bluuebunny/crossref_metadata_2025 huggingface dataset:
Outraged by Compensation: Implications for Public Pension Performance
Authors: Dyck Alexander , Manoel Paulo , Morse Adair
Published: September 2021

Public pension boards fear inciting stakeholder outrage if they compensate internal investment managers with market-level salaries. We derive theoretical implications in an agency-portfolio-choice model motivated by inequality aversion. In a global sample, relaxing the effect of outrage on contracting leads to an average annual incremental value-added of $49 million generated through 11 bps in higher excess returns from risky assets, at the cost of $302,429 in additional compensation. Governance reforms that address outrage by reducing political appointees or requiring independent skills-based boards can increase the annual value-added. These findings are orthogonal to costly political distortions from underfunding and pay-to-play schemes.

Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Digital Refugee Lawyering: Risk, Legal Knowledge, and Accountability
Authors: Sandvik Kristin Bergtora
Published: September 2021

This article explores how the digital transformation of humanitarianism, and the refugee regime reshapes refugee lawyering. Much refugee lawyering is based on a traditional understanding of legal protection – and a focus on legal aid, law reform advocacy, and specific protection procedures (such as refugee status determination). Refugee lawyering must now grapple with the challenges offered by the digital transformation of international protection. This entails identifying emergent protection issues and how they relate to the law and legal claims. To that end, the article puts forward suggestions regarding the risks of the digital transformation as it pertains to the humanitarian space, the refugee management infrastructure, and refugee lawyering. The article also considers its implications for legal knowledge and the possibility that law may be “displaced” by technology. The article concludes by discussing what it means for refugee lawyering and for being accountable to the norms and values of rule of law standards, international protection, and to individual clients.
Default and executive networks’ roles in diverse adolescents’ emotionally engaged construals of complex social issues
Authors: Gotlieb Rebecca , Yang Xiao-Fei , Immordino-Yang Mary Helen
Published: September 2021

Across adolescence, individuals enrich their concrete, empathic, context-specific interpretations of social-world happenings with abstract, situation-transcending, system-level considerations—invoking values, bigger implications and broader emotional perspectives. To investigate neural mechanisms involved in abstract construals vs concrete construals and the effects of emotional engagement on these mechanisms, 65 mid-adolescents aged 14–18 years reacted to compelling video mini-documentaries during private, open-ended interviews and again during functional magnetic resonance imaging. Following calls to diversify samples, participants were ethnically diverse low-socioeconomic status (SES) urban adolescents performing well in school. Participants spontaneously produced both concrete and abstract construals in the interview, and tendencies to produce each varied independently. As hypothesized, participants who made more abstract construals showed a greater subsequent default mode network (DMN) activity; those who made more concrete construals showed greater executive control network (ECN) activity. Findings were independent of IQ, SES, age and gender. Within individuals, DMN activation, especially when individuals were reporting strong emotional engagement, and ECN deactivation together predicted an abstract construal to a trial. Additionally, brief ECN activation early in the trial strengthened the DMN–abstraction relationship. Findings suggest a neural mechanism for abstract social thought in adolescence. They also link adolescents’ natural construals of social situations to distinct networks’ activity and suggest separable sociocognitive traits that may vary across youths.
Motherhood and theory of mind: increased activation in the posterior cingulate cortex and insulae
Authors: Plank Irene Sophia , Hindi Attar Catherine , Kunas Stefanie Lydia , Dziobek Isabel , Bermpohl Felix
Published: September 2021

Despite growing evidence on effects of parenthood on social understanding, little is known about the influence of parenthood on theory of mind (ToM), the capacity to infer mental and affective states of others. It is also unclear whether any possible effects of parenthood on ToM would generalise to inferring states of adults or are specific to children. We investigated neural activation in mothers and women without children while they predicted action intentions from child and adult faces. Region-of-interest analyses showed stronger activation in mothers in the bilateral posterior cingulate cortex, precuneus (ToM-related areas) and insulae (emotion-related areas). Whole-brain analyses revealed that mothers compared to non-mothers more strongly activated areas including the left angular gyrus and the ventral prefrontal cortex but less strongly activated the right supramarginal gyrus and the dorsal prefrontal cortex. These differences were not specific to child stimuli but occurred in response to both adult and child stimuli and might indicate that mothers and non-mothers employ different strategies to infer action intentions from affective faces. Whether these general differences in affective ToM between mothers and non-mothers are due to biological or experience-related changes should be subject of further investigation.
Legal Cynicism and System Avoidance: Roma Marginality in Central and Eastern Europe
Authors: Sendroiu Ioana , Levi Ron , Hagan John
Published: September 2021

The Roma are Europe’s largest minority group and face extensive discrimination across the continent. Drawing on a survey of Roma and non-Roma households in twelve Central and Eastern European countries, we analyze the extent to which legal cynicism, as a cognitive frame, is connected to the avoidance of helpful social institutions. We thus expand existing research on legal cynicism to focus on individuals’ contacts with potentially helpful institutions that can buffer inequality. We conclude that the interplay of legal cynicism and system avoidance, which have provided deep insights into the reproduction of structural disadvantage in American cities, also provide us with international insights into the causes of inequality and minority disadvantage across hundreds of towns in Central and Eastern Europe. In this way, legal cynicism and system avoidance work to reproduce durable inequality.
Engaging with mathematics during Covid-19: students aged 16+ responding to a mathematics ‘Box Set’ of enrichment video materials
Authors: Lyakhova Sofya , Oakes Dominic , Joubert Marie
Published: September 2021

