bluuebunny/crossref_metadata_2025 huggingface dataset:
Realistic retinal modeling unravels the differential role of excitation and
inhibition to starburst amacrine cells in direction selectivity
Authors: Ezra-Tsur Elishai , Amsalem Oren , Ankri Lea , Patil Pritish , Segev Idan , Rivlin-Etzion Michal
Published: May 2022

Retinal direction-selectivity originates in starburst amacrine cells (SACs),
which display a centrifugal preference, responding with greater depolarization
to a stimulus expanding from soma to dendrites than to a collapsing stimulus.
Various mechanisms were hypothesized to underlie SAC centrifugal preference, but
dissociating them is experimentally challenging and the mechanisms remain
debatable. To address this issue, we developed the Retinal Stimulation Modeling
Environment (RSME), a multifaceted data-driven retinal model that encompasses
detailed neuronal morphology and biophysical properties, retina-tailored
connectivity scheme and visual input. Using a genetic algorithm, we demonstrated
that spatiotemporally diverse excitatory inputs – sustained in the proximal and
transient in the distal processes – are sufficient to generate experimentally
validated centrifugal preference in a single SAC. Reversing these input kinetics
did not produce any centrifugal-preferring SAC. We then explored the
contribution of SAC-SAC inhibitory connections in establishing the centrifugal
preference. SAC inhibitory network enhanced the centrifugal preference, but
failed to generate it in its absence. Embedding a direction selective ganglion
cell (DSGC) in a SAC network showed that the known SAC-DSGC asymmetric
connectivity by itself produces direction selectivity. Still, this selectivity
is sharpened in a centrifugal-preferring SAC network. Finally, we use RSME to
demonstrate the contribution of SAC-SAC inhibitory connections in mediating
direction selectivity and recapitulate recent experimental findings. Thus, using
RSME, we obtained a comprehensive mechanistic understanding of SACs’ centrifugal
preference and its contribution to direction selectivity.
Leveraging Allele-Specific Expression for Therapeutic Response Gene Discovery
in Glioblastoma
Authors: Sen Arko , Prager Briana C. , Park Donglim , Zhu Zhe , Gimple Ryan C. , Bernatchez Jean A. , Beck Sungjun , Clark Alex E. , Siqueira-Neto Jair L. , Rich Jeremy N. , McVicker Graham
Published: May 2022

Glioblastoma is the most prevalent primary malignant brain tumor in adults
and is characterized by poor prognosis and universal tumor recurrence. Effective
glioblastoma treatments are lacking, in part due to somatic mutations and
epigenetic reprogramming that alter gene expression and confer drug resistance.
Here, we interrogated allele-specific expression (ASE) in 43 patient-derived
glioblastoma stem cells (GSCs) to identify recurrently dysregulated genes in
glioblastoma. We identified 118 genes with recurrent ASE preferentially found in
GSCs compared to normal tissues. These genes were enriched for apoptotic
regulators, including Schlafen Family Member 11
(SLFN11). Loss of
SLFN11 gene expression was associated with
aberrant promoter methylation and conferred resistance to chemotherapy and poly
ADP ribose polymerase inhibition. Conversely, low
SLFN11 expression rendered GSCs susceptible to
the oncolytic flavivirus Zika, which suggests a potential alternative treatment
strategy for chemotherapy resistant GBMs.
Whole-genome sequence analysis unveils different origins of European and Asiatic mouflon and domestication-related genes in sheep
Authors: Chen Ze-Hui , Xu Ya-Xi , Xie Xing-Long , Wang Dong-Feng , Aguilar-Gómez Diana , Liu Guang-Jian , Li Xin , Esmailizadeh Ali , Rezaei Vahideh , Kantanen Juha , Ammosov Innokentyi , Nosrati Maryam , Periasamy Kathiravan , Coltman David W. , Lenstra Johannes A. , Nielsen Rasmus , Li Meng-Hua
Published: May 2022

The domestication and subsequent development of sheep are crucial events in the history of human civilization and the agricultural revolution. However, the impact of interspecific introgression on the genomic regions under domestication and subsequent selection remains unclear. Here, we analyze the whole genomes of domestic sheep and all their wild relative species. We found introgression from wild sheep such as the snow sheep and its American relatives (bighorn and thinhorn sheep) into urial, Asiatic and European mouflons. We observed independent events of adaptive introgression from wild sheep into the Asiatic and European mouflons, as well as shared introgressed regions from both snow sheep and argali into Asiatic mouflon before or during the domestication process. We revealed European mouflons arose through hybridization events between a now extinct sheep in Europe and feral domesticated sheep around 6,000 – 5,000 years BP. We also unveiled later introgressions from wild sheep to their sympatric domestic sheep after domestication. Several of the introgression events contain loci with candidate domestication genes (e.g.,PAPPA2,NR6A1,SH3GL3,RFX3andCAMK4), associated with morphological, immune, reproduction or production traits (wool/meat/milk). We also detected introgression events that introduced genes related to nervous response (NEURL1), neurogenesis (PRUNE2), hearing ability (USH2A) and placental viability (PAG11andPAG3) to domestic sheep and their ancestral wild species from other wild species.
Approaches to generating virtual patient cohorts with applications in oncology
Authors: Surendran Anudeep , Sauteur-Robitaille Justin Le , Kleimeier Dana , Gevertz Jana , Wilkie Kathleen , Jenner Adrianne L. , Craig Morgan
Published: May 2022

