bluuebunny/crossref_metadata_2025 huggingface dataset:
Surveillance for TB drug resistance using routine rapid diagnostic testing data: Methodological development and application in Brazil
Authors: Baum Sarah E. , Pelissari Daniele M. , Costa Fernanda Dockhorn , Harada Luiza O. , Sanchez Mauro , Bartholomay Patricia , Cohen Ted , Castro Marcia C. , Menzies Nicolas A.
Published: July 2024

Effectively responding to drug-resistant tuberculosis (TB) requires accurate and timely information on resistance levels and trends. In contexts where use of drug susceptibility testing has not been universal, surveillance for rifampicin-resistance—one of the core drugs in the TB treatment regimen—has relied on resource-intensive and infrequent nationally-representative prevalence surveys. The expanded availability of rapid diagnostic tests (RDTs) over the past decade has increased testing coverage in many settings, however, RDT data collected in the course of routine (but not universal) use may provide biased estimates of resistance. Here, we developed a method that attempts to correct for non-random use of RDT testing in the context of routine TB diagnosis to recover unbiased estimates of resistance among new and previously treated TB cases. Specifically, we employed statistical corrections to model rifampicin resistance among TB notifications with observed Xpert MTB/RIF (a WHO-recommended RDT) results using a hierarchical generalized additive regression model, and then used model output to impute results for untested individuals. We applied this model to case-level data from Brazil. Modeled estimates of the prevalence of rifampicin resistance were substantially higher than naïve estimates, with estimated prevalence ranging between 28-44% higher for new cases and 2-17% higher for previously treated cases. Our estimates of RR-TB incidence were considerably more precise than WHO estimates for the same time period, and were robust to alternative model specifications. Our approach provides a generalizable method to leverage routine RDT data to derive timely estimates of RR-TB prevalence among notified TB cases in settings where testing for TB drug resistance is not universal.

Author Summary

While data on drug-resistant tuberculosis (DR-TB) may be routinely collected by National TB Control Programs using rapid diagnostic tests (RDTs), these data streams may not be fully utilized for DR-TB surveillance where low testing coverage may bias inferences due to systematic differences in RDT access. Here, we develop a method to correct for potential biases in routine RDT data to estimate trends in the prevalence of TB drug resistance among notified TB cases. Applying this approach to Brazil, we find that modeled estimates were higher than naïve estimates, and were more precise compared to estimates produced by the World Health Organization. We highlight the value of this approach to settings where testing coverage is low or variable, as well as settings where coverage may surpass existing coverage thresholds, but that could nonetheless benefit from additional statistical correction.
Chromosomal genome assembly resolves drug resistance loci in the parasitic nematode Teladorsagia circumcincta
Authors: McIntyre Jennifer , Morrison Alison , Maitland Kirsty , Berger Duncan , Price Daniel R. G. , Dougan Sam , Grigoriadis Dionysis , Tracey Alan , Holroyd Nancy , Bull Katie , Rose Vineer Hannah , Glover Mike J. , Morgan Eric R. , Nisbet Alasdair J. , McNeilly Tom , Bartley Yvonne , Sargison Neil , Bartley Dave , Berriman Matt , Cotton James , Devaney Eileen , Laing Roz , Doyle Stephen R.
Published: July 2024

The parasitic nematode Teladorsagia circumcincta is one of the most important pathogens of sheep and goat farming in temperate climates worldwide and can rapidly evolve resistance to drugs used to control it. To understand the genetics of drug resistance, we have generated a highly contiguous genome assembly for the UK T. circumcincta isolate MTci2. Assembly using PacBio long-reads and Hi-C long-molecule scaffolding together with manual curation resulted in a 573 Mb assembly (N50 = 84 Mb, n = 1,286) with five autosomal and one sex-linked chromosomal-scale scaffolds consistent with its karyotype. The genome resource was further improved via annotation of 22,948 genes, with manual curation of over 3,200 of these, resulting in a robust and near complete resource (96.3% complete protein BUSCOs) to support basic and applied research on this important veterinary pathogen. Genome-wide analyses of drug resistance, combining evidence from three distinct experiments, identified selection around known candidate genes for benzimidazole, levamisole and ivermectin resistance, as well as novel regions associated with ivermectin and moxidectin resistance. These insights into contemporary and historic genetic selection further emphasise the importance of contiguous genome assemblies in interpreting genome-wide genetic variation associated with drug resistance and identified key loci to prioritise in developing diagnostic markers of anthelmintic resistance to support parasite control.
Gene expression evolution during adaptation is predicted by stronger genetic selection at more pleiotropic genes inTribolium castaneum
Authors: Koch Eva L. , Rocabert Charles , Beeravolu Reddy Champak , Guillaume Frédéric
Published: July 2024

