bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction andin vitrosilencing of two lipid biosynthetic genes viz.SCDandSREBP1in chicken using RNA interference
Authors: Sagar N. Govardhana , Prasad A. Rajendra , Chatterjee R.N. , Kumar Pushpendra , Bhushan Bharat , Vishnu P. Guru , Bhattacharya T. K.
Published: October 2020

RNA interference is a widely used post transcriptional silencing mechanism for suppressing expression of the target gene. In the current study, five shRNA molecules each againstSCDandSREBP1genes were designed after considering the parameters like secondary structures of shRNA constructs, mRNA target regions, GC content and thermodynamic properties (ΔG overall, ΔG duplex and ΔG break-target) to knockdown their expression. After successful transfection of these shRNA molecules into the chicken embryonic hepatocyte culture, expression of the target genes were monitored by real time PCR. Significant reduction (P<0.05) in the expression ofSCDandSREBP1genes with minimal activation of immune response genes in hepatocytes was observed after transfecting the shRNA molecules into them. The shRNA constructs againstSCDgene showed the knock down efficiency ranged from 20.4% to 74.2%. In case of shRNA constructs againstSREBP1gene, they showed knock down efficiency ranging from 26.8% to 95.85%. These results clearly demonstrated the successful down regulation of the gene expression by designed shRNA molecules against both the target genes underin vitrocondition. The shRNA2 molecule forSCDgene and the shRNA1 molecule forSREBP1gene were found as the best among all the shRNA molecules used for silencing the target genes under cell culture system. It is concluded that the shRNA molecules designed against SCD and SREBP1 genes showed potential to silence the expression of these genes under in vitro chicken embryonic hepatocyte cell culture system.
MutatingPINK1gene by paired truncated sgRNA/Cas9-D10A in Cynomolgus Monkey
Authors: Chen Zhenzhen , Wang Jianying , Kang Yu , Yang Qiaoyan , Gu Xueying , Zhi Dalong , Yan Li , Shen Bin , Niu Yuyu
Published: October 2020

Mutations ofPINK1cause early-onset Parkinson’s disease (PD) with selective neurodegeneration in humans. However,currentPINK1knockout mouse and pig models are unable to recapitulate the typical neurodegenerative phenotypes observed in PD patients, indicating that it is essential to generatePINK1disease models in non-human primates (NHPs) that are highly close to humans, to investigate the unique function of PINK1 in primate brains. Paired single guide RNA (sgRNA)/Cas9-D10A nickases and truncated sgRNA/Cas9, both enabling the reduction of the off-target effect without apparently compromising the on-target editing, are two optimized strategies in applying the CRISPR/Cas9 system to establish disease animal models. Here, we combined the two strategies and injected Cas9-D10A mRNA and two truncated sgRNAs into one-cell-stage cynomolgus zygotes to targetPINK1gene. We show precise and efficient gene editing of the target site in the three new born cynomolgus monkeys. The frame shift mutations ofPINK1in mutant fibroblasts leaded to the reduction of the mRNA, However, western-blot and immunofluorescencestaining confirmed the PINK1 proteinlevels werecomparable to that in the wild-type fibroblasts. We further reprogramed mutant fibroblast into induced pluripotent stem cells (iPSCs) and they show similar ability of differentiation into dopamine (DA) neurons. Taken together, our results showed that coinjection of Cas9-D10A nickase mRNA and sgRNA into one-cell-stage cynomolgus embryos enable the generation of human disease models in NHPs and the target editing by paired truncated sgRNA/Cas9-D10A inPINK1gene exon 2 did not impact the protein expression.
Viral susceptibility across host species is largely independent of dietary protein to carbohydrate ratios
Authors: Roberts Katherine E , Longdon Ben
Published: October 2020

The likelihood of a successful host shift of a parasite to a novel host species can be influenced by environmental factors that can act on both the host and parasite. Changes in nutritional resource availability have been shown to alter pathogen susceptibility and the outcome of infection in a range of systems. Here we examined how dietary protein to carbohydrate altered susceptibility in a large cross infection experiment. We infected 27 species of Drosophilidae with an RNA virus on three food types of differing protein to carbohydrate ratios. We then measured how viral load and mortality across species was affected by changes in diet. We found that changes in the protein:carbohydrate in the diet did not alter the outcomes of infection, with strong positive inter-species correlations in both viral load and mortality across diets, suggesting no species by diet interaction. Mortality and viral load were strongly positively correlated, and this association was consistent across diets. This suggests changes in diet may give consistent outcomes across host species, and may not be universally important in determining host susceptibility to pathogens.

Twitter summary

No role of host diet in susceptibility to a novel viral pathogen across host species

Impact Statement

A successful host shift of a parasite from one susceptible species to a novel host can be influenced by many ecological factors. Changes in host diet can alter the immune response and outcomes of host–parasite interactions and could potentially alter the outcome of a virus host shift. To investigate, we infected 27 species of Drosophilidae with an RNA virus (DCV) across three food types with differing protein to carbohydrate ratios. We then looked at pathogen loads and survival of infected hosts compared to uninfected controls. Changes in the ratio of protein to carbohydrate did not alter susceptibility to DCV across host species.
Compensatory hepatic adaptation accompanies permanent absence of intrahepatic biliary network due to YAP1 loss in liver progenitors
Authors: Molina Laura M. , Zhu Junjie , Li Qin , Pradhan-Sundd Tirthadipa , Sayed Khaled , Jenkins Nathaniel , Vats Ravi , Ko Sungjin , Hu Shikai , Poddar Minakshi , Singh Sucha , Tao Junyan , Sundd Prithu , Singhi Aatur , Watkins Simon , Ma Xiaochao , Benos Panayiotis V. , Feranchak Andrew , Nejak-Bowen Kari , Watson Alan , Bell Aaron , Monga Satdarshan P.
Published: October 2020

