungal culture was positive in all patients, including eight cases of Cryptococcus neoformans and one case of Candida parapsilosis. 8.33 days following antifungal treatment, the body temperature of the eight patients affected by cryptococcal disease had returned to normal. Our study indicates that the primary pathogen in IFD was Cryptococcus neoformans in children who had no other underlying disease. Eosinophils can be considered to be indicators of cryptococcal infection. IFD in children with no other underlying disease has a satisfactory prognosis.
Complete de novo assembly of Wolbachia endosymbiont of Diaphorina citri Kuwayama (Hemiptera: Liviidae) using long-read genome sequencing
Authors: Neupane Surendra , Bonilla Sylvia I. , Manalo Andrew M. , Pelz-Stelinski Kirsten S.
Published: January 2022

Wolbachia, a gram-negative$$\mathrm{\alpha }$$α-proteobacterium, is an endosymbiont found in some arthropods and nematodes. Diaphorina citri Kuwayama, the vector of ‘Candidatus Liberibacter asiaticus’ (CLas), are naturally infected with a strain of Wolbachia (wDi), which has been shown to colocalize with the bacteria pathogens CLas, the pathogen associated with huanglongbing (HLB) disease of citrus. The relationship betweenwDi and CLas is poorly understood in part because the complete genome ofwDi has not been available. Using high-quality long-read PacBio circular consensus sequences, we present the largest complete circularwDi genome among supergroup-B members. The assembled circular chromosome is 1.52 megabases with 95.7% genome completeness with contamination of 1.45%, as assessed by checkM. We identified Insertion Sequences (ISs) and prophage genes scattered throughout the genomes. The proteins were annotated using Pfam, eggNOG, and COG that assigned unique domains and functions. ThewDi genome was compared with previously sequenced Wolbachia genomes using pangenome and phylogenetic analyses. The availability of a complete circular chromosome ofwDi will facilitate understanding of its role within the insect vector, which may assist in developing tools for disease management. This information also provides a baseline for understanding phylogenetic relationships among Wolbachia of other insect vectors.
Regression of liver fibrosis and hepatocellular carcinoma development after HCV eradication with oral antiviral agents
Authors: Yoo Hae Won , Park Jun Yong , Kim Sang Gyune , Jung Young Kul , Lee Sae Hwan , Kim Moon Young , Jun Dae Won , Jang Jae Young , Lee Jin Woo , Kwon Oh Sang
Published: January 2022

We prospectively investigated the changes of liver stiffness (LS) and the occurrence of hepatocellular carcinoma (HCC) after hepatitis C virus (HCV) eradication using direct antiviral agents (DAA) over three years. LS measurement using transient elastography and serum fibrosis surrogate markers before treatment and at 48, 96, 144 weeks after starting direct-acting antivirals (DAA) according to the protocol were evaluated. Patients were also compared with historical cohort treated with pegylated interferon (peg-IFN). Sustained viral response (SVR) was observed in 95.8%. LS value in the patients achieving SVR significantly decreased over time (19.4 ± 12.9 kPa [baseline], 13.9 ± 9.1 kPa [48 weeks], 11.7 ± 8.2 kPa [96 weeks], 10.09 ± 6.23 [144 weeks], all p < 0.001). With matched analysis, the decrease in LS value was significantly larger in DAA group than peg-IFN group at both 48 weeks (29% vs. 9%) and 96 weeks (39% vs. 17%). The incidence of HCC was not significantly different between DAA and peg-IFN groups (5.5% vs. 5.4%) at 144 weeks. HCV eradication with DAA can lead to improvement of liver stiffness over time. The regression of fibrosis was greater in the group with DAA than peg-IFN.