Changes in gene expression play a fundamental role in the process of adaptation and can inform on the genetic basis of adaptation. We utilized transcriptome-wide variation in gene expression as a means to uncover genes under selection for expression changes during adaptation to heat and drought stress and to understand the nature of selection on gene expression traits of the red flour beetleTribolium castaneum. We showed that estimates of genetic selection on transcript abundance were predictive of evolutionary changes in gene expression after 20 generations of adaptation in seven independent experimental lines. Having measured the genetic covariance between gene expression and relative fitness and among expression traits, we showed that evolutionary changes were caused by indirect selection acting on genetically correlated partners rather than direct selection acting on isolated genes. Consequently, pleiotropic genes with central positions in gene co-expression networks experienced stronger selection and exhibited larger evolutionary changes in expression. Our genomic analysis revealed that selection on expression levels drives parallel allele frequency changes (AFC) in the respective genes. More pleiotropic genes and those carrying expression quantitative trait loci (eQTLs) showed a higher degree of parallel evolution. More generally, genes with more parallel AFCs were under stronger genetic selection. Contrary to previous evidence of constrained evolution at more connected genes, adaptation was driven by selection acting disproportionately on genes central to co-expression gene networks. We demonstrated that measures of selection at the transcriptome level can provide accurate evolutionary predictions and critical information on the molecular basis of rapid adaptation.
Promotion of RNF168-Mediated Nucleosomal H2A Ubiquitylation by Structurally-defined K63-Polyubiquitylated Linker Histone H1
Authors: Shi Qiang , Deng Zhiheng , Zhang Liying , Tong Zebin , Li Jia-Bin , Chu Guo-Chao , Ai Huasong , Liu Lei
Published: July 2024

The chemical synthesis of histones with homogeneous modifications is a potent approach for quantitatively deciphering the functional crosstalk between different post-translational modifications (PTMs). Here, we developed an expedient site-specific (poly)ubiquitylation strategy (CAEPL, Cysteine-Aminoethylation coupled with Enzymatic Protein Ligation), which integrates the Cys-aminoethylation reaction with the process of ubiquitin-activating enzyme UBA1-assisted native chemical ligation. Using this strategy, we successfully prepared monoubiquitylated and K63-linked di- and tri-ubiquitylated linker histone H1.0 proteins, which were incorporated into individual chromatosomes. Quantitative biochemical analysis of different RNF168 constructs on ubiquitylated chromatosomes with different ubiquitin lengths demonstrated that K63-linked polyubiquitylated H1.0 could directly stimulate RNF168 ubiquitylation activity by enhancing the affinity between RNF168 and chromatosome. Subsequent cryo-EM structural analysis of the RNF168/UbcH5c–Ub/H1.0–K63-Ub3chromatosome complex revealed the potential recruitment orientation between RNF168 UDM1 domain and K63-linked ubiquitin chain on H1.0. Finally, we explored the impact of H1.0 ubiquitylation on RNF168 activity in the context of asymmetric H1.0–K63-Ub3di-nucleosome substrate, revealing a comparable stimulation effect of both the inter- and intra-nucleosomal crosstalk. Overall, our study highlights the significance of access to structurally-defined polyubiquitylated H1.0 by CAEPL strategy, enabling in-depth mechanistic investigations ofin-transPTM crosstalk between linker histone H1.0 and core histone H2A ubiquitylation.
Inhibition ofFusarium oxysporumgrowth in banana by silver nanoparticles:in vitroandin vivoassays
Authors: Mendoza Natalia , Yánez Paola , Magdama Freddy , Pacheco Ricardo , Vielma Joel , Vanegas María Eulalia , Bogdanchikova Nina , Pestryakov Alexey , Chong Pablo
Published: July 2024

Fusarium wilt is a devastating disease that affects banana crops worldwide. In Ecuador, bananas are one of the most important commodities and staple food. Nanoparticles are emerging as innovative solutions to control fungal diseases in plant protection. In this study,in vitroandin vivoassays were carried out to validateFusarium oxysporumgrowth and disease inhibition. 96-well plates experiments were used to calculate the IC50of three different silver nanoparticle formulations (Argovit-1220, Argovit-1221, and Argovit-C) against four EcuadorianFusariumstrains (EC15-E-GM1, EC19-LR-GM3, EC35-G-GM6, EC40-M-GM2). More than 95% inhibition rate was obtained at 25 mg L-1concentration. Fusarium wiltin vivoassay was carried out with Gros Michel plants, where better control was obtained by applying silver nanoparticles to the roots, reducing disease development by an average of 68%. This study shows that silver nanoparticles have a high antifungal potential for controlling the Fusarium wilt of bananas. To the best of our knowledge, this is the first study to test the potential of silver nanoparticles againstFusarium oxysporumin planta under greenhouse conditions.
An extinct clade sister to Eumetazoa: On the phylogeny of the Cambrian chancelloriids
Authors: Yun Hao , Zhang Xingliang , Brock Glenn A. , Han Jian , Li Luoyang , Pan Bing , Li Guoxiang , Reitner Joachim
Published: July 2024

The notable disparity of animal body plans can be traced back to the morphological innovations during the Cambrian explosion and represented by a number of exceptionally preserved soft-bodied and skeletal fossils that provide a compelling narrative for animal evolution. Chancelloriids, one of the extinct groups of Cambrian animals, have a distinctive body that characterized by a sclerite-bearing, flexible integument and a single apical opening leading into a central cavity devoid of unequivocal internal organs. Their phylogenetic position within the Metazoa, however, is controversial. Here, we describe new soft-bodied fossils of chancelloriids from the 518-million-year-old Chengjiang biota of China, which corroborate the unique bauplan pattern and reveal exquisite integument microstructures. The tiny protuberances and wrinkling structures of the integument are interpreted to be related to primitive epithelial contraction, suggesting that chancelloriids were a group of basal epitheliozoans and constitute an evolutionary clade that branched below all extant eumetazoans while above or close to the placozoans. Thus, the chancelloriid body plan likely filled one of the anatomical gaps between the Placozoa and the Eumetazoa.
Functional gene embeddings improve rare variant polygenic risk scores
Authors: Londhe Shubhankar , Lindner Jonas , Chen Zhifen , Holtkamp Eva , Hölzlwimmer Florian R. , Casale Francesco Paolo , Brechtmann Felix , Gagneur Julien
Published: July 2024