YAP1 regulates cell plasticity during liver injury, regeneration and cancer, but its role in liver development is unknown. YAP1 activity was detected in biliary cells and in cells at the hepato-biliary bifurcation in single-cell RNA-sequencing analysis of developing livers. Hepatoblast deletion ofYap1led to no impairment in Notch-driven SOX9+ ductal plate formation, but prevented the formation of the abutting second layer of SOX9+ ductal cells, blocking the formation of a patent intrahepatic biliary tree. Intriguingly, the mice survived for 8 months with severe cholestatic injury and without any hepatocyte-to-biliary transdifferentiation. Ductular reaction in the perihilar region suggested extrahepatic biliary proliferation likely seeking the missing intrahepatic biliary network. Long-term survival of these mice occurred through hepatocyte adaptation via reduced metabolic and synthetic function including altered bile acid metabolism and transport. Overall, we show YAP1 as a key regulator of bile duct development while highlighting a profound adaptive capability of hepatocytes.
Regulation of neural gene expression by estrogen receptor alpha
Authors: Gegenhuber Bruno , Wu Melody V. , Bronstein Robert , Tollkuhn Jessica
Published: October 2020

The transcription factor estrogen receptor α (ERα) is a principal regulator of sex differences in the vertebrate brain and can modulate mood, behavior, and energy balance in females and males. However, the genes regulated by ERα in the brain remain largely unknown. Here we reveal the genomic binding of ERα within a sexually dimorphic neural circuit that regulates social behaviors. We profiled gene expression and chromatin accessibility and show ERα induces a neurodevelopmental gene program in adulthood. We further demonstrate that ERα binds with Nuclear factor I X-type (Nfix) to regulate a male-biased gene expression program that initiates in early life. Our results reveal a neural strategy for ERα-mediated gene regulation and provide molecular targets that underlie estrogen’s effects on brain development, behavior, and disease.
Efficacy and immunogenicity of different BCG doses in BALB/c and CB6F1 mice when challenged with H37Rv or Beijing HN878
Authors: Khatri Bhagwati , Keeble James , Dagg Belinda , Kaveh Daryan A. , Hogarth Philip J. , Ho Mei Mei
Published: October 2020

In this study, 2 strains of mice (BALB/c and CB6F1) were vaccinated with a range of Bacille Calmette-Guérin (BCG) Danish doses from 3×105to 30 CFU/mouse, followed by either immunogenicity evaluation or aerosol infection withMycobacterium tuberculosis(a laboratory strain H37Rv or West-Beijing HN878 strain). The results indicated that both strains of mice when infected with HN878 exhibited significant protection in their lungs with BCG doses at 3×105– 3000 CFU (BALB/c) and 3×105-300 CFU (CB6F1). Whereas, both strains of mice when infected with H37Rv, significant protection was seen in BCG doses at 3×105- 300 CFU. Immunological evaluation revealed interesting results; i) both strains of mice demonstrated a significant increase in the frequencies of BCG-specific IFNγ+IL2+TNFα+CD4 T cells in the BCG doses at 3×105– 3000 CFU (BALB/c) and 3×105- 300 CFU (CB6F1); ii) secretion of IL2 and IFNγ were correlated with the bacterial burden in the lungs of HN878 infected CB6F1 mice. The study demonstrated a BCG dose at 3000 CFU (an equivalent single human dose in the mice by body weight index) is protective in both strains of mice and the use of a virulent clinical isolate in testing new tuberculosis vaccine/advancing research is recommended.
Discovery of ciliary G protein-coupled receptors regulating pancreatic islet insulin and glucagon secretion
Authors: Wu Chien-Ting , Hilgendorf Keren I. , Bevacqua Romina J. , Hang Yan , Demeter Janos , Kim Seung K. , Jackson Peter K.
Published: October 2020

Multiple G protein coupled receptors (GPCRs) are expressed in pancreatic islet cells but the majority have unknown functions. We observe specific GPCRs localized to primary cilia, a prominent signaling organelle, in pancreatic α- and β-cells. Loss of cilia disrupts β-cell endocrine function, but the molecular drivers are unknown. Using functional expression, we identified multiple GPCRs localized to cilia in mouse and human islet α- and β-cells, including FFAR4, PTGER4, DRD5, ADRB2, KISS1R, and P2RY14. Free fatty acid receptor 4 (FFAR4) and prostaglandin E receptor 4 (PTGER4) agonists stimulate ciliary cAMP signaling and promote glucagon and insulin secretion by α- and β-cell lines, and by mouse and human islets. Transport of GPCRs to primary cilia requiresTULP3, whose knockdown in primary human and mouse islets depleted ciliary FFAR4 and PTGER4, and impaired regulated glucagon or insulin secretion, without affecting ciliary structure. Our findings provide index evidence that regulated hormone secretion by islet α- and β-cells is regulated by ciliary GPCRs providing new targets for diabetes.
Insights into the mitochondrial transcriptome landscapes of two Brassicales plant species,Arabidopsis thaliana(var. Col-0) andBrassica oleracea(var. botrytis)
Authors: Best Corinne , Sultan Laure , Murik Omer , Ostersetzer-Biran Oren
Published: October 2020