Clinical trials registration: ClinicalTrials.gov (NCT02865369).
Resilience of countries to COVID-19 correlated with trust
Authors: Lenton Timothy M. , Boulton Chris A. , Scheffer Marten
Published: January 2022

We characterized > 150 countries’ resilience to COVID-19 as the nationwide decay rate of daily cases or deaths from peak levels. Resilience to COVID-19 varies by a factor of ~ 40 between countries for cases/capita and ~ 25 for deaths/capita. Trust within society is positively correlated with country-level resilience to COVID-19, as is the adaptive increase in stringency of government interventions when epidemic waves occur. By contrast, countries where governments maintain greater background stringency tend to have lower trust within society and tend to be less resilient. All countries where > 40% agree “most people can be trusted” achieve a near complete reduction of new cases and deaths, but so do several less-trusting societies. As the pandemic progressed, resilience tended to decline, as adaptive increases in stringency also declined. These results add to evidence that trust can improve resilience to epidemics and other unexpected disruptions, of which COVID-19 is unlikely to be the last.
Genome-wide identification and characterization of functionally relevant microsatellite markers from transcription factor genes of Tea (Camellia sinensis (L.) O. Kuntze)
Authors: Parmar Rajni , Seth Romit , Sharma Ram Kumar
Published: January 2022

Tea, being one of the most popular beverages requires large set of molecular markers for genetic improvement of quality, yield and stress tolerance. Identification of functionally relevant microsatellite or simple sequence repeat (SSR) marker resources from regulatory “Transcription factor (TF) genes” can be potential targets to expedite molecular breeding efforts. In current study, 2776 transcripts encoding TFs harbouring 3687 SSR loci yielding 1843 flanking markers were identified from traits specific transcriptome resource of 20 popular tea cultivars. Of these, 689 functionally relevant SSR markers were successfully validated and assigned to 15 chromosomes (Chr) of CSS genome. Interestingly, 589 polymorphic markers including 403 core-set of TF-SSR markers amplified 2864 alleles in key TF families (bHLH, WRKY, MYB-related, C2H2, ERF, C3H, NAC, FAR1, MYB and G2-like). Their significant network interactions with key genes corresponding to aroma, quality and stress tolerance suggests their potential implications in traits dissection. Furthermore, single amino acid repeat reiteration in CDS revealed presence of favoured and hydrophobic amino acids. Successful deployment of markers for genetic diversity characterization of 135 popular tea cultivars and segregation in bi-parental population suggests their wider utility in high-throughput genotyping studies in tea.
Working memory and pattern separation in founder strains of the BXD recombinant inbred mouse panel
Authors: Dickson Price E. , Mittleman Guy
Published: January 2022

Working memory and pattern separation are fundamental cognitive abilities which, when impaired, significantly diminish quality of life. Discovering genetic mechanisms underlying innate and disease-induced variation in these cognitive abilities is a critical step towards treatments for common and devastating neurodegenerative conditions such as Alzheimer's disease. In this regard, the trial-unique nonmatching-to-location assay (TUNL) is a touchscreen operant conditioning procedure allowing simultaneous quantification of working memory and pattern separation in mice and rats. In the present study, we used the TUNL assay to quantify these cognitive abilities in C57BL/6J and DBA/2J mice. These strains are the founders of the BXD recombinant inbred mouse panel which enables discovery of genetic mechanisms underlying phenotypic variation. TUNL testing revealed that pattern separation was significantly influenced by mouse strain, whereas working memory was not. Moreover, horizontal distance and vertical distance between choice-phase stimuli had dissociable effects on TUNL performance. These findings provide novel data on mouse strain differences in pattern separation and support previous findings of equivalent working memory performance in C57BL/6J and DBA/2J mice. Although working memory of the BXD founder strains was equivalent in this study, working memory of BXD strains may be divergent because of transgressive segregation. Collectively, data presented here indicate that pattern separation is heritable in the mouse and that the BXD panel can be used to identify mechanisms underlying variation in pattern separation.
Functional assays of non-canonical splice-site variants in inherited retinal dystrophies genes
Authors: Rodriguez-Muñoz Ana , Liquori Alessandro , García-Bohorquez Belén , Jaijo Teresa , Aller Elena , Millán José M. , García-García Gema
Published: January 2022