Rare variant association testing is a powerful strategy for identifying effector genes underlying common traits. However, its effectiveness is limited by the scarcity of high-impact rare allele carriers, posing challenges for sensitivity and robustness. Here, we introduce FuncRVP, a rare variant association framework addressing this issue by leveraging functional information across genes. FuncRVP models the effects of rare variants as a weighted sum of gene impairment scores, with weights regularized through a prior based on functional gene embeddings. Modeling 41 quantitative traits from unrelated UK Biobank participants showed that FuncRVP consistently outperformed linear regressions on significantly associated genes and did so more effectively for traits with higher burden heritability. The framework demonstrated versatility, yielding consistent improvements across diverse gene embeddings. Moreover, FuncRVP generated more robust gene effect estimates and yielded more gene discoveries, especially among genetically constrained genes. These findings demonstrate the value of integrating functional information in rare variant association studies and showcase FuncRVP as a promising tool for enhancing phenotype prediction and gene discovery.
Unravelling Plankton Adaptation in Global Oceans through the Analysis of Lipidomes
Authors: Liu Weimin , Holm Henry C. , Lipp Julius S. , Fredricks Helen F. , Van Mooy Benjamin A. S. , Hinrichs Kai-Uwe
Published: July 2024

A recent global survey of planktonic lipids showed a fundamental temperature-mediated regulation of lipid unsaturation in the global oceans [Holm H, et al. (2022) Science 376:1487–1491]. We expand the analysis of this dataset, both spatially and methodologically, to examine diverse environmental stressors across the ocean. Utilizing weighted correlation network analysis, we analyzed 3,164 lipid features in the dataset comprising 930 samples of suspended particulate matter, taken across a broad range of oceanographic conditions and water depths up to 600 meters. A total of 16 lipid clusters being co-expressed across diverse environments were identified. This analysis reveals universal relationships between environmental factors and the lipidome of the planktonic community. The largest lipid cluster, comprising 481 lipid features, including glycerolipids with polyunsaturated fatty acids, exhibited a significant enrichment in polar oceans, suggesting the highest lipid diversity in these ocean regions. Remarkably, marine plankton in these regions employ both desaturation and chain shortening for cold acclimation. Additionally, one lipid cluster strongly linked to the plankton residing in the surface of tropical and subtropical oceans was enriched with non-phosphorus lipids. We suggest this adaptive response enables the plankton to cope with phosphorous scarcity and heat stress. Notably, in the subsurface of these regions, a co-expressed cluster of highly unsaturated lipids is consistent with an enhanced production of polyunsaturated fatty acids by phytoplankton, possibly for low light adaptation. This adaptation is important as it may represent a source of essential fatty acids below the warm sea surface where such vital compounds may be diminished in the warmer future.

Significance

Marine plankton is vital for marine ecosystems and climate regulation. We analyzed a large lipidomics dataset of 930 samples collected from global oceans. This allowed us to explore how plankton adapt their lipidomes across different environments. Our findings show distinct lipid clusters correlating with specific environmental conditions, revealing mechanisms like chain shortening to cope with cold stress, enrichment of non-phosphorus lipids in tropical surface waters, and increased polyunsaturated fatty acids in low-light tropical subsurface areas. These adaptations are crucial for understanding how climate change will impact marine ecosystems.
ERβ mediates sex-specific protection in theApp-NL-G-Fmouse model of Alzheimer’s disease
Authors: Demetriou Aphrodite , Lindqvist Birgitta , Ali Heba G. , Shamekh Mohamed M. , Maioli Silvia , Inzunza Jose , Varshney Mukesh , Nilsson Per , Nalvarte Ivan
Published: July 2024

Menopausal loss of neuroprotective estrogen is thought to contribute to the sex differences in Alzheimer’s disease (AD). Activation of estrogen receptor beta (ERβ) can be clinically relevant since it avoids the negative systemic effects of ERα activation. However, very few studies have explored ERβ-mediated neuroprotection in AD, and no information on its contribution to the sex differences in AD exists. In the present study we specifically explored the role of ERβ in mediating sex-specific protection against AD pathology in the clinically relevantAppNL-G-Fknock-in mouse model of amyloidosis, and if surgical menopause (ovariectomy) modulates pathology in this model. We treated male and femaleAppNL-G-Fmice with the selective ERβ agonist LY500307 and subset of the females was ovariectomized prior to treatment. Memory performance was assessed and a battery of biochemical assays were used to evaluate amyloid pathology and neuroinflammation. Primary microglial cultures from male and female wild-type and ERβ-knockout mice were used to assess ERβ’s effect on microglial activation and phagocytosis. We find that ERβ activation protects against amyloid pathology and cognitive decline in male and femaleAppNL-G-Fmice. Ovariectomy increased soluble amyloid beta (Aβ) in cortex and insoluble Aβ in hippocampus, but had otherwise limited effects on pathology. We further identify that ERβ does not alter APP processing, but rather exerts its protection through amyloid scavenging that at least in part is mediated via microglia in a sex-specific manner. Combined, we provide new understanding to the sex differences in AD by demonstrating that ERβ protects against AD pathology differently in males and females, warranting reassessment of ERβ in combating AD.
Range geographies, not functional traits, explain convergent range and phenology shifts under climate change
Authors: Sirois-Delisle Catherine , Gordon Susan C.C. , Kerr Jeremy T.
Published: July 2024