Virtual clinical trials (VCTs) have gained popularity for their ability to rationalize the drug development process using mathematical and computational modelling, and to provide key insights into the mechanisms regulating patient responses to treatment. In this chapter, we cover approaches for generating virtual cohorts with applications in cancer biology and treatment. VCTs are an effective tool for predicting clinical responses to novel therapeutics and establishing effective treatment strategies. These VCTs allow us to capture inter-individual variability (IIV) which can lead to diversity in patient drug responses. Here we discuss three main methodologies for capturing IIV with a VCT. First, we highlight the use of population pharmacokinetic (PopPK) models, which extrapolate from empirical data population PK parameters that best fits the individual variability seen in drug disposition using non-linear mixed effects models. Next, we show how virtual patients may be sampled from a normal distribution with mean and standard deviation informed from experimental data to estimate parameters in a mechanistic model that regulates drug PKs. Lastly, we show how optimization techniques can be used to calibrate virtual patient parameter values and generate the VCT. Throughout, we compare and contrast these methods to provide a broader view of the generation of virtual patients, and to aid the decision-making process for those looking to leverage virtual clinical trials in their research.
A Proximity Biotinylation Assay with a Host Protein Bait Reveals Multiple Factors Modulating Enterovirus Replication
Authors: Moghimi Seyedehmahsa , Viktorova Ekaterina , Gabaglio Samuel , Zimina Anna , Budnik Bogdan , Wynn Bridge G. , Sztul Elizabeth , Belov George A.
Published: May 2022

As ultimate parasites, viruses depend on host factors for every step of their life cycle. On the other hand, cells evolved multiple mechanisms of detecting and interfering with viral replication. Yet, our understanding of the complex ensembles of pro- and anti-viral factors is very limited in virtually every virus-cell system. Here we investigated the proteins recruited to the replication organelles of poliovirus, a representative of the genus Enterovirus of the Picornaviridae family. We took advantage of a strict dependence of enterovirus replication on a host protein GBF1, and established a stable cell line expressing a truncated GBF1 fused to APEX2 peroxidase that effectively supported viral replication upon inhibition of the endogenous GBF1. This construct biotinylated multiple host and viral proteins on the replication organelles. Among the viral proteins, the polyprotein cleavage intermediates were overrepresented, arguing that the GBF1 environment is linked to the viral polyprotein processing. The proteomics characterization of biotinylated host proteins identified those previously associated with the enterovirus replication, as well as more than 200 new factors recruited to the replication organelles. RNA metabolism proteins many of which normally localize in the nucleus constituted the largest group, underscoring the massive release of nuclear factors in the cytoplasm of infected cells and their involvement in the viral replication. Analysis of several newly identified proteins revealed both pro- and anti-viral factors, including a novel component of infection-induced stress granules. Depletion of these proteins similarly affected the replication of diverse enteroviruses indicating broad conservation of the replication mechanisms. Thus, our data significantly increase the knowledge about the organization of enterovirus replication organelles and may provide new targets for anti-viral interventions.
A high throughput screen with a clonogenic endpoint to identify radiation modulators of cancer
Authors: Gomes Nathan P. , Frederick Barbara , Jacobsen Jeremy R. , Chapnick Doug , Su Tin Tin
Published: May 2022

Gomes, N. P., Frederick, B., Jacobsen, J. R., Chapnick. D. and Su, T. T. A high throughput screen with a clonogenic endpoint to identify radiation modulators of cancer. Radiat. Res.

Clonogenic assays evaluate the ability of single cells to proliferate and form colonies. This process approximates the regrowth and recurrence of tumors after treatment with radiation or chemotherapy, and thereby provides a drug discovery platform for compounds that block this process. However, because of their labor-intensive and cumbersome nature, adapting canonical clonogenic assays for high throughput screening (HTS) has been challenging. We overcame these barriers by developing an integrated system that automates cell- and liquid-handling, irradiation, dosimetry, drug administration, and incubation. Further, we developed a fluorescent live-cell based automated colony scoring methodology that identifies and counts colonies precisely based upon actual nuclei number rather than colony area, thereby eliminating errors in colony counts caused by radiation induced changes in colony morphology. We identified 13 cell lines from 7 cancer types, where radiation is a standard treatment module, that exhibit identical radiation and chemoradiation response regardless of well format and are amenable to miniaturization into small-well HTS formats. We performed pilot screens through a 1584 compound NCI Diversity Set library using two cell lines representing different cancer indications. Radiation modulators identified in the pilot screens were validated in traditional clonogenic assays, providing proof-of-concept for the screen. The integrated methodology, hereafter ‘clonogenic HTS’, exhibits excellent robustness (Z’ values >0.5) and shows high reproducibility (>95%). We propose that clonogenic HTS we developed can function as a drug discovery platform to identify compounds that inhibit tumor regrowth following radiation therapy, to identify new efficacious pair-wise combinations of known oncologic therapies, or to identify novel modulators of approved therapies.
CspZ FH-binding sites as epitopes promote antibody-mediated Lyme borreliae clearance
Authors: Chen Yi-Lin , Marcinkiewicz Ashley L. , Nowak Tristan A. , Kundu Rakhi Tyagi , Liu Zhuyun , Strych Ulrich , Bottazzi Maria-Elena , Chen Wen-Hsiang , Lin Yi-Pin
Published: May 2022