Inherited retinal dystrophies are a group of disorders characterized by the progressive degeneration of photoreceptors leading to loss of the visual function and eventually to legal blindness. Although next generation sequencing (NGS) has revolutionized the molecular diagnosis of these diseases, the pathogenicity of some mutations casts doubts. After the screening of 208 patients with a panel of 117 genes, we obtained 383 variants that were analysed in silico with bioinformatic prediction programs. Based on the results of these tools, we selected 15 variants for their functional assessment. Therefore, we carried out minigene assays to unveil whether they could affect the splicing of the corresponding gene. As a whole, seven variants were found to induce aberrant splicing in the following genes: BEST1, CACNA2D4, PRCD, RIMS1, FSCN2, MERTK and MAK. This study shows the efficacy of a workflow, based on the association of the Minimum Allele Frequency, family co-segregation, in silico predictions and in vitro assays to determine the effect of potential splice site variants identified by DNA-based NGS. These findings improve the molecular diagnosis of inherited retinal dystrophies and will allow some patients to benefit from the upcoming gene-based therapeutic strategies.
Transcranial direct current stimulation (tDCS) reduces motivation to drink ethanol and reacquisition of ethanol self-administration in female mice
Authors: Pedron Solène , Dumontoy Stéphanie , González-Marín Maria del Carmen , Coune Fabien , Van Schuerbeek Andries , Haffen Emmanuel , Naassila Mickael , Van Waes Vincent
Published: January 2022

Transcranial direct current stimulation (tDCS) is an emerging noninvasive brain neuromodulation technique aimed at relieving symptoms associated with psychiatric disorders, including addiction. The goal of the present study was to better identify which phase of alcohol-related behavior (hedonic effect, behavioral sensitization, self-administration, or motivation to obtain the drug) might be modulated by repeated anodal tDCS over the frontal cortex (0.2 mA, 20 min, twice a day for 5 consecutive days), using female mice as a model. Our data showed that tDCS did not modulate the hedonic effects of ethanol as assessed by a conditioned place preference test (CPP) or the expression of ethanol-induced behavioral sensitization. Interestingly, tDCS robustly reduced reacquisition of ethanol consumption (50% decrease) following extinction of self-administration in an operant paradigm. Furthermore, tDCS significantly decreased motivation to drink ethanol on a progressive ratio schedule (30% decrease). Taken together, our results show a dissociation between the effects of tDCS on “liking” (hedonic aspect; no effect in the CPP) and “wanting” (motivation; decreased consumption on a progressive ratio schedule). Our tDCS procedure in rodents will allow us to better understand its mechanisms of action in order to accelerate its use as a complementary and innovative tool to help alcohol-dependent patients maintain abstinence or reduce ethanol intake.
Calpain-mediated protein targets in cardiac mitochondria following ischemia–reperfusion
Authors: Li Ling , Thompson Jeremy , Hu Ying , Lesnefsky Edward J. , Willard Belinda , Chen Qun
Published: January 2022

Calpain 1 and 2 (CPN1/2) are calcium-dependent cysteine proteases that exist in cytosol and mitochondria. Pharmacologic inhibition of CPN1/2 decreases cardiac injury during ischemia (ISC)–reperfusion (REP) by improving mitochondrial function. However, the protein targets of CPN1/2 activation during ISC–REP are unclear. CPN1/2 include a large subunit and a small regulatory subunit 1 (CPNS1). Genetic deletion of CPNS1 eliminates the activities of both CPN1 and CPN2. Conditional cardiomyocyte specific CPNS1 deletion mice were used in the present study to clarify the role of CPN1/2 activation in mitochondrial damage during ISC–REP with an emphasis on identifying the potential protein targets of CPN1/2. Isolated hearts from wild type (WT) or CPNS1 deletion mice underwent 25 min in vitro global ISC and 30 min REP. Deletion of CPNS1 led to decreased cytosolic and mitochondrial calpain 1 activation compared to WT. Cardiac injury was decreased in CPNS1 deletion mice following ISC–REP as shown by the decreased infarct size compared to WT. Compared to WT, mitochondrial function was improved in CPNS1 deletion mice following ischemia–reperfusion as shown by the improved oxidative phosphorylation and decreased susceptibility to mitochondrial permeability transition pore opening. H2O2 generation was also decreased in mitochondria from deletion mice following ISC–REP compared to WT. Deletion of CPNS1 also resulted in less cytochrome c and truncated apoptosis inducing factor (tAIF) release from mitochondria. Proteomic analysis of the isolated mitochondria showed that deletion of CPNS1 increased the content of proteins functioning in regulation of mitochondrial calcium homeostasis (paraplegin and sarcalumenin) and complex III activity. These results suggest that activation of CPN1 increases cardiac injury during ischemia–reperfusion by impairing mitochondrial function and triggering cytochrome c and tAIF release from mitochondria into cytosol.
Highly efficient removal of thallium(I) by facilely fabricated amorphous titanium dioxide from water and wastewater
Authors: Zhang Gaosheng , Luo Jinglin , Cao Hanlin , Hu Shengping , Li Huosheng , Wu Zhijing , Xie Yuan , Li Xiangping
Published: January 2022