Climate change may introduce conditions beyond species’ tolerances; to survive, species must avoid these extremes. Phenological shifts are one strategy, as species move their activity or life history events in time to avoid extreme conditions. Species may also shift in space, moving their ranges poleward to escape extremes. However, whether species are more likely to exhibit one or both strategies, and whether this can be predicted based on a species’ functional traits, is unknown. Using a powerful macroecological dataset of European and North American odonate observations, we assessed range and phenology shifts between two time periods (1980-2002 and 2008-2018) to measure the strength and direction of the association between responses. Species with the greatest poleward range shifts also showed the largest phenological shifts toward earlier annual activity periods, with half of all species shifting in both space and time. This response was consistent across continents, despite highly divergent land use and biogeographical histories in these regions. Surprisingly, species’ range and phenology shifts were not related to functional traits; rather, southern species shifted their range limits more strongly, while increasing temperature variability hindered range shifts. By reducing risk through phenological shifts, the resulting larger populations may be more likely to disperse and expand species’ ranges. While species shifting in both space and time may be more resilient to extreme conditions, we identified a small number of species (approximately 10%) that failed to shift at all; these species are likely to be particularly vulnerable to climate change, and should be prioritized for conservation intervention.
ASO-enhancement ofTARDBPexitron splicing mitigates TDP-43 proteinopathies
Authors: Yamagishi Takuma , Koide Shingo , Toyama Genri , Washida Aya , Yamada Yumi , Hanyu Ryutaro , Nadbitova Ekaterina , Koike Yuka Mitsuhashi , Konno Takuya , Ishihara Tomohiko , Kato Taisuke , Onodera Osamu , Sugai Akihiro
Published: July 2024

Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are fatal neurodegenerative diseases characterized by pathological aggregation and nuclear functional loss of TDP-431,2. Current therapies inadequately address this core pathology3,4, necessitating innovative approaches that target aggregation while preserving TDP-43’s essential functions. Here we demonstrate that enhancing the splicing of theTARDBPexitron—a cryptic intron encoding the aggregation-prone intrinsically disordered region (IDR) of TDP-435,6— effectively mitigates TDP-43 pathology. This exitron splicing event, directly regulated by nuclear TDP-437–9, suppresses the expression of IDR-containing TDP-43 isoforms and generates IDR-spliced-out TDP-43 isoforms7,9,10(which we term “IDRsTDP”). Our findings reveal that IDRsTDP, known to heterodimerize with full-length TDP-4310, inhibits TDP-43 aggregation by suppressing IDR-mediated clustering and enhances TDP-43 clearance via chaperone-mediated autophagy. In disease states, however, impaired nuclear TDP-43 function disrupts exitron splicing, leading to increased levels of IDR-containing TDP-439,11and reduced levels of IDRsTDP, exacerbating aggregation and nuclear dysfunction6,12–17. By identifying HNRNPA1 and HNRNPC as key repressors ofTARDBPexitron splicing, we designed antisense oligonucleotides (ASOs) to block their binding and restore splicing. These ASOs suppressed TDP-43 pathology and neurodegeneration in both neuronal cell models with impaired nuclear transport and a mouse model of proteasome dysfunction-induced TDP-43 proteinopathy. Our strategy, by rescuing the impaired autoregulatory pathway, inhibits the pathological cycle of TDP-43 aggregation and nuclear dysfunction, offering a promising avenue for treating these currently intractable neurodegenerative diseases.
The Physical Basis of Osmosis in a Donnan Ionic System
Authors: Manning Gerald S.
Published: July 2024

1

The osmotic flow of water is driven by the repulsive force between semipermeable membrane and impermeable solute that creates a pressure drop at the interface between membrane and aqueous solution. An analysis of the physical principles involved is relatively simple for a neutral solute that is absolutely impermeable. Extension to partially permeable neutral solutes is more complicated but has been accomplished. In this paper the analysis is further extended to include Donnan ionic systems. The electric forces due to the charges on the ions give rise to non-uniform ionic concentrations and trans-membrane electric voltages as well as pressure gradients, and the relationships among all of these Donnan effects have an impact on osmosis. The supplementary effect of an ion pump, acting to prevent the osmotic danger of cell swelling and rupture, is explored.
mRNA stability fine tunes gene expression in the developing cortex to control neurogenesis
Authors: Serdar Lucas D. , Egol Jacob R. , Lackford Brad , Bennett Brian D. , Hu Guang , Silver Debra L.
Published: July 2024

