bluuebunny/crossref_metadata_2025 huggingface dataset:
Small-molecule endoplasmic reticulum proteostasis regulator acts as a broad-spectrum inhibitor of dengue and Zika virus infections
Authors: Almasy Katherine M. , Davies Jonathan P. , Lisy Samantha M. , Tirgar Reyhaneh , Tran Sirena C. , Plate Lars
Published: January 2021

Significance

Viral infections continue to pose a grave global health threat, necessitating the development of new broadly applicable therapeutic strategies, including the targeting of conserved host processes that are exploited during viral infections. Flaviviruses, such as dengue and Zika, depend on extensive engagement of the endoplasmic reticulum (ER) proteostasis network to aid with replication, production, and secretion of virions. Here, we identify a host-centered antiviral approach by targeting these conserved ER protein quality-control processes that are required for viral infection. We find that the small-molecule regulator of ER proteostasis 147 can broadly and safely inhibit dengue and Zika infection without inducing toxicity to the host cells.
Genomic evolution of antibiotic resistance is contingent on genetic background following a long-term experiment with
Escherichia coli
Authors: Card Kyle J. , Thomas Misty D. , Graves Joseph L. , Barrick Jeffrey E. , Lenski Richard E.
Published: January 2021

Significance

A fundamental question in evolution is the repeatability of adaptation. Will independently evolving populations respond similarly when facing the same environmental challenge? This question also has important public-health implications related to the growing problem of antibiotic resistance. For example, efforts to control resistance might benefit from accurately predicting mutational paths to resistance. However, this goal is complicated when a lineage’s prior history alters its subsequent evolution. We recently found that differences between genetic backgrounds can lead to unpredictable responses in phenotypic resistance. Here, we report that genetic background can similarly alter genotypic paths to resistance. This historical contingency underscores the importance of accounting for stochasticity, in the past as well as at present, when designing evolutionarily informed treatment strategies.
Physiological role of the 3′IgH CBEs super-anchor in antibody class switching
Authors: Zhang Xuefei , Yoon Hye Suk , Chapdelaine-Williams Aimee M. , Kyritsis Nia , Alt Frederick W.
Published: January 2021

Significance

B lymphocytes change antibody heavy chain (IgH) isotypes by a recombination/deletion process called IgH class switch recombination (CSR). CSR involves introduction of DNA breaks into a donor switch (S) region and also into one of six downstream S regions, with joining of the breaks changing antibody isotype. A chromatin super-anchor, of unknown function, is located just downstream of the IgH locus. We show that complete deletion of this super-anchor variably decreases CSR to most S regions and creates an ectopic S region downstream of IgH locus that undergoes aberrant CSR-driven chromosomal rearrangements. Based on these and other findings, we conclude that the super-anchor downstream of IgH is a critical insulator for focusing potentially dangerous CSR rearrangements to the IgH locus.
Biotechnology.
Authors: Gosal Satbir
Published: January 2021

Biotechnology is the fusion of biology and technology. It changes and improves the characteristics of an organism at a cellular and molecular level for the benefit of mankind. Unlike conventional plant breeding methods, biotechnological techniques operate at tissue, cell, protoplast and molecular level for the genetic modification and subsequent screening for superior genotypes (Gosal et al., 2010). Biotechnology in a broad sense has been practiced for centuries for curd making, food preservation, pickle making and fermentation. However, biotechnology got a boost during the 1970s with the discovery of restriction enzymes, which led to the development of a variety of gene technologies; it is thus considered to be the greatest scientific revolution of the 20th century.
Dynamic modulation in graphene-integrated silicon photonic crystal nanocavity*
Authors: Wang Long-Pan , Ren Cheng , Cao De-Zhong , Lan Rui-Jun , Kang Feng
Published: January 2021

Silicon-based electro-optic modulators are the key devices in integrated optoelectronics. Integration of the graphene layer and the photonic crystal (PC) cavity is a promising way of achieving compact modulators with high efficiency. In this paper, a high-quality (Q) acceptor-type PC nanocavity is employed to integrate with a single-layer graphene for realizing strong modulation. Through tuning the chemical potential of graphene, a large wavelength shift of 2.62 nm and a Q factor modulation of larger than 5 are achieved. A modulation depth (12.8 dB) of the reflection spectrum is also obtained. Moreover, the optimized PC nanocavity has a large free spectral range of 131.59 nm, which can effectively enhance the flexibility of the modulator. It shows that the proposed graphene-based PC nanocavity is a potential candidate for compact, high-contrast, and low-power absorptive modulators in integrated silicon chips.
What Is Slowing Us Down? Six Challenges to Accelerating Advances in Health Behavior Change
Authors: Rothman Alexander J , Sheeran Paschal
Published: January 2021

Background

Accelerating advances in health behavior change requires releasing the brake, as well as applying the throttle. This paper discusses six challenges or “brakes” that have slowed progress.