In this study, amorphous hydrous titanium dioxide was synthesized by a facile precipitation method at room temperature, aiming to effectively remove thallium(I) from water. The titanium dioxide prepared using ammonia as precipitant (TiO2I) is more effective for thallium(I) uptake than the one synthesized with sodium hydroxide (TiO2II). The TiO2 obtained particles are amorphous, aggregates of many nanoparticles and irregular in shape. The thallium(I) uptake increases with the rise of solution pH value. Under neutral pH conditions, the maximal thallium(I) adsorption capacities of TiO2I and TiO2II are 302.6 and 230.3 mg/g, respectively, outperforming most of the reported adsorbents. The amorphous TiO2 has high selectivity towards thallium(I) in the presence of multiple cations such as K+, Ca2+, Mg2+, Zn2+ and Ni2+. Moreover, the TiO2I is efficient in removing thallium(I) from real river water and mining wastewater. Additionally, the spent TiO2I can be regenerated using hydrochloric acid solution and reused. The Tl(I) adsorption is achieved via replacing the H+ in hydroxyl group on the surface of TiO2 and forming inner-sphere surface complexes. Owing to its high efficiency, facile synthesis and environmental friendliness, the TiO2I has the potential to be used as an alternative adsorbent to remove Tl(I) from water.
Comprehensive quantitative analysis of alternative splicing variants reveals the HNF1B mRNA splicing pattern in various tumour and non-tumour tissues
Authors: Hojny Jan , Michalkova Romana , Krkavcova Eva , Bui Quang Hiep , Bartu Michaela , Nemejcova Kristyna , Kalousova Marta , Kleiblova Petra , Dundr Pavel , Struzinska Ivana
Published: January 2022

Hepatocyte nuclear factor-1-beta (HNF1B) is a transcription factor and putative biomarker of solid tumours. Recently, we have revealed a variety ofHNF1BmRNA alternative splicing variants (ASVs) with unknown, but potentially regulatory, functions. The aim of our work was to quantify the most common variants and compare their expression in tumour and non-tumour tissues of the large intestine, prostate, and kidney. TheHNF1BmRNA variants 3p, Δ7, Δ7–8, and Δ8 were expressed across all the analysed tissues in 28.2–33.5%, 1.5–2%, 0.8–1.7%, and 2.3–6.9% of overallHNF1BmRNA expression, respectively, and occurred individually or in combination. The quantitative changes of ASVs between tumour and non-tumour tissue were observed for the large intestine (3p, Δ7–8), prostate (3p), and kidney samples (Δ7). Decreased expression of the overallHNF1BmRNA in the large intestine and prostate cancer samples compared with the corresponding non-tumour samples was observed (p = 0.019 and p = 0.047, respectively). The decreased mRNA expression correlated with decreased protein expression in large intestine carcinomas (p < 0.001). The qualitative and quantitative pattern of the ASVs studied by droplet digital PCR was confirmed by next-generation sequencing, which suggests the significance of the NGS approach for further massive evaluation of the splicing patterns in a variety of genes.
Three-step matching algorithm to enhance between-group comparability and minimize confounding in comparative effectiveness studies
Authors: Yang Chen-Yi , Kuo Shihchen , Lai Edward Chia-Cheng , Ou Huang-Tz
Published: January 2022