RNA expression levels are controlled by the complementary processes of synthesis and degradation. Although mis-regulation of RNA turnover is linked to neurodevelopmental disorders, how it contributes to cortical development is largely unknown. Here, we profile the RNA stability landscape of the cortex across development and demonstrate that control of stability by the CCR4-NOT complex is essential for corticogenesisin vivo. First, we use SLAM-seq to measure RNA half-lives transcriptome-wide across multiple stages of cortical development. We characterizecis-acting features associated with RNA stability and find that RNAs that are upregulated across development tend to be more stable, while downregulated RNAs are less stable. To probe how disruption of RNA turnover impacts cortical development, we assess developmental requirements of CNOT3, a core component of the CCR4-NOT deadenylase complex. Mutations inCNOT3are associated with human neurodevelopmental disorders, however its role in cortical development is unknown. Conditional knockout ofCnot3in neural progenitors and their progeny in the developing mouse cortex leads to severe microcephaly due to reduced neuron production and p53-dependent apoptosis. Collectively, our findings demonstrate that fine-tuned control of RNA turnover is crucial for brain development.
An arylsulphonamide that targets cell wall biosynthesis inMycobacterium tuberculosis
Authors: Allen Renee , Ames Lauren , Baldin Vanessa Pietrowski , Butts Arielle , Henry Kenneth J. , Quach Diana , Sugie Joseph , Pogliano Joe , Parish Tanya
Published: July 2024

We investigated the mechanism of action of an arylsulphonamide with whole cell activity againstMycobacterium tuberculosis. We newly synthesized the molecule and confirmed it had activity against both extracellular and intracellular bacilli. The molecule had some activity against HepG2 cells but maintained some selectivity. Bacterial cytological profiling suggested that mechanism of action was via disruption of cell wall synthesis, with similarities to an inhibitor of the mycolic acid exporter MmpL3. The compound induced expression from the IniB promoter and caused a boost in ATP production but did not induce reactive oxygen species. A mutation in MmpL3 (S591I) led to low-level resistance. Taken together these data confirm the molecule targets cell wall biosynthesis with MmpL3 as the most probable target.
Synapse protein signatures in cerebrospinal fluid and plasma predict cognitive maintenance versus decline in Alzheimer’s disease
Authors: Oh Hamilton Se-Hwee , Urey Deniz Yagmur , Karlsson Linda , Zhu Zeyu , Shen Yuanyuan , Farinas Amelia , Timsina Jigyasha , Guldner Ian H. , Morshed Nader , Yang Chengran , Western Daniel , Ali Muhammad , Le Guen Yann , Trelle Alexandra , Herukka Sanna-Kaisa , Rauamaa Tuomas , Hiltunen Mikko , Lipponen Anssi , Luikku Antti J. , Poston Kathleen L. , Mormino Elizabeth , Wagner Anthony D. , Wilson Edward N. , Channappa Divya , Leinonen Ville , Stevens Beth , Ehrenberg Alexander J. , Zetterberg Henrik , Bennett David A. , Franzmeier Nico , Hansson Oskar , Cruchaga Carlos , Wyss-Coray Tony
Published: July 2024

Rates of cognitive decline in Alzheimer’s disease (AD) are extremely heterogeneous, with ages of symptom onset ranging from age 40-100 years and conversion from mild cognitive impairment to AD dementia taking 2-20 years. Development of biomarkers for amyloid-beta (Aβ) and tau protein aggregates, the hallmark pathologies of AD, have improved patient monitoring/stratification and drug development, but they still only explain 20-40% of the variance in cognitive impairment (CI) in AD. To discover additional molecular drivers and biomarkers of AD dementia, we perform cerebrospinal fluid (CSF) proteomics on 3,416 individuals from six deeply phenotyped prospective AD case-control cohorts. We identify synapse proteins as the strongest correlates of CI, independent of Aβ and tau. Using machine learning we derive the CSF YWHAG:NPTX2 synapse protein ratio, a robust correlate of CI, which explains 27% of the variance in CI beyond CSF PTau181:Aβ42, 10% beyond tau PET, and 50% beyond CSF NfL in Aβ positive individuals. We find YWHAG:NPTX2 also increases with normal aging as early as age 20 and increases at a faster rate inAPOE4carriers and autosomal dominant-AD mutation carriers. Most notably, YWHAG:NPTX2+ individuals (top 25thpercentile) are 15-times (HR=15.4 [10.6-22.2]) more likely to experience cognitive decline over 15 years compared to YWHAG:NPTX2– individuals (bottom 25thpercentile), and this rises to 19-times (HR=18.9 [10.83-32.9]) with additional stratification by Aβ and phosphorylated tau status. Lastly, we perform plasma proteomics on 4,245 individuals to develop a plasma-based signature of CI which partly recapitulates CSF YWHAG:NPTX2. Overall, our findings underscore CSF YWHAG:NPTX2 and the corresponding plasma signature as robust prognostic biomarkers for AD onset and progression beyond gold-standard biomarkers of Aβ, tau, and neurodegeneration and implicate synapse dysfunction as a core driver of AD dementia.
Rapid review of Allied Health Professionals working in neonatal services
Authors: Bromham Nathan , Batten Leona , Jarrom David , Gillen Elizabeth , Hounsome Juliet , Davies Jacob , Tudor Edwards Rhiannon , Manton Margaret , Cooper Alison , Edwards Adrian , Lewis Ruth
Published: July 2024

Background

This review aimed to quantify the impact of allied health professionals (AHPs) embedded in neonatal services on outcomes by asking the following review questions:

Q1. What is the effectiveness of neonatal services with embedded allied health professionals compared to neonatal services without embedded allied health professionals?