This paper reports on a mathematics outreach programme, ‘Bridging KS5 to University’, which offered video materials to students aged 16+ during the school closures in spring/summer 2020 in Wales. The 13 videos, provided by the Further Mathematics Support Programme in Wales, ranging from 20 to 50 min long, included activities and exercises addressing mathematical topics outside the school curriculum, and engaging with them can thus be seen as enrichment activities. The study is primarily concerned with the ways in which students engaged with the materials and what motivated them to begin watching them and then continue to watch them. Interviews with students found that the students’ behavioural and emotional engagement with the materials was much as might have been expected, but that their cognitive engagement was perhaps higher than expected. Considerations for developing further similar enrichment programmes for use in times of crisis, including equity issues, as well as for up-cycling the bridging programme for ‘normal’ times are also discussed.
Levelling the playing field in assessment: an analysis of attainment gaps for widening participation, black and minority ethnic mathematics undergraduates before and after the COVID-19 lockdown
Authors: Shaw L M , Tranter M R
Published: September 2021

The 2019/20 Level 4 mathematics cohort at the Nottingham Trent University sat a full set of mid-year assessments in January 2020 under completely normal circumstances. However, the Covid-19 lockdown meant that their end of year assessments, along with all of their teaching and learning from March 2020 onwards, moved fully online. This has given us a unique opportunity to understand how the same cohort perform in contrasting situations. In this study we consider the issue of attainment gaps and find that the attainment gap closed in this cohort for black and minority ethnic students but that students from a lower socio-economic background may have been put at a disadvantage by the move to online teaching, learning and assessment. We use a linear mixed effect models approach to present statistical evidence to support these two claims as well as investigating the specific aspects of the move online, which may have caused these results.
Iron Status of the Moderate and Late Preterm Infant: A Prospective Cohort Study
Authors: M.K Alok Kumar , Pournami Femitha , Prabhakar Jyothi , Nandakumar Anand , Jain Naveen
Published: September 2021

Guidelines on micronutrient supplementation in moderate to late preterm infants (MLP) are mostly extrapolated from those for smaller preterms, largely due to lack of systematic studies on physiological status in this special group of infants. Actual practices vary widely. We prospectively studied iron status by measurement of serum ferritin (SF) and haematological indices at 4 months corrected age in infants born between 32 and 36 weeks gestation (MLP), after they received 2 mg/kg/day oral iron from 6 weeks of postnatal age. Proportion of MLP having normal iron status (iron replete), i.e., neither iron deficiency (ID) nor iron excess was measured. ID anaemia, growth and development, risk factors for ID were also analysed. Of the 82 infants studied, 78% babies were late preterm. Seventy-four (90.3%) were iron replete (no deficiency or excess) at 4 months. High variability in SF levels (minimum of 9.8 to maximum of 252.2 μg/l) with median (IQR) of 57.45 μg/l (37.02–98.85) was noted in the entire cohort; and also within those who were iron deficient with median (IQR) of 17.50 μg/l (11.70–18.90). There was no difference in haematological indices of ID infants when compared to those with normal iron status. Inspite of oral iron supplementation with reasonable compliance, 8.5% MLP were iron deficient at 4 months corrected age. The high variability noted in SF levels could justify the need for monitoring iron status in this group of preterm infants. This could quintessentially aid individualization of iron supplementation advice.
Pathotype Identification and Virulence Variation in Cochliobolus sativus in China
Authors: Chen Lin , Yao Quanjie , Wang Fengtao , Pang Yunxing , Lang Xiaowei , Sun Dan , Zhou Jun , Feng Jing , Lin Ruiming
Published: September 2021

Spot blotch caused by Cochliobolus sativus has become an important disease in the wheat-growing regions in China that has resulted from changes in the regional climate, agricultural cultivation patterns, and the susceptible wheat varieties that are widely grown. Little information is available about virulence variability and pathogenic specialization of the C. sativus isolates from major wheat-growing regions in China. Here, 12 representative wheat varieties and foundation breeding stocks were selected to characterize the pathotypes of C. sativus isolates from infected wheat plants. Based on the infection phenotypes in the 12 differential genotypes at the seedling stage, 70 Chinese pathotypes were identified from 110 isolates and clustered into three virulence groups. The high virulence isolates were collected from wheat leaves, crowns, and roots, with most (10 of 14) from the Henan province in the Huang-Huai plain. No relationship was evident between virulence variability of C. sativus isolates and their geographic origins or types of diseased wheat tissues. C. sativus showed a significant pathogenic specialization in hosts of wheat and barley. Most of the wheat isolates (50 of 65) were avirulent to all the differential barley genotypes, and a few were virulent only to highly susceptible barley genotypes. These results indicated that C. sativus isolates from the wheat-growing regions in China varied considerably for their virulence in wheat varieties, and showed significant pathogenic specialization to the wheat and barley hosts.
Endophytic Fungi as a Promising Biocontrol Agent to Protect Wheat from Fusarium graminearum Head Blight
Authors: Noel Zachary A. , Roze Ludmilla V. , Breunig Mikaela , Trail Frances
Published: September 2021