Purpose/Methods/Results

We engage with six issues that limit investigators’ ability to delineate and test the strategy–target and target–behavior relations that underlie effective interventions according to the experimental medicine approach. We discuss the need for guidance on how to identify the relevant mechanism of action (target) in an intervention and whether a periodic table of health behavior constructs might aid investigators. Experimental and correlational analyses (prospective surveys and behavior change techniques) have been used to test the validity of targets, and we present evidence that there is little agreement among the findings from different research designs. Whereas target engagement is typically analyzed in terms of increasing scores on constructs that impel behavior change, we discuss the role of impeding targets and the benefits of adopting a broader construal of potential targets and approaches to engagement. There is presently a paucity of competitive tests regarding which strategies best engage targets and we discuss empirical criteria and conceptual developments that could enhance the evidence base. Finally, we highlight the need to take “context” or conditional intervention effects more seriously by leveraging the interplay between questions about why interventions work and questions about when and for whom they work.

Conclusion

Candid appraisal of the challenges facing research on health behavior change can generate new opportunities for theoretical development and offer direction and cumulative impetus for empirical work.
Forging Forward Together: Transforming Scientific Practice to Accelerate Scientific Progress
Authors: Hall Kara L
Published: January 2021

Rapidly advancing solutions requires our community to continuously re-examine successes of yesterday to inspire new approaches for today while collaboratively envisioning what’s needed for tomorrow.
Contribution of Sleep Disruption and Sedentary Behavior to Fatigue in Survivors of Allogeneic Hematopoietic Cell Transplant
Authors: Nelson Ashley M , Hyland Kelly A , Small Brent , Kennedy Brittany , Mishra Asmita , Hoogland Aasha I , Bulls Hailey W , Jim Heather S L , Jacobsen Paul B
Published: January 2021

Background

Fatigue is a prominent quality of life concern among recipients of hematopoietic cell transplantation (HCT).

Purpose

The present study investigated whether objectively measured sleep efficiency and sedentary behavior are related to greater reports of fatigue.

Methods

Eighty-two allogeneic HCT recipients who were 1–5 years post-transplant and returning for a follow-up visit participated (age M = 56, 52% female, 56% leukemia). They wore an actigraph assessing sleep efficiency and sedentary behavior for one week and completed an electronic log assessing fatigue each evening during the same period.

Results

Twenty-six percent of patients reported clinically meaningful fatigue. On average, fatigue was mild (M = 2.5 on 0–10 scale, SD = 2.0), sleep was disturbed (sleep efficiency M = 78.9%, SD = 8.9), and patients spent the majority of time in sedentary (M = 55.4%, SD = 10.2) or light (M = 35.9%, SD = 8.6) activity. Multilevel model analysis of between-person differences indicated that patients who experienced less efficient sleep the previous evening provided greater evening reports of average fatigue, b = –0.06, 95% CI (–0.11, –0.01). Similarly, within-person analyses indicated that when patients experienced less efficient sleep the previous evening or were more sedentary as compared to their average, they provided greater evening reports of average fatigue, b = –0.02, 95% CI (–0.05, –0.004); b = 4.46, 95% CI (1.95, 6.97), respectively.

Conclusions

Findings demonstrate that poor sleep and daily sedentary behavior are related to evening reports of fatigue and should be considered modifiable targets for intervention.
Bioactive 3D structures of naturally occurring peptides and their application in drug design
Authors: Masuda Yuichi
Published: January 2021

Naturally occurring peptides form unique 3D structures, which are critical for their bioactivities. To gain useful insights into drug design, the relationship between the 3D structure and bioactivity of the peptides has been studied. Solid-state nuclear magnetic resonance (NMR) analysis of the 42-residue amyloid β-protein (Aβ42) suggested the presence of toxic conformers with a turn structure at positions 22 and 23 in the aggregates. Antibodies specific to this turn structure could be utilized for immunotherapy and early diagnosis of Alzheimer's disease. Solution NMR analysis of apratoxin A, a cyclic depsipeptide with potent cytotoxicity, proposed an accurate structural model with an important bend structure, which led to the development of highly active mimetics. X-ray crystal analysis of PF1171F, a cyclic hexapeptide with insecticidal activity, indicated the formation of 4 intramolecular hydrogen bonds, which play an important role in cell membrane permeability of PF1171F.
Concise synthesis and in vitro anticancer activity of benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-ones (BBPIs), topoisomerase I inhibitors based on the marine alkaloid lamellarin
Authors: Ishibashi Fumito , Fukuda Tsutomu , Zha Shijiao , Hashirano Aya , Hirao Shotaro , Iwao Masatomo
Published: January 2021

Benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-ones (BBPIs) are potent anticancer compounds having unique BBPIs ring system designed on the basis of the marine natural product lamellarin D. In this study, we describe an alternative synthesis of a 2-demethoxy series of BBPIs, employing van Leusen pyrrole synthesis and an intramolecular Heck reaction as the key reactions. Cytotoxicity of the derivatives against several cancer and normal cell lines is reported.
Ribosome occupancy profiles are conserved between structurally and evolutionarily related yeast domains
Authors: Nissley Daniel A , Carbery Anna , Chonofsky Mark , Deane Charlotte M
Published: January 2021

Motivation

Protein synthesis is a non-equilibrium process, meaning that the speed of translation can influence the ability of proteins to fold and function. Assuming that structurally similar proteins fold by similar pathways, the profile of translation speed along an mRNA should be evolutionarily conserved between related proteins to direct correct folding and downstream function. The only evidence to date for such conservation of translation speed between homologous proteins has used codon rarity as a proxy for translation speed. There are, however, many other factors including mRNA structure and the chemistry of the amino acids in the A- and P-sites of the ribosome that influence the speed of amino acid addition.