Q2. What is the effectiveness of early interventions provided by allied health professionals in neonatal units?

Research Implications and Evidence Gaps

There was very little directly relevant evidence on AHPs embedded in neonatal services. Most of the evidence related to multidisciplinary team working or early interventions provided by AHPs. Few early intervention trials were from the UK, leading to uncertainty about the availability and applicability of interventions in the UK setting. Further UK-based research is needed to better understand the best way to integrate allied health professionals in neonatal services.

Economic considerations

There is no published evidence on the cost of AHPs working within neonatal units. There is marked variability in the reporting of cost estimates for neonatal care units in the UK, making the evaluation of cost implications of adopting AHP recommendations difficult. Subsequent economic evaluations could explore the Budget Impact to the NHS of increasing AHP presence in neonatal units to align with recommendations from AHP professional bodies and Royal Colleges.

Funding statement

Health Technology Wales were funded for this work by the Health and Care Research Wales Evidence Centre, itself funded by Health and Care Research Wales on behalf of Welsh Government.
HIBRID: Histology and ct-DNA based Risk-stratification with Deep Learning
Authors: Loeffler Chiara M.L. , Bando Hideaki , Sainath Srividhya , Muti Hannah Sophie , Jiang Xiaofeng , van Treeck Marko , Reitsam Nic Gabriel , Carrero Zunamys I. , Nishikawa Tomomi , Misumi Toshihiro , Mishima Saori , Kotani Daisuke , Taniguchi Hiroya , Takemasa Ichiro , Kato Takeshi , Oki Eiji , Yuan Tanwei , Wankhede Durgesh , Foersch Sebastian , Brenner Hermann , Hoffmeister Michael , Nakamura Yoshiaki , Yoshino Takayuki , Kather Jakob Nikolas
Published: July 2024

Background

Although surgical resection is the standard therapy for stage II/III colorectal cancer (CRC), recurrence rates exceed 30%. Circulating tumor DNA (ctDNA) emerged as a promising recurrence predictor, detecting molecular residual disease (MRD). However, spatial information about the tumor and its microenvironment is not directly measured by ctDNA. Deep Learning (DL) can predict prognosis directly from routine histopathology slides.

Methods

We developed a DL pipeline utilizing vision transformers to predict disease-free survival (DFS) based on histological hematoxylin & eosin (H&E) stained whole slide images (WSIs) from patients with resectable stage II-IV CRC. This model was trained on the DACHS cohort (n=1766) and independently validated on the GALAXY cohort (n=1555). Patients were categorized into high- or low-risk groups based on the DL-prediction scores. In the GALAXY cohort, the DL-scores were combined with the four-weeks post-surgery MRD status measured by ctDNA for prognostic stratification.

Results

In GALAXY, the DL-model categorized 307 patients as DL high-risk and 1248 patients as DL low-risk (p<0.001; HR 2.60, CI 95% 2.11-3.21). Combining the DL scores with the MRD status significantly stratified both the MRD-positive group into DL high-risk (n=81) and DL low-risk (n=160) (HR 1.58 (CI 95% 1.17-2.11; p=0.002) and the MRD-negative group into DL high-risk (n=226) and DL low-risk (n=1088) (HR 2.37 CI 95% 1.73-3.23; p<0.001). Moreover, MRD-negative patients had significantly longer DFS when predicted as DL high-risk and treated with ACT (HR 0.48, CI 95% 0.27-0.86; p= 0.01), compared to the MRD-negative patients predicted as DL low-risk (HR=1.14, CI 95% 0.8-1.63; p=0.48).

Conclusion

DL-based spatial assessment of tumor histopathology slides significantly improves the risk stratification provided by MRD alone. Combining histologic information with ctDNA yields the most powerful predictor for disease recurrence to date, with the potential to improve follow-up, withhold adjuvant chemotherapy in low-risk patients and escalate adjuvant chemotherapy in high-risk patients.

Highlights

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This study combines MRD status measured by ctDNA with a DL-based risk assessment trained on histological image data to enhance recurrence prediction.

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DL-based spatial assessment of tumor histopathology slides significantly improves the risk stratification provided by MRD alone.

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MRD-negative patients with high DL-based risk had a significantly longer DFS if treated with ACT, compared to MRD-negative and DL low risk patients

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The DL model is fully open-source and publicly available.
Sputum Proteomics reveals unique signatures linked to key outcomes in cystic fibrosis trials
Authors: Pottenger Sian , Nazareth Dilip , Wat Dennis , Bellina Bruno , Langini Maike , Walshaw Martin , Neill Daniel R. , Schwarz Carsten , Frost Freddy , Fothergill Joanne L.
Published: July 2024

Rationale

Lung function (FEV1) and quality of life (QoL) are key outcomes in most interventional clinical trials conducted in people living with cystic fibrosis. However, no robust pre-clinical surrogates for FEV1 and QoL exist. The precise physiological mechanisms leading to treatment-related improvements in these outcomes are incompletely understood. In this post-hoc analysis we explored the relationship between changes in the sputum proteome and these outcomes with the aim of identifying translational biomarkers.