We developed a three-step matching algorithm to enhance the between-group comparability for comparative drug effect studies involving prevalent new-users of the newer study drug versus older comparator drug(s). The three-step matching scheme is to match on: (1) index date of initiating the newer study drug to align the cohort entry time between study groups, (2) medication possession ratio measures that consider prior exposure to all older comparator drugs, and (3) propensity scores estimated from potential confounders. Our approach is illustrated with a comparative cardiovascular safety study of glucagon-like peptide-1 receptor agonist (GLP-1ra) versus sulfonylurea (SU) in type 2 diabetes patients using Taiwan’s National Health Insurance Research Database 2003–2015. 66% of 3195 GLP-1ra users had previously exposed to SU. The between-group comparability was well-achieved after implementing the matching algorithm (i.e., standardized mean difference < 0.2 for all baseline patient characteristics). Compared to SU, the use of GLP-1ra yielded a significantly reduced risk of the primary composite cardiovascular events (hazard ratio [95% confidence interval]: 0.71 [0.54–0.95],p = 0.022). Our matching scheme can enhance the between-group comparability in prevalent new-user cohort designs to minimize time-related bias, improve confounder adjustment, and ensure the reliability and validity of study findings.
Intelligent pharmaceutical patent search on a near-term gate-based quantum computer
Authors: Wang Pei-Hua , Chen Jen-Hao , Tseng Yufeng Jane
Published: January 2022

Pharmaceutical patent analysis is the key to product protection for pharmaceutical companies. In patent claims, a Markush structure is a standard chemical structure drawing with variable substituents. Overlaps between apparently dissimilar Markush structures are nearly unrecognizable when the structures span a broad chemical space. We propose a quantum search-based method which performs an exact comparison between two non-enumerated Markush structures with a constraint satisfaction oracle. The quantum circuit is verified with a quantum simulator and the real effect of noise is estimated using a five-qubit superconductivity-based IBM quantum computer. The possibilities of measuring the correct states can be increased by improving the connectivity of the most computation intensive qubits. Depolarizing error is the most influential error. The quantum method to exactly compares two patents is hard to simulate classically and thus creates a quantum advantage in patent analysis.
Non-invasive metabolomics biomarkers of production efficiency and beef carcass quality traits
Authors: Artegoitia Virginia M. , Newman J. W. , Foote A. P. , Shackelford S. D. , King D. A. , Wheeler T. L. , Lewis R. M. , Freetly H. C.
Published: January 2022

The inter-cattle growth variations stem from the interaction of many metabolic processes making animal selection difficult. We hypothesized that growth could be predicted using metabolomics. Urinary biomarkers of cattle feed efficiency were explored using mass spectrometry-based untargeted and targeted metabolomics. Feed intake and weight-gain was measured in steers (n = 75) on forage-based growing rations (stage-1, 84 days) followed by high-concentrate finishing rations (stage-2, 84 days). Urine from days 0, 21, 42, 63, and 83 in each stage were analyzed from steers with the greater (n = 14) and least (n = 14) average-daily-gain (ADG) and comparable dry-matter-intake (DMI; within 0.32 SD of the mean). Steers were slaughtered after stage-2. Adjusted fat-thickness and carcass-yield-grade increased in greater-ADG-cattle selected in stage-1, but carcass traits did not differ between ADG-selected in stage-2. Overall 85 untargeted metabolites segregated greater- and least-ADG animals, with overlap across diets (both stages) and breed type, despite sampling time effects. Total 18-bile acids (BAs) and 5-steroids were quantified and associated with performance and carcass quality across ADG-classification depending on the stage. Stepwise logistic regression of urinary BA and steroids had > 90% accuracy identifying efficient-ADG-steers. Urine metabolomics provides new insight into the physiological mechanisms and potential biomarkers for feed efficiency.
Predicting pathogenicity for novel hearing loss mutations based on genetic and protein structure approaches
Authors: Buonfiglio Paula I. , Bruque Carlos D. , Lotersztein Vanesa , Luce Leonela , Giliberto Florencia , Menazzi Sebastián , Francipane Liliana , Paoli Bibiana , Goldschmidt Ernesto , Elgoyhen Ana Belén , Dalamón Viviana
Published: January 2022