Results

Ribosome profiling experiments provide a signal directly proportional to the underlying translation times at the level of individual codons. We compared ribosome occupancy profiles (extracted from five different large-scale yeast ribosome profiling studies) between related protein domains to more directly test if their translation schedule was conserved. Our analysis reveals that the ribosome occupancy profiles of paralogous domains tend to be significantly more similar to one another than to profiles of non-paralogous domains. This trend does not depend on domain length, structural classes, amino acid composition or sequence similarity. Our results indicate that entire ribosome occupancy profiles and not just rare codon locations are conserved between even distantly related domains in yeast, providing support for the hypothesis that translation schedule is conserved between structurally related domains to retain folding pathways and facilitate efficient folding.

Availability and implementation

Python3 code is available on GitHub at https://github.com/DanNissley/Compare-ribosome-occupancy.

Supplementary information

Supplementary data are available at Bioinformatics online.
EARRINGS: an efficient and accurate adapter trimmer entails no a priori adapter sequences
Authors: Wang Ting-Hsuan , Huang Cheng-Ching , Hung Jui-Hung
Published: January 2021

Motivation

Cross-sample comparisons or large-scale meta-analyses based on the next generation sequencing (NGS) involve replicable and universal data preprocessing, including removing adapter fragments in contaminated reads (i.e. adapter trimming). While modern adapter trimmers require users to provide candidate adapter sequences for each sample, which are sometimes unavailable or falsely documented in the repositories (such as GEO or SRA), large-scale meta-analyses are therefore jeopardized by suboptimal adapter trimming.

Results

Here we introduce a set of fast and accurate adapter detection and trimming algorithms that entail no a priori adapter sequences. These algorithms were implemented in modern C++ with SIMD and multithreading to accelerate its speed. Our experiments and benchmarks show that the implementation (i.e. EARRINGS), without being given any hint of adapter sequences, can reach comparable accuracy and higher throughput than that of existing adapter trimmers. EARRINGS is particularly useful in meta-analyses of a large batch of datasets and can be incorporated in any sequence analysis pipelines in all scales.

Availability and implementation

EARRINGS is open-source software and is available at https://github.com/jhhung/EARRINGS.

Supplementary information

Supplementary data are available at Bioinformatics online.
SeeCiTe: a method to assess CNV calls from SNP arrays using trio data
Authors: Lavrichenko Ksenia , Helgeland Øyvind , Njølstad Pål R , Jonassen Inge , Johansson Stefan
Published: January 2021

Motivation

Single nucleotide polymorphism (SNP) genotyping arrays remain an attractive platform for assaying copy number variants (CNVs) in large population-wide cohorts. However, current tools for calling CNVs are still prone to extensive false positive calls when applied to biobank scale arrays. Moreover, there is a lack of methods exploiting cohorts with trios available (e.g. nuclear family) to assist in quality control and downstream analyses following the calling.

Results

We developed SeeCiTe (Seeing CNVs in Trios), a novel CNV-quality control tool that postprocesses output from current CNV-calling tools exploiting child-parent trio data to classify calls in quality categories and provide a set of visualizations for each putative CNV call in the offspring. We apply it to the Norwegian Mother, Father and Child Cohort Study (MoBa) and show that SeeCiTe improves the specificity and sensitivity compared to the common empiric filtering strategies. To our knowledge, it is the first tool that utilizes probe-level CNV data in trios (and singletons) to systematically highlight potential artifacts and visualize signal intensities in a streamlined fashion suitable for biobank scale studies.

Availability and implementation

The software is implemented in R with the source code freely available at https://github.com/aksenia/SeeCiTe

Supplementary information

Supplementary data are available at Bioinformatics online.
Morphological and performance modifications in the world’s only marine lizard, the Galápagos marine iguana,Amblyrhynchus cristatus
Authors: Berry Kate A , Muñoz-Pérez Juan Pablo , Vintimilla-Palacios Cristina P , Clemente Christofer J
Published: January 2021

The Galápagos marine iguana (Amblyrhynchus cristatus), the world’s only extant marine lizard, may have had one of the most unique and challenging transitions to aquatic life. Curiously, previous studies have identified relatively few physiological adaptations in the marine iguana; however, little is known about the extent of morphological specialization and performance trade-offs associated with the marine environment. By examining the morphology and locomotory performance of the marine iguana in comparison to their closely related mainland ancestors, the black spiny-tailed iguana (Ctenosaura similis) and green iguana (Iguana iguana), we found variation reflected specialization to ecological niches. However, variation was more pronounced among subspecies of marine iguana, suggesting that little morphological or performance modification is required for iguanids to successfully invade aquatic environments, thus raising the question why there are so few extant aquatic reptilian lineages. Our findings indicate that specialization for the marine environment likely resulted in a trade-off in sprint speed in a terrestrial environment, which may explain why other lizards have not undergone transitions to the marine environment. Additionally, we found that the magnitude of morphological and performance variation was more pronounced between subspecies of marine iguana than between iguanid species. This illustrates that the form-function relationship is more complex than previously thought and sheds light on the ecomorphological mysteries of the marine iguana.
Toxicant effects on mammalian oocyte mitochondria†
Authors: Malott Kelli F , Luderer Ulrike
Published: January 2021