Transmitted by ticks, the bacterium Borrelia burgdorferi sensu lato (Bbsl) is the causative agent of Lyme disease (LD), the most common vector-borne disease in the Northern hemisphere. No effective vaccines are currently available. Bbsl produces the CspZ protein that binds to the complement inhibitor, Factor H (FH), promoting evasion of the host complement system. We previously showed that while vaccination with CspZ did not protect mice from Bb infection, mice can be protected after immunization with CspZ-Y207A/Y211A (CspZ-YA), a CspZ mutant protein without FH-binding activity. To further study the mechanism of this protection, herein we evaluated both poly-and monoclonal antibodies recognizing CspZ FH-binding or non-FH-binding sites. We found that the anti-CspZ antibodies that recognize the FH-binding sites (i.e., block FH-binding activity) more efficiently eliminate Bbsl in vitro than those that bind to the non-FH-binding sites, and passive inoculation with anti-FH binding site antibodies eradicated Bbsl in vivo. Antibodies against non-FH-binding sites did not have the same effect. These results emphasize the importance of CspZ FH-binding sites in triggering a protective antibody response against Bbsl in future LD vaccines.
ChromGene: Gene-Based Modeling of Epigenomic Data
Authors: Jaroszewicz Artur , Ernst Jason
Published: May 2022

Background

Various computational approaches have been developed to annotate epigenomes on a per-position basis by modeling combinatorial and spatial patterns within epigenomic data. However, such annotations are less suitable for gene-based analyses, in which a single annotation for each gene is desired.

Results

To address this, we developed ChromGene, which annotates genes based on the combinatorial and spatial patterns of multiple epigenomic marks across the gene body and flanking regions. Specifically, ChromGene models the epigenomics maps using a mixture of hidden Markov models learned de novo. Using ChromGene, we generated annotations for the human protein-coding genes for over 100 cell and tissue types. We characterize the different mixture components and their associated gene sets in terms of gene expression, constraint, and other gene annotations. We also characterize variation in ChromGene gene annotations across cell and tissue types.

Conclusions

We expect that the ChromGene method and provided annotations will be a useful resource for gene-based epigenomic analyses.
Genome-wide identification of microsatellite markers and their application in genetic studies of wolfberry (Lycium barbarum)
Authors: Yin Yue , Qin Xiaoya , Zhao Jianhua , An Wei , Li Yanlong , Fan Yunfang , Wang Yajun , Cao Youlong
Published: May 2022

The wolfberry (Lycium barbarum) has been an important traditional Chinese food and medicine for hundreds of years. However, few microsatellite markers have been developed for assessing the genetic diversity and genetic linkage maps among Lycium species in genetic research. In the present study, a total of 397,558 microsatellite loci were identified from whole wolfberry genome sequences with an overall density of 212.1 Mb/SSRs. Dinucleotide microsatellites were the most abundant type, representing 58.26% of the total microsatellite loci, followed by tri-, penta-, hexa-, and tetranucleotide. The AT motifs were the most abundant of all nucleotide repeat motifs, accounting for 44.52%. A set of 600 primer pairs were synthesized and preliminarily screened among four wolfberry accessions. Of these, 277 primer pairs were selected as polymorphic markers. In total, 22 highly polymorphic SSR markers were selected for the characterization of genetic diversity among 37 wolfberry accessions. A total of 323 alleles were detected with an average of 14.7 alleles per marker. The polymorphic information content (PIC) values ranged from 0.612 to 0.911. The dendrogram revealed that the phylogenetic relationships among these wolfberry accessions were consistent with their genetic background. Thus, the large number of genome-wide microsatellite markers developed from the wolfberry genome provides a valuable resource for genetic diversity, genetic map construction, quantitative trait locus (QTL) mapping, and marker-assisted selection breeding in Lycium species.
ssDNA is an allosteric regulator of the C. crescentus SOS-independent DNA damage response transcription activator, DriD
Authors: Gozzi Kevin , Salinas Raul , Nguyen Viet D. , Laub Michael T. , Schumacher Maria A.
Published: May 2022

DNA damage repair systems are critical for genomic integrity. However, they must be coordinated with DNA replication and cell division to ensure accurate genomic transmission. In most bacteria, this coordination is mediated by the SOS response through LexA, which triggers a halt in cell division until repair is completed. Recently, an SOS-independent damage response system was revealed in Caulobacter crescentus. This pathway is controlled by the transcription activator, DriD, but how DriD senses and signals DNA damage is unknown. To address this question, we performed biochemical, cellular, and structural studies. We show that DriD binds a specific promoter DNA site via its N-terminal HTH domain to activate transcription of genes, including the cell division inhibitor didA. A structure of the C-terminal portion of DriD revealed a WYL motif domain linked to a WCX dimerization domain. Strikingly, we found that DriD binds ssDNA between the WYL and WCX domains. Comparison of apo and ssDNA-bound DriD structures reveals that ssDNA binding orders and orients the DriD domains, indicating a mechanism for ssDNA-mediated operator DNA binding activation. Biochemical and in vivo studies support the structural model. Our data thus reveal the molecular mechanism underpinning an SOS-independent DNA damage repair pathway.
Senescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance
Authors: Yin Kelvin , Patten Daniel , Gough Sarah , de Barros Gonçalves Susana , Chan Adelyne , Olan Ioana , Cassidy Liam , Poblocka Marta , Zhu Haoran , Lun Aaron , Schuijs Martijn , Young Andrew , Martinez-Jimenez Celia , Halim Timotheus Y.F. , Shetty Shishir , Narita Masashi , Hoare Matthew
Published: May 2022