Methods

Paired sputum samples collected during the AZTEC-CF study (NCT02894684) pre and post 14 days of antibiotic treatment for an acute pulmonary exacerbation were included. Samples were analysed usingin vitroMesoscale Discovery (MSD) assays and by nano LC-MS/MS. Peptide identification and quantification was performed and the log-fold change for individual proteins and relationships between protein change and changes in FEV1 and QoL were evaluated.

Results

Distinct patterns were found between proteins that correlated with FEV1 and those that correlated with QoL improvements. FEV1 improvement was characterised by increases in bacterially-derived proteins accompanied by decreases in proteins relating to neutrophil degranulation. Conversely, changes in QoL were associated with increases in antiprotease and antioxidant proteins. MSD analysis revealed changes in some neutrophil-associated markers significantly correlated with FEV1 improvements, but no markers significantly correlated with QoL improvements.

Conclusions

These results suggest changes in two key CF clinical trial outcomes (FEV1 and QoL) may be underpinned by different physiological mechanisms. Understanding these divergent mechanisms is vital to fortify optimal clinical trial design in CF and panels of biomarkers may be needed to improve translational confidence.
Possible Wigner states in
CrI3
heterostructures with graphene: A tight-binding model perspective
Authors: Rozhansky Igor , Fal'ko Vladimir
Published: July 2024

In this study, we present an effective tight-binding model for an accurate description of the lowest energy quadruplet of a conduction band in a ferromagnetic CrX3 monolayer, tuned to the complementary density functional theory simulations. This model, based on a minimum number of chromium orbitals, captures a distinctively flat dispersion in those bands but requires taking into account hoppings beyond nearest neighbors, revealing ligand-mediated electron pathways connecting remote chromium sites. Doping of states in the lowest conduction band of CrX3 requires charge transfer, which, according to recent studies [Tenasini , ; Tseng , ; Cardoso , , can occur in graphene(G)/CrX3 heterostructures. Here, we use the detailed description of the lowest conduction band in CrI3 to show that G/CrI3/G and G/CrI3 are type-II heterostructures where light holes in graphene would coexist with heavy electrons in the magnetic layer, where the latter can be characterized by Wigner-Seitz radius rs∼25−35 (as estimated for hBN-encapsulated structures).

Published by the American Physical Society
2024
Symmetric conformity functions make decision-making processes independent of the distribution of learning strategies
Authors: Jędrzejewski Arkadiusz , Hernández Laura
Published: July 2024

Two main procedures characterize the way in which social actors evaluate the qualities of the options in decision-making processes: they either seek to evaluate their intrinsic qualities (individual learners), or they rely on the opinion of the others (social learners). For the latter, social experiments have suggested that the mathematical form of the probability of adopting an option, called the , is symmetric in the adoption rate. However, the literature on decision-making includes models where social learners employ either symmetric or nonsymmetric conformity functions. We generalize a particular case studied in a previous work, and we show analytically that if the conformity function is symmetric, the details of the probability distribution of the propensity of the agents to behave as a social or an individual learner do not matter, only its expected value influences the determination of the steady state. We also show that in this case, the same steady state is reached for two extreme dynamical processes: one that considers propensities as idiosyncratic properties of the agents (each agent being an individual learner always with the same probability), and the opposite one, which allows them to change their propensity during the dynamics. This is not the case if the conformity function is nonsymmetric. This fact can inspire experiments that could shed light on the debate about mathematical properties of conformity functions.

Published by the American Physical Society
2024
Chlorido[(1,2,5,6-η)-cycloocta-1,5-diene](1-ethyl-4-isobutyl-1,2,4-triazol-5-ylidene)rhodium(I)
Authors: Lerch Timothy G. , Gau Michael , Albert Daniel R. , Rajaseelan Edward
Published: July 2024

A new neutral triazole-based N-heterocyclic carbene rhodium(I) complex [RhCl(C8H12)(C8H15N3)], has been synthesized and structurally characterized. The complex crystallizes with two molecules in the asymmetric unit. The central rhodium(I) atom has a distorted square-planar coordination environment, formed by a cycloocta-1,5-diene (COD) ligand, an N-heterocyclic carbene (NHC) ligand, and a chlorido ligand. The bond lengths are unexceptional. A weak intermolecular non-standard hydrogen-bonding interaction exists between the chlorido and NHC ligands.
Research on insect-like long endurance hovering double-wing FMAV prototype
Authors: Zhang Yichen , Cui Feng , Liu Wu , Zhu Wenhao , Xiao Yiming , Guo Qingcheng , Mou Jiawang
Published: July 2024

Purpose

Endurance time is an important factor limiting the progress of flapping-wing aircraft. In this study, this paper developed a prototype of a double-wing flapping-wing micro air vehicle (FMAV) that mimics insect-scale flapping wing for flight. Besides, novel methods for optimal selection of motor, wing length and battery to achieve prolonged endurance are proposed. The purpose of this study is increasing the flight time of double-wing FMAV by optimizing the flapping mechanism, wings, power sources, and energy sources.

Design/methodology/approach

The 20.4 g FMAV prototype with wingspan of 21.5 cm used an incomplete gear flapping wing mechanism. The motor parameters related to the lift-to-power ratio of the prototype were first identified and analyzed, then theoretical analysis was conducted to analyze the impact of wing length and flapping frequency on the lift-to-power ratio, followed by practical testing to validate the theoretical findings. After that, analysis and testing examined the impact of battery energy density and efficiency on endurance. Finally, the prototype’s endurance duration was calculated and tested.

Findings

The incomplete gear facilitated 180° symmetric flapping. The motor torque constant showed a positive correlation with the prototype’s lift-to-power ratio. It was also found that the prototype achieved the best lift-to-power ratio when using 100 mm wings.

Originality/value

A gear-driven flapping mechanism was designed, capable of smoothly achieving 180° symmetric flapping. Besides, factors affecting long-duration flight – motor, wings and battery – were identified and a theoretical flight duration analysis method was developed. The experimental result proves that the FMAV could achieve the longest hovering time of 705 s, outperforming other existing research on double-wing FMAV for improving endurance.
Development of a blockchain-based embodied carbon estimator
Authors: Rodrigo Navodana , Perera Srinath , Senaratne Sepani , Jin Xiaohua
Published: July 2024

Purpose

Carbon management in the construction industry plays a vital role as carbon emissions have a significant impact on the environment. Current emphasis on reducing operational carbon through passive designs, zero carbon buildings and so forth has resulted in losing focus on embodied carbon (EC) reduction. Though there are various databases and tools to estimate EC in construction, these estimates are lacking in accuracy and consistency. A Blockchain-based Embodied Carbon (BEC) Estimator was developed as a solution to accurately estimate EC using a supply chain value addition concept as a methodology.

Design/methodology/approach

This study focused on developing, testing and validating the blockchain-based prototype system identified as BEC Estimator. The system was developed using Hyperledger Fabric following a waterfall model. Case studies and an expert forum were used to test and validate BEC Estimator.

Findings

The system architecture, development process and the user interface of BEC Estimator are presented in this paper. The comparative evaluation with existing EC databases/tools and the expert forum validated the functioning of BEC Estimator and proved it to be an accurate, secure and trustworthy EC estimating system. SWOT (Strengths, Weaknesses, Opportunities, Threats) analysis identified the strengths and opportunities that will benefit the industry as well as the weaknesses and threats in the system that could be mitigated in future.

Originality/value

BEC Estimator accurately accounts for EC additions happening at each supply chain node for any product that gets incorporated in a building, thereby facilitating EC-related decision-making for all relevant stakeholders.
Urban planning approaches to support community-based flood adaptation in North Jakarta Kampungs
Authors: Prana Adam Madigliani , Curl Angela , Dionisio Maria Rita , Gomez Christopher , Hart Deirdre , Apriyanto Heri , Prasetya Hermawan
Published: July 2024

Purpose

The ineffectiveness of flood control in climate-impacted majority-world cities like Jakarta highlights the need for policies that integrate local knowledge and embrace water harmony rather than resistance. This study explores flood adaptation in North Jakarta's kampungs (urban informal settlements), aiming to enhance the efficacy of current flood disaster management. The outcomes of the participatory planning mechanism simulation that we propose are expected to provide valuable insights for the urban planning approach in that city.

Design/methodology/approach

We employed focus groups and design charrettes with a bottom-up approach to explore how local knowledge can enhance spatial flood management and urban planning policies. In total, 17 diverse participants, covering various ages and professions, engaged in these activities. Our methods aimed to be culturally sensitive and inclusive, embracing indigenous values like musyawarah and gotong royong. The research methodically examined flood implications and adaptations in informal settlements, progressing through preliminary understanding, data triangulation, and a reflective synthesis of the findings.

Findings

Amid worsening global changes like sea level rise, community-focussed, collaborative planning can help create tailored flood-resilience solutions. The research reveals that partnerships between communities and organisations promote city-wide, flood-adapted environments, aligning policy with the needs and goals of those most affected by flooding. This collaboration enhances flood disaster management and planning policies.

Research limitations/implications

This research focusses on Jakarta's flood adaptation and urban planning, reflecting on historical situations relevant to urbanising majority-world countries. Whilst specific to Jakarta, it offers perspectives on managing global environmental challenges such as sea level rise. Subsequent research should prudently consider each locale's distinct geographic and social milieu and the trust in planning systems in applying these findings, methodologies and approaches.

Originality/value

This study clarifies the relationship between disaster management, policy and flood adaptation, focussing on local knowledge in North Jakarta, pertinent to urbanising majority-world nations. Jakarta's historical and modern dynamics, including globalisation, reveal specific prospects and obstacles to applying vernacular knowledge to planning and disaster response. It highlights crucial points for policymakers in the majority of the world to address growing flood risks and create strategies that integrate local and traditional wisdom.
Estimating vulnerability to income and multidimensional poverty: a new methodological approach
Authors: Mekonnen Andualem Goshu
Published: July 2024

Purpose

The purpose of this paper is to propose a new vulnerability to income and multidimensional poverty estimation index (VIMPI). This index is designed to measure the likelihood of individuals falