bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison among presepsin, procalcitonin, and C-reactive protein in predicting blood culture positivity and pathogen in sepsis patients
Authors: Xiao Hongli , Zhang Hanyu , Wang Guoxing , Wang Yan , Tan Zhimin , Sun Xuelian , Zhou Jie , Duan Meili , Zhi Deyuan , Hang Chenchen , Zhang Guoqiang , Li Yan , Wu Caijun , Zhang Haiyan , Xie Miaorong , Li Chunsheng
Published: October 2023

Background

Sepsis is caused by the invasion of the bloodstream by microorganisms from local sites of infection, leading to high mortality. This study aimed to compare the predictive ability of the biomarkers presepsin, procalcitonin (PCT) and C-reactive protein (CRP) for bacteraemia.

Methods

In this retrospective, multicentre study, a dataset of patients with sepsis who were prospectively enrolled between November 2017 and June 2021 was analysed. The performances of the biomarkers for predicting positive blood cultures and infection with specific pathogens were assessed by the areas under the receiver operating characteristic curves (AUCs). The independent effects of the pathogen and foci of infection on presepsin and PCT levels were assessed by linear logistic regression models.

Results

A total of 577 patients with 170 (29.5%) positive blood cultures were enrolled. The AUC achieved using PCT levels (0.856) was significantly higher than that achieved using presepsin (0.786,p= 0.0200) and CRP (0.550,p< 0.0001) levels in predicting bacteraemia. The combined analysis of PCT and presepsin levels led to a significantly higher AUC than the analysis of PCT levels alone for predicting blood culture positivity (0.877 vs. 0.856,p= 0.0344) and gram-negative bacteraemia (0.900 vs. 0.875,p= 0.0216). In a linear regression model, the elevated concentrations of presepsin and PCT were both independently related toE. coli,Klebsiellaspp.,Pseudomonasspp., andStreptococcusspp. infections and Sequential Organ Failure Assessment (SOFA) score. Presepsin levels were also associated withAcinetobacterspp. and abdominal infection, and PCT levels were positively associated with otherEnterobacteriaceaeand negatively associated with respiratory infection. Combined analysis of presepsin and PCT levels provided a high sensitivity and specificity in identifyingEscherichia coliorKlebsiellaspp infection.

Conclusions

Presepsin and PCT were promising markers for predicting bacteraemia and common pathogens at the time of sepsis onset with a synergistic effect.
Secreted tryptophanyl–tRNA synthetase 1 is a prognostic marker in sepsis patients without monocytopenia
Authors: Kim Kyung Su , Suh Gil Joon , Jin Mirim , Kwon Woon Yong , Jung Yoon Sun , Kim Taegyun , Kim Yoon Tae , Kim Hayoung , Park Heesu
Published: October 2023

Objective

This study aimed to test whether the prognostic value of tryptophanyl–tRNA synthetase 1 (WARS1) for 28-day mortality in patients with sepsis was affected by monocytopenia.

Methods

A prospective analysis of retrospectively collected samples from 74 sepsis patients was performed. WARS1, C-reactive protein (CRP), and procalcitonin were measured at admission and 24 and 72 hours after admission. The prognostic value of WARS1, CRP, and procalcitonin for 28-day mortality was compared using repeated measures analysis of variance (ANOVA) and the area under the receiver operating characteristic curve (AUROC). All analyses were performed in patients with or without monocytopenia, defined as an absolute monocyte count less than 0.1 × 109 cells/L.

Results

WARS1 levels differed significantly between survivors and nonsurvivors when all patients and patients without monocytopenia were assessed (p = 0.008, p < 0.001, respectively). In contrast, the WARS1 level did not differ between survivors and nonsurvivors with monocytopenia. CRP and procalcitonin levels were not different between survivors and nonsurvivors regardless of whether they had monocytopenia. The AUROCs of WARS1 at admission and 24 hours for mortality were significantly higher in patients without monocytopenia (0.830, 0.818) than in patients with monocytopenia (0.232, 0.196; p < 0.001, both). When patients without monocytopenia were analyzed, the AUROCs of WARS1 for mortality were 0.830 and 0.818 at admission and 24 hours, respectively, which were significantly higher than those of CRP (0.586, 0.653) and procalcitonin (0.456, 0.453) at the same time points (p = 0.024 and 0.034, respectively).

Conclusion

WARS1 is a useful biomarker for prognosis in sepsis patients without monocytopenia.
Association Between Genital Hiatus Size 8 Weeks Postpartum and Pelvic Organ Prolapse 1 Year After the First Vaginal Delivery
Authors: Rosett Heather A. , Allshouse Amanda A. , Nygaard Ingrid E. , Hill A. Jolyn , Swenson Carolyn W.
Published: October 2023

Importance

Evidence suggests that genital hiatus (GH) enlargement precedes pelvic organ prolapse development remote from delivery. However, the association of postpartum GH enlargement and prolapse is unknown.

Objective

The aim of this study was to determine the association between enlarged GH at 8 weeks postpartum and prolapse 1 year after first vaginal delivery.

Study Design

This is a secondary analysis of the Motherhood and Pelvic Health study, a prospective cohort of women after their first vaginal delivery. Enlarged GH was defined as ≥4 cm. Prolapse was defined as Pelvic Organ Prolapse Quantification points Ba, Bp, or C at or beyond the hymen. Kaplan-Meier analysis and proportional hazards modeling were used to analyze the association between enlarged GH at 8 weeks postpartum and prolapse at 1 year postpartum. Diagnostic test characteristics of enlarged GH were calculated.