Oocyte mitochondria are unique organelles that establish a founder population in primordial germ cells (PGCs). As the oocyte matures in the postnatal mammalian ovary during folliculogenesis it increases exponentially in volume, and the oocyte mitochondria population proliferates to about 100 000 mitochondria per healthy, mature murine oocyte. The health of the mature oocyte and subsequent embryo is highly dependent on the oocyte mitochondria. Mitochondria are especially sensitive to toxic insults, as they are a major source of reactive oxygen species (ROS), they contain their own DNA (mtDNA) that is unprotected by histone proteins, they contain the electron transport chain that uses electron donors, including oxygen, to generate ATP, and they are important sensors for overall cellular stress. Here we review the effects that toxic insults including chemotherapeutics, toxic metals, plasticizers, pesticides, polycyclic aromatic hydrocarbons (PAHs), and ionizing radiation can have on oocyte mitochondria. This is very clearly a burgeoning field, as our understanding of oocyte mitochondria and metabolism is still relatively new, and we contend much more research is needed to understand the detrimental impacts of exposure to toxicants on oocyte mitochondria. Developing this field further can benefit our understanding of assisted reproductive technologies and the developmental origins of health and disease (DOHaD).
Casting Light on the Distinctive Contribution of Social Work in Multidisciplinary Teams for Older People
Authors: Willis Paul , Lloyd Liz , Hammond Jackie , Milne Alisoun , Nelson-Becker Holly , Perry Emma , Ray Mo , Richards Sally , Tanner Denise
Published: January 2021

The current policy emphasis in adult social care in England is on promoting independence, preventing or delaying the need for more intensive support and the provision of personalised services. However, there is little evidence available on how social workers (SWs) identify and meet the complex needs of older service users in practice. In this article, we present findings from a study of innovative social work practice with older adults in England (2018–2019). We present five case studies of social care and integrated services in which SWs are integral team members. Twenty-one individuals participated in interviews; this included service managers and practitioners with social work backgrounds, and other professionals, including nurses and occupational therapists. Specific practices contributing to innovative service delivery included: the strong demonstration of social work values influencing the practice of multidisciplinary teams; positive risk management; importance of timing and ensuring continuity of relationships; and, the proactive application of legal knowledge to promote older people’s rights. While some of these features can be seen as returning to the ‘heart’ of social work, we argue that they are promising in forging new paths for social work with older people that turn away from more managerialist- and procedurally driven approaches.
Reinstatement and recircumscription ofJupunbaandPunjuba(Fabaceae) based on phylogenetic evidence
Authors: Soares Marcos Vinicius Batista , Guerra Ethiéne , Morim Marli Pires , Iganci João Ricardo Vieira
Published: January 2021

Among the mimosoid legumes (Fabaceae, Caesalpinioideae, mimosoid clade), many genera have complex nomenclatural histories, including Abarema that stands out due to numerous nomenclatural changes. Abarema is a Neotropical genus that currently comprises c. 50 species, with centres of diversity in the Amazon and Atlantic rain forests. Recent phylogenetic studies of Abarema have demonstrated the non-monophyly of the genus, which was shown to be polyphyletic with species traditionally recognized under the genus placed in three main clades that are intermingled with other genera of the former tribe Ingeae. The type species of Abarema groups with Inga, Macrosamanea, Enterolobiump.p., Zygia and Blanchetiodendron, whereas the other two clades correspond to the former genera Jupunba and Punjuba. The aim of this study is to build a phylogenetic tree of Abarema s.l. supporting the reinstatement of Jupunba and Punjuba, based on morphological and phylogenetic evidence, and to carry out a nomenclatural overhaul of the species and implement necessary typifications. For Punjuba we reinstate three species and add three new combinations. Jupunba comprises 37 species, of which eight are reinstated; in addition, the resurrection of one species with a new synonym is proposed and 29 new combinations are made. In total, 63 taxa are revised, including accepted names, synonyms and excluded names. A taxonomic key is presented for the identification of Punjuba, Jupunba and related genera. We present 40 new combinations, one new taxonomic status and 18 corrections of nomenclature category for lectotypes and two neotypes. One lectotype is designated, one species is reinstated with a new synonym and a second step neotypification is made. We located 97 unreported types during the revision, which are cited here for the first time.
Molecular mechanism mediating enteric bacterial translocation after severe burn: the role of cystic fibrosis transmembrane conductance regulator
Authors: Liu Xinzhu , Chen Yu , You Bo , Peng Yuan , Chen Yajie , Yang Zichen , Zhang Yixin , Chen Jing
Published: January 2021

Background

Gut ischemia and hypoxia post severe burn leads to breakdown of intestinal epithelial barrier and enteric bacterial translocation (EBT), resulting in serious complications, such as systemic inflammatory response syndrome, sepsis and multiple organ failure. Cystic fibrosis transmembrane conductance regulator (CFTR) is known to be downregulated by hypoxia and modulate junctional complexes, which are crucial structures maintaining the intestinal barrier. This study aimed to investigate whether CFTR plays a role in both regulating the intestinal barrier and mediating EBT post severe burn, as well as the signaling pathways involved in these processes.