Hearing loss is a heterogeneous disorder. Identification of causative mutations is demanding due to genetic heterogeneity. In this study, we investigated the genetic cause of sensorineural hearing loss in patients with severe/profound deafness. After the exclusion of GJB2-GJB6 mutations, we performed whole exome sequencing in 32 unrelated Argentinean families. Mutations were detected in 16 known deafness genes in 20 patients: ACTG1, ADGRV1 (GPR98), CDH23, COL4A3, COL4A5, DFNA5 (GSDDE), EYA4, LARS2, LOXHD1, MITF, MYO6, MYO7A, TECTA, TMPRSS3, USH2A and WSF1. Notably, 11 variants affecting 9 different non-GJB2 genes resulted novel: c.12829C > T, p.(Arg4277*) in ADGRV1; c.337del, p.(Asp109*) and c.3352del, p.(Gly1118Alafs*7) in CDH23; c.3500G > A, p.(Gly1167Glu) in COL4A3; c.1183C > T, p.(Pro395Ser) and c.1759C > T, p.(Pro587Ser) in COL4A5; c.580 + 2 T > C in EYA4; c.1481dup, p.(Leu495Profs*31) in LARS2; c.1939 T > C, p.(Phe647Leu), in MYO6; c.733C > T, p.(Gln245*) in MYO7A and c.242C > G, p.(Ser81*) in TMPRSS3 genes. To predict the effect of these variants, novel protein modeling and protein stability analysis were employed. These results highlight the value of whole exome sequencing to identify candidate variants, as well as bioinformatic strategies to infer their pathogenicity.
Single-cell transcriptomics defines keratinocyte differentiation in avian scutate scales
Authors: Lachner Julia , Ehrlich Florian , Wielscher Matthias , Farlik Matthias , Hermann Marcela , Tschachler Erwin , Eckhart Leopold
Published: January 2022

The growth of skin appendages, such as hair, feathers and scales, depends on terminal differentiation of epidermal keratinocytes. Here, we investigated keratinocyte differentiation in avian scutate scales. Cells were isolated from the skin on the legs of 1-day old chicks and subjected to single-cell transcriptomics. We identified two distinct populations of differentiated keratinocytes. The first population was characterized by mRNAs encoding cysteine-rich keratins and corneous beta-proteins (CBPs), also known as beta-keratins, of the scale type, indicating that these cells form hard scales. The second population of differentiated keratinocytes contained mRNAs encoding cysteine-poor keratins and keratinocyte-type CBPs, suggesting that these cells form the soft interscale epidermis. We raised an antibody against keratin 9-like cysteine-rich 2 (KRT9LC2), which is encoded by an mRNA enriched in the first keratinocyte population. Immunostaining confirmed expression of KRT9LC2 in the suprabasal epidermal layers of scutate scales but not in interscale epidermis. Keratinocyte differentiation in chicken leg skin resembled that in human skin with regard to the transcriptional upregulation of epidermal differentiation complex genes and genes involved in lipid metabolism and transport. In conclusion, this study defines gene expression programs that build scutate scales and interscale epidermis of birds and reveals evolutionarily conserved keratinocyte differentiation genes.
Homogeneity of Arabian Peninsula dromedary camel populations with signals of geographic distinction based on whole genome sequence data
Authors: Bahbahani Hussain , Almathen Faisal
Published: January 2022

Dromedary camels in the Arabian Peninsula distribute along different geographical and ecological locations, e.g. desert, mountains and coasts. Here, we are aiming to explore the whole genome sequence data of ten dromedary populations from the Arabian Peninsula to assess their genetic structure, admixture levels, diversity and similarity indices. Upon including reference dromedary and Bactrian camel populations from Iran and Kazakhstan, we characterise inter-species and geographic genetic distinction between the dromedary and the Bactrian camels. Individual-based alpha genetic diversity profiles are found to be generally higher in Bactrian camels than dromedary populations, with the exception of five autosomes (NC_044525.1, NC_044534.1, NC_044540.1, NC_044542.1, NC_044544.1) at diversity orders (q ≥ 2). The Arabian Peninsula camels are generally homogenous, with a small degree of genetic distinction correlating with three geographic groups: North, Central and West; Southwest; and Southeast of the Arabian Peninsula. No significant variation in diversity or similarity indices are observed among the different Arabian Peninsula dromedary populations. This study contributes to our understanding of the genetic diversity of Arabian Peninsula dromedary camels. It will help conserve the genetic stock of this species and support the design of breeding programmes for genetic improvement of favorable traits.