Senescence is a stress-responsive tumor suppressor mechanism associated with expression of the senescence-associated secretory phenotype (SASP). Through the SASP, senescent cells trigger their own immune-mediated elimination, which if evaded leads to tumorigenesis. Senescent parenchymal cells are separated from circulating immunocytes by the endothelium, which is targeted by microenvironmental signaling. Here we show that SASP induces endothelial cell NF-κB activity and that SASP-induced endothelial expression of the canonical NF-κB componentRelaunderpins senescence surveillance. Using human liver sinusoidal endothelial cells (LSECs), we show that SASP-induced endothelial NF-κB activity regulates a conserved transcriptional program supporting immunocyte recruitment. Furthermore, oncogenic hepatocyte senescence drives murine LSEC NF-κB activity in vivo. Critically, we show two distinct endothelial pathways in senescence surveillance. First, endothelial-specific loss ofRelaprevents development of Stat1-expressing CD4+T lymphocytes. Second, the SASP up-regulates ICOSLG on LSECs, with the ICOS–ICOSLG axis contributing to senescence cell clearance. Our results show that the endothelium is a nonautonomous SASP target and an organizing center for immune-mediated senescence surveillance.
Crystal structure and Hirshfeld surface analysis of 2-(4-chlorophenyl)-4-(dimethoxymethyl)-5-phenyl-1,3-thiazole
Authors: Guseinov Firudin I. , Kobrakov Konstantin I. , Shuvalova Elena V. , Tuzharov Egor I. , Akkurt Mehmet , Yıldırım Sema Öztürk , Bhattarai Ajaya
Published: May 2022

In the title compound, C18H16ClNO2S, the thiazole ring subtends dihedral angles of 13.12 (14) and 43.79 (14) ° with the attached chlorophenyl and phenyl rings, respectively. In the crystal, C—H...π interactions link the molecules, forming a three-dimensional network. The roles of the various intermolecular interactions were clarified by Hirshfeld surface analysis, which reveals that the most important contributions to the crystal packing are from H...H (39.2%), H...C/C...H (25.2%), Cl...H/H...Cl (11.4%) and O...H/H...O (8.0%) contacts.
How environmental gain messages affect cause involvement, attitude and behavioural intentions: the moderating effects of CSR scepticism and biospheric values
Authors: Stadlthanner Katja Anna , Andreu Luisa , Font Xavier , Ribeiro Manuel Alector , Currás-Pérez Rafael
Published: May 2022

Purpose

This study examines the direct effect of outcome message frames (gain vs loss) on cause involvement and the moderating roles of consumers' corporate social responsibility (CSR) scepticism and biospheric values. Furthermore, the authors analyse (1) the effects of gain-framed messages on consumer attitudes towards an environmental cause (i.e. the use of reusable coffee cups) and towards the company promoting the cause (a coffee shop chain); (2) how consumer attitudes towards the cause affect their attitudes towards the company; and (3) how consumer attitudes towards both the cause and the company affect their behavioural intentions towards both the cause and the company.

Design/methodology/approach

Using a 2 × 1 scenario-based, experimental design with a gain vs loss stimuli, Study 1 (n = 466) examines the moderating effects of CSR scepticism and biospheric values on the relationship between message framing and consumer cause involvement. Using gain-framed stimuli, Study 2 (n = 958) analyses the effects of cause involvement variations on attitudes and behaviours, through structural equation modelling.

Findings

Gain-framed messages are more effective than loss-framed messages at increasing cause involvement in consumers. Both CSR scepticism and biospheric values moderate the relationship between gain-framed messages and cause involvement. Cause involvement enhances consumer attitudes towards both the cause and the company promoting it, while company attitudes towards a cause positively influence consumers' behavioural intentions.

Originality/value

This study recommends that environmental CSR advertising managers should use gain-framed messages to positively influence consumer cause involvement.
Leading peers in an academic setting: insights from the front lines
Authors: Haskins Mark E.
Published: May 2022

Purpose

This article highlights and discusses numerous, specific leadership attributes that contribute greatly to enabling a university faculty member to be an effective leader of a group of their peers. As such, this article provides additional insights into the important construct of “transcollegial leadership” (Burns and Mooney, 2018).

Design/methodology/approach

The personal “reflections on practice” (Schon, 1983) presented here are based on 40+ years of observing and experiencing university faculty leading groups of peers as well as numerous personal experiences of serving in such a leadership role.

Findings

This article presents a robust array of specific, real-world-based insights that can contribute to enhancing the effectiveness of a leader of peers in a higher education institutional setting. Moreover, the ideas presented are offered to leaders of academic institutions as foci for potential faculty development initiatives and discussions. The ideas presented are clustered into six categories – process, resolve, integrity, mindset, excitement/energy, and respect.

Practical implications

The actions and ideas presented pertaining to a university faculty member's capability to effectively lead a group of peers are widely and immediately actionable. The insights presented are also amenable to ongoing faculty development activities and discussions.

Originality/value

This article addresses the common challenge of effectively leading a group of one's faculty peers in an academic setting. As such, the article extends and embellishes the conceptual, institutional-level perspective presented by Burns and Mooney (2018) in this journal.
Keratosis pilaris and filaggrin loss‐of‐function mutations in patients with atopic dermatitis – Results of a Finnish cross‐sectional study
Authors: Salava Alexander , Salo Ville , Remitz Anita
Published: May 2022

Keratosis pilaris (KP) associates with epidermal barrier defects in atopic dermatitis (AD) but its role in disease severity and concomitant atopic diseases seems to vary between populations. We performed a cross‐sectional observational study with 502 randomly selected AD patients of a Finnish tertiary health care center. At a single clinical examination, disease severity (Rajka Langeland severity score and EASI), clinical signs and patient history were evaluated and total IgE levels and frequent filaggrin (FLG) loss‐of‐function mutations were investigated. There was no link with disease severity (p = 0.649, 95% CI 0.569–0.654), asthma (p = 0.230, 95% CI 0.206–0.281) or atopic sensitization (p = 0.351, 95% CI 0.309–0.392). Keratosis pilaris was significantly associated with palmar hyperlinearity (p < 0.000, 95% CI 0.000–0.006, OR 4.664, 95% CI 2.072–10.496) and the filaggrin loss‐of‐function mutation 2282del4 (p < 0.000, 95% CI 0.000–0.009, OR 4.917, 95%CI 1.961–12.330). The prevalence of KP in the cohort was generally low and KP seems to be infrequent in Finnish AD patients. This may be explained by the fact that the tested FLG loss‐of‐function mutations are rarer in the Finnish population compared for example, with central Europe or Asia. Mutations in other locations of the FLG gene or other genes of the epidermal barrier may play a more important role.
Children's version of the systemic clinical outcome and routine evaluation (C‐SCORE): Exploring the psychometric qualities in the Portuguese context
Authors: Vilaça Margarida , Veloso Bruna , Stratton Peter , Relvas Ana Paula
Published: May 2022

Current literature presents a gap in family functioning assessment instruments directed to children. The Child Systemic Clinical Outcome and Routine Evaluation (C‐SCORE) is a self‐report instrument, based on the original SCORE‐15, that measures different aspects of family functioning from the child's perspective. This study aims to explore the psychometric qualities of the Portuguese version of C‐SCORE using a sample of 119 children, aged 8–11 years, recruited from public (state) schools located in North Portugal. Results showed good internal consistency for the total scale and were consistent with the original factorial structure. Correlation analyses using the Perception Scale of Parenting Communication – Children (COMPA‐C) provided support for convergent validity. This study represents the first psychometric evaluation of the C‐SCORE using a sample of Portuguese children, with exploratory results suggesting that this version presents acceptable psychometric qualities, and may be especially useful to assess family functioning from the child's view.
Do we really want to know? The journey to implement empirical research recommendations in the ICRC's responses in Myanmar and Lebanon
Authors: Leresche Enrica , Hossain Mazeda , Rossi Rodolfo , Truppa Claudia , Barth Cornelia Anne , Mactaggart Islay , Leaning Jennifer , Singh Neha
Published: May 2022

Efforts to reduce the gap between the research evidence base and humanitarian responses have focused on producing quality evidence and ensuring its use in decision‐making. Yet, how evidence translates into field‐level implementation is not well understood in humanitarian contexts. This study analysed how recommendations produced through academic research partnerships were implemented by the International Committee of the Red Cross (ICRC) in Lebanon and Myanmar. The methodology included: social network analysis to represent collective dynamics; document reviews to assess implementation; qualitative interviews to comprehend why actors engaged; and a critical appraisal of these combined results. The application of Extended Normalization Process Theory provided information on ‘anticipation of constraints’ (access to information, staff turnover, context specificity, and the need to engage as a cohesive group). Future research efforts should concentrate explicitly on identifying and tackling implementation barriers such as power imbalances and ethical dilemmas related to service delivery by humanitarian actors.
Enhanced electrocaloric response and energy storage performance of Li‐substituted BaTiO3 ceramics
Authors: Sarraf Sonu , Singh Satyendra
Published: May 2022

Recently, ferroelectric and antiferroelectric ceramic materials have gained a lot of interest for the development of environment‐friendly highly‐efficient electrocaloric refrigeration and energy‐storage devices. In this work, lead‐free Ba1−xLixTiO3 ceramics with x = 0, 0.01, 0.02, 0.03, 0.04, and 0.05 were synthesized by the conventional solid‐state reaction method, and the effect of Li doping on dielectric, leakage current, ferroelectric, electrocaloric, and energy storage properties of BaTiO3 ceramics was systematically investigated. The XRD and Raman studies confirmed that the structure of Ba1−xLixTiO3 remains tetragonal as for BaTiO3. The Li substitution shifted the phase transition (TC) of BaTiO3 slightly towards the lower temperature side. Significant drop in leakage current was observed with an addition of Li content. The maximum values of the electrocaloric effect (ΔT), electrocaloric responsivity, and coefficient of performance were found to be 1.44 K, 0.24 × 10−6 K m/V, and 5.75, respectively, for x = 0.04 at an applied field of 60 kV/cm near the Curie temperature. The maximal value of energy storage density was found to be 0.42 J/cm3 with an energy storage efficiency of 60% for x = 0.05. Our results suggested that lead‐free Ba1−xLixTiO3 ceramic material is a promising candidate for potential applications in solid‐state refrigeration technology and high‐efficiency energy storage devices.
Must We Vaccinate the Most Vulnerable? Efficiency, Priority, and Equality in the Distribution of Vaccines
Authors: Curran Emma J. , John Stephen D.
Published: May 2022

In this article, we aim to map out the complexities which characterise debates about the ethics of vaccine distribution, particularly those surrounding the distribution of the COVID‐19 vaccine. In doing so, we distinguish three general principles which might be used to distribute goods and two ambiguities in how one might wish to spell them out. We then argue that we can understand actual debates around the COVID‐19 vaccine – including those over prioritising vaccinating the most vulnerable – as reflecting disagreements over these principles. Finally, we shift our attention away from traditional discussions of distributive justice, highlighting the importance of concerns about risk imposition, special duties, and social roles in explaining debates over the COVID‐19 vaccine. We conclude that the normative complexity this article highlights deepens the need for decision‐making bodies to be sensitive to public input.
UBE2C triggers HIF‐1α‐glycolytic flux in head and neck squamous cell carcinoma
Authors: Yang Yi‐Fang , Chang Yu‐Chan , Tsai Kuo‐Wang , Hung Ming‐Hsin , Kang Bor‐Hwang
Published: May 2022

Head and neck squamous cell carcinoma (HNSCC) is the most common malignancy in Taiwan. Therefore, refining the diagnostic sensitivity of biomarkers for early‐stage tumours and identifying therapeutic targets are critical for improving the survival rate of HNSCC patients. Metabolic reprogramming contributes to cancer development and progression. Metabolic pathways, specifically, play a crucial role in these diverse biological and pathological processes, which include cell proliferation, differentiation, apoptosis and carcinogenesis. Here, we investigated the role and potential prognostic value of the ubiquitin‐conjugating enzyme E2 (UBE2) family in HNSCC. Gene expression database analysis followed by tumour comparison with non‐tumour tissue showed that UBE2C was upregulated in tumours and was associated with lymph node metastasis in HNSCC patients. Knockdown of UBE2C significantly reduced the invasion/migration abilities of SAS and CAL27 cells. UBE2C modulates glycolysis pathway activation and HIF‐1α expression in SAS and CAL27 cells. CoCl2 (HIF‐1α inducer) treatment restored the expression of glycolytic enzymes and the migration/invasion abilities of UBE2C knockdown cells. Based on our findings, UBE2C expression mediates HIF‐1α activation, increasing glycolysis pathway activation and the invasion/migration abilities of cancer cells. UBE2C may be an independent prognostic factor and a therapeutic target in HNSCC.
Carbohydrate quantity is more closely associated with glycaemic control than weight in pregnant women with type 1 diabetes: Insights from the Diabetes and Pre‐eclampsia Intervention Trial (DAPIT)
Authors: Hill Alyson J. , Patterson C. C. , Young I. S. , Holmes V. A. , McCance D. R.
Published: May 2022

Background

The present study aimed to explore the relationships between carbohydrate intake, body mass index (BMI) and glycaemic control (HbA1c) in pregnant women with type 1 diabetes mellitus (T1DM)

Methods

Secondary analysis of data was undertaken to assess dietary intake in a cohort of women who participated in a randomised controlled trial (RCT) of antioxidant supplementation to prevent preeclampsia (DAPIT10). Study‐specific peripheral venous blood samples were obtained for HbA1c at 26 and 34 weeks. Diet was collected using a validated semiquantitative food frequency questionnaire at 26–28 weeks of gestation which assessed dietary intake over 2 weeks. Mean daily average nutrient intakes were analysed using Q Builder nutritional software and SPSS, version 25.

Results

Dietary data were available for 547 pregnant women (72% of cohort) aged 29 years (95% confidence interval [CI] = 28.9–29.9) with average diabetes duration 11.8 years (95% confidence interval = 11.1–12.6). Average body mass index (BMI) (<16 weeks of gestation) was 26.7 kg/m2 (95% CI = 26.3 −27, range 18.8–45.6 kg/m2); 43% (n = 234) were overweight (BMI = 25.0−29.9 kg/m2) and 20% (n = 112) were obese (BMI ≥ 30 kg/m2). Differences in HbA1c and carbohydrate quantity and quality were found when adjusted for age and insulin dose. No differences between BMI group were observed for total carbohydrate and glycaemic control; however, differences were noted in fibre and glycaemic index.

Conclusions

Average quantity of dietary carbohydrate influenced HbA1c when adjusted for insulin dose however, BMI had less impact. More research is required on the relationship between carbohydrate consumption and glycaemic control in pregnancy.
Disseminated intravascular coagulation complicated by amniotic band syndrome associated with deceased fetal umbilical cord following fetoscopic laser surgery
Authors: Ogoyama Manabu , Takahashi Hironori , Kagawa Keiko , Shimozawa Hironori , Yada Yukari , Wada Seiji , Sago Haruhiko , Fujiwara Hiroyuki
Published: May 2022

Fetoscopic laser surgery occasionally causes amniotic band syndrome, in which the disrupted amniotic membrane constricts fetal body parts, leading to functional or morphological loss. We report a case of fetal distress at 31 weeks of gestation in the larger surviving twin after fetoscopic laser surgery for selective intrauterine growth restriction, necessitating emergent cesarean section. Physical examination of the infant showed constriction rings caused by a disrupted amniotic membrane on the digits, and the distal part of the right index finger was necrotic because of tight strangulation by an amniotic band with the umbilical cord of the deceased smaller twin. Laboratory data showed severe coagulopathy, and the infant was diagnosed with disseminated intravascular coagulation (DIC). Immediate treatment improved his condition. DIC may have been associated with the necrotic finger, which was strangulated by the umbilical cord of the deceased fetus, because neither maternal coagulopathy nor an underlying neonatal disorder was detected.
L‐arginine stimulates the proliferation of mouse mammary epithelial cells and the development of mammary gland in pubertal mice by activating the GPRC6A/PI3K/AKT/mTOR signalling pathway
Authors: Ge Yusong , Li Feng , He Yuan , Cao Yu , Guo Wenjin , Hu Guiqiu , Liu Juxiong , Fu Shoupeng
Published: May 2022

Amino acids have been shown to affect the development of mammary gland (MG). However, it is unclear whether L‐arginine promotes the development of pubertal MG. Therefore, our study aims to explore the effect of L‐arginine on the development of MG in pubertal mice. To investigate its internal mechanism of action, we will use mouse mammary epithelial cells (mMECs) line. Whole‐mount staining showed that L‐arginine can promote the extension of MG duct. In vitro, 0.4 mM L‐arginine could activate the G protein‐coupled receptor family C, group 6, subtype A (GPRC6A)/phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway and increase the phosphorylation of eukaryotic initiation factor 4E binding protein 1 (4EBP1) to promote the synthesis of cell cycle regulatory protein D1 (Cyclin D1), leading to the dissociation of the retinoblastoma tumour suppressor protein (Rb)‐E2F1 transcription factor (E2F1) complex in mMECs and releasing E2F1 to promote cell proliferation. Furthermore, GPRC6A was knocked down or inhibition of the PI3K/AKT/mTOR signalling pathway with corresponding inhibitors completely abolished the arginine‐induced promotion of mMECs proliferation. In vivo, it was further confirmed that 0.1% L‐arginine can activate the PI3K/AKT/mTOR signalling pathway in the MG of pubertal mice. These results were able to indicate that L‐arginine stimulates the development of MG in pubertal mice through the GPRC6A/PI3K/AKT/mTOR signalling pathway.
Influence of weaning management at 30, 75 and 180 days of age on non‐esterified fatty acids and reproductive performance in beef cows
Authors: Alforma Antónia Mendes Paizano , Pereira Gabriel Ribas , da Rocha Marcela Kuczynski , Teixeira Odilene de Souza , de Oliveira Maria Carolina Muniz , Lima Júlia Abud , Cumbe Télis Adolfo , Barcellos Júlio Otávio Jardim
Published: May 2022

This study aimed to investigate the effect of age at weaning of calves on non‐esterified fatty acids (NEFA) and reproductive parameters of beef cows. Animals (n = 65) were randomly assigned to three treatments after calving: hyper‐early weaning (W30) at 32 ± 0.89 days, early weaning (W75) at 77 ± 0.95 days, and conventional weaning (W180) at 183 ± 0.82 days. Body weight (BW) and body condition score (BCS) were evaluated at parturition (AP) and at 30, 45, 64, 81, 100 and 115 days postpartum (dPP). Blood samples were collected to analyze NEFA levels and progesterone (P4) at 30, 45, 64 and 81 dPP. Higher BW and BCS were observed from 64 to 115 dPP in W30 cows than W180 ones (p < 0.05). Cows subjected to W30 condition had higher levels of NEFA at 30 dPP compared to 64 and 81 dPP (p < 0.05). We also observed that cows from W180 group showed decreased levels of NEFA at 30 dPP compared to 45 (p < 0.01) and 64 dPP (p < 0.05). The highest P4 level was observed at 64 dPP in W30 cows compared to W75 and W180 (p < 0.05). We also observed higher CR of W30 (86%) compared to W180 (47%) at 45 dPP (p < 0.05). The overall pregnancy rate (PR) was higher for W30 (95.5%) than W180 (73.9%). In addition, higher BW at calving and P4 levels at 30 dPP were positively correlated with the possibility of pregnancy (p < 0.05). Improvement in BW and BCS were observed in cows subjected to hyper‐early weaning management. However, levels of NEFA decreased as the postpartum period progressed. We concluded that cows who weaned calves hyper‐early have greater chances of increasing cyclicity and PRs.
Effect of parity on non‐esterified fatty acid, oxidant/antioxidant status, and zinc and copper levels around periparturient period in Beetal goats of Himalayan Region
Authors: Singh Rajiv , Singh Virampal , Beigh Shafayat A.
Published: May 2022

The study was conducted to evaluate the effect of parity and physiological status on non‐esterified fatty acid (NEFA), oxidative stress, and zinc and copper levels among the Beetal breed of goat. Thirty dual‐purpose Beetal goats reared under the semi‐intensive system were selected and based on parity were divided into three groups with 10 animals each viz. Early parity (EP; ≤2 parity), mid parity (MP; 3–6 parity), and late parity (LP; ≥7 parity). Blood samples were collected 3 weeks and 1 week pre‐kidding followed by 1, 2, 4, and 8 weeks post‐kidding for the estimation of NEFA, oxidant (malondialdehyde [MDA], antioxidant (superoxide dismutase [SOD], catalase [CAT], glutathione [GSH], glutathione peroxidase [GSH‐Px], and glutathione S‐transferase [GST]), and zinc and copper levels. Significant (p < 0.01) increase was observed in NEFA and MDA levels as the goats approached kidding and continued till 2 weeks post‐kidding in MP and LP and 1 week post‐kidding in EP goats. Significant decrease in SOD (p < 0.05), CAT (p < 0.05), GSH‐Px (p < 0.01), GSH (p < 0.01), and GST (p < 0.05) activities were observed as goats approached kidding and continued to decrease up to 2 weeks post‐kidding. Zinc and copper levels showed a significant decline from 3 weeks pre‐kidding to 2 weeks post‐kidding in MP and LP and 1 week post‐kidding in EP goats. A significant effect of parity was observed on MDA (p < 0.05), GSH (p < 0.05), and GSH‐Px (p < 0.05) activities only; however, parity × sampling time interaction was observed in all the parameters. Findings highlight a different metabolic, trace mineral (zinc and copper), and oxidative response around the periparturient period in Beetal goats, with the EP goats, responding first to increased metabolic and oxidative stress and also first to recover from oxidant/antioxidant imbalance.
Pharmacokinetics of isavuconazole in healthy cats after oral and intravenous administration
Authors: Woerde Dennis J. , Wittenburg Luke A. , Dear Jonathan D.
Published: May 2022

Background

Isavuconazole is a triazole antifungal drug that has shown good efficacy in human patients. Absorption and pharmacokinetics have not been evaluated in cats.

Objectives

To determine the pharmacokinetics of isavuconazole in cats given a single IV or PO dose.

Animals

Eight healthy, adult research cats.

Methods

Four cats received 100 mg capsules of isavuconazole PO. Four cats received 5 mg/kg isavuconazole solution IV. Serum was collected at predetermined intervals for analysis using ultra‐high performance liquid chromatography‐tandem mass spectrometry. Data were analyzed using a 2‐compartment uniform weighting pharmacokinetic analysis with lag time for PO administration and a 2 compartment, 1/y2 weighting for IV administration. Predicted 24 and 48‐hour dosing intervals of 100 mg isavuconazole administered PO were modeled and in vitro plasma protein binding was assessed.

Results

Both PO and IV drug administration resulted in high serum concentrations. Intravenous and PO formulations of isavuconazole appear to be able to be used interchangeably. Peak serum isavuconazole concentrations occurred 5 ± 3.8 hours after PO administration with an elimination rate half‐life of 66.2 ± 55.3 hours. Intersubject variability was apparent in both the PO and IV groups. Two cats vomited 6 to 8 hours after PO administration. No adverse effects were observed in the IV group. Oral bioavailability was estimated to be approximately 88%. Serum protein binding was calculated to be approximately 99.0% ± 0.03%.

Conclusions and Clinical Importance

Isavuconazole might prove to be useful in cats with fungal disease given its favorable pharmacokinetics. Additional studies on safety, efficacy, and tolerability of long‐term isavuconazole use are needed.
Characterization of a small tRNA‐binding protein that interacts with the archaeal proteasome complex
Authors: Hogrel Gaëlle , Marino‐Puertas Laura , Laurent Sébastien , Ibrahim Ziad , Covès Jacques , Girard Eric , Gabel Frank , Fenel Daphna , Daugeron Marie‐Claire , Clouet‐d'Orval Béatrice , Basta Tamara , Flament Didier , Franzetti Bruno
Published: May 2022

The proteasome system allows the elimination of functional or structurally impaired proteins. This includes the degradation of nascent peptides. In Archaea, how the proteasome complex interacts with the translational machinery remains to be described. Here, we characterized a small orphan protein, Q9UZY3 (UniProt ID), conserved in Thermococcales. The protein was identified in native pull‐down experiments using the proteasome regulatory complex (proteasome‐activating nucleotidase [PAN]) as bait. X‐ray crystallography and small‐angle X‐ray scattering experiments revealed that the protein is monomeric and adopts a β‐barrel core structure with an oligonucleotide/oligosaccharide‐binding (OB)‐fold, typically found in translation elongation factors. Mobility shift experiment showed that Q9UZY3 displays transfer ribonucleic acid (tRNA)‐binding properties. Pull‐downs, co‐immunoprecipitation and isothermal titration calorimetry (ITC) studies revealed that Q9UZY3 interacts in vitro with PAN. Native pull‐downs and proteomic analysis using different versions of Q9UZY3 showed that the protein interacts with the assembled PAN–20S proteasome machinery in Pyrococcus abyssi (Pa) cellular extracts. The protein was therefore named Pbp11, for Proteasome‐Binding Protein of 11 kDa. Interestingly, the interaction network of Pbp11 also includes ribosomal proteins, tRNA‐processing enzymes and exosome subunits dependent on Pbp11's N‐terminal domain that was found to be essential for tRNA binding. Together these data suggest that Pbp11 participates in an interface between the proteasome and the translational machinery.
No Evidence of Induced Skin Cancer or Other Skin Abnormalities after Long‐Term (66 week) Chronic Exposure to 222‐nm Far‐UVC Radiation
Authors: Welch David , Kleiman Norman J. , Arden Peter C. , Kuryla Christine L. , Buonanno Manuela , Ponnaiya Brian , Wu Xuefeng , Brenner David J.
Published: May 2022

Far‐UVC radiation, typically defined as 200–235 nm, has similar or greater anti‐microbial efficacy compared with conventional 254‐nm germicidal radiation. In addition, biophysical considerations of the interaction of far‐UVC with tissue, as well as multiple short‐term safety studies in animal models and humans, suggest that far‐UVC exposure may be safe for skin and eye tissue. Nevertheless, the potential for skin cancer after chronic long‐term exposure to far‐UVC has not been studied. Here, we assessed far‐UVC induced carcinogenic skin changes and other pathological dermal abnormalities in 96 SKH‐1 hairless mice of both sexes that were exposed to average daily dorsal skin doses of 400, 130 or 55 mJ cm−2 of 222 nm far‐UVC radiation for 66 weeks, 5 days per week, 8 h per day, as well as similarly‐treated unexposed controls. No evidence for increased skin cancer, abnormal skin growths or incidental skin pathology findings was observed in the far‐UVC‐exposed mice. In addition, there were no significant changes in morbidity or mortality. The findings from this study support the long‐term safety of long‐term chronic exposure to far‐UVC radiation, and therefore its potential suitability as a practical anti‐microbial approach to reduce airborne viral and bacterial loads in occupied indoor settings.