Mitochondria play key roles in cellular energy metabolism within eukaryotic cells. As relics of endosymbiotic bacteria, most (but not all) mitochondria contain their own genome (mitogenome, mtDNA), as well as intrinsic biosynthetic machinery for making organelle RNAs and proteins. The expression of the mtDNA requires regulated metabolism of its transcriptome by nuclear-encoded factors. Post-transcriptional mtRNA modifications play a central role in the expression of the plant mitogenomes, and hence in organellar biogenesis and plant physiology. Despite extensive investigations, a full map of angiosperm mitochondrial transcriptomes, a prerequisite for the elucidation of the basic RNA biology of mitochondria, has not been reported yet. Using RNA-seq data, RT-PCR and bioinformatics, we sought to explore the gene expression profiles of land plant mitochondria. Here, we present the mitochondrial transcriptomic maps of two keyBrassicaceaespecies,Arabidopsis thaliana(var Col-0) and cauliflower (Brassica oleraceavar. botrytis). The revised transcriptome landscapes of Arabidopsis and cauliflower mitogenomes provide with more detail into mtRNA biology and processing in angiosperm mitochondria, and we expect that they would serve as a valuable resource for the plant organellar community.

Accession numbers

Sequences are available at the Sequence Read Archive (accession no. PRJNA472433), for bothArabidopsis thalianavar. Col-0 mtRNA (SRA no. SRX4110179) andBrassica oleraceavar. botrytis mtRNA (SRA no. SRX4110177).
Creation and analysis of enzymatically active micrometer protein-capsules
Authors: Schakowski Kai Melvin , Elm Christian , Linders Jürgen , Kirsch Michael
Published: October 2020

This work describes a general method for the encapsulation of enzymes with albumin as wall material and the enzyme catalase as prime example. Care was taken for the preparation of biochemically active sub-micrometer particles in order to prevent oxygen toxicity induced by artificial oxygen carriers of any type. In cell culture experiments, capsules containing catalase did not exhibit any harmful activities in the absence of peroxides. In the presence of hydrogen peroxide application of low and medium dosed capsules below 0.05 vol% (final concentration 0.001 vol%) even increased the cell damaging process. However, a higher dosage of capsules (> 0.05 vol%) prevented completely cellular disruption induced by 5 mM hydrogen peroxide and decreased up to 90% of cellular damage at higher peroxide concentrations. These results demonstrated that encapsulated catalase was enzymatically active and the over-all activity of prepared catalase capsules was determined to be > 1000 U ∙ mL−1∙ vol%−1.
Investigation of the damping wiggler effect and application on the PAL fourth-generation storage ring
Authors: Jang Gyeongsu , Yoon M. , Lee J. , Oh B.-H. , Kim J. , Kim D.-E. , Shin S.
Published: October 2020

An investigation of the damping wiggler effect to reduce the emittance in the Pohang Accelerator Laboratory (PAL), a fourth-generation storage ring (4GSR) that uses a multi-bend achromat, is presented. A 4GSR lattice which has reduced emittance and increased dynamic aperture to amplify the synergy with two existing light sources (PLS-II and PAL-XFEL) at PAL is described.
Aerodynamic performance enhancement of an Airfoil using trapezoidal vortex generators
Authors: Himo Rawad , Bou-Mosleh Charbel , Habchi Charbel
Published: October 2020

Purpose

Flow separation on wings, blades and vehicles can be delayed or even suppressed by the use of vortex generators (VG). Numerous studies, documented in the literature, extensively describe the performance of triangular and rectangular VG winglets. This paper aims to focus on the use of non-conventional VG shapes, more specifically an array of trapezoildal-perforated VG tabs.

Design/methodology/approach

In this study, computational fluid dynamic simulations are performed on an inline array of trapezoidal VG with various dimensions and inclination angles, in addition to considering perforations in the VG centers. The methodology of the present numerical study is validated with experimental data from the literature.

Findings

The performance and the associated flow structures of these tested non-conventional VG are compared to classical triangular winglets. For the proposed non-conventional trapezoidal VG, at the onset of stall, a 21% increase of lift over drag on the airfoil is observed. The trapezoidal VG enhancement is also witnessed during stall where the lift over drag ratio is increased by 120% for the airfoil and by 10% with respect to the triangular winglets documented in the literature.

Originality/value

The originality of this paper is the use of non-conventional vortex generator shape to enhance lift over drag coefficient using three-dimensional numerical simulations.
The creative economy: an ethnographic framework for handcrafts in the Alto Solimões region of the Brazilian Amazon
Authors: Petry Jonas Fernando , Uchôa Antônio Giovanni Figliuolo , Mendonça Maurício Brilhante de , Magalhães Karinny de Lima , Benchimol Rafaella Marlene Barbosa
Published: October 2020

Purpose

The purpose of this paper is to draw on concepts from the creative economy literature to present a proposal for conceptualizing the creative industries from the perspective of the ideas underlying the concepts of industrial districts and the triple helix. The analysis lays out the foundations with a review of the literature on the creative economy and builds upon them with the terminology of creative industries and industrial districts.

Design/methodology/approach

The analysis lays out the foundations with a review of the literature on the creative economy and builds upon them with the terminology of creative industries and industrial districts. A three-dimensional representation is developed, from a perspective in which the three dimensions comprise university, creative industries and government, combined with seven underlying factors that define the archetypal framework from the perspective of the creative economy of the region's handcrafts.

Findings

Working from the principal of an analysis of underlying factors, the paper presents an ethnographic study of the potentials and obstacles present in the handcrafts sector and delineates the work that remains to be done to enable construction of a creative economy.

Originality/value

A prominent possibility based on the ethnographic study of the potentials listed, the creative economy of the handicraft sector is underexplored in the Amazon. Based on the Amazon heritage of the people in the Alto Solimões region, future prospects such as establishment of guilds, clusters and internationalization of production in a tourism association represent sui generis potentials for the economic development of the Alto Solimões region of the Brazilian Amazon.
Contextual reflections on COVID-19 and informal workers in Nigeria
Authors: Omobowale Ayokunle Olumuyiwa , Oyelade Olufikayo Kunle , Omobowale Mofeyisara Oluwatoyin , Falase Olugbenga Samuel
Published: October 2020

Purpose

The index case of COVID-19 in Nigeria was reported on 27 February 2020. Subsequently, the exponential increase in cases has brought about the partial and total lockdown of cities, the closure of all schools and the shutdown of government offices in order to curtail the spread of COVID-19. COVID-19 and its subsequent drastic curtailment policies have implications on vulnerable groups, especially, informal workers who constitute about 70% of the active working population in Nigeria. This reflective discourse critically engages the plight of informal workers in the context of the COVID-19 pandemic in Nigeria.

Design/methodology/approach

The research was guided by the epistemology of pandemic interpretationism. It engages contextual reflections of the plight of economically vulnerable informal workers in Nigeria. Data were collected from secondary sources while rapid case studies were conducted with ten informal workers in Lagos and Ibadan. Afterwards, data were contextually analysed.

Findings

Economically vulnerable informal workers in Nigeria have contextually interpreted COVID-19 as an elite disease, imported into Nigeria by the wealthy. In addition, the mass population views COVID-19 containment measures such as lockdowns, movement restrictions and stay-at-home orders as elitist policies, which are aimed at protecting the wealthy and frustrating the poor and economically vulnerable who live on the fringes of poverty. Many informal workers have slipped below the poverty line while struggling to supply livelihood needs, as they were unable to earn daily income and cannot access palliatives. Consequently, they are of the opinion that “Hunger Virus is deadlier than Corona Virus”.

Originality/value

This paper is a contextual reflection on the plight of economically vulnerable informal workers during the COVID-19 pandemic lockdown and movement restrictions in Nigeria. It presents pandemic interpretationism as an epistemological guide and reflectively examines the poverty impact of COVID-19 on the Nigerian informal sector via contextual analyses of secondary data and rapid case studies. The paper uncovers various COVID-19 livelihood experiences and the responses of the informal workers; furthermore, it provides policy recommendations.
Immigrant children and school bullying:the “unrecognized” victim?
Authors: Morales Danielle Xiaodan
Published: October 2020

Purpose

The current study aims to investigate whether the victimization of immigrant children is more likely to be unrecognized by teachers and parents and what demographic factors contribute to children's unrecognized bullying victimization.

Design/methodology/approach

Data from the publicly accessible US Early Childhood Longitudinal Study, Kindergarten Cohort, 2011 were utilized (N = 10,587 children across 2,194 schools), and the hierarchical linear model was used for modeling.

Findings

Among all bullying victims included in this study, only 32% were recognized by both parents and teachers. Bullied children who had only foreign-born parent/s were more likely to be unnoticed by adults than those who had only US-born parent/s. Among all bullied children, girls were more likely to be overlooked by adults than boys, and Asian and Hispanic children were more likely to be overlooked by adults than White children.

Social implications

To better protect and support all victimized children, schools should develop innovative strategies to engage more immigrant parents; teachers and parents need to learn how not to rely on social and cultural biases to guide their interpretations and response to school bullying; parents and teachers should keep good communication with children.

Originality/value

Previous research demonstrates that immigrant children have a high risk of being bullied in school, but it is unclear whether parents and teachers are sufficiently aware of their victimization. This paper is the first study to demonstrate how parents' nativity, gender and race/ethnicity are associated with children's unrecognized bullying victimization.
The link between intellectual capital and business performance: a mediation chain approach
Authors: Campos Susana , Dias José G. , Teixeira Mário Sérgio , Correia Ricardo Jorge
Published: October 2020

Purpose

This study focuses on intellectual capital (IC) as a driver of better business performance. Recent studies suggest that a set of variables may mediate this relationship. This research discusses the mediating role of dynamic capabilities, network competence, technological capabilities, absorptive capabilities and innovation performance between intellectual capital and business performance.

Design/methodology/approach

The conceptual model is tested using a sample of 533 Portuguese firms by means of a structural equation model.

Findings

It confirms that intellectual capital impacts business performance. Moreover, this only happens indirectly through the mediating chain defined by the variables dynamic capabilities, network competence, technological capabilities, absorptive capabilities and innovation performance.

Originality/value

This study analyzes new mediator variables between the dimensions of the intellectual capital and Portuguese business performance.
No evidence for fitness signatures consistent with increasing trophic mismatch over 30 years in a population of European shag Phalacrocorax aristotelis
Authors: Keogan Katharine , Lewis Sue , Howells Richard J. , Newell Mark A. , Harris Michael P. , Burthe Sarah , Phillips Richard A. , Wanless Sarah , Phillimore Albert B. , Daunt Francis
Published: October 2020

As temperatures rise, timing of reproduction is changing at different rates across trophic levels, potentially resulting in asynchrony between consumers and their resources. The match–mismatch hypothesis (MMH) suggests that trophic asynchrony will have negative impacts on average productivity of consumers. It is also thought to lead to selection on timing of breeding, as the most asynchronous individuals will show the greatest reductions in fitness.

Using a 30‐year individual‐level dataset of breeding phenology and success from a population of European shags on the Isle of May, Scotland, we tested a series of predictions consistent with the hypothesis that fitness impacts of trophic asynchrony are increasing.

These predictions quantified changes in average annual breeding success and strength of selection on timing of breeding, over time and in relation to rising sea surface temperature (SST) and diet composition.

Annual average (population) breeding success was negatively correlated with average lay date yet showed no trend over time, or in relation to increasing SST or the proportion of principal prey in the diet, as would be expected if trophic mismatch was increasing. At the individual level, we found evidence for stabilising selection and directional selection for earlier breeding, although the earliest birds were not the most productive. However, selection for earlier laying did not strengthen over time, or in relation to SST or slope of the seasonal shift in diet from principal to secondary prey. We found that the optimum lay date advanced by almost 4 weeks during the study, and that the population mean lay date tracked this shift.

Our results indicate that average performance correlates with absolute timing of breeding of the population, and there is selection for earlier laying at the individual level. However, we found no fitness signatures of a change in the impact of climate‐induced trophic mismatch, and evidence that shags are tracking long‐term shifts in optimum timing. This suggests that if asynchrony is present in this system, breeding success is not impacted. Our approach highlights the advantages of examining variation at both population and individual levels when assessing evidence for fitness impacts of trophic asynchrony.
Review article: Rapid review of the emergency department‐initiated buprenorphine for opioid use disorder
Authors: Salter Helen , Hutton Jennie , Cantwell Kate , Dietze Paul , Higgs Peter , Straub Adam , Zordan Rachel , Lloyd‐Jones Martyn
Published: October 2020

Opioid‐related harms have been increasing in Australia over the last 5 years. Patients with opioid use disorder are over‐represented in ED presentations. Opioid agonist treatment is the most effective community‐based treatment. Buprenorphine is considered the safest of these treatments to use in the ED setting. This rapid review investigated the effectiveness of initiating buprenorphine in the ED setting. Medline, Embase, Emcare, PSYCinfo, CINAHL and Cochrane Central Register of Controlled Trials databases were searched. Randomised and non‐randomised studies published in peer‐reviewed journals that involved the initiation of buprenorphine in the ED setting were considered eligible. The search revealed 350 articles of which 11 were included in the review; three articles representing two randomised controlled trials (RCTs) and eight observational studies. Data were extracted from included papers and risk of bias assessed on the RCTs. One well‐conducted RCT showed that buprenorphine initiated in the ED does improve treatment engagement up to 2 months after an ED visit. Eight observational studies, one with a comparator group reported positive results for this intervention. There is strong evidence that clinicians should consider commencing buprenorphine in the ED for patients with opioid use disorder when combined with a direct and supported referral or ‘warm handover’ to community care. Further implementation studies and investigation of long‐acting injectable buprenorphine treatment are required.
The steroid‐induced microRNA let‐7 regulates developmental growth by targeting cdc7 in the Drosophila fat body
Authors: Huang Dan‐Yan , Xia Xiao‐Ling , Huang Run , Li Sheng , Yuan Dong‐Wei , Liu Su‐Ning
Published: October 2020

In insects, 20‐hydroxyecdysone (20E) limits systemic growth by triggering developmental transitions. Previous studies have shown that 20E‐induced let‐7 exhibits crosstalk with the cell cycle. Here, we examined the underlying molecular mechanisms and physiological functions of 20E‐induced let‐7 in the fat body, an organ for energy storage and nutrient mobilization which plays a critical role in the larval growth. First, the overexpression of let‐7 decreased the body size and led to the reduction of both nucleolus and cell sizes in the larval fat body. In contrast, the overexpression of let‐7‐Sponge increased the nucleolus and cell sizes. Moreover, we found that cdc7, encoding a conserved protein kinase that controls the endocycle, is a target of let‐7. Notably, the mutation of cdc7 in the fat body resulted in growth defects. Overall, our findings revealed a novel role of let‐7 in the control of endoreduplication‐related growth during larval‐prepupal transition in Drosophila.
Survival and causes of death for Takayasu’s arteritis in Korea: A retrospective population‐based study
Authors: Jang Shin Yi , Park Taek Kyu , Kim Duk‐Kyung
Published: October 2020

Objective

Few studies have evaluated survival of Takayasu's arteritis (TAK; M31.4) in Korea. The purpose of this study was to assess the survival rate (SR) and causes of death for TAK.

Methods

Newly diagnosed TAK data (N = 2731) were collected from the National Health Insurance Service in Korea from 2006 through 2017. The Kaplan‐Meier method was used. Korean death data was used from 2006 through 2018.

Results

The mean age was 48.1 (±16.9) years. The proportion of female patients was 74.4%. The most common cause of death in TAK was diseases of the circulatory system. The 1‐, 3‐, 5‐, and 10‐year SRs were 97.5%, 94.7%, 91.7%, and 84.7%, respectively. The 1‐, 3‐, 5‐, and 10‐year SRs by gender were 97.8%, 95.6%, 92.9%, and 86.3%, respectively, among females and 96.8%, 92.2%, 88.4%s and 79.7%, respectively, among males (P < .001).

Conclusions

The overall 10‐year SR was about 85%. The 10‐year SR in males was lower than that in females. The most common cause of death in TAK was diseases of the circulatory system.
Plasma proteomic profile of age, health span, and all‐cause mortality in older adults
Authors: Sathyan Sanish , Ayers Emmeline , Gao Tina , Weiss Erica F. , Milman Sofiya , Verghese Joe , Barzilai Nir
Published: October 2020

Aging is a complex trait characterized by a diverse spectrum of endophenotypes. By utilizing the SomaScan® proteomic platform in 1,025 participants of the LonGenity cohort (age range: 65–95, 55.7% females), we found that 754 of 4,265 proteins were associated with chronological age. Pleiotrophin (PTN; β[SE] = 0.0262 [0.0012]; p = 3.21 × 10−86), WNT1‐inducible‐signaling pathway protein 2 (WISP‐2; β[SE] = 0.0189 [0.0009]; p = 4.60 × 10−82), chordin‐like protein 1 (CRDL1; β[SE] = 0.0203[0.0010]; p = 1.45 × 10−77), transgelin (TAGL; β[SE] = 0.0215 [0.0011]; p = 9.70 × 10−71), and R‐spondin‐1(RSPO1; β[SE] = 0.0208 [0.0011]; p = 1.09 × 10−70), were the proteins most significantly associated with age. Weighted gene co‐expression network analysis identified two of nine modules (clusters of highly correlated proteins) to be significantly associated with chronological age and demonstrated that the biology of aging overlapped with complex age‐associated diseases and other age‐related traits. The correlation between proteomic age prediction based on elastic net regression and chronological age was 0.8 (p < 2.2E−16). Pathway analysis showed that inflammatory response, organismal injury and abnormalities, cell and organismal survival, and death pathways were associated with aging. The present study made novel associations between a number of proteins and aging, constructed a proteomic age model that predicted mortality, and suggested possible proteomic signatures possessed by a cohort enriched for familial exceptional longevity.
Use of narrowband ultraviolet B (NBUVB) in paediatric psoriasis: A systematic literature review and meta‐analysis
Authors: Kim Emma , Lee Geoffrey , Fischer Gayle
Published: October 2020

Background/ Objectives

Phototherapy is used commonly in adult psoriasis; however, there is little data on its use in the paediatric population. We performed a systematic review and meta‐analysis on current available literature to review the safety and efficacy of NBUVB in paediatric psoriasis.

Methods

A systematic review and meta‐analysis according to PRISMA guidelines. Meta‐analysis of proportions was used to obtain efficacy, and meta‐regression was used to explore the impact of treatment variables on efficacy.

Results

We identified 10 prospective and retrospective studies for inclusion. From pooled data, we determined the efficacy of NBUVB in paediatric psoriasis to be 80% (CI 70%‐88%). There was a positive association between the number of treatments and efficacy of NBUVB. There was no association between the cumulative dose and efficacy. Erythema was the most commonly described side effect. There were no studies of long‐term safety of NBUVB in paediatric psoriasis. Limitations included that studies had small patient numbers and were observational in nature.

Conclusions

NBUVB is effective in the treatment of paediatric psoriasis with a good short‐term safety profile. More studies are required to assess the influence of variables on efficacy and to elucidate the long‐term safety profile of NBUVB in paediatric psoriasis.
Meta‐analysis of survival outcomes following surgical and non surgical treatments for colorectal cancer metastasis to the lung
Authors: Ratnayake Chathura B. B. , Wells Cameron I. , Atherton Phillip , Hammond John S. , White Steve , French Jeremy J. , Manas Derek , Pandanaboyana Sanjay
Published: October 2020

Background

Controversy exists regarding the optimal management of colorectal lung metastases (CRLM). This meta‐analysis compared surgical (Surg) versus interventional (chemotherapy and/or radiotherapy) and observational non‐surgical (NSurg) management of CRLM.

Methods

A systematic review of the major databases including Medline, Embase, SCOPUS and the Cochrane library was performed.

Results

One randomized and nine observational studies including 2232 patients: 1551 (69%) comprised the Surg cohort, 521 (23%) the interventional NSurg group and 160 (7%) the observational NSurg group. A significantly higher overall survival (OS) was observed when Surg was compared to interventional NSurg at 1 year (Surg 88%, 310/352; interventional NSurg 64%, 245/383; odds ratio (OR) 2.77 (confidence interval (CI) 1.94–3.97),P= 0.001), at 3 years (Surg 59%, 857/1444; interventional NSurg 26%, 138/521; OR 2.61 (CI 1.65–4.15),P= 0.002), at 5 years (Surg 47%, 533/1144; interventional NSurg 23%, 45/196; OR 3.24 (CI 1.42–7.39),P= 0.009) and at 10 years (Surg 27%, 306/1122; interventional NSurg 1%, 2/168; OR 15.64 (CI 1.87–130.76),P= 0.031). Surg was associated with a greater OS than observational NSurg at only 1 year (Surg 92%, 98/107; observational NSurg 83%, 133/160; OR 6.69 (CI 1.33–33.58),P= 0.037) and was similar to observational NSurg at all other OS time points. Comparable survival was observed among Surg and overall NSurg cohorts at 3‐ and 5‐year survival in articles published within the last 3 years.

Conclusions

Recent evidence suggests comparable survival with Surg and NSurg modalities for CRLM, contrasting to early evidence where Surg had an improved survival. Significant selection bias contributes to this finding, prompting the need for high powered randomized controlled trials and registry data.
The geopolitics of improvised language: President John F. Kennedy’s ‘Ich bin ein Berliner’ address
Authors: Bryan Ed
Published: October 2020

It is shortly after 13.00 outside Berlin’s Schöneberg Rathaus (City Hall) on 26 June 1963. A strong breeze tosses the banner which hangs behind a narrow speaker’s platform as some 450,000 people listen expectantly to the figure standing before them. Having already been speaking for just over eight minutes, President John F. Kennedy has reached the closing lines of his address: ‘All free men, wherever they may live, are citizens of Berlin, and, therefore, as a free man, I take pride in the words “Ich bin ein Berliner”.’ Although Kennedy’s ‘Ich bin ein Berliner’ address has gained something of an iconic status, few are aware of its improvisational and contentious nature. Crucially, the U.S. President would follow only a quarter of the prepared text during its delivery, and geopolitically frame Berlin in such a manner as to imperil his own foreign policy. Developing insights from the so‐called ‘more‐than‐representational’ turn and informed by materials from the John F. Kennedy Presidential Library (JFKPL), this paper records both how and why Kennedy elected to stray from the script. More specifically, it examines those agencies – the objects, atmospheres, emotions, and affects – which converged during Kennedy’s address and led him to employ an improvised, geopolitically volatile mode of language.
Variation in rostral anterior cingulate functional connectivity with amygdala and caudate during first manic episode distinguish bipolar young adults who do not remit following treatment
Authors: Lippard Elizabeth T. C. , Weber Wade , Welge Jeffrey , Adler Caleb M. , Fleck David E. , Almeida Jorge , DelBello Melissa P. , Strakowski Stephen M.
Published: October 2020

Objectives

Altered activity in the ventrolateral prefrontal and anterior cingulate cortices, as well as subcortical and amygdala projection sites, was previously reported during a first manic episode in youth with bipolar disorder and observed to be associated with treatment response. To extend these findings, we investigated functional connectivity among these regions in first‐episode manic participants who remitted after 8 weeks of treatment compared to those who did not.

Methods

Forty‐two participants with bipolar disorder (60% female) during their first manic episode were recruited and received 8 weeks of treatment. Twenty‐one remitted following treatment. Participants completed fMRI scans, at baseline and following 8 weeks of treatment, while performing a continuous performance task with emotional and neutral distractors. A healthy comparison group (n = 41) received fMRI evaluations at the same intervals. Differences in functional connectivity of the amygdala and caudate with the rostral anterior cingulate and ventrolateral prefrontal cortices at baseline (and changes in functional connectivity following treatment) were modeled between groups.

Results

At baseline, non‐remitters showed an increase in positive connectivity between right anterior cingulate and caudate and a loss of negative connectivity between right anterior cingulate and amygdala, compared to healthy participants. Individuals who remitted following treatment showed an increase in negative connectivity between amygdala and left anterior cingulate 8 weeks following treatment.

Conclusions

Results provide evidence of alterations in anterior cingulate amygdala and caudate functional connectivity in bipolar disorder non‐remitters during a first manic episode and changes in anterior cingulate functional connectivity associated with remission suggesting targets to predict treatment response.

Registered at ClinicalTrials.Gov; Functional and Neurochemical Brain Changes in First‐episode Bipolar Mania. NCT00609193. URL: https://clinicaltrials.gov/ct2/show/NCT00609193?term=strakowskirank=1.
Contribution of the astrocytic tau pathology to synapse loss in progressive supranuclear palsy and corticobasal degeneration
Authors: Briel Nils , Pratsch Katrin , Roeber Sigrun , Arzberger Thomas , Herms Jochen
Published: October 2020

Primary 4‐repeat tauopathies with frontotemporal lobar degeneration (FTLD) like Progressive Supranuclear Palsy (PSP) or Corticobasal Degeneration (CBD) show diverse cellular pathology in various brain regions. Besides shared characteristics of neuronal and oligodendroglial cytoplasmic inclusions of accumulated hyperphosphorylated tau protein (pTau), astrocytes in PSP and CBD contain pathognomonic pTau aggregates — hence, lending the designation tufted astrocytes (TA) or astrocytic plaques (AP), respectively. pTau toxicity is most commonly assigned to neurons, whereas the implications of astrocytic pTau for maintaining neurotransmission within the tripartite synapse of human brains is not well understood. We performed immunofluorescent synapse labeling and automated puncta quantification in the medial frontal gyrus (MFG) and striatal regions from PSP and CBD postmortem samples to capture morphometric synaptic alterations. This approach indicated general synaptic losses of both, excitatory and inhibitory bipartite synapses in the frontal cortex of PSP cases, whereas in CBD lower synapse densities were only related to astrocytic plaques. In contrast to tufted astrocytes in PSP, affected astrocytes in CBD could not preserve synaptic integrity within their spatial domains, when compared to non‐affected internal astrocytes or astrocytes in healthy controls. These findings suggest a pTau pathology‐associated role of astrocytes in maintaining connections within neuronal circuits, considered as the microscopic substrate of cognitive dysfunction in CBD. By contrasting astrocytic‐synaptic associations in both diseases, we hereby highlight astrocytic pTau as an important subject of prospective research and as a potential cellular target for therapeutic approaches in the primary tauopathies PSP and CBD.
INEXAS: A Phase 2 Randomized Trial of On‐demand Inhaled Interferon Beta‐1a in Severe Asthmatics
Authors: McCrae Christopher , Olsson Marita , Gustafson Per , Malmgren Anna , Aurell Malin , Fagerås Malin , Da Silva Carla A. , Cavallin Anders , Paraskos Jonathan , Karlsson Karin , Wingren Cecilia , Monk Phillip , Marsden Richard , Harrison Tim
Published: October 2020

Background

Upper respiratory tract infections (URTIs) are important triggers for asthma exacerbations. We hypothesized that inhalation of the anti‐viral cytokine, interferon (IFN)‐β, during URTI, could prevent these exacerbations.

Objective

To evaluate the efficacy of on‐demand inhaled IFN‐β1a (AZD9412) to prevent severe asthma exacerbations following symptomatic URTI.

Methods

This was a randomized, double‐blind, placebo‐controlled trial in which patients with severe asthma (GINA 4‐5; n = 121) reporting URTI symptoms were randomized to 14 days of once‐daily nebulized AZD9412 or placebo. The primary endpoint was severe exacerbations during treatment. Secondary endpoints included 6‐item asthma control questionnaire (ACQ‐6) and lung function. Exploratory biomarkers included IFN‐response markers in serum and sputum, blood leucocyte counts and serum inflammatory cytokines.

Results

Following a pre‐planned interim analysis, the trial was terminated early due to an unexpectedly low exacerbation rate. Asthma worsenings were generally mild and tended to peak at randomization, possibly contributing to the lack of benefit of AZD9412 on other asthma endpoints. Numerically, AZD9412 did not reduce severe exacerbation rate, ACQ‐6, asthma symptom scores or reliever medication use. AZD9412 improved lung function (morning peak expiratory flow; mPEF) by 19.7 L/min. Exploratory post hoc analyses indicated a greater mPEF improvement by AZD9412 in patients with high blood eosinophils (>0.3 × 109/L) at screening and low serum interleukin‐18 relative change at pre‐treatment baseline. Pharmacodynamic effect of AZD9412 was confirmed using IFN‐response markers.

Conclusions & Clinical Relevance

Colds did not have the impact on asthma patients that was expected and, due to the low exacerbation rate, the trial was stopped early. On‐demand AZD9412 treatment did not numerically reduce the number of exacerbations, but did attenuate URTI‐induced worsening of mPEF. Severe asthma patients with high blood eosinophils or low serum interleukin‐18 response are potential subgroups for further investigation of inhaled IFN‐β1a.
Novel loss‐of‐function variants in DNAH17 cause multiple morphological abnormalities of the sperm flagella in humans and mice
Authors: Zhang Beibei , Khan Ihsan , Liu Chunyu , Ma Ao , Khan Asad , Zhang Yuanwei , Zhang Huan , Kakakhel Mian Basit Shah , Zhou Jianteng , Zhang Wen , Li Yang , Ali Asim , Jiang Xiaohua , Murtaza Ghulam , Khan Ranjha , Zubair Muhammad , Yuan Limin , Khan Mazhar , Wang Li , Zhang Feng , Wang Xiong , Ma Hui , Shi Qinghua
Published: October 2020

Multiple morphological abnormalities of the flagella (MMAF) is a genetically heterogeneous disorder leading to male infertility. Recent studies have revealed that DNAH17 variants are associated with MMAF, yet there is no functional evidence in support of their pathnogenicity. Here, we recruited two consanguineous families of Pakistani and Chinese origins, respectively, diagnosed with MMAF. Whole‐exome sequencing identified novel homozygous DNAH17 variants, which led to loss of DNAH17 proteins, in the patients. Transmission electron microscope analyses revealed completely disorganized axonemal structure as the predominant anomaly and increased frequencies of missings of microtubule doublet(s) 4–7 in sperm flagella of patients. Similar to those found in patients, Dnah17−/− mice also displayed MMAF phenotype along with completely disorganized axonemal structures. Clusters of disorganized microtubules and outer dense fibers were observed in developing spermatids, indicating impaired sperm flagellar assembly. Besides, we also noticed many elongating spermatids with a deformed nuclear shape and abnormal step 16 spermatids that failed to spermiate, which subsequently underwent apoptosis in Dnah17‐null mice. These findings present direct evidence establishing that DNAH17 is a MMAF‐related gene in humans and mice, extend the clinical interpretations of DNAH17 variants, and highlight an essential and complex role of DNAH17 in spermatogenesis.
A theory‐based framework for understanding the establishment, persistence, and diffusion of community‐based conservation
Authors: Mahajan Shauna L. , Jagadish Arundhati , Glew Louise , Ahmadia Gabby , Becker Hannah , Fidler Robert Y. , Jeha Lena , Mills Morena , Cox Courtney , DeMello Nicole , Harborne Alastair R. , Masuda Yuta J. , McKinnon Madeleine C. , Painter Michael , Wilkie David , Mascia Michael B.
Published: October 2020

Over decades, biodiversity conservation researchers and practitioners have developed theories and conceptual frameworks to inform the planning, implementation, and evaluation of community‐based conservation (CBC). While a diversity of mechanisms for understanding and supporting CBC has helped tailor approaches to local needs and conditions, the absence of a unified lens to understand CBC has limited the capacity for integrating foundational theory into practice more systemically, and for learning across different projects, stakeholders, and institutions. We introduce a theory‐based framework called “the CBC framework” that draws upon three foundational theories from sociology, economics, and political science to understand the establishment, persistence, and diffusion of CBC. Experience applying aspects of the framework within different conservation organizations demonstrates how this integrative approach can provide a gateway for practitioners to engage with social science theory to understand the status and context of CBC interventions and efforts. For practitioners, scientists, evaluators, and strategists, the framework can guide the design of CBC interventions and monitoring and evaluation systems to facilitate theory‐based learning and enable evidence‐informed decision‐making. Approaches like the CBC framework that facilitate collaborative planning, evaluation, and research can help better integrate social science theory in conservation practice while increasing the capacity for conservation scientists, practitioners, and stakeholders to learn together and adaptively manage CBC to deliver positive results for both people and nature.