The search for beneficial endophytes that can be part of a constructed microbial community has increased in recent years. We characterized three endophytic fungi previously isolated from wheat for their in vitro and in planta antagonism toward the Fusarium head blight pathogen, Fusarium graminearum. The endophytes were phylogenetically characterized and shown to be Alternaria destruens, Fusarium commune, and Fusarium oxysporum. Individual fungal endophytes significantly increased seed weight and lowered the accumulation of the mycotoxin deoxynivalenol compared with F. graminearum-infected wheat heads without endophyte pretreatment. Investigation into the mechanism of competition in vitro showed that endophytes competitively excluded F. graminearum by preemptive colonization and possible inhibition over a distance. Investigations on the use of these endophytes in the field are in progress. Identification of these three endophytes highlights a common quandary in searching for beneficial microbes to use in agriculture: species definitions often do not separate individual isolates’ lifestyles. A greater understanding of the risks in using intraspecies variants for biocontrol is needed and should be examined in the context of the ecology of the individuals being investigated.
Basics of Intra-arterial Y-90 Microsphere Therapy for Liver Tumors—Part II
Authors: Fani Bozkurt Murat
Published: September 2021

Yttrium-90 (Y-90)-loaded glass and resin microspheres are used for intra-arterial Y-90 microsphere therapy of the primary and metastatic liver tumors. Therapeutic dose assessment and dose administration vary according to the microsphere type used for this therapy.
Nucleobindin-2 (NUCB2) gene transcription activity and nesfatin-1 levels in correlation with anthropometric and biochemical parameters in type 2 diabetes mellitus patient groups in Vietnam
Authors: Nguyen Duc Minh , Nguyen Minh Thi , Van Can Mao , Thu Trinh Huong Ngoc , Ngo Linh Bao , Bich Vo Thuy Thi , Nghiem Minh Ngoc
Published: September 2021

Introduction

Nucleobindin-2 (NUCB2) was identified as a DNA/Ca2+ binding protein with multiple functions in humans. Prohormone convertase-mediated NUCB2 processing produced nesfatin-1 - a biologically active. Nesfatin-1, an 82-amino acid peptide, was extracted from the N-terminus of nucleobindin-2. Recently, it was described as an anorexia peptide related to weight loss, malnutrition, and appetite regulation in type 2 diabetes mellitus patients.

Research design and methods

In this study, we collected samples and divided them into groups of patients with long-term type 2 diabetes and newly diagnosed type 2 diabetes group. Serum nesfatin-1 level and mRNA NUCB2 gene expression level of the groups were analyzed and compared with those of the healthy group.Biometric parameters and biochemical indices were also analyzed to determine the correlation with nesfatin-1 level.

Results

Levels of nesfatin-1 were found to be higher in the newly diagnosed group than in the other groups. Similar results were also reported in the analysis of mRNA NUCB2 gene expression by Realtime-PCR. Meanwhile, no significant difference was found in both analyzes of nesfatin-1 levels and NUCB2 mRNA expression in subjects with long-term type 2 diabetes compared with the control group. This result can be explained by the effects of long-term treatment. In the correlation of anthropometric parameters and biochemical indices, nesfatin-1 exhibited a significant correlation with BMI (r=0.569), HbA1c (r=-0.468), HDL-C (r=0.731), LDL-C (r=-0.482), Creatinine serum (r=0.525), and Creatinine urine (r=0.592), with p<0.001, in regression analysis.

Conclusions

These results indicate that the serum nesfatin-1 level and the NUCB2 mRNA gene expression level may be associated with newly diagnosed type 2 diabetes in Vietnamese patients. However, more specific studies with larger sample sizes were still needed in future studies.
Inequalities in COVID-19 inequalities research: who had the capacity to respond?
Authors: Benach Joan , Padilla Alvaro , Cash-Gibson Lucinda , Rojas-Gualdrón Diego F. , Fernández-Gracia Juan , Eguíluz Víctor M. ,   the COVID-SHINE group
Published: September 2021

The COVID-19 pandemic has been testing countries’ capacities and scientific preparedness to actively respond, and collaborate on a common cause. It has also heightened awareness of the urgent need to empirically describe and analyse health inequalities, to be able to act effectively. What is known about the rapidly emerging COVID-19 inequalities research field? We analysed the volume of COVID-19 inequalities scientific production (2020-2021), its distribution by country income groups and world regions, and inter-country collaborations, to provide a first snapshot. COVID-19 inequalities research has been highly collaborative, however inequalities exist within this field, and new dynamics have emerged in comparison to the global health inequalities research field. To ensure preparedness for future crises, investment in health inequalities research capacities must be a priority for all.
Mutational Signatures as Sensors of Environmental Exposures: Role of Smoking in COVID-19 Vulnerabilities
Authors: Kim Yoo-Ah , Hodzic Ermin , Saslafsky Ariella , Wojtowicz Damian , Amgalan Bayarbaatar , Przytycka Teresa M.
Published: September 2021

Background

Environmental exposures such as smoking are widely recognized risk factors in the emergence of lung diseases including lung cancer and acute respiratory distress syndrome (ARDS). However, the strength of environmental exposures is difficult to measure, making it challenging to understand their impacts. On the other hand, some COVID-19 patients develop ARDS in an unfavorable disease progression and smoking has been suggested as a potential risk factor among others. Yet initial studies on COVID-19 cases reported contradictory results on the effects of smoking on the disease – some suggest that smoking might have a protective effect against it while other studies report an increased risk. A better understanding of how the exposure to smoking and other environmental factors affect biological processes relevant to SARS-CoV-2 infection and unfavorable disease progression is needed.