Results

Five hundred eighty women were included. At 1 year postpartum, the prevalence of prolapse was 3 times higher in women with, versus without, an enlarged GH at 8 weeks postpartum (16% vs 5%, P < 0.001). This was confirmed in a Cox proportional hazards model while adjusting for age, body mass index, and early postpartum prolapse (adjusted hazard ratio, 3.3; 95% confidence interval, 1.85–6.06; P < 0.001). The diagnostic properties of postpartum GH to predict prolapse at 1 year are as follows: sensitivity, 0.63; specificity, 0.67; positive predictive value, 0.17; and negative predictive value, 0.95.

Conclusions

Women with an enlarged GH at 8 weeks postpartum have a 3.3-fold increased risk of prolapse at 1 year. As a screening tool, GH <4 cm at 8 weeks postpartum has high negative predictive value.
Healthcare Resource Utilization After Apical Prolapse Surgery in Women Who Received In-Office Versus Telephone-Only Preoperative Teaching
Authors: Lua-Mailland Lannah L. , Roversi Gustavo , Yao Meng , Ferrando Cecile A.
Published: October 2023

Importance

Despite increasing use of telehealth, no studies have evaluated telehealth use for preoperative teaching and its impact on healthcare resource utilization (HRU) after gynecologic surgery.

Objectives

This study aimed to compare HRU after apical prolapse surgery in women receiving in-office versus telephone-only preoperative teaching and identify factors associated with postoperative HRU.

Study Design

A retrospective cohort study of women who underwent apical prolapse surgery from 2017 to 2020 at a tertiary referral center was conducted. Women were grouped based on the preoperative teaching type they received. Healthcare resource utilization was defined as a composite of patient-initiated calls, unscheduled outpatient visits, emergency department visits, and readmissions before the scheduled 6-week postoperative visit. Healthcare resource utilization was compared between in-office and telephone-only groups. Multivariable regression analysis was performed to identify factors associated with HRU.

Results

A total of 1,168 women underwent in-office teaching, and 181 had telephone-only teaching. Of the 1,349 women, 980 (72.6%) had ≥1 HRU encounter and 222 (16.5%) had ≥5 HRU encounters within 6 weeks after surgery. There was no difference between telephone and office groups for composite outcomes of ≥1 HRU (78.5% vs 71.7%, P = 0.06) and ≥5 HRU (13.3% vs 17.0%, P = 0.21) encounters. A failed voiding trial was associated with a 4.4-fold increased risk of ≥5 encounters. Increasing age and body mass index, concomitant hysterectomy, and abdominal route were associated with a decreased likelihood of ≥5 encounters.

Conclusions

Three of 4 women had at least 1 unanticipated HRU encounter within 6 weeks after apical prolapse surgery. Preoperative teaching type was not associated with postoperative HRU. Telephone visits may be considered as an alternative to in-office visits for preoperative teaching.
A new archosauriform species from the Panchet Formation of India and the diversification of Proterosuchidae after the end-Permian mass extinction
Authors: Ezcurra Martín D. , Bandyopadhyay Saswati , Sengupta Dhurjati P. , Sen Kasturi , Sennikov Andrey G. , Sookias Roland B. , Nesbitt Sterling J. , Butler Richard J.
Published: October 2023

Proterosuchidae represents the oldest substantial diversification of Archosauromorpha and plays a key role in understanding the biotic recovery after the end-Permian mass extinction. Proterosuchidae was long treated as a wastebasket taxon, but recent revisions have reduced its taxonomic content to five valid species from the latest Permian of Russia and the earliest Triassic (Induan) of South Africa and China. In addition to these occurrences, several isolated proterosuchid bones have been reported from the Induan Panchet Formation of India for over 150 years. Following the re-study of historical specimens and newly collected material from this unit, we erect the new proterosuchid species
Samsarasuchus pamelae
, which is represented by most of the presacral vertebral column. We also describe cf. proterosuchid and proterosuchid cranial, girdle and limb bones that are not referred to
Samsarasuchus pamelae
. Phylogenetic analyses recovered
Samsarasuchus pamelae
within the new proterosuchid clade Chasmatosuchinae. The taxonomic diversity of Proterosuchidae is substantially expanded here, with at least 11 nominal species and several currently unnamed specimens, and a biogeographical range encompassing present-day South Africa, China, Russia, India, Brazil, Uruguay and Australia. This indicates a broader taxonomic, phylogenetic and biogeographic diversification of Proterosuchidae than previously thought in the aftermath of the end-Permian mass extinction.
Validation of a musculoskeletal model for simulating muscle mechanics and energetics during diverse human hopping tasks
Authors: Jessup Luke N. , Kelly Luke A. , Cresswell Andrew G. , Lichtwark Glen A.
Published: October 2023

Computational musculoskeletal modelling has emerged as an alternative, less-constrained technique to indirect calorimetry for estimating energy expenditure. However, predictions from modelling tools depend on many assumptions around muscle architecture and function and motor control. Therefore, these tools need to continue to be validated if we are to eventually develop subject-specific simulations that can accurately and reliably model rates of energy consumption for any given task. In this study, we used OpenSim software and experimental motion capture data to simulate muscle activations, muscle fascicle dynamics and whole-body metabolic power across mechanically and energetically disparate hopping tasks, and then evaluated these outputs at a group- and individual-level against experimental electromyography, ultrasound and indirect calorimetry data. Comparing simulated and experimental outcomes, we found weak to strong correlations for peak muscle activations, moderate to strong correlations for absolute fascicle shortening and mean shortening velocity, and strong correlations for gross metabolic power. These correlations tended to be stronger on a group-level rather than individual-level. We encourage the community to use our publicly available dataset from SimTK.org to experiment with different musculoskeletal models, muscle models, metabolic cost models, optimal control policies, modelling tools and algorithms, data filtering etc. with subject-specific simulations being a focal goal.
Reproductive tactics, birth timing and the risk-resource trade-off in an income breeder
Authors: Benoit Laura , Morellet Nicolas , Bonnot Nadège C. , Cargnelutti Bruno , Chaval Yannick , Gaillard Jean-Michel , Loison Anne , Lourtet Bruno , Marchand Pascal , Coulon Aurélie , Hewison A. J. Mark
Published: October 2023

In variable environments, habitats that are rich in resources often carry a higher risk of predation. As a result, natural selection should favour individuals that balance allocation of time to foraging versus avoiding predation through an optimal decision-making process that maximizes fitness. The behavioural trade-off between resource acquisition and risk avoidance is expected to be particularly acute during gestation and lactation, when the energetic demands of reproduction peak. Here, we investigated how reproductive female roe deer adjust their foraging activity and habitat use during the birth period to manage this trade-off compared with non-reproductive juveniles, and how parturition date constrains individual tactics of risk-resource management. Activity of reproductive females more than doubled immediately following parturition, when energy demand is highest. Furthermore, compared with non-reproductive juveniles, they increased their exposure to risk by using open habitat more during daytime and ranging closer to roads. However, these post-partum modifications in behaviour were particularly pronounced in late-parturient females who adopted a more risk-prone tactic, presumably to compensate for the growth handicap of their late-born offspring. In income breeders, individuals that give birth late may be constrained to trade risk avoidance for foraging during peak allocation to reproduction, with probable consequences for individual fitness.
Habitat fragmentation increases specialization of multi-trophic interactions by high species turnover
Authors: Zhang Xue , Dalsgaard Bo , Staab Michael , Zhu Chen , Zhao Yuhao , Gonçalves Fernando , Ren Peng , Cai Chang , Qiao Gexia , Ding Ping , Si Xingfeng
Published: October 2023

Habitat fragmentation is altering species interactions worldwide. However, the mechanisms underlying the response of network specialization to habitat fragmentation remain unknown, especially for multi-trophic interactions. We here collected a large dataset consisting of 2670 observations of tri-trophic interactions among plants, sap-sucking aphids and honeydew-collecting ants on 18 forested islands in the Thousand Island Lake, China. For each island, we constructed an antagonistic plant–aphid and a mutualistic aphid–ant network, and tested how network specialization varied with island area and isolation. We found that both networks exhibited higher specialization on smaller islands, while only aphid–ant networks had increased specialization on more isolated islands. Variations in network specialization among islands was primarily driven by species turnover, which was interlinked across trophic levels as fragmentation increased the specialization of both antagonistic and mutualistic networks through bottom-up effects via plant and aphid communities. These findings reveal that species on small and isolated islands display higher specialization mainly due to effects of fragmentation on species turnover, with behavioural changes causing interaction rewiring playing only a minor role. Our study highlights the significance of adopting a multi-trophic perspective when exploring patterns and processes in structuring ecological networks in fragmented landscapes.
Genetic and environmental architecture of synaesthesia and its association with the autism spectrum—a twin study
Authors: Taylor Mark J. , van Leeuwen Tessa M. , Kuja-Halkola Ralf , Lundström Sebastian , Larsson Henrik , Lichtenstein Paul , Bölte Sven , Neufeld Janina
Published: October 2023

Synaesthesia is a sensory phenomenon where external stimuli, such as sounds or letters, trigger additional sensations (e.g. colours). Synaesthesia aggregates in families but its heritability is unknown. The phenomenon is more common in people on the autism spectrum compared with the general population and associated with higher autistic traits. Using classical twin design, we assessed the heritability of individual differences in self-reported synaesthesia and the genetic and environmental contributions to their association with autistic traits within a population twin cohort (
n
= 4262, age = 18 years). We estimated individual differences in synaesthesia to be heritable and influenced by environmental factors not shared between twins. The association between individual differences in synaesthesia and autistic traits was estimated to be predominantly under genetic influence and seemed to be mainly driven by non-social autistic traits (repetitive behaviours, restricted interests and attention to detail). Our study suggests that the link between synaesthesia and autism might reside in shared genetic causes, related to non-social autistic traits such as alterations in perception. Future studies building on these findings may attempt to identify specific groups of genes that influence both autism, synaesthesia and perception.
Identification of prosthetic joint infection by Candida using metagenomic shotgun sequencing
Authors: Lin Liqiong , Shen Kaiwei , Xiao Lili , lin Yu , Feng Eryou , Zhang Yiyuan
Published: October 2023

Background. Periprosthetic joint infection (PJI) is a serious complication after total knee arthroplasty. Fungal infections are prone to biofilm formation, which makes it hard to diagnose and clarify the pathogenic species.

Case Presentation. This case study provides evidence of a novel PJI pathogen that is otherwise difficult to detect using conventional methods. A patient was reviewed with persistent postoperative pain, swelling and eventually drainage around the left knee after undergoing a bilateral total knee arthroplasty 2 years previously for progressive osteoarthritis. By using metagenomic shotgun sequencing to analyse both bacterial and fungal agent sequences, we were able to identify fungal strains of Candida tropicalis, a rarely reported and difficult-to-culture PJI pathogen.

Conclusion. Metagenomic shotgun sequencing enables the detection of difficult-to-detect pathogens and the formulation of treatment recommendations for fungal infections with low positive rates based on gene content analysis.
Classification of Bisgaard taxon 6 and taxon 10 as Exercitatus varius gen. nov., sp. nov.
Authors: Christensen Henrik , Sells Stephen F. , MacGlover Chris , Bisgaard Magne
Published: October 2023

Forty-one isolates of Bisgaard taxon 6 obtained from guinea pigs, pandas, pigs and muskrat and isolates of taxon 10 from horses and horse bites in humans were subjected phenotypic characterization. Production of acid from (−)-d-mannitol, (−)-d-sorbitol and (+)-d-glycogen separated taxon 10 (positive) from taxon 6 (negative), while from two to 11 phenotypic characteristics separated taxa 6 and 10 from the 32 genera of

Pasteurellaceae

reported so far. Forty-four strains were genetically characterized. Sequencing of 16S rRNA genes documented a monophyletic relationship at the species level and the highest 16S rRNA gene sequence similarity of 95.6 % to other species was found between strain CCUG 15568T and the type strain of

Mannheimia glucosida

(CCUG 38457T). Digital DNA–DNA hybridization (dDDH) values predicted from whole genomic sequences between CCUG 15568T and other characterized strains of taxa 6 and 10 were 69.3–99.9 %. The average nucleotide identity values were higher than 95 % for all strains. The highest dDDH value of 29 % outside the taxa 6 and 10 group was obtained with the genome of the type strain of [

Actinobacillus

] succinogenes, indicating a separate taxonomic status at species level to taxa 6 and 10. The phylogenetic comparison of concatenated conserved protein sequences showed the unique position of the taxa investigated in the current study which qualified for the status of a new genus since the highest identity was found with

Basfia

with 79 %, well below the upper threshold between genera of 85 %. Based upon the low genetic similarity to other genera of the family

Pasteurellaceae

and a unique phenotype, we suggest that Bisgaard taxa 6 and 10 should be classified as Exercitatus varius gen. nov., sp. nov. The G+C of the type strain of Exercitatus varius, 8.5T (=CCUG 15568T=DSM 115565T), is 46.2 mol%, calculated from the whole genome.
Mental maps without vision: Neural signatures of cognitive maps based on haptic input in the hippocampal formation
Authors: Ottink Loes , van den Berg Lennard , Peters Imke , van der Geest Thea , Haak Koen , Doeller Christian , van Wezel Richard
Published: October 2023

The human hippocampus is the key region for forming cognitive maps of our environment. Such a map can support spatial navigation. It is unclear whether this area is similarly involved when an environment is explored with our haptic sense. In this study, we investigated the neural representation of distances on a tactile map in the hippocampal formation, in visually impaired and sighted persons. To this end, 47 participants (22 persons with a visual impairment, PVIs, and 25 sighted controls) performed a navigation task where they learned a tactile city-like map including five item locations. We combined magnetic resonance imaging with adaptation analysis to assess representation of distances between item locations in the hippocampus and entorhinal cortex. Additionally, we assessed cognitive map formation on a behavioural level. We also looked at functional connectivity between navigation-related areas during a subsequent resting-state block. Our data reveal across all participants that the left entorhinal cortex represents distances between locations on a tactile map. Here, we provide the first evidence that maps in the hippocampal formation is preserved when an environment is presented in a non-visual modality. The results also suggest that both PVIs and sighted persons constructed accurate cognitive maps of the tactile environment on a behavioural level. However, early PVIs showed lower performance compared to late PVIs, suggesting an advantage of visual experience. Additionally, we reveal functional connectivity between areas that were involved in the navigation task during a subsequent resting-state block. This might suggest either visual imagination of stimuli during the preceding tasks, or cognitive processes related to our spatial navigation task, which possibly involve replay of stimulus-specific activity.
XGBoosting Early Detection: Advancing Parkinson’s Disease Diagnosis through Machine Learning
Authors: Santos Dheiver Francisco
Published: October 2023

Parkinson’s disease (PD) is a significant neurodegenerative disorder, affecting millions worldwide. Early and accurate diagnosis is pivotal for effective treatment. In this study, we explore the application of XGBoost, a powerful machine learning algorithm, for classifying PD based on speech signal features. Our research presents a systematic methodology, addressing data preparation, model development, and performance evaluation. The XGBoost model achieved an accuracy of 80.09% in distinguishing individuals with and without PD, demonstrating its promise for disease classification. Moreover, we discuss the potential for XGBoost in healthcare and highlight the need for further research in the intersection of machine learning and disease diagnosis.
Biolistics-mediated transformation of hornworts and its application to study pyrenoid protein localization
Authors: Lafferty Declan J. , Robison Tanner A. , Gunadi Andika , Gunn Laura H. , Van Eck Joyce , Li Fay-Wei
Published: October 2023

Hornworts are a deeply diverged lineage of bryophytes that are sister to mosses and liverworts. Hornworts have an array of unique features that can be leveraged to illuminate not only the early evolution of land plants, but also alternative paths for nitrogen and carbon assimilation via cyanobacterial symbiosis and a pyrenoid-based CO2-concentrating mechanism (CCM), respectively. Despite this, hornworts are one of the few plant lineages with limited available genetic tools. Here we report an efficient biolistics method for generating transient-expression and stable transgenic lines in the model hornwort,Anthoceros agrestis. An average of 569 (± 268) cells showed transient expression per bombardment, with green fluorescent protein expression observed within 48 hours. A total of 81 stably transformed lines were recovered across three separate experiments, averaging six lines per bombardment. We followed the same method to transiently transform nine additional hornwort species, and obtained stable transformants from one. This method was further used to verify the localization of Rubisco and Rubisco activase in pyrenoids, which are central proteins for CCM function. Together, our biolistics approach offers key advantages over existing methods as it enables rapid transient expression and can be applied to widely diverse hornwort species.

Highlight

We developed a new transformation method for hornworts, a lineage of understudied bryophytes, and demonstrated its effectiveness in studying subcellular localization of proteins involved in pyrenoid-based CO2-concentrating mechanism.
Mapping the landscape of lineage-specific dynamic regulation of gene expression using single-cell transcriptomics and application to genetics of complex disease
Authors: Abe Hanna , Lin Phillip , Zhou Dan , Ruderfer Douglas M. , Gamazon Eric R.
Published: October 2023

Single-cell transcriptome data can provide insights into how genetic variation influences biological processes involved in human biology and disease. However, the identification of gene-level associations in distinct cell types faces several challenges, including the limited reference resource from population scale studies, data sparsity in single-cell RNA sequencing, and the complex cell-state pattern of expression within individual cell types. Here we develop genetic models of cell type specific and cell state adjusted gene expression in mid-brain neurons in the process of specializing from induced pluripotent stem cells. The resulting framework quantifies the dynamics of the genetic regulation of gene expression and estimates its cell type specificity. As an application, we show that the approach detects known and new genes associated with schizophrenia and enables insights into context-dependent disease mechanisms. We provide a genomic resource from a phenome-wide application of our models to more than 1500 phenotypes from the UK Biobank. Using longitudinal genetically determined expression, we implement a predictive causality framework, evaluating the prediction of future values of a target gene expression using prior values of a putative regulatory gene. Collectively, this work demonstrates the insights that can be gained into the molecular underpinnings of diseases by quantifying the genetic control of gene expression at single-cell resolution.
Targeting cancer with small molecule pan-KRAS degraders
Authors: Popow Johannes , Farnaby William , Gollner Andreas , Kofink Christiane , Fischer Gerhard , Wurm Melanie , Zollman David , Wijaya Andre , Mischerikow Nikolai , Hasenoehrl Carina , Prokofeva Polina , Arnhof Heribert , Arce-Solano Silvia , Bell Sammy , Boeck Georg , Diers Emelyne , Frost Aileen B , Goodwin-Tindall Jake , Karolyi-Oezguer Jale , Khan Shakil , Klawatsch Theresa , Koegl Manfred , Kousek Roland , Kratochvil Barbara , Kropatsch Katrin , Lauber Arnel A , McLennan Ross , Olt Sabine , Peter Daniel , Petermann Oliver , Roessler Vanessa , Stolt-Bergner Peggy , Strack Patrick , Strauss Eva , Trainor Nicole , Vetma Vesna , Whitworth Claire , Zhong Siying , Quant Jens , Weinstabl Harald , Küster Bernhard , Ettmayer Peter , Ciulli Alessio
Published: October 2023

Despite the high prevalence of cancers driven by KRAS mutations, to date only the G12C mutation has been clinically proven to be druggable via covalent targeting of the mutated cysteine amino acid residue (1). However, in many cancer indications other KRAS mutations, such as G12D and -V, are far more prevalent and small molecule concepts that can address a wider variety of oncogenic KRAS alleles are in high clinical demand (2). Here we show that a single small molecule can be used to simultaneously and potently degrade 13 out of 17 of the most prevalent oncogenic KRAS alleles, including those not yet tractable by inhibitors. Compared with inhibition, degradation of oncogenic KRAS results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines. As a result, KRAS degraders inhibit growth of the majority of cancer cell lines driven by KRAS mutations while sparing models without genetic KRAS aberrations. Finally, we demonstrate that pharmacological degradation of oncogenic KRAS leads to tumour regression in vivo. Together, these findings unveil a new path towards addressing KRAS driven cancers with small molecule degraders.
Mixotrophic microalgal mixed cultures for cheese whey valorization
Authors: de Almeida Maria Paula Giulianetti , Mondini Camille , Bruant Guillaume , Tremblay Julien , Mockaitis Gustavo , Weissbrodt David G.
Published: October 2023

Microalgae cultivation, and phycoremediation, can be a polishing step in wastewater treatment. Depending on the stream utilized for microalgal cultivation, biomass can be contaminated with considerable quantities of heavy metals and xenobiotics. Given the economic value of microalgae bioproducts, we suggest coupling anaerobic fermentation with microalgae mixotrophic growth. Cheese whey, a product from cheese production, has a 2022 forecast production of 160.7 million m3year−1in which about 66.5 million m3y−1is used as animal feed, fertilizers or illegally discharged causing eutrophication. Anaerobic fermentation of cheese whey produces volatile fatty acids (VFAs) such as acetate which serves as an organic carbon source for photoorganoheterotrophic microalgal biomass growth. Our work selected three organic sources derived from cheese whey: 40% demineralized whey powder (WPC40), lactose, and acetate. In photolitoautotrophic conditions, green phototrophic growth was successful. In batch tests, acetate was the best organic carbon source among photoorganoheterotrophs with a higher yield of 1.15 mg VSS mg Carbon−1(C) in anaerobic conditions. Also, acetate uptake was thought to be via the glyoxylate cycle. When upscaling the experiment in a chemostat, a lower dilution rate of 0.17 d−1was more suitable for green photoorganoheterotrophs selection, as they were not washed out in the process. These findings show that acetate uptake by microalgae in mixotrophic regimes must be better understood as well as reinforce the advantages of coupling microalgal biomass growth with cheese whey acidogenic fermentation, avoiding contaminations as in phycoremediation processes and fully valorizing cheese whey.

Graphical abstract
Rapid DNA methylation-based classification of pediatric brain tumours from ultrasonic aspirate specimens
Authors: Simon Michèle , Kuschel Luis P. , von Hoff Katja , Yuan Dongsheng , Driever Pablo Hernáiz , Hain Elisabeth G. , Koch Arend , Capper David , Schulz Matthias , Thomale Ulrich-Wilhelm , Euskirchen Philipp
Published: October 2023

Background

Although cavitating ultrasonic aspirators are commonly used in neurosurgical procedures, the suitability of ultrasonic aspirator-derived tumor material for diagnostic procedures is still controversial. Here, we explore the feasibility of using ultrasonic aspirator-resected tumor tissue to classify otherwise discarded sample material by fast DNA methylation-based analysis using low pass nanopore whole genome sequencing.

Methods

ultrasonic aspirator-derived specimens from pediatric patients undergoing brain tumour resection were subjected to low-pass nanopore whole genome sequencing. DNA methylation-based classification using a neural network classifier and copy number variation analysis were performed. Tumor purity was estimated from copy number profiles. Results were compared to microarray (EPIC)-based routine neuropathological histomorphological and molecular evaluation.

Results

18 samples with confirmed neuropathological diagnosis were evaluated. All samples were successfully sequenced and passed quality control for further analysis. DNA and sequencing characteristics from ultrasonic aspirator-derived specimens were comparable to routinely processed tumor tissue. Classification of both methods was concordant regarding methylation class in 16/18 (89%) cases. Application of a platform-specific threshold for nanopore-based classification ensured a specificity of 100%, whereas sensitivity was 78%. Copy number variation profiles were generated for all cases and matched EPIC results in 16/18 (89%) samples, even allowing the identification of diagnostically or therapeutically relevant genomic alterations.

Conclusion

Methylation-based classification of pediatric CNS tumors based on ultrasonic aspirator-reduced and otherwise discarded tissue is feasible using time- and cost-efficient nanopore sequencing.
A comparison of the EQ-5D-5L and the SF-6Dv2 among patients with hypertrophic obstructive cardiomyopathy
Authors: Wang Xiaoyu , Sang Haiqiang , Meng Rui , Su Xin , Liu Peng
Published: October 2023

Background

Hypertrophic obstructive cardiomyopathy (HOCM) is a serious and complex chronic disease severely affecting patients’ daily lives and health-related quality of life (HRQoL). The psychometric performance of generic preference-based instruments has not been compared in Chinese patients with HOCM. We aimed to identify an applicable vehicle to determine HRQoL and explore the psychometric properties of SF-6Dv2 and EQ- 5D-5L in adults with HOCM. The interchangeability of the tools in cost-utility analysis was also investigated.

Methods

We collected data from 131 patients with HOCM from the First Affiliated Hospital of Zhengzhou University, China. Assessments were performed on the day of admission and three and six months after discharge using SF-6Dv2 and EQ-5D-5L. The responses were converted to utility values using the corresponding Chinese value sets. The tool distributions were explored, and the floor and ceiling effects were analyzed. The agreement was assessed using intra-class correlation coefficients (ICCs) and Bland–Altman plots. Convergent validity was tested using Spearman’s rank correlation coefficient. Known group validity was measured across various clinical and sociodemographic indicators using relative efficiency (RE) statistics.

Results

The mean utility scores for SF-6Dv2 and EQ-5D- 5L at baseline and 6-month follow-up were 0.61, 0.62, 0.736, and 0.797, respectively. The EQ-5D-5L and SF-6Dv2 distribution scores showed no normality. EQ-5D-5L was more sensitive to changes over time and showed a moderate to good correlation with the SF-6Dv2 (ICC: 0.598–0.862). The instruments’ agreement and convergent validity worsened in patients with a higher New York Heart Association (NYHA) cardiac function classification and lower general health status. SF-6Dv2 showed higher relative efficiency statistics and a greater ability to distinguish external health status.

Conclusions

The measured results can be used for future cost-utility analyses. SF-6Dv2 and EQ-5D-5L presented different results and should not be used interchangeably. SF-6Dv2 is optimal for detecting differences between subgroups with various health states.
Estimated transmission dynamics of SARS-CoV-2 variants from wastewater are robust to differential shedding
Authors: Dreifuss David , Huisman Jana S. , Rusch Johannes C. , Caduff Lea , Ganesanandamoorthy Pravin , Devaux Alexander J. , Gan Charles , Stadler Tanja , Kohn Tamar , Ort Christoph , Beerenwinkel Niko , Julian Timothy R.
Published: October 2023

The COVID-19 pandemic has accelerated the development and adoption of wastewater-based epidemiology. Wastewater samples can provide genomic information for detecting and assessing the spread of SARS-CoV-2 variants in communities and for estimating important epidemiological parameters such as the growth advantage of the variant. However, despite demonstrated successes, epidemiological data derived from wastewater suffers from potential biases. Of particular concern are differential shedding profiles that different variants of concern exhibit, because they can shift the relationship between viral loads in wastewater and prevalence estimates derived from clinical cases. Using mathematical modeling, simulations, and Swiss surveillance data, we demonstrate that this bias does not affect estimation of the growth advantage of the variant and has only a limited and transient impact on estimates of the effective reproduction number. Thus, population-level epidemiological parameters derived from wastewater maintain their advantages over traditional clinical-derived estimates, even in the presence of differential shedding among variants.
Cardiovascular and Neurological Outcomes in Patients Treated with Edoxaban for Atrial Fibrillation and Characteristics in Patients with Cancer
Authors: Cheng Kai-Hung , Tu Hung-Pin , Cheng Kai-Chun , Scherrer-Crosbie Marielle , Hsu Ting-Yuan
Published: October 2023

BACKGROUND

Direct oral anticoagulants (DOACs) outperform warfarin in vascular and bleeding events in atrial fibrillation (AF) patients. Yet, effects of DOACs on congestive heart failure (CHF) and Alzheimer’s disease (AD) remain less explored.

METHODS

Using the Taiwan National Health Insurance Research Database, a nationwide retrospective cohort study was conducted. The study matched 5,683 non-valvular atrial fibrillation (NVAF) edoxaban patients with 11,366 warfarin patients, and 703 NVAF with cancer (NVAF-C) edoxaban patients with 1,406 warfarin patients. Vasular and non-vascular outcomes, with focuses on CHF and AD, were compared between the edoxaban and warfarin users.

RESULTS

Edoxaban significantly lowered adjusted hazrad ratio (aHR) of all-cause mortality, hospitalization for gastrointestinal bleeding, and CHF (0.37, 0.74, and 0.26, respectively, in NVAF; 0.39, 0.67, and 0.31, respectively, in NVAF-C, allp< 0.05), compared to warfarin. Edoxaban was associated with significantly lower aHRs of acute myocardial infarction, peripheral artery disease, venous thromboembolism, pulmonary embolism, and AD (0.71, 0.48, 0.55, 0.20, and 0.66, respectively; allp< 0.05) in NVAF patients versus warfarin. However, edoxaban had higher aHR of hospitalized bleeding (1.19,p= 0.002) than warfarin in NVAF patients, but not in NVAF-C patients.

CONCLUSIONS

Edoxaban demonstrated lowered CHF risks in both NVAF and NVAF-C patients, and reduced AD occurrence in NVAF patients versus warfarin. These findings advocate for edoxaban’s use in AF cases.

CLINICAL PERSPECTIVE

What Is New?

The study reveals that in patients with atrial fibrillation (AF), edoxaban, a direct oral anticoagulant (DOAC), demonstrates significant advantages over warfarin. Notably, edoxaban is associated with a reduced risk of congestive heart failure (CHF) and Alzheimer’s disease (AD) when compared to warfarin.

Clinical Implications?

These findings have important clinical implications. Edoxaban appears to be a superior anticoagulant choice for AF patients, as it lowers the risk of CHF and AD. This highlights the potential of edoxaban to improve patient outcomes and underscores its relevance for managing AF cases.
CYP2C19Polymorphisms and Clinical Outcomes Following Percutaneous Coronary Intervention (PCI) in the Million Veterans Program
Authors: Chanfreau-Coffinier Catherine , Friede Kevin A. , Plomondon Mary E. , Lee Kyung Min , Lu Zhenyu , Lynch Julie A. , DuVall Scott L. , Vassy Jason L. , Waldo Stephen W. , Cleator John H. , Maddox Thomas M. , Rader Daniel J. , Assimes Themistocles L. , Damrauer Scott M. , Tsao Philip S. , Chang Kyong-Mi , Voora Deepak , Giri Jay , Tuteja Sony ,   VA Million Veteran Program
Published: October 2023

Background

CYP2C19loss-of-function (LOF) alleles decrease the antiplatelet effect of clopidogrel following percutaneous coronary intervention (PCI) in patients presenting with acute coronary syndrome (ACS). The impact of genotype in stable ischemic heart disease (SIHD) is unclear.

Objectives

Determine the association ofCYP2C19genotype with major adverse cardiac events (MACE) after PCI for ACS or SIHD.

Methods

Million Veterans Program (MVP) participants age <65 years with a PCI documented in the VA Clinical Assessment, Reporting and Tracking (CART) Program between 1/1/2009 to 9/30/2017, treated with clopidogrel were included. Time to MACE defined as the composite of all-cause death, stroke or myocardial infarction within 12 months following PCI.

Results

Among 4,461 Veterans (mean age 59.1 ± 5.1 years, 18% Black); 44% had ACS, 56% had SIHD and 29% carried aCYP2C19LOF allele. 301 patients (6.7%) experienced MACE while being treated with clopidogrel, 155 (7.9%) in the ACS group and 146 (5.9%) in the SIHD group. Overall, MACE was not significantly different between LOF carriers vs. noncarriers (adjusted hazard ratio [HR] 1.18, confidence interval [95%CI] 0.97-1.45, p=0.096). Among patients presenting with ACS, MACE risk in LOF carriers versus non-carriers was numerically higher (HR 1.30, 95%CI 0.98-1.73, p=0.067). There was no difference in MACE risk in patients with SIHD (HR 1.09, 95%CI 0.82-1.44; p=0.565).

Conclusions

CYP2C19LOF carriers presenting with ACS treated with clopidogrel following PCI experienced a numerically greater elevated risk of MACE events.CYP2C19LOF genotype is not associated with MACE among patients presenting with SIHD.
Sprr1 and miR-130b contribute to the senescence-like phenotype in aging
Authors: Hong Ji Yeon , Nam Hee Jin , Ji Hong , Kim Yoon Young , Hyun Miri , Park Hee Jung , Bae Seung Min , McCrea Pierre D
Published: October 2023

Aging is an inevitable process with senescence being one of its hallmarks. Recent advances have indicated that the elimination of senescent cells can reduce the signs of aging and increase healthy life span. Here, we identify a negative modulator of aging, Sprr1a, and in turn a negative modulator of Sprr1a, miR-130b. We show that reductions in Sprr1a levels, including via miR-130b expression, promotes cell senescence-like phenotype. We find that mediators of senescence, such as inflammatory cytokines and cell cycle regulators, are modulated by the miR-130b and Sprr1a-related pathway. For example, the levels of p16, p53 and p21 become decreased or increased upon the respective expression of Sprr1a versus miR-130b. Further, as shown in relation to p16 levels and β-galactosidase levels, cells expressing Sprr1a exhibit significant protection from senescence-inducing factors such as radiation or Doxorubicin, suggesting that Sprr1a might contribute to protection against age-related pathologies. Taken together, we introduce two modulators of properties associated with senescence-like phenotype.
A non-canonical Arp2/3 complex is essential forPlasmodiumDNA segregation and transmission of malaria
Authors: Hentzschel Franziska , Jewanski David , Sokolowski Yvonne , Agarwal Pratika , Kraeft Anna , Hildenbrand Kolja , Dorner Lilian P. , Singer Mirko , Frischknecht Friedrich , Marti Matthias
Published: October 2023

The malaria-causing parasitePlasmodiumhas a complex life cycle involving both vertebrate and mosquito hosts. Sexual stages or gametocytes are the only stage competent for transmission to mosquitoes. Formation of flagellated male gametes from gametocytes requires rapid rounds of genome replication. Here we discovered a non-canonicalPlasmodiumactin-related protein 2/3 (Arp2/3) complex essential for DNA segregation during male gametogenesis.PlasmodiumArp2/3 dynamically localizes within the nucleus to the endomitotic spindles and interacts with a kinetochore protein. Deletion of key Arp2/3 subunits or interfering with actin polymerisation leads to the formation of sub-haploid male gametes and a complete block in transmission through delayed developmental arrest at the oocyst stage. Our work identified an evolutionary divergent protein complex in malaria parasites that offers potential targets for transmission-blocking interventions.
Extracellular domain, hinge, and transmembrane determinants affecting surface CD4 expression of a novel anti-HIV chimeric antigen receptor (CAR) construct
Authors: Zenere Giorgio , Wu Chengxiang , Midkiff Cecily C. , Johnson Nathan M. , Grice Christopher P. , Wimley William C. , Kaur Amitinder , Braun Stephen E.
Published: October 2023

Chimeric antigen receptor (CAR)-T cells have demonstrated clinical potential, but current receptors still need improvements to be successful against chronic HIV infection. In this study, we address some requirements of CAR motifs for strong surface expression of a novel anti-HIV CAR by evaluating important elements in the extracellular, hinge, and transmembrane (TM) domains. When combining a truncated CD4 extracellular domain and CD8α hinge/TM, the novel CAR did not express extracellularly but was detectable intracellularly. By shortening the CD8α hinge, CD4-CAR surface expression was partially recovered and addition of the LYC motif at the end of the CD8α TM fully recovered both intracellular and extracellular CAR expression. Mutation of LYC to TTA or TTC showed severe abrogation of CAR expression by flow cytometry and confocal microscopy. Additionally, we determined that CD4-CAR surface expression could be maximized by the removal of FQKAS motif at the junction of the extracellular domain and the hinge region. CD4-CAR surface expression also resulted in cytotoxic CAR T cell killing of HIV Env+target cells. In this study, we identified elements that are crucial for optimal CAR surface expression, highlighting the need for structural analysis studies to establish fundamental guidelines of CAR designs.
Widespread fungal-bacterial competition for magnesium enhances antibiotic resistance
Authors: Hsieh Yu-Ying Phoebe , Sun Wanting Wendy , Young Janet M. , Cheung Robin , Hogan Deborah A. , Dandekar Ajai A. , Malik Harmit S.
Published: October 2023

Fungi and bacteria coexist in many polymicrobial communities, yet the molecular basis of their interactions remains poorly understood. Using unbiased genomic approaches, we discover that the fungusCandida albicanssequesters essential Mg2+ions from the bacteriumPseudomonas aeruginosa. In turn, the bacterium competes using a Mg2+transporter, MgtA. We show that Mg2+sequestration by fungi is a general mechanism of antagonism against gram-negative bacteria. But the resultant Mg2+limitation enhances bacterial resistance to polymyxin antibiotics like colistin, which target gram-negative bacterial membranes. Experimental evolution reveals that bacteria in co-culture with fungi become phenotypically, but not genetically, resistant to colistin; antifungal treatment renders resistant bacteria from co-cultures to become colistin-sensitive. Fungal-bacterial nutritional competition may thus profoundly impact treatments of polymicrobial infections with antibiotics of last resort.

One Sentence Summary

Magnesium sequestration by fungi lowers bacterial fitness but enhances antibiotic resistance.