bluuebunny/crossref_metadata_2025 huggingface dataset:
TARGET-HF: Developing a model for detecting incident heart failure among symptomatic patients in general practice using routine health care data
Authors: De Clercq Lukas , Schut Martijn C. , Bossuyt Patrick , van Weert Henk , Handoko M. Louis , Harskamp Ralf
Published: March 2022

Background

Timely diagnosis of heart failure (HF) is essential to optimize treatment opportunities that improve symptoms, quality of life, and survival. While most patients consult their general practitioner (GP) prior to HF, early stages of HF may be difficult to identify. An integrated clinical support tool may aid in identifying patients at high risk of HF. We therefore constructed a prediction model using routine health care data.

Methods

Our study involved a dynamic cohort of patients (≥35 years) who consulted their GP with either dyspnea and/or peripheral edema within the Amsterdam metropolitan area in 2011-2020. The outcome of interest was incident HF, verified by an expert panel. We developed a regularized multivariable proportional hazards model (TARGET-HF). The model was evaluated with bootstrapping on an isolated validation set and compared to an existing model developed with hospital insurance data as well as patient age as a sole predictor.

Results

Data from 31,905 patients were included (40% male, median age 60) of whom 1,301 (4.1%) were diagnosed with HF over 124,676 person-years of follow-up. Data were allocated to a development (n=25,524) and validation (n=6,381) set. TARGET-HF attained a C-statistic of 0.853 (95%-CI:0.834-0.872) on the validation set, which proved to provide a better discrimination than C=0.822 for age alone (95% CI:0.801-0.842, p<0.001) and C=0.824 for the hospital-based model (95% CI:0.802-0.843, p<0.001).

Conclusion

The TARGET-HF model illustrates that routine consultation codes can be used to build a performant model to identify patients at risk for HF at time of GP consultation.
An immune dysfunction score for stratification of patients with acute infection based on whole blood gene expression
Authors: Cano-Gamez Eddie , Burnham Katie L , Goh Cyndi , Malick Zunaira H , Kwok Andrew , Smith David A , Peters-Sengers Hessel , Antcliffe David ,   GAinS Investigators, McKechnie Stuart , Scicluna Brendon P , van der Poll Tom , Gordon Anthony C , Hinds Charles J , Davenport Emma E , Knight Julian C
Published: March 2022

Dysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of deaths globally each year. To alleviate this burden, improved prognostication and biomarkers of response are urgently needed. We investigated the use of whole blood transcriptomics for stratification of patients with severe infection by integrating data from 3,149 samples of sepsis patients and healthy individuals into a gene expression reference map. We used this map to derive a quantitative sepsis response signature (SRSq) score reflective of immune dysfunction and predictive of clinical outcomes, which can be estimated using a 19-gene signature. Finally, we built a machine learning framework, SepstratifieR, to deploy SRSq in sepsis, H1N1 influenza, and COVID-19, demonstrating clinically relevant stratification across diseases and revealing the physiological alterations linking immune dysregulation to mortality. Our method enables early identification of individuals with dysfunctional immune profiles, thus bringing us closer to precision medicine in infection.
Bone morphogenetic protein 2 is a new molecular target linked to nonalcoholic fatty liver disease with potential value as non-invasive screening tool
Authors: Marañón Patricia , Fernández-García Carlos Ernesto , Isaza Stephania C , Rey Esther , Gallego-Durán Rocío , Montero-Vallejo Rocío , Rodríguez de Cía Javier , Ampuero Javier , Romero-Gómez Manuel , García-Monzón Carmelo , González-Rodríguez Águeda
Published: March 2022

Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide, being nonalcoholic steatohepatitis (NASH) its most clinically relevant form. Given the risks associated with taking a liver biopsy, the design of accurate non-invasive methods to identify NASH patients is of upmost importance. BMP2 plays a key role in metabolic homeostasis; however, little is known about its involvement in NAFLD onset and progression. This study aimed to elucidate the impact of BMP2 in NAFLD pathophysiology. Hepatic and circulating levels of BMP2 were quantified in serum and liver specimens from 115 biopsy-proven NAFLD patients and 75 subjects with histologically normal liver (NL). In addition, BMP2 content and release was determined in cultured human hepatocytes upon palmitic acid (PA) overload. We found that BMP2 expression was abnormally increased in livers from NAFLD patients than in subjects with NL and this was reflected in higher serum BMP2 levels. Notably, we observed that PA upregulated BMP2 expression and secretion by human hepatocytes. An algorithm based on serum BMP2 levels and clinically relevant variables to NAFLD showed an AUROC of 0.886 (95%CI, 0.83–0.94) to discriminate NASH. We used this algorithm to develop SAN (Screening Algorithm for NASH): a SAN < 0.2 implied a low risk and a SAN ≥ 0.6 indicated high risk of NASH diagnosis. This proof-of-concept study shows BMP2 as a new molecular target linked to NAFLD and introduces SAN as a simple and efficient algorithm to screen individuals at risk for NASH.
Plasma iron controls neutrophil production and function
Authors: Frost Joe N. , Wideman Sarah K. , Preston Alexandra E. , Teh Megan R , Ai Zhichao , Wang Lihui , Cross Amy , White Natasha , Yazicioglu Yavuz , Bonadonna Michael , Clarke Alexander J. , Armitage Andrew E. , Galy Bruno , Udalova Irina A. , Drakesmith Hal
Published: March 2022

Low plasma iron (hypoferremia) induced by hepcidin is a conserved inflammatory response that protects against infections but inhibits erythropoiesis. How hypoferremia influences leukocytogenesis is unclear. Using proteomic data, we predicted that neutrophil production would be profoundly more iron-demanding than generation of other white blood cell types. Accordingly in mice, hepcidin-mediated hypoferremia substantially reduced numbers of granulocytes but not monocytes, lymphocytes or dendritic cells. Neutrophil rebound after anti-GR1-induced neutropenia was blunted during hypoferremia, but was rescued by supplemental iron. Similarly, hypoferremia markedly inhibited pharmacologically-stimulated granulopoiesis mediated by GCSF and inflammation-induced accumulation of neutrophils in the spleen and peritoneal cavity. Furthermore, hypoferremia specifically altered neutrophil effector functions, suppressing antibacterial mechanisms but enhancing mitochondrial ROS-dependent NETosis associated with chronic inflammation. Notably, antagonising endogenous hepcidin during acute inflammation enhanced production of neutrophils. We propose plasma iron modulates the profile of innate immunity by controlling monocyte-to-neutrophil ratio and neutrophil activity in a therapeutically targetable system.
Inka2, a novel Pak4 inhibitor, regulates actin dynamics in neuronal development
Authors: Yamada Seiya , Mizukoshi Tomoya , Tokunaga Akinori , Sakakibara Shin-ichi
Published: March 2022

The actin filament is a fundamental part of the cytoskeleton defining cell morphology and regulating various physiological processes, including filopodia formation and dendritic spinogenesis of neurons. Serine/threonine-protein kinase Pak4, an essential effector, links Rho GTPases to control actin polymerization. Previously, we identified the Inka2 gene, a novel mammalian protein exhibiting sequence similarity to Inka1, which serves as a possible inhibitor for Pak4. Although Inka2 is dominantly expressed in the nervous system and involved in focal-adhesion dynamics, its molecular role remains unclear. Here, we found that Inka2-iBox directly binds to Pak4 catalytic domain to suppress actin polymerization. Inka2 promoted actin depolymerization and inhibited the formation of cellular protrusion caused by Pak4 activation. We further generated the conditional knockout mice of the Inka2 gene. The beta-galactosidase reporter indicated the preferential Inka2 expression in the dorsal forebrain neurons. Cortical pyramidal neurons of Inka2-/- mice exhibited decreased density and aberrant morphology of dendritic spines with marked activation/phosphorylation of downstream molecules of Pak4 signal cascade, including LIMK and cofilin. These results uncovered the unexpected function of endogenous Pak4 inhibitor in neurons. Unlike Inka1, Inka2 is a critical mediator for actin reorganization required for dendritic spine development.
Coverage-preserving sparsification of overlap graphs for long-read assembly
Authors: Jain Chirag
Published: March 2022

Read-overlap-based graph data structures play a central role in computing de novo genome assembly using long reads. Many assembly tools use the string graph model [Myers, Bioinformatics 2005] to sparsify overlap graphs. Graph sparsification improves accuracy by removing spurious and redundant connections. However, a graph model must be coverage-preserving, i.e., it must ensure that each chromosome can be spelled as a walk in the graph, given sufficient sequencing coverage. This property becomes even more important for diploid genomes, polyploid genomes and metagenomes where there is a risk of losing haplotype-specific information.

We develop a novel theoretical framework under which the coverage-preserving properties of a graph model can be analysed. We first prove that de Bruijn graph and overlap graph models are guaranteed to be coverage-preserving. We also show that the standard string graph model lacks this guarantee. The latter result is consistent with the observation made in [Hui et al. ISIT’16] that removal of contained reads during string graph construction can lead to coverage gaps. To remedy this, we propose practical heuristics that are well-supported by our theoretical results to sparsify overlap graphs. In our experiments conducted by using simulated long reads from HG002 human diploid genome, we find that 50 coverage gaps are introduced on average by ignoring contained reads from nanopore datasets. We tested the proposed heuristics for deciding which contained reads should be retained to avoid the coverage gaps. The proposed method retains a small fraction of contained reads (1 – 2%) and closes majority of the coverage gaps.
A single amino acid transporter controls the uptake of priming-inducing beta-amino acids and the associated trade-off between induced resistance and plant growth
Authors: Tao Chia-Nan , Buswell Will , Zhang Peijun , Walker Heather , Johnson Irene , Schwarzenbacher Roland , Ton Jurriaan
Published: March 2022

Selected beta-amino acids, such as beta-aminobutyric acid (BABA) and R-beta-homoserine (RBH), can prime plants for resistance against broad-spectrum diseases. Here, we describe a genome-wide screen of fully annotated Arabidopsis T-DNA insertion lines for impaired in RBH-induced immunity (iri) against the downy mildew pathogenHyaloperonospora arabidopsidis, yielding 104 lines that were partially affected and 4 lines that were completely impaired in RBH-induced resistance. Theiri1-1mutant phenotype could be confirmed by an independent T-DNA insertion in the same gene, encoding the high-affinity amino acid transporter LHT1. Using uptake experiments withIRI1/LHT1-expressing yeast cells and mass spectrometry-based quantification of RBH and BABA in leaves of mutant and over-expression lines ofIRI1/LHT1, we demonstrate that IRI1/LHT1 acts as the main transporter for cellular uptake and systemic distribution of RBH and BABA. Subsequent characterisation of mutant and over-expression lines ofIRI1/LHT1for induced resistance and growth responses revealed that the level ofIRI1/LHT1expression determines the trade-off between induced resistance and plant growth by RBH and BABA.
Glial control of sphingolipid levels sculpts diurnal remodeling of circadian circuits
Authors: Vaughen John P. , Theisen Emma , Rivas-Sema Irma Magaly , Berger Andrew B. , Kalakuntla Prateek , Anreiter Ina , Mazurak Vera C. , Rodriguez Tamy Portillo , Mast Joshua D , Hartl Tom , Perlstein Ethan O. , Reimer Richard J. , Clandinin M. Thomas , Clandinin Thomas R.
Published: March 2022

Structural plasticity in the brain often necessitates dramatic remodeling of neuronal processes and attendant reorganization of the cytoskeleton and membranes. While cytoskeletal restructuring has been studied extensively, how lipids might orchestrate structural plasticity remains unclear. We show that specific glial cells in Drosophila produce Glucocerebrosidase (GBA) to locally catabolize sphingolipids. Sphingolipid accumulation drives lysosomal dysfunction, causing gba1b mutants to harbor protein aggregates that cycle across circadian time and are regulated by neural activity, the circadian clock, and sleep. While the vast majority of membrane lipids are stable across the day, a specific subset, highly enriched in sphingolipids, cycles daily in a gba1b-dependant fashion. In parallel, circadian clock neurons remodel their neurites, growing and shrinking across the day to shape circadian behavior. Remarkably, this neuronal remodeling relies on a cycle of temporally offset sphingolipid biosynthesis and catabolism. Thus, dynamic sphingolipid regulation by glia enables diurnal circuit remodeling and proper circadian behavior.
Whole-brain comparison of rodent and human brains using spatial transcriptomics
Authors: Beauchamp Antoine , Yee Yohan , Darwin Ben , Raznahan Armin , Mars Rogier B. , Lerch Jason P.
Published: March 2022

The ever-increasing use of mouse models in preclinical neuroscience research calls for an improvement in the methods used to translate findings between mouse and human brains. Using openly accessible brain-wide transcriptomic data sets, we evaluated the similarity of mouse and human brain regions on the basis of homologous gene expression. Our results suggest that mouse-human homologous genes capture broad patterns of neuroanatomical organization, but that the resolution of cross-species correspondences can be improved using a novel supervised machine learning approach. Using this method, we demonstrate that sensorimotor subdivisions of the neocortex exhibit greater similarity between species, compared with supramodal sub-divisions, and that mouse isocortical regions separate into sensorimotor and supramodal clusters based on their similarity to human cortical regions. We also find that mouse and human striatal regions are strongly conserved, with the mouse caudoputamen exhibiting an equal degree of similarity to both the human caudate and putamen.
DISTINCTIVE FEATURES OF THE RESPIRATORY SYNCYTIAL VIRUS PRIMING LOOP COMPARED TO OTHER NON-SEGMENTED NEGATIVE STRAND RNA VIRUSES
Authors: Cressey Tessa N. , Shareef Afzaal M. , Kleiner Victoria A. , Noton Sarah L. , Byrne Patrick O. , McLellan Jason S. , Muhlberger Elke , Fearns Rachel
Published: March 2022

De novo initiation by viral RNA-dependent RNA polymerases often requires a polymerase priming residue, located within a priming loop, to stabilize the initiating NTPs. Polymerase structures from three different non-segmented negative strand RNA virus (nsNSV) families revealed putative priming loops in different conformations, and an aromatic priming residue has been identified in the rhabdovirus polymerase. In a previous study of the respiratory syncytial virus (RSV) polymerase, we found that Tyr1276, the L protein aromatic amino acid residue that most closely aligns with the rhabdovirus priming residue, is not required for RNA synthesis but two nearby residues, Pro1261 and Trp1262, were required. In this study, we examined the roles of Pro1261 and Trp1262 in RNA synthesis initiation. Biochemical studies showed that substitution of Pro1261 inhibited RNA synthesis initiation without inhibiting back-priming, indicating a defect in initiation. Biochemical and minigenome experiments showed that the initiation defect incurred by a P1261A substitution could be rescued by factors that would be expected to increase the stability of the initiation complex, specifically increased NTP concentration, manganese, and a more efficient promoter sequence. These findings indicate that Pro1261 of the RSV L protein plays a role in initiation, most likely in stabilizing the initiation complex. However, we found that substitution of the corresponding proline residue in a filovirus polymerase had no effect on RNA synthesis initiation or elongation. These results indicate that despite similarities between the nsNSV polymerases, there are differences in the features required for RNA synthesis initiation.

Author Summary

RSV has a significant impact on human health. It is the major cause of respiratory disease in infants and exerts a significant toll on the elderly and immunocompromised. RSV is a member of the Mononegavirales, the non-segmented, negative strand RNA viruses (nsNSVs). Like other viruses in this order, RSV encodes an RNA dependent RNA polymerase, which is responsible for transcribing and replicating the viral genome. Due to its essential role during the viral replication cycle, the polymerase is a promising candidate target for antiviral inhibitors and so a greater understanding of the mechanistic basis of its activities could aid antiviral drug development. In this study, we identified an amino acid residue within the RSV polymerase that appears to stabilize the RNA synthesis initiation complex and showed that it plays a role in both transcription and RNA replication. However, the corresponding residue in a different nsNSV polymerase does not appear to play a similar role. This work reveals a key feature of the RSV polymerase but identifies differences with the polymerases of other related viruses.
Post-transcriptional regulation by copper with a new upstream Open Reading Frame
Authors: Roy Gauthier , Antoine Rudy , Schwartz Annie , Slupek Stéphanie , Rivera-Millot Alex , Boudvillain Marc , Jacob-Dubuisson Françoise
Published: March 2022

Copper is essential to most living beings but also toxic. Bacteria have thus developed homeostatic mechanisms to tightly control its intracellular concentration. The 3-gene operon bp2923-bfrG-bp2921 is down-regulated by copper and notably encodes a TonB-dependent transporter in Bordetella pertussis. We show that the protein encoded by bp2923, which is a member of the DUF2946 family, represents a new type of upstream Open Reading Frame (uORF) involved in post-transcriptional regulation of the downstream genes. In the absence of copper, the entire operon is transcribed and translated. Perception of copper by the nascent bp2923-coded protein via its conserved CXXC motif triggers Rho-dependent transcription termination between the first and second genes by relieving translation arrest on a conserved C-terminal RAPP motif. Homologues of bp2923 are widespread in bacterial genomes, where they head operons predicted to participate in copper homeostasis. This work has unveiled an original mode of genetic regulation by a transition metal and identified a regulatory function for a member of an uncharacterized family of bacterial proteins that we have named CruR, for copper-responsive upstream regulator.
The coordination between penicillin-binding protein 1a (PBP1a) and the hydrolytic peptidase DacB determines the integrity of bacterial cell poles
Authors: Zhang Huan , Venkatesan Srutha , Ng Emily , Nan Beiyan
Published: March 2022

Peptidoglycan (PG) defines cell shape and protects bacteria against osmotic stress. The growth and integrity of PG require coordinated actions between synthases that insert new PG strands and hydrolases that generate openings to allow the insertion. However, the mechanisms of their coordination remain elusive. Here we show that moenomycin that inhibits a family of PG synthases known as Class-A penicillin-binding proteins (aPBPs), triggers cell lysis despite aPBPs being non-essential for cell integrity. We demonstrate that inhibited PBP1a2, an aPBP, accelerates the degradation of cell poles by DacB, a hydrolytic PG peptidase, in the bacterium Myxococcus xanthus. Moenomycin reduces the mobility of DacB molecules through PBP1a2, potentially promoting the binding between DacB and PG. Conversely, DacB also regulates the distribution and dynamics of aPBPs. These findings reveal the lethal action of moenomycin and suggest that disrupting the coordination between PG synthases and hydrolases could be more lethal than eliminating individual enzymes.
Female reproductive fluid composition differs based on mating system in Peromyscus mice
Authors: Hook Kristin A. , Liu Catherine , Joyner Katherine A. , Duncan Gregg A. , Fisher Heidi S.
Published: March 2022

Post-copulatory sexual selection is theorized to favor female traits that allow them to control sperm use and fertilization, leading to the prediction that female reproductive traits that influence sperm migration should differ between polyandrous and monogamous species. Here we exploit natural variation in the female mating strategies of closely related Peromyscus mice to compare female traits that influence sperm motility – the viscosity, pH, and calcium concentration of fluids in the reproductive tract – between polyandrous and monogamous species. We find that the viscosity and pH, but not calcium concentration, of fluids collected from both the uterus and the oviduct significantly differ between species based on mating system. Our results demonstrate the existence of a viscosity gradient within the female reproductive tract that increases in monogamous species but decreases in polyandrous species. Both species have a more alkaline environment in the uterus than oviduct, but only in the polyandrous species did we observe a decrease in calcium in the distal end of the tract. These results suggest that fluid viscosity and pH in the female reproductive tracts of these mice may be influenced by post-copulatory sexual selection and provide a promising potential mechanism for female sperm control given their importance in modulating sperm behavior.
Breakthrough Covid-19 cases despite tixagevimab and cilgavimab (Evusheld™) prophylaxis in kidney transplant recipients
Authors: Benotmane Ilies , Velay Aurélie , Vargas Gabriela Gautier , Olagne Jérôme , Fafi-Kremer Samira , Thaunat Olivier , Caillard Sophie
Published: March 2022

While the combination of casirivimab-imdevimab (Ronapreve™ Roche Regeneron) has been shown to confer satisfactory protection against the delta variant kidney transplant recipients (KTRs) with COVID-19, it has limited neutralizing activity against the current variants of concern (Omicron BA.1, BA.1.1 and BA.2). In contrast, cilgavimab-tixagevimab combination (Evusheld™, Astra Zeneca) retains a partial neutralizing activity against omicron in vitro. We examined whether preexposure prophylaxis with Evusheld™ can effectively protect kidney transplant recipients (KTRs) against the Omicron variant.

Of the 416 KTRs who received intramuscular prophylactic injections of Evusheld™ (150 mg tixagevimab and 150 mg cilgavimab), 39 (9.4%) developed COVID-19. With the exception of one patient, all KTRs were symptomatic. Hospitalization and admission to an intensive care unit were required for 14 (35.9%) and three patients, respectively. Two KTRs died of COVID-19-related acute respiratory distress syndrome. SARS-CoV-2 sequencing was carried out in 15 cases (BA.1, n = 5; BA.1.1, n = 9; BA.2, n=1). Viral neutralizing activity of the serum against BA.1 variant was negative in the 12 tested patients, suggesting that this prophylaxis strategy provides insufficient protection against this variant of concern.

Preexposure prophylaxis with Evusheld™ does not adequately protect KTRs against Omicron. Further clarification of the optimal dosing can assist in our understanding of how best to harness its protective potential.
Reproductive skew, fighting costs and winner–loser effects in social dominance evolution
Authors: Leimar Olof , Bshary Redouan
Published: March 2022

Social hierarchies are often found in group‐living animals and can be formed through pairwise aggressive interactions. The dominance rank can influence reproductive success (RS) with a skew towards high‐ranking individuals.

Using game theory, we investigate how the opportunity for differently ranked individuals to achieve RS influences the costs of hierarchy formation and the strength of winner and loser effects.

In our model, individuals adjust their aggressive and submissive behaviour towards others through reinforcement learning. The learning is based on rewards and penalties, which depend on relative fighting ability. From individual‐based simulations, we determine evolutionary equilibria of traits such as learning rates. We examine situations that differ in the extent of monopolisation of contested RS by dominants and in the proportion of total RS that is contested.

The model implements two kinds of fighting costs: a decrease in effective fighting ability from damage (loss of condition) and a risk of mortality that increases with the total accumulated damage. Either of these costs can limit the amount of fighting.

We find that individuals form stable dominance hierarchies, with a positive correlation between dominance position and fighting ability. The accumulated costs differ between dominance positions, with the highest costs paid by low or intermediately ranked individuals. Costs tend to be higher in high‐skew situations.

We identify a ‘stay‐in, opt‐out’ syndrome, comprising a range from weaker (stay‐in) to stronger (opt‐out) winner–loser effects. We interpret the opt‐out phenotype to be favoured by selection on lower ranked individuals to opt out of contests over social dominance, because it is more pronounced when more of the total RS is uncontested.

We discuss our results in relation to field and experimental observations and argue that there is a need for empirical investigation of the behaviour and reproductive success of lower ranked individuals.
Abundant and persistent sulfur‐oxidizing microbial populations are responsive to hypoxia in the Chesapeake Bay
Authors: Arora‐Williams Keith , Holder Christopher , Secor Maeve , Ellis Hugh , Xia Meng , Gnanadesikan Anand , Preheim Sarah P.
Published: March 2022

The number, size and severity of aquatic low‐oxygen dead zones are increasing worldwide. Microbial processes in low‐oxygen environments have important ecosystem‐level consequences, such as denitrification, greenhouse gas production and acidification. To identify key microbial processes occurring in low‐oxygen bottom waters of the Chesapeake Bay, we sequenced both 16S rRNA genes and shotgun metagenomic libraries to determine the identity, functional potential and spatiotemporal distribution of microbial populations in the water column. Unsupervised clustering algorithms grouped samples into three clusters using water chemistry or microbial communities, with extensive overlap of cluster composition between methods. Clusters were strongly differentiated by temperature, salinity and oxygen. Sulfur‐oxidizing microorganisms were found to be enriched in the low‐oxygen bottom water and predictive of hypoxic conditions. Metagenome‐assembled genomes demonstrate that some of these sulfur‐oxidizing populations are capable of partial denitrification and transcriptionally active in a prior study. These results suggest that microorganisms capable of oxidizing reduced sulfur compounds are a previously unidentified microbial indicator of low oxygen in the Chesapeake Bay and reveal ties between the sulfur, nitrogen and oxygen cycles that could be important to capture when predicting the ecosystem response to remediation efforts or climate change.
Beyond the pest: Life history, ecology and ethnoentomology of the giant wood moth (Endoxyla cinereus)
Authors: Thurman Jessa H.
Published: March 2022

The giant wood moth,Endoxyla cinereus(Tepper, 1890) (Cossidae: Zeuzerinae), is the heaviest known moth in the world and a traditional food resource to Indigenous Australians, but it is primarily understood as a pest. Research on its pest status has highlighted the different interactions this moth has with plants and animals, suggesting that it plays an important role in Australian ecosystems. Here, I review the literature onEndoxyla cinereusto compile and illustrate its life history and species‐specific ecological interactions for the first time. This life history is then applied to interpret the ecological role that this species plays in shaping forest communities, serving as a key food resource to other animals and creating habitat in the form of tree hollows. Based on this, the giant wood moth is an ecosystem engineer. The human impact of this species is then reviewed including indigenous use ofE. cinereusand otherEndoxylaspp., and the forestry pest status of these moths. Consideration of the moth's long, cryptic life history reveals the scientific knowledge possessed by Indigenous Australians on harvesting wood moth larvae, while future studies on earlier life stages and pest, identity may aid the development of sustainable pest management. Finally, the taxonomic status ofEndoxyla cinereusis briefly discussed, as previous research suggests the presence of either cryptic or misidentified species. Future research on the giant wood moth may aid both natural and cultural conservation programmes and provide novel solutions for managing the species as a pest. This review provides a framework for studying the giant wood moth and documenting the life history of other wood moths.
Comparison of immune defense and antioxidant capacity between broodstock and hybrid offspring of juvenile shrimp (Macrobrachium nipponense): Response to acute ammonia stress
Authors: Li Yiming , Xiang Yuqian , Jiang Qichen , Yang Ying , Huang Yingying , Fan Wujiang , Zhao Yunlong
Published: March 2022

Ammonia is a major environmental pollutant in the aquatic system that poses a great threat to the health of shrimp. Macrobrachium nipponense, as one of the large‐yield farmed shrimp, is facing germplasm degradation. Genetic improvement through hybridization is one of the effective methods to solve this problem. However, there are few studies on the effects of ammonia nitrogen on the germplasm resources of M. nipponense. In this study, the broodstock populations (Dianshan, DS) and hybrid offspring (DS ♀ × CD [Changjiang, CJ ♂ × Dongting, DT ♀], SCD) were exposed to 0, 5, or 20 mg/L of ammonia for 96 h. The survival rate of the SCD group was greater than the DS group, although there were no significant differences in weight gain rate and length gain rate (p > 0.05). The number of positive cells and apoptosis rates in the DS group were significantly greater than in the SCD group after ammonia exposure (p < 0.05). As the ammonia concentration increased, the antioxidant enzyme activities in the SCD group were significantly higher than DS group, while the hepatotoxicity enzyme activities in the SCD group were significantly lower than DS group (p < 0.05). The trends in the expression of antioxidant‐ and immune‐related genes were generally consistent with the activities of antioxidant enzymes. Our study found that the hybrid population had stronger stress resistance than their parent populations at the same ammonia concentration. This study confirms our speculation that hybrid population has a greater advantage in antioxidant immunity, which also provides reference for the follow‐up study of chronic ammonia toxicity.
Evaluation of adherence monitoring in buprenorphine treatment: A pilot study using timed drug assays to determine accuracy of testing
Authors: Jamshidi Nazila , Athavale Akshay , Tremonti Christopher , McDonald Catherine , Banukumar Shanmugam , Vazquez Santiago , Luquin Natasha , Santiago Marina , Murnion Bridin
Published: March 2022

Aims

Buprenorphine is effective at reducing relapse to opioid misuse, morbidity and mortality in opioid‐dependent patients. Urine drug screening (UDS) to assess adherence is used routinely in opioid agonist treatment (OAT). The primary aim of this study was to determine factors which may be associated with a negative qualitative urine drug screen for buprenorphine in OAT patients.

Methods

This prospective pilot study was conducted at a tertiary addiction medicine centre. Twenty participants on stable treatment underwent supervised administration of sublingual buprenorphine. Matched urine and blood samples were collected prior to and 2, 4 and 6 hours after buprenorphine administration. Qualitative urine drug screen results were obtained using gas chromatography–mass spectrometry (GC–MS), while quantitative blood and urine results were obtained using ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS).

Results

Qualitative urine assay yielded a negative result for buprenorphine in 57% of tested samples. The median concentration of urinary buprenorphine was 167 mcg/L (range: 2–1730 mcg/L). Thirty percent of all blood samples did not detect buprenorphine (range 0–18 mcg/L). Positive qualitative urine drug screen results were associated with higher urine (343 mcg/L compared with 75 mcg/L; P < .05) and blood (4 mcg/L compared with 2 mcg/L; P < .05) buprenorphine concentrations. Median urine concentrations of buprenorphine were highest at 2 hours and were higher in participants receiving CYP3A4 inhibitors.

Conclusion

Interpretation of qualitative urine drug screens to assess adherence in OAT is complex. Poor adherence with treatment cannot be assumed in patients returning a negative qualitative GC–MS urine drug screen.
Decomposition of Variation of Mixed Variables by a Latent Mixed Gaussian Copula Model
Authors: Liu Yutong , Darville Toni , Zheng Xiaojing , Li Quefeng
Published: March 2022

Many biomedical studies collect data of mixed types of variables from multiple groups of subjects. Some of these studies aim to find the group-specific and the common variation among all these variables. Even though similar problems have been studied by some previous works, their methods mainly rely on the Pearson correlation, which cannot handle mixed data. To address this issue, we propose a latent mixed Gaussian copula (LMGC) model that can quantify the correlations among binary, ordinal, continuous, and truncated variables in a unified framework. We also provide a tool to decompose the variation into the group-specific and the common variation over multiple groups via solving a regularized M-estimation problem. We conduct extensive simulation studies to show the advantage of our proposed method over the Pearson correlation-based methods. We also demonstrate that by jointly solving the M-estimation problem over multiple groups, our method is better than decomposing the variation group by group. We also apply our method to a Chlamydia trachomatis genital tract infection study to demonstrate how it can be used to discover informative biomarkers that differentiate patients.
Therapy‐related myeloid neoplasms with normal karyotype show distinct genomic and clinical characteristics compared to their counterparts with abnormal karyotype
Authors: Tariq Hamza , Barnea Slonim Liron , Coty Fattal Zachary , Alikhan Mir B. , Segal Jeremy , Gurbuxani Sandeep , Helenowski Irene B. , Zhang Hui , Sukhanova Madina , Lu Xinyan , Altman Jessica K. , Chen Qing C. , Behdad Amir
Published: March 2022

Therapy‐related myeloid neoplasms (t‐MNs) are a complication of treatment with cytotoxic chemotherapy and/or radiation therapy. The majority of t‐MNs show chromosomal abnormalities associated with myelodysplastic syndrome (MDS) or KMT2A rearrangements and are characterized by poor clinical outcomes. A small but substantial subset of patients have normal karyotype (NK) and their clinical characteristics and mutational profiles are not well studied. We retrospectively studied patients diagnosed with t‐MN at three institutions and compared the mutational profile and survival data between t‐MNs with NK and t‐MNs with abnormal karyotype (AK). A total of 204 patients with t‐MN were identified including 158 with AK and 46 with NK. NK t‐MNs, compared to AK, were enriched for mutations in TET2 (p < 0.0001), NPM1 (p < 0.0001), ASXL1 (p = 0.0003), SRSF2 (p < 0.0001), RUNX1 (p = 0.0336) and STAG2 (p = 0.0099) and showed a significantly lower frequency of TP53 mutations (p < 0.0001). Overall survival (OS) was significantly lower in AK t‐MNs as compared to NK cases (p = 0.0094). In our study, NK t‐MNs showed a significantly better OS, a higher prevalence of MN‐associated mutations and a lower frequency of TP53 mutations compared to their AK counterparts. The distinct clinical and mutational profile of NK t‐MNs merits a separate classification.
Drymarchon corais(Colubridae) andCaiman crocodilus(Alligatoridae) use different feeding behaviors to consume poisonous toads
Authors: Oda Fabrício Hiroiuki , Signorelli Luciana , de Souza Franciele Cristina , de Souza Valter Calheiros , Almeida Waltécio de Oliveira , Pereira Luana Nazareno , de Morais Alessandro Ribeiro
Published: March 2022

Drymarchon coraisandCaiman crocodilusare reported here using different feeding behaviors for consuming poisonous toads of the genusRhinella(Bufonidae).Drymarchon coraiswas observed feeding on specimens ofRhinella diptychawithout avoiding contact with the parotoid macroglands, suggesting that this snake species is immune to toad toxins.Caiman crocodiluswas recorded avoiding contact with the parotoid macroglands of specimens ofRhinella marinaby consuming only the front and rear legs, suggesting that this caiman may be sensitive to toad toxins. Further experimental and field studies are needed to better understand the feeding behavior ofD. coraisandC. crocodilusand the effects ofRhinellatoxins on these predators.

Abstract in Portuguese is available with online material.
Uptake of the culturally appropriate ASQ‐TRAK developmental screening tool in the Australian Aboriginal and Torres Strait Islander context
Authors: D'Aprano Anita , Brookes Isabel , Browne Linda , Bartlett Claire
Published: March 2022

Background

Recently in Australia, access to culturally safe developmental practices for Aboriginal and Torres Strait Islander families has been enhanced by the availability of a culturally appropriate developmental screening tool, the Ages and Stages Questionnaire – Talking about Raising Aboriginal Kids (ASQ‐TRAK). This paper aims (i) to describe the uptake of the ASQ‐TRAK developmental screening tool in Aboriginal Community Controlled Organizations and mainstream services in Australia and (ii) to explore the extent to which organizations using the ASQ‐TRAK have engaged training for staff.

Methods

A retrospective review of ASQ‐TRAK sales and training records from January 2015 to May 2020 to determine the ASQ‐TRAK distribution by jurisdiction and service type and the number of services that have engaged training.

Results

Five hundred ASQ‐TRAK kits have been distributed across 77 agencies. Of those, 100 kits (20%) have been purchased by Aboriginal Community Controlled Organizations. Most have been distributed in the Northern Territory (NT) (178, 36%), Western Australia (165, 33%) and South Australia (64, 13%). Of the 15 ASQ‐TRAK training workshops, nine have been in the NT. Of the 196 practitioners trained, 25 were identified as facilitators for their organization.

Conclusion

Despite substantive research translation across Australia, with evidence of its acceptability in different contexts, most Aboriginal Community Controlled Organizations have not yet accessed the ASQ‐TRAK, and most organizations have not participated in training. There is an imperative to progress knowledge translation to improve quality and accessibility of culturally appropriate developmental care. Adequately resourced ASQ‐TRAK implementation support is needed to ensure sustainable implementation at scale.
Leukocyte redistribution as immunological biomarker of corticosteroid resistance in severe asthma
Authors: Cardoso‐Vigueros Carlos , von Blumenthal Tobias , Rückert Beate , Rinaldi Arturo O. , Tan Ge , Dreher Anita , Radzikowska Urszula , Menz Günter , Schmid‐Grendelmeier Peter , Akdis Cezmi A. , Sokolowska Milena
Published: March 2022

Background

Earlier studies have suggested that the leukocyte redistribution can be considered as an immunological marker of the clinical response to corticosteroids (CS), representing an easy measurable potential biomarker in severe asthma.

Objective

The aim of this study was to determinate the utility of the leukocyte redistribution as a biomarker of disease heterogeneity in patients with severe asthma and as a bioindicator of potential CS resistance.

Methods

We developed an unbiased clustering approach based on the clinical data and the flow cytometry results of peripheral blood leukocyte phenotypes of 142 patients with severe asthma before and after systemic CS administration.

Results

Based on the differences in the blood count eosinophils, neutrophils and lymphocytes, together with the flow cytometry measurements of basic T cell, B cell and NK cell subpopulations before and after systemic CS administration, we identified two severe asthma clusters, which differed in the cell frequencies, response to CS and atopy status. Patients in cluster 1 had higher frequency of blood eosinophils at baseline, were sensitized to less allergens and had better steroid responsiveness, measured as the pronounced leukocyte redistribution after the administration of systemic CS. Patients in cluster 2 were determined by the higher frequency of B‐cells and stronger IgE sensitization status to the multiple allergens. They also displayed higher steroid resistance, as the clinical correlate for the lower leukocyte redistribution after administration of systemic CS.

Conclusion

The flow cytometry‐based profiling of the basic populations of immune cells in the blood and its analysis before and after systemic corticosteroid administration could improve personalized treatment approaches in patients with severe asthma.
Mast cell activation test: A new asset in the investigation of the chlorhexidine cross‐sensitization profile
Authors: Ebo Didier G. , Elst Jessy , Moonen Nele , van der Poorten Marie‐Line M. , Van Gasse Athina L. , Garvey Lene H. , Bridts Chris H. , Mertens Christel , Hagendorens Margo M. , Sabato Vito
Published: March 2022

Background

Insights into the IgE cross‐sensitization and possible cross‐reactivity patterns of sera reactive to chlorhexidine (CHX) are still incomplete and are likely to benefit from a functional exploration using a passive mast cell activation test (pMAT). Therefore, we want to study whether the pMAT with CHX‐specific IgE (sIgE) enables to depict effector cell degranulation in response to alexidine (ALX), octenidine (OCT) and/or polyhexamethylene biguanide (PHMB) indicative of cross‐reactivity between these compounds and CHX.

Methods

Serum of 10 CHX‐allergic patients, nine individuals with an isolated sIgE CHX and five healthy controls were included. Human cultured mast cells (MCs) were, before and after sensitization, challenged with CHX, ALX, OCT or PHMB. Degranulation was measured via quantification of upregulation of CD63.

Results

Mast cell responsiveness to ALX and OCT was demonstrable with 4/10 and 3/10 of the sera of CHX‐allergic patients respectively. Percentage of degranulation varied between 12 and 34% for ALX‐reactive MCs and between 4 and 22% for OCT‐reactive MCs. No reactivity to ALX or OCT was demonstrable when using sera obtained from individuals with an isolated sIgE CHX or from healthy controls. Unlike CHX, ALX and OCT, PHMB turned out to be a direct MC activator via occupation of MRGPRX2. PHMB‐reactive sIgEs were demonstrable in some patients with an isolated sIgE CHX but were unable to trigger PHMB‐induced degranulation in MRGPRX2 knockdown MCs.

Conclusion

Mast cells constitute an attractive tool to explore cross‐reactivity between structurally similar compounds. Along with the identification of safe alternatives for the individual patient, the pMAT can advance our insights into sIgE cross‐reactivity patterns including assessment of molecules not yet approved for human use.
Gepo with a G, or Jepo with a J? Skilled Readers Generate Orthographic Expectations for Novel Spoken Words Even When Spelling is Uncertain
Authors: Jevtović Mina , Antzaka Alexia , Martin Clara D.
Published: March 2022

English‐speaking children and adults generate orthographic skeletons (i.e., preliminary orthographic representations) solely from aural exposure to novel words. The present study examined whether skilled readers generate orthographic skeletons for all novel words they learn or do so only when the words have a unique possible spelling. To that end, 48 Spanish adults first provided their preferred spellings for all novel words that were to appear in the experiment. Critically, consistent words had only one, while inconsistent words had two possible spellings. Two weeks later, they were trained on the pronunciations of the novel words through aural instruction. They then saw the spellings of these newly acquired words, along with a set of untrained words, in a self‐paced sentence reading task. Participants read previously acquired consistent and inconsistent words presented in their preferred spellings faster than inconsistent words with unpreferred spellings. Importantly, no differences were observed in reading untrained consistent and inconsistent words (either preferred or unpreferred). This suggests that participants had generated orthographic skeletons for trained words with two possible spellings according to their individual spelling preferences. These findings provide further evidence for the orthographic skeleton account and show that initial orthographic representations are generated even when the spelling of a newly acquired word is uncertain.
Epidemiologie von Hautkrankheiten in Deutschland: systematische Literaturanalyse des aktuellen Forschungsstands – Teil 1: Tumorerkrankungen der Haut
Authors: Hansen Inga , Augustin Matthias , Schäfer Ines , Mohr Nicole
Published: March 2022

Epidemiologische Daten sind für die Identifizierung des Versorgungsbedarfs, das Aufdecken von Versorgungslücken, die Entwicklung gezielter Präventionsmaßnahmen sowie zur Optimierung der Ressourcenallokation von großer Bedeutung. Das Ziel dieser Arbeit ist die systematische Erfassung aller publizierten bevölkerungsbezogenen epidemiologischen Daten zu Hauterkrankungen in Deutschland. Der vorliegende Teil 1 der Publikationsserie thematisiert Tumorerkrankungen der Haut. Ergebnisse zu nichtinfektiösen (Teil 2) und infektiösen Hauterkrankungen (Teil 3) bilden weitere Teile dieser Reihe.

Es wurde eine systematische Literaturrecherche mit PubMed/MEDLINE für den Zeitraum der letzten 15 Jahre durchgeführt. Mit dem Ziel, alle dermatologischen Erkrankungen einzuschließen, wurde eine Diagnoseliste auf Basis des ICD‐11‐Katalogs erstellt. Diese Liste umfasste 1347 Hautkrankheiten. Die Literaturrecherche ergab 4650 Publikationen. Nach zweistufigem Screening wurden 72 Studien zu 43 verschiedenen Hautkrankheiten in die Synthese eingeschlossen. Darunter waren 30 Publikationen zu kutanen Tumorerkrankungen, von denen sich die Mehrheit auf das maligne Melanom bezog.

Diese Arbeit ist die erste systematische Literaturrecherche, die zum Ziel hatte, alle verfügbaren epidemiologischen Daten zu Hautkrankheiten in Deutschland zu berichten. Bezüglich der Studienlage zu den unterschiedlichen Hautkrankheiten zeigte sich eine hohe Heterogenität. Auch wenn die Methodik der eingeschlossenen epidemiologischen Studien erheblich variierte, ist der Nutzen dieser epidemiologischen Daten sehr vielseitig. Somit kann diese Arbeit als Referenz verschiedenster epidemiologischer Fragestellungen dienen.