Approach

In this study, we utilize mutational signatures associated with environmental factors as sensors of their exposure level. Many environmental factors including smoking are mutagenic and leave characteristic patterns of mutations, called mutational signatures, in affected genomes. We postulated that analyzing mutational signatures, combined with gene expression, can shed light on the impact of the mutagenic environmental factors to the biological processes. In particular, we utilized mutational signatures from lung adenocarcinoma (LUAD) data set collected in TCGA to investigate the role of environmental factors in COVID-19 vulnerabilities. Integrating mutational signatures with gene expression in normal tissues and using a pathway level analysis, we examined how the exposure to smoking and other mutagenic environmental factors affects the infectivity of the virus and disease progression.

Results

By delineating changes associated with smoking in pathway-level gene expression and cell type proportions, our study demonstrates that mutational signatures can be utilized to study the impact of exogenous mutagenic factors on them. Consistent with previous findings, our analysis showed that smoking mutational signature (SBS4) is associated with activation of cytokine-mediated signaling pathways, leading to inflammatory responses. Smoking related changes in cell composition were also observed, including the correlation of SBS4 with the expansion of goblet cells. On the other hand, increased basal cells and decreased ciliated cells in proportion were associated with the strength of a different mutational signature (SBS5), which is present abundantly but not exclusively in smokers. In addition, we found that smoking increases the expression levels of genes that are up-regulated in severe COVID-19 cases. Jointly, these results suggest an unfavorable impact of smoking on the disease progression and also provide novel findings on how smoking impacts biological processes in lung.
Functional and Highly Crosslinkable HIV-1 Envelope Glycoproteins Enriched in a Pretriggered Conformation
Authors: Nguyen Hanh T. , Qualizza Alessandra , Anang Saumya , Zhao Meiqing , Zou Shitao , Zhou Rong , Wang Qian , Zhang Shijian , Deshpande Ashlesha , Ding Haitao , Smith Amos B. , Kappes John C. , Sodroski Joseph G.
Published: September 2021

Binding to the receptor, CD4, drives the pretriggered, “closed” (State-1) conformation of the human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer into more “open” conformations (States 2 and 3). Broadly neutralizing antibodies, which are elicited inefficiently, mostly recognize the State-1 Env conformation, whereas the more commonly elicited poorly neutralizing antibodies recognize States 2/3. HIV-1 Env metastability has created challenges for defining the State-1 structure and developing immunogens mimicking this labile conformation. The availability of functional State-1 Envs that can be efficiently crosslinked at lysine and/or acidic amino acid residues might assist these endeavors. To that end, we modified HIV-1AD8Env, which exhibits an intermediate level of triggerability by CD4. We introduced lysine/acidic residues at positions that exhibit such polymorphisms in natural HIV-1 strains. Env changes that were tolerated with respect to gp120-gp41 processing, subunit association and virus entry were further combined. Two common polymorphisms, Q114E and Q567K, as well as a known variant, A582T, additively rendered pseudoviruses resistant to cold, soluble CD4 and a CD4-mimetic compound, phenotypes indicative of stabilization of the pretriggered State-1 Env conformation. Combining these changes resulted in two lysine-rich HIV-1AD8Env variants (E.2 and AE.2) with neutralization- and cold-resistant phenotypes comparable to those of natural, less triggerable Tier 2/3 HIV-1 isolates. Compared with these and the parental Envs, the E.2 and AE.2 Envs were cleaved more efficiently and exhibited stronger gp120-trimer association in detergent lysates. These highly crosslinkable Envs enriched in a pretriggered conformation should assist characterization of the structure and immunogenicity of this labile state.

IMPORTANCE

The development of an efficient vaccine is critical for combating HIV-1 infection worldwide. However, the instability of the pretriggered shape (State 1) of the viral envelope glycoprotein (Env) makes it difficult to raise neutralizing antibodies against HIV-1. Here, by introducing multiple changes in Env, we derived two HIV-1 Env variants that are enriched in State 1 and can be efficiently crosslinked to maintain this shape. These Env complexes are more stable in detergent, assisting their purification. Thus, our study provides a path to a better characterization of the native pretriggered Env, which should assist vaccine development.
Analysis of overdispersion in airborne transmission of Covid-19
Authors: Chaudhuri Swetaprovo , Kasibhatla Prasad , Mukherjee Arnab , Pan William , Morrison Glenn , Mishra Sharmistha , Murty Vijaya Kumar
Published: September 2021

Superspreading events and overdispersion are hallmarks of the Covid-19 pandemic. To gain insight into the nature and controlling factors of these superspreading events and heterogeneity in transmission, we conducted mechanistic modeling of SARS-CoV-2 transmission by infectious aerosols using real-world occupancy data from a large number of full-service restaurants in ten US metropolises. Including a large number of factors that influence disease transmission in these settings, we demonstrate the emergence of a stretched tail in the probability density function of secondary infection numbers indicating strong heterogeneity in individual infectivity. Derived analytical results further demonstrate that variability in viral loads and variability in occupancy, together, lead to overdispersion in the number of secondary infections arising from individual index cases. Our analysis, connecting mechanistic understanding of SARS-CoV-2 transmission by aerosols with observed large-scale epidemiological characteristics of Covid-19 outbreaks, adds an important dimension to the mounting body of evidence with regards to the determinants of airborne transmission of SARS-CoV-2 by aerosols in indoor settings.
Comparison of pretraining models and strategies for health-related social media text classification
Authors: Guo Yuting , Ge Yao , Yang Yuan-Chi , Al-Garadi Mohammed Ali , Sarker Abeed
Published: September 2021

Motivation

Pretrained contextual language models proposed in the recent past have been reported to achieve state-of-the-art performances in many natural language processing (NLP) tasks. There is a need to benchmark such models for targeted NLP tasks, and to explore effective pretraining strategies to improve machine learning performance.