Methods

An in vitro Caco-2 cell model subjected to hypoxic injury and an in vivo mouse model with a 30% total body surface area full-thickness dermal burn were established. DF 508 mice (mice with F508del CFTR gene mutation) were used as an in vivo model to further demonstrate the role of CFTR in maintaining normal intestinal barrier function. QRT-PCR, western blot, ELISA, TER assay and immunofluorescence staining were used to detect the expression and localization of CFTR and tight junction proteins, as well as the function of tight junctions.

Results

Our data indicated that, in Caco-2 cells, the hypoxia condition significantly reduced CFTR expression; activated extracellular signal-regulated kinase and nuclear factor-κB signaling; elevated secretion of inflammatory factors (tumor necrosis factor-α, interleukin-1β and interleukin-8); downregulated zonula occludens-1, occludin and E-cadherin expression; decreased transepithelial electrical resistance values; and led to a cellular mislocation of ZO-1. More importantly, knockdown of CFTR caused similar alterations. The upregulation of inflammatory factors and downregulation of tight junction proteins (ZO-1 and occludin) induced by knockdown of CFTR could be reversed by specific extracellular signal-regulated kinase or nuclear factor-κB inhibition. In support of the in vitro data, exuberant secretion of pro-inflammatory mediators and EBT was observed in the intestine of severely burnt mice in vivo. EBT occurred in DF508 mice (mice with the F508del CFTR gene mutation), accompanied by augmented tumor necrosis factor-α, interleukin-1β and interleukin-8 levels in the ileum compared to wildtype mice. In addition, vitamin D3 was shown to protect the intestinal epithelial barrier from hypoxic injury.

Conclusions

Collectively, the present study illustrated that CFTR and downstream signaling were critical in modulating the intestinal epithelial junction and EBT post severe burn.
Sulcal Morphology in Cingulate Cortex is Associated with Voluntary Oro-Facial Motor Control and Gestural Communication in Chimpanzees (Pan troglodytes)
Authors: Hopkins William D , Procyk Emmanuel , Petrides Michael , Schapiro Steven J , Mareno Mary Catherine , Amiez Celine
Published: January 2021

Individual differences in sulcal variation within the anterior and mid-cingulate cortex of the human brain, particularly the presence or absence of a paracingulate sulcus (PCGS), are associated with various motor and cognitive processes. Recently, it has been reported that chimpanzees possess a PCGS, previously thought to be a unique feature of the human brain. Here, we examined whether individual variation in the presence or absence of a PCGS as well as the variability in the intralimbic sulcus (ILS) are associated with oro-facial motor control, handedness for manual gestures, and sex in a sample of MRI scans obtained in 225 chimpanzees. Additionally, we quantified the depth of the cingulate sulcus (CGS) along the anterior–posterior axis and tested for association with oro-facial motor control, handedness, and sex. Chimpanzees with better oro-facial motor control were more likely to have a PCGS, particularly in the left hemisphere compared to those with poorer control. Male chimpanzees with better oro-facial motor control showed increased leftward asymmetries in the depth of the anterior CGS, whereas female chimpanzees showed the opposite pattern. Significantly, more chimpanzees had an ILS in the left compared to the right hemisphere, but variability in this fold was not associated with sex, handedness, or oro-facial motor control. Finally, significant population-level leftward asymmetries were found in the anterior portion of the CGS, whereas significant rightward biases were evident in the posterior regions. The collective results suggest that the emergence of a PCGS and enhanced gyrification within the anterior and mid-cingulate gyrus may have directly or indirectly evolved in response to selection for increasing oro-facial motor control in primates.
Development of a Treatment-decision Algorithm for Human Immunodeficiency Virus–uninfected Children Evaluated for Pulmonary Tuberculosis
Authors: Gunasekera Kenneth S , Walters Elisabetta , van der Zalm Marieke M , Palmer Megan , Warren Joshua L , Hesseling Anneke C , Cohen Ted , Seddon James A
Published: January 2021

Background

Limitations in the sensitivity and accessibility of diagnostic tools for childhood tuberculosis contribute to the substantial gap between estimated cases and cases notified to national tuberculosis programs. Thus, tools to make accurate and rapid clinical diagnoses are necessary to initiate antituberculosis treatment in more children.

Methods

We analyzed data from a prospective cohort of children <13 years old being routinely evaluated for pulmonary tuberculosis in Cape Town, South Africa, from March 2012 to November 2017. We developed a regression model to describe the contributions of baseline clinical evaluation to the diagnosis of tuberculosis using standardized, retrospective case definitions. We included baseline chest radiographic and Xpert MTB/RIF assay results to the model to develop an algorithm with ≥90% sensitivity in predicting tuberculosis.

Results

Data from 478 children being evaluated for pulmonary tuberculosis were analyzed (median age, 16.2 months; interquartile range, 9.8–30.9 months); 242 (50.6%) were retrospectively classified with tuberculosis, bacteriologically confirmed in 104 (43.0%). The area under the receiver operating characteristic curve for the final model was 0.87. Clinical evidence identified 71.4% of all tuberculosis cases in this cohort, and inclusion of baseline chest radiographic results increased the proportion to 89.3%. The algorithm was 90.1% sensitive and 52.1% specific, and maintained a sensitivity of >90% among children <2 years old or with low weight for age.

Conclusions

Clinical evidence alone was sufficient to make most clinical antituberculosis treatment decisions. The use of evidence-based algorithms may improve decentralized, rapid treatment initiation, reducing the global burden of childhood mortality.
Chitinase 3 like 1 is a regulator of smooth muscle cell physiology and atherosclerotic lesion stability
Authors: Tsantilas Pavlos , Lao Shen , Wu Zhiyuan , Eberhard Anne , Winski Greg , Vaerst Monika , Nanda Vivek , Wang Ying , Kojima Yoko , Ye Jianqin , Flores Alyssa , Jarr Kai-Uwe , Pelisek Jaroslav , Eckstein Hans-Henning , Matic Ljubica , Hedin Ulf , Tsao Philip S , Paloschi Valentina , Maegdefessel Lars , Leeper Nicholas J
Published: January 2021

Aims 

Atherosclerotic cerebrovascular disease underlies the majority of ischaemic strokes and is a major cause of death and disability. While plaque burden is a predictor of adverse outcomes, plaque vulnerability is increasingly recognized as a driver of lesion rupture and risk for clinical events. Defining the molecular regulators of carotid instability could inform the development of new biomarkers and/or translational targets for at-risk individuals.

Methods and results 

Using two independent human endarterectomy biobanks, we found that the understudied glycoprotein, chitinase 3 like 1 (CHI3L1), is up-regulated in patients with carotid disease compared to healthy controls. Further, CHI3L1 levels were found to stratify individuals based on symptomatology and histopathological evidence of an unstable fibrous cap. Gain- and loss-of-function studies in cultured human carotid artery smooth muscle cells (SMCs) showed that CHI3L1 prevents a number of maladaptive changes in that cell type, including phenotype switching towards a synthetic and hyperproliferative state. Using two murine models of carotid remodelling and lesion vulnerability, we found that knockdown of Chil1 resulted in larger neointimal lesions comprised by de-differentiated SMCs that failed to invest within and stabilize the fibrous cap. Exploratory mechanistic studies identified alterations in potential downstream regulatory genes, including large tumour suppressor kinase 2 (LATS2), which mediates macrophage marker and inflammatory cytokine expression on SMCs, and may explain how CHI3L1 modulates cellular plasticity.

Conclusion 

CHI3L1 is up-regulated in humans with carotid artery disease and appears to be a strong mediator of plaque vulnerability. Mechanistic studies suggest this change may be a context-dependent adaptive response meant to maintain vascular SMCs in a differentiated state and to prevent rupture of the fibrous cap. Part of this effect may be mediated through downstream suppression of LATS2. Future studies should determine how these changes occur at the molecular level, and whether this gene can be targeted as a novel translational therapy for subjects at risk of stroke.
Coronary stent CD31-mimetic coating favours endothelialization and reduces local inflammation and neointimal development in vivo
Authors: Diaz-Rodriguez Sergio , Rasser Charlotte , Mesnier Jules , Chevallier Pascale , Gallet Romain , Choqueux Christine , Even Guillaume , Sayah Neila , Chaubet Frédéric , Nicoletti Antonino , Ghaleh Bijan , Feldman Laurent J , Mantovani Diego , Caligiuri Giuseppina
Published: January 2021

Aims

The rapid endothelialization of bare metal stents (BMS) is counterbalanced by inflammation-induced neointimal growth. Drug-eluting stents (DES) prevent leukocyte activation but impair endothelialization, delaying effective device integration into arterial walls. Previously, we have shown that engaging the vascular CD31 co-receptor is crucial for endothelial and leukocyte homeostasis and arterial healing. Furthermore, we have shown that a soluble synthetic peptide (known as P8RI) acts like a CD31 agonist. The aim of this study was to evaluate the effect of CD31-mimetic metal stent coating on the in vitro adherence of endothelial cells (ECs) and blood elements and the in vivo strut coverage and neointimal growth.

Methods and results

We produced Cobalt Chromium discs and stents coated with a CD31-mimetic peptide through two procedures, plasma amination or dip-coating, both yielding comparable results. We found that CD31-mimetic discs significantly reduced the extent of primary human coronary artery EC and blood platelet/leukocyte activation in vitro. In vivo, CD31-mimetic stent properties were compared with those of DES and BMS by coronarography and microscopy at 7 and 28 days post-implantation in pig coronary arteries (n = 9 stents/group/timepoint). Seven days post-implantation, only CD31-mimetic struts were fully endothelialized with no activated platelets/leukocytes. At day 28, neointima development over CD31-mimetic stents was significantly reduced compared to BMS, appearing as a normal arterial media with the absence of thrombosis contrary to DES.

Conclusion

CD31-mimetic coating favours vascular homeostasis and arterial wall healing, preventing in-stent stenosis and thrombosis. Hence, such coatings seem to improve the metal stent biocompatibility.
All-cause mortality and location of death in patients with established cardiovascular disease before, during, and after the COVID-19 lockdown: a Danish Nationwide Cohort Study
Authors: Butt Jawad H , Fosbøl Emil L , Gerds Thomas A , Andersson Charlotte , Kragholm Kristian , Biering-Sørensen Tor , Andersen Julie , Phelps Mathew , Andersen Mikkel Porsborg , Gislason Gunnar , Torp-Pedersen Christian , Køber Lars , Schou Morten
Published: January 2021

Background

On 13 March 2020, the Danish authorities imposed extensive nationwide lockdown measures to prevent the spread of the coronavirus disease 2019 (COVID-19) and reallocated limited healthcare resources. We investigated mortality rates, overall and according to location, in patients with established cardiovascular disease before, during, and after these lockdown measures.

Methods and results

Using Danish nationwide registries, we identified a dynamic cohort comprising all Danish citizens with cardiovascular disease (i.e. a history of ischaemic heart disease, ischaemic stroke, heart failure, atrial fibrillation, or peripheral artery disease) alive on 2 January 2019 and 2020. The cohort was followed from 2 January 2019/2020 until death or 16/15 October 2019/2020. The cohort comprised 340 392 and 347 136 patients with cardiovascular disease in 2019 and 2020, respectively. The overall, in-hospital, and out-of-hospital mortality rate in 2020 before lockdown was significantly lower compared with the same period in 2019 [adjusted incidence rate ratio (IRR) 0.91, 95% confidence interval (CI) CI 0.87–0.95; IRR 0.95, 95% CI 0.89–1.02; and IRR 0.87, 95% CI 0.83–0.93, respectively]. The overall mortality rate during and after lockdown was not significantly different compared with the same period in 2019 (IRR 0.99, 95% CI 0.97–1.02). However, the in-hospital mortality rate was lower and out-of-hospital mortality rate higher during and after lockdown compared with the same period in 2019 (in-hospital, IRR 0.92, 95% CI 0.88–0.96; out-of-hospital, IRR 1.04, 95% CI1.01–1.08). These trends were consistent irrespective of sex and age.

Conclusions

Among patients with established cardiovascular disease, the in-hospital mortality rate was lower and out-of-hospital mortality rate higher during lockdown compared with the same period in the preceding year, irrespective of age and sex.
Genotype-environment interactions and the maintenance of polygenic variation.
Authors: Gillespie J H , Turelli M
Published: January 2021

Genotype-environment interactions may be a potent force maintaining genetic variation in quantitative traits in natural populations. This is shown by a simple model of additive polygenic inheritance in which the additive contributions of alleles vary with the environment. Under simplifying symmetry assumptions, the model implies that the variance of the phenotypes produced across environments by a multilocus genotype decreases as the number of heterozygous loci increases. In the region of an optimal phenotype, the mapping from the quantitative trait into fitness is concave, and the mean fitness of a genotype will increase with the number of heterozygous loci. This leads to balancing selection, polymorphism, and potentially high levels of additive genetic variance, even though all allelic effects remain additive within each specific environment. An important implication of the model is that the variation maintained by genotype-environment interactions is difficult to study with the restricted range of environments represented in typical experiments. In particular, if fluctuations in allelic effects are pervasive, as suggested by the extensive literature on genotype-environment interactions, efforts to estimate genetic parameters in a single environment may be of limited value.
Repair of single- and multiple-substitution mismatches during recombination in Streptococcus pneumoniae.
Authors: Gasc A M , Sicard A M , Claverys J P
Published: January 2021

The use as genetic markers, during transformation of Streptococcus pneumoniae, of 19 sequences differing from wild type, located throughout the amiA locus, enabled us to examine the fate of 24 single- and 11 multiple-mismatches during recombination. Tentative mismatch ranking as a function of decreasing repair efficiency by the Hex mismatch repair system is G/T = A/C = G/G (maximum repair: 90-95%) greater than C/T (mostly 75 to 90% repair) greater than A/A (from 50 to 90% repair) greater than T/T (50-65% repair) greater than A/G (from 0 to 20% repair) greater than C/C. No indication of correction of the latter has been obtained. Over the limited number of samples examined, we observed no influence of the base composition of the surrounding sequence on correction efficiency for both transition mismatches and for G/G and C/C. Variations in the surrounding sequence affect repair of A/G and C/T, and, even more strongly, of A/A and T/T. No simple correlation to the G:C content of the surrounding sequence is apparent from our results, in contrast to the conclusion drawn for the Mut mismatch repair system of Escherichia coli. Examination of the fate of multiple mismatches suggests that C/C may sometimes impede recognition of otherwise corrected mismatches.
Hybrid dysgenesis in Drosophila simulans lines transformed with autonomous P elements.
Authors: Daniels S B , Chovnick A , Kidwell M G
Published: January 2021

The molecular and phenotypic analysis of several previously described P element-transformed lines of Drosophila simulans was extended in order to determine whether they had the potential to produce a syndrome of P-M hybrid dysgenesis analogous to the one in Drosophila melanogaster. The transformed line with the highest number of P elements at the beginning of the analysis, DsP pi-5C, developed strong P activity potential and P element regulation, properties characteristic of D. melanogaster P strains. The subsequent analysis of sublines derived from 34 single pair matings of DsP pi-5C revealed that they were heterogeneous with respect to both their P element complements and P activity potentials, but similar with respect to their regulatory capabilities. The subline with the highest P activity, DsP pi-5C-27, was subsequently used as a reference P strain in the genetic analysis of the D. simulans transformants. In these experiments, the reciprocal cross effect was observed with respect to both gonadal sterility and male recombination. As in D. melanogaster, the induction of gonadal sterility in D. simulans was shown to be temperature-dependent. Molecular analysis of DsP pi-5C-27 revealed that it has approximately 30 P elements per genome, at least some of which are defective. The number of potentially complete P elements in its genome is similar to the number in the D. melanogaster P strain, Harwich-77. Overall our analysis indicates that P-transformed lines of D. simulans are capable of expressing the major features of P-M hybrid dysgenesis previously demonstrated in D. melanogaster and that P elements appear to behave in a similar way in the two sibling species.
Phage genetic sites involved in lambda growth inhibition by the Escherichia coli rap mutant.
Authors: Guzmán P , Guarneros G
Published: January 2021

The rap mutation of Escherichia coli prevents the growth of bacteriophage lambda. We have isolated phage mutants that compensate for the host deficiency. The mutations, named bar, were genetically located to three different loci of the lambda genome: barI in the attP site, barII in the cIII ea10 region, and barIII within or very near the imm434 region. The level of lambda leftward transcription correlates with rap exclusion. Phage lambda mutants partially defective in the pL promoter or in pL-transcript antitermination showed a Bar- phenotype. Conversely, mutants constitutive for transcription from the pI or pL promoters were excluded more stringently by rap bacteria. We conclude that rap exclusion depends on the magnitude of transcription through the wild type bar loci in the phage genome.
The maintenance of genetic variability in two-locus models of stabilizing selection.
Authors: Nagylaki T
Published: January 2021

The maintenance of genetic variability at two diallelic loci under stabilizing selection is investigated. Generations are discrete and nonoverlapping; mating is random; mutation and random genetic drift are absent; selection operates only through viability differences. The determination of the genotypic values is purely additive. The fitness function has its optimum at the value of the double heterozygote and decreases monotonically and symmetrically from its optimum, but is otherwise arbitrary. The resulting fitness scheme is identical to the symmetric viability model. Linkage disequilibrium is neglected, but the results are otherwise exact. Explicit formulas are found for all the equilibria, and explicit conditions are derived fro their existence and stability. A complete classification of the six possible global convergence patterns is presented. In addition to the symmetric equilibrium (with gene frequency 1/2 at both loci), a pair of unsymmetric equilibria may exist; the latter are usually, but not always, unstable. If the ratio of the effect of the major locus to that of the minor one exceeds a critical value, both loci will be stably polymorphic. If selection is weak at the minor locus, the more rapidly the fitness function decreases near the optimum, the lower is this critical value; for rapidly decreasing fitness functions, the critical value is close to one. If the fitness function is smooth at the optimum, then a stable polymorphism exists at both loci only if selection is strong at the major locus.
Genetic and physical analysis of plasmid recombination in recB recC sbcB and recB recC sbcA Escherichia coli K-12 mutants.
Authors: Luisi-DeLuca C , Lovett S T , Kolodner R D
Published: January 2021

The effect of mutations in known recombination genes (recA, recB, recC, recE, recF, recJ, recN, recO, recQ and ruv) on intramolecular recombination of plasmids was studied in recB recC sbcB and recB recC sbcA Escherichia coli mutants. The rate of recombination of circular dimer plasmids was at least 1000-fold higher in recB recC sbcB or recB recC sbcA mutants as compared to wild-type cells. The rate was decreased by mutations in recA, recF, recJ, recO, ruv or mutS in recB recC sbcB mutants, and by mutations in recE, recN, recO, recQ, ruv or mutS in recB recC sbcA mutants. In addition to measuring the recombination rate of circular dimer plasmids, the recombination-mediated transformation of linear dimer plasmids was also studied. Linear dimer plasmids transformed recB recC sbcB and recB recC sbcA mutants 20- to 40-fold more efficiently than wild-type cells. The transformation efficiency of linear dimer plasmids in recB recC sbcB mutants was decreased by mutations in recA, recF, recJ, recO, recQ or lexA (lexA3). In recB recC sbcA mutants the transformation efficiency of linear dimers was decreased only by a recE mutation. Physical analysis of linear dimer- or circular dimer-transformed recB recC sbcB mutants revealed that all transformants contained recombinant monomer genotypes. This suggests that recombination in recB recC sbcB cells is very efficient.
Mutations at the smo genetic locus affect the shape of diverse cell types in the rice blast fungus.
Authors: Hamer J E , Valent B , Chumley F G
Published: January 2021

Teflon film surfaces are highly conducive to the formation of infection structures (appressoria) in the plant pathogenic fungus, Magnaporthe grisea. We have utilized Teflon films to screen and select for mutants of M. grisea that are defective in appressorium formation. This approach and several others yielded a group of 14 mutants with a similar phenotype. All the mutant strains make abnormally shaped conidia and appressoria. When two mutant strains are crossed, abnormally shaped asci are formed. Ascus shape is normal when a mutant strain is crossed with a wild-type strain. Despite dramatic alterations in cell shape these strains otherwise grow, form conidia, undergo meiosis, and infect plants normally. This mutant phenotype, which we have termed Smo(-), for abnormal spore morphology, segregates in simple Mendelian fashion in crosses with wild-type strains. Some ascospore lethality is associated with smo mutations. In genetic crosses between mutants, smo mutations fail to recombine and do not demonstrate complementation of the abnormal ascus shape phenotype. We conclude that the smo mutations are alleles of a single genetic locus and are recessive with regard to the the ascus shape defect. Mutations at the SMO locus also permit germinating M. grisea conidia to differentiate appressoria on surfaces that are not normally conducive to infection structure formation. A number of spontaneous smo mutations have been recovered. The frequent occurrence of this mutation suggests that the SMO locus may be highly mutable.