Results

In this work, we addressed the task of health-related social media text classification. We benchmarked five models—RoBERTa, BERTweet, TwitterBERT, BioClinical_BERT, and BioBERT on 22 tasks. We attempted to boost performance for the best models by comparing distinct pretraining strategies—domain-adaptive pretraining (DAPT), source-adaptive pretraining (SAPT), and topic-specific pretraining (TSPT). RoBERTa and BERTweet performed comparably in most tasks, and better than others. For pretraining strategies, SAPT performed better or comparable to the off-the-shelf models, and significantly outperformed DAPT. SAPT+TSPT showed consistently high performance, with statistically significant improvement in one task. Our findings demonstrate that RoBERTa and BERTweet are excellent off-the-shelf models for health-related social media text classification, and extended pretraining using SAPT and TSPT can further improve performance.

Availability and implementation

Source code for our model and data preprocessing is available under the Github repository https://github.com/yguo0102/transformer_dapt_sapt_tapt. Datasets must be obtained from original sources, as described in supplementary material.

Supplementary information

Supplementary data are available at Bioinformatics online.
No Significant Difference in Viral Load Between Vaccinated and Unvaccinated, Asymptomatic and Symptomatic Groups When Infected with SARS-CoV-2 Delta Variant
Authors: Acharya Charlotte B. , Schrom John , Mitchell Anthea M. , Coil David A. , Marquez Carina , Rojas Susana , Wang Chung Yu , Liu Jamin , Pilarowski Genay , Solis Leslie , Georgian Elizabeth , Petersen Maya , DeRisi Joseph , Michelmore Richard , Havlir Diane
Published: September 2021

We found no significant difference in cycle threshold values between vaccinated and unvaccinated, asymptomatic and symptomatic groups infected with SARS-CoV-2 Delta. Given the substantial proportion of asymptomatic vaccine breakthrough cases with high viral levels, interventions, including masking and testing, should be considered for all in settings with elevated COVID-19 transmission.
Reference genomes of 545 silkworms enable high-throughput exploring genotype-phenotype relationships
Authors: Tong Xiaoling , Han Min-Jin , Lu Kunpeng , Tai Shuaishuai , Liang Shubo , Liu Yucheng , Hu Hai , Shen Jianghong , Long Anxing , Zhan Chengyu , Ding Xin , Gao Qiang , Zhang Bili , Tan Duan , Yuan Yajie , Guo Nangkuo , Li Yanhong , Wu Zhangyan , Liu Lulu , Li Chunlin , Lu Yaru , Gai Tingting , Zhang Yahui , Yang Renkui , Qian Heying , Liu Yanqun , Luo Jiangwen , Zheng Lu , Lou Jinghou , Peng Yunwu , Zuo Weidong , Song Jiangbo , He Songzhen , Wu Songyuan , Zou Yunlong , Zhou Lei , Zhou Linli , Cheng Lan , Tang Yuxia , Cheng Guotao , Yuan Lianwei , He Weiming , Xu Jiabao , Fu Tao , Xiao Yang , Lei Ting , Xu Anying , Yin Ye , Wang Jian , Monteiro Antónia , Westhof Eric , Lu Cheng , Tian Zhixi , Wang Wen , Xiang Zhonghuai , Dai Fangyin
Published: September 2021

The silkworm Bombyx mori is a domestic insect for silk production and a lepidopteran model. The currently available genomes limit a full understanding of its genetic and phenotypic diversity. Here we assembled long-read genomes of 545 domestic and wild silkworms and constructed a high-resolution pan-genome dataset. We found that the silkworm population harbors extremely variable genomes containing 7,308 new gene families, 4,260 (22%) core gene families, and 3,432,266 non-redundant SVs. We deciphered a series of causal genes and variants associated with domestication, breeding, and ecological adaptation traits, and experimentally validated two of those genes using CRISPR-Cas9 or RNA interference. This unprecedented large-scale genomic resource allows for high-throughput screening of interesting traits for functional genomic research and breeding improvement of silkworms and may serve as a guideline for traits decoding in other species.
Neuronal glucose metabolism sets cholinergic tone and controls thermo-regulated signaling at the neuromuscular junction
Authors: Tang Yan , Zong Haihong , Kwon Hyokjoon , Qiu Yunping , Pessin Jacob B. , Wu Licheng , Buddo Katherine A. , Boykov Ilya , Schmidt Cameron A. , Lin Chien-Te , Darrell Neufer P. , Schwartz Gary J. , Kurland Irwin J. , Pessin Jeffrey E.
Published: September 2021

Cholinergic and sympathetic counter-regulatory networks control numerous physiologic functions including learning/memory/cognition, stress responsiveness, blood pressure, heart rate and energy balance. As neurons primarily utilize glucose as their primary metabolic energy source, we generated mice with increased glycolysis in cholinergic neurons by specific deletion of the fructose-2,6-phosphatase protein TIGAR. Steady-state and stable isotope flux analyses demonstrated increased rates of glycolysis, acetyl-CoA production, acetylcholine levels and density of neuromuscular synaptic junction clusters with enhanced acetylcholine release. The increase in cholinergic signaling reduced blood pressure and heart rate with a remarkable resistance to cold-induced hypothermia. These data directly demonstrate that increased cholinergic signaling through the modulation of glycolysis has several metabolic benefits particularly to increase energy expenditure and heat production upon cold exposure.

Highlights

Deficiency of a negative regulator of glycolysis (TIGAR) in cholinergic neurons increases the biosynthesis and content of the neurotransmitter acetylcholine.

Increased cholinergic tone reduces blood pressure and heart rate while enhancing signaling at neuromuscular junction.

Upregulation of neuromuscular junction activation provides protection against the paralytic curare and cold-induced hypothermia.

Modulation of cholinergic neuron glycolysis may provide a novel therapeutic approach for treatment of diseases stemming from reduced acetylcholine signaling such as myasthenia gravis and sarcopenic pre-synaptic dysfunction.
An anti-inflammatory activation sequence governs macrophage transcriptional dynamics during tissue injury
Authors: Denans Nicolas , Tran Nhung T. T. , Swall Madeleine E. , Diaz Daniel C. , Blanck Jillian , Piotrowski Tatjana
Published: September 2021

Macrophages are essential for tissue repair and regeneration. Yet, the molecular programs, as well as the timing of their activation during and after tissue injury are poorly defined. Using a high spatio-temporal resolution single cell analysis of macrophages coupled with live imaging after sensory hair cell death in zebrafish, we find that the same population of macrophages transitions through a sequence of three major anti-inflammatory activation states. Macrophages first show a signature of glucocorticoid activation, then IL10 signaling and finally the induction of oxidative phosphorylation by IL4/Polyamine signaling. Importantly, loss-of-function of glucocorticoid and IL10 signaling shows that each step of the sequence is independently activated. Our results provide the first evidence that macrophages, in addition to a switch from M1 to M2, sequentially and independently transition though three anti-inflammatory pathways in vivo during tissue injury in a regenerating organ.

One-Sentence Summary

We show that macrophages are sequentially activated by three different anti-inflammatory pathways during tissue injury.
The spread of the first introns in proto-eukaryotic paralogs
Authors: Vosseberg Julian , Schinkel Michelle , Gremmen Sjoerd , Snel Berend
Published: September 2021

Spliceosomal introns are a unique feature of eukaryotic genes. Previous studies have established that many introns were present in the protein-coding genes of the last eukaryotic common ancestor (LECA). Intron positions shared between genes that duplicated before LECA could in principle provide insight into the emergence of the first introns. In this study we use ancestral intron position reconstructions in two large sets of duplicated families to systematically identify these ancient paralogous intron positions. We found that 20-35% of introns inferred to have been present in LECA were shared between paralogs. These shared introns, which likely preceded ancient duplications, were widespread across different functions, with the notable exception of nuclear transport. Since we observed a clear signal of pervasive intron loss prior to LECA, it is likely that substantially more introns were shared at the time of duplication than we can detect in LECA. The large extent of shared introns indicates an early origin of introns during eukaryogenesis and suggests an early origin of a nuclear structure, before most of the other complex eukaryotic features were established.
Chromosome-scale genome assembly of the brown anole (Anolis sagrei), a model species for evolution and ecology
Authors: Geneva Anthony J. , Park Sungdae , Bock Dan , de Mello Pietro , Sarigol Fatih , Tollis Marc , Donihue Colin , Reynolds R. Graham , Feiner Nathalie , Rasys Ashley M. , Lauderdale James D. , Minchey Sergio G. , Alcala Aaron J. , Infante Carlos R. , Kolbe Jason J. , Schluter Dolph , Menke Douglas B. , Losos Jonathan B.
Published: September 2021

Rapid technological improvements are democratizing access to high quality, chromosome-scale genome assemblies. No longer the domain of only the most highly studied model organisms, now non-traditional and emerging model species can be genome-enabled using a combination of sequencing technologies and assembly software. Consequently, old ideas built on sparse sampling across the tree of life have recently been amended in the face of genomic data drawn from a growing number of high-quality reference genomes. Arguably the most valuable are those long-studied species for which much is already known about their biology; what many term emerging model species. Here, we report a new, highly complete chromosome-scale genome assembly for the brown anole, Anolis sagrei – a lizard species widely studied across a variety of disciplines and for which a high-quality reference genome was long overdue.
Bcr4 is a Chaperone for the Inner Rod Protein in the Bordetella Type III Secretion System
Authors: Goto Masataka , Abe Akio , Hanawa Tomoko , Suzuki Masato , Kuwae Asaomi
Published: September 2021

Bordetella bronchiseptica injects virulence proteins called effectors into host cells via a type III secretion system (T3SS) conserved among many Gram-negative bacteria. Small proteins called chaperones are required for stabilizing some T3SS components or localizing them to the T3SS machinery. In a previous study, we identified a chaperone-like protein named Bcr4 that regulates T3SS activity in B. bronchiseptica. Bcr4 does not show strong sequence similarity to well-studied T3SS proteins of other bacteria, and its function remains to be elucidated. Here, we investigated the mechanism by which Bcr4 controls T3SS activity. A pull-down assay revealed that Bcr4 interacts with BscI, based on its homology to other bacterial proteins, to be an inner rod protein of the T3SS machinery. An additional pull-down assay using truncated Bcr4 derivatives and secretion profiles of B. bronchiseptica producing truncated Bcr4 derivatives showed that the Bcr4 C-terminal region is necessary for the interaction with BscI and activation of the T3SS. Moreover, the deletion of BscI abolished the secretion of type III secreted proteins from B. bronchiseptica and the translocation of a cytotoxic effector into cultured mammalian cells. Finally, we showed that BscI is unstable in the absence of Bcr4. These results suggest that Bcr4 supports the construction of the T3SS machinery by stabilizing BscI. This is the first demonstration of a chaperone for the T3SS inner rod protein among the virulence bacteria possessing the T3SS.

Importance

The type III secretion system (T3SS) is a needle-like complex that projects outward from bacterial cells. Bordetella bronchiseptica uses the T3SS to inject virulence proteins into host cells. Our previous study reported that a protein named Bcr4 is essential for the secretion of virulence proteins from B. bronchiseptica bacterial cells and delivery through the T3SS. Because other bacteria lack a Bcr4 homologue, the function of Bcr4 has not been elucidated. In this study, we discovered that Bcr4 interacts with BscI, a component of the T3SS machinery. We showed that a B. bronchiseptica BscI-deficient strain was unable to secrete type III secreted proteins. Furthermore, in a B. bronchiseptica strain that overproduces T3SS component proteins, Bcr4 is required to maintain BscI in bacterial cells. These results suggest that Bcr4 stabilizes BscI to allow construction of the T3SS in B. bronchiseptica.
Spontaneous Clearance of Vertically Acquired Hepatitis C Infection: Implications for Testing and Treatment
Authors: Ades A E , Gordon Fabiana , Scott Karen , Collins Jeannie , Thorne Claire , Pembrey Lucy , Chappell Elizabeth , Mariné-Barjoan Eugènia , Butler Karina , Indolfi Giuseppe , Gibb Diana M , Judd Ali
Published: September 2021

Background

Current guidelines recommend that infants born to women with hepatitis C (HCV) viremia are screened for HCV antibody at age 18 months, and if positive, referred for RNA testing at 3 years to confirm chronic infection. This policy is based in part on analyses suggesting 25%-40% of vertically acquired HCV infections clear spontaneously within 4-5 years.

Methods

Data on 179 infants with RNA and/or anti-HCV evidence of vertically acquired viraemia (single PCR+) or confirmed infection (2 PCR+ or anti-HCV beyond 18 months) in three prospective European cohorts were investigated. Ages at clearance of viremia and confirmed infection were estimated taking account of interval censoring and delayed entry. We also investigated clearance in infants in whom RNA was not detectable until after 6 weeks.

Results

Clearance rates decline rapidly over the first 6 months. An estimated 90.6% (95%CrI: 83.5-95.9) of viremia cleared by 5 years, most within 3 months, and 65.9% (50.1-81.6) of confirmed infection cleared by 5 years, at a median 12.4 (7.1-18.9) months. If treatment began at age 6 months, 18 months or 3 years, at least 59.0% (42.0-76.9), 39.7 (17.9-65.9), and 20.9 (4.6-44.8) of those treated would clear without treatment. In seven (6.6%) confirmed infections, RNA was not detectable until after 6 weeks, and in 2 (1.9%) not until after 6 months. However, all such cases subsequently cleared.

Conclusions

Most viraemia clears within 3 months, and most confirmed infection by 3 years. Delaying treatment avoids but does not eliminate over-treatment and should be balanced against loss to follow-up.

Key points

Based on a re-analysis of the largest purely prospective dataset assembled so far, 66% (50-82) of confirmed vertically acquired HCV clears spontaneously by age 5 years, rather than the 25-40% assumed in guidelines.
Intragenic proviral elements support transcription of defective HIV-1 proviruses
Authors: Kuniholm Jeffrey , Armstrong Elise , Bernabe Brandy , Coote Carolyn , Berenson Anna , Drinan Samantha D. , Olson Alex , He Xianbao , Lin Nina , Fuxman Bass Juan I. , Henderson Andrew J.
Published: September 2021

HIV-establishes a persistent proviral reservoir by integrating into the genome of infected host cells. Current antiretroviral treatments do not target this persistent population of proviruses which include latently infected cells that upon treatment interruption can be reactivated to contribute to HIV-1 rebound. Deep sequencing of persistent HIV proviruses has revealed that greater than 90% of integrated HIV genomes are defective and unable to produce infectious virions. We hypothesized that intragenic elements in the HIV genome support transcription of aberrant HIV-1 RNAs from defective proviruses that lack long terminal repeats (LTRs). Using an intact provirus detection assay, we observed that resting CD4+ T cells and monocyte-derived macrophages (MDMs) are biased towards generating defective HIV-1 proviruses. Multiplex reverse transcription digital drop PCR identified Env and Nef transcripts which lacked 5’ untranslated regions (UTR) in acutely infected CD4+ T cells and MDMs indicating transcripts are generated that do not utilize the promoter within the LTR. 5’UTR-deficient Env transcripts were also identified in a cohort of people living with HIV (PLWH) on ART, suggesting that these aberrant RNAs are produced in vivo. Using 5’ rapid amplification of cDNA ends (RACE), we mapped the start site of these transcripts within the Env gene. This region bound several cellular transcription factors and functioned as a transcriptional regulatory element that could support transcription and translation of downstream HIV-1 RNAs. These studies provide mechanistic insights into how defective HIV-1 proviruses are persistently expressed to potentially drive inflammation in PLWH.

Author Summary

People living with HIV establish a persistent reservoir which includes latently infected cells that fuel viral rebound upon treatment interruption. However, the majority of HIV-1 genomes in these persistently infected cells are defective. Whether these defective HIV genomes are expressed and whether they contribute to HIV associated diseases including accelerated aging, neurodegenerative symptoms, and cardiovascular diseases are still outstanding questions. In this paper, we demonstrate that acute infection of macrophages and resting T cells is biased towards generating defective viruses which are expressed by DNA regulatory elements in the HIV genome. These studies describe an alternative mechanism for chronic expression of HIV genomes.
Enhancement of Chikungunya virus genome replication in mammalian cells at sub-physiological temperatures
Authors: Guo Jinchao , Harris Mark
Published: September 2021

Chikungunya virus (CHIKV) is an Alphavirus transmitted by Aedes mosquitoes, causing fever, rash and arthralgia. The function of the CHIKV non-structural protein 3 (nsP3) remains enigmatic. Building on previous studies (Gao et al, 2019), we generated a panel of mutants in a conserved and surface-exposed cluster in the nsP3 alphavirus unique domain (AUD) and tested their replication phenotype using a sub-genomic replicon (SGR) in mammalian and mosquito cells. Three mutants that replicated poorly in mammalian cells showed no defect in mosquito cells. These mutants were temperature-sensitive, rather than species-specific, as they exhibited no replication defect in mammalian cells at sub-physiological temperature (28°C). Similar effects were observed in the context of infectious CHIKV and the closely related O’Nyong Nyong virus. This analysis also revealed that the wildtype SGR replicated more efficiently at 28°C compared to 37°C. This was not due to either impaired interferon responses as the enhancement was observed in Vero cells, or to a defect in eIF2α phosphorylation as treatment with ISRIB, an inhibitor of global translation attenuation, did not compensate for replication defects at 37°C. The phenotype did correlate with enhanced recruitment of stress granule proteins (G3BP, eIF4G and TIA-1) into cytoplasmic sites of genome replication at 28°C. As cells in the periphery will be at sub-physiological temperatures, and will be the first cells infected in the mammalian host following a mosquito bite, we propose that alphaviruses such as CHIKV have evolved mechanisms to both promote viral genome replication and concomitantly limit antiviral responses in these cells.

Importance

Chikungunya virus (CHIKV) is a re-emerging arbovirus, transmitted by Aedes mosquitos and posing epidemic threats. Arboviruses must be able to replicate efficiently in both the mosquito vector and the mammalian host, at different temperatures. Following a mosquito bite the first cells infected will be in the skin and at sub-physiological temperature (less than 37°C). We show that mutants in one of the CHIKV proteins (nsP3) could not replicate at 37°C, but replicated efficiently in mammalian cells at 28°C. We also showed that wildtype CHIKV replicated more efficiently at 28°C in comparison to 37°C in mammalian cells. We investigated the mechanism behind this observation and showed that at sub-physiological temperatures proteins present in cytoplasmic stress granules were more efficiently recruited to sites of virus replication. We propose that CHIKV has evolved mechanisms to promote their replication in mammalian cells at sub-physiological temperatures to facilitate infection of mammals via a mosquito bite.
Keap1 recognizes EIAV early accessory protein Rev to promote antiviral defense
Authors: Wang Yan , Ma Guanqin , Wang Xue-Feng , Na Lei , Guo Xing , Zhang Jiaqi , Liu Cong , Du Cheng , Lin Yuezhi , Wang Xiaojun
Published: September 2021

The Nrf2/Keap1 axis plays a complex role in viral susceptibility, virus-associated inflammation and immune regulation. However, whether or how the Nrf2/Keap1 axis is involved in the interactions between equine lentiviruses and their hosts remains unclear. Here, we demonstrate that the Nrf2/Keap1 axis was activated during EIAV infection. Mechanistically, EIAV-Rev competitively binds to Keap1 and releases Nrf2 from Keap1-mediated repression, leading to the accumulation of Nrf2 in the nucleus and promoting Nrf2 responsive genes transcription. Subsequently, we demonstrated that the Nrf2/Keap1 axis represses EIAV replication via two independent molecular mechanisms: directly increasing antioxidant enzymes to promote effective cellular resistance against EIAV infection, and repression of Rev-mediated RNA transport through direct interaction between Keap1 and Rev. Together, these data suggest that activation of the Nrf2/Keap1 axis mediates a passive defensive response to combat EIAV infection. The Nrf2/Keap1 axis could be a potential target for developing the strategies for combating EIAV infection.

Author summary

Here we report that the Nrf2/Keap1 axis acts as an antiviral effector on EIAV replication through two-way regulation of Rev. On the one hand, EIAV-Rev activates the Nrf2/Keap1 axis by competitive interaction with Keap1, which promotes the transcription of cytoprotective genes implicated in the antiviral response. On the other hand, Keap1 restricts Rev/RRE-dependent RNA transport, leading to inhibition of viral protein synthesis and reduction in viral replication. This study highlights the importance of the Nrf2/Keap1 axis in controlling EIAV replication, and identifies this pathway as a potential new entry-point for treating lentivirus infection. Importantly, this report provides new insights into the regulation of viral replication by the Nrf2/Keap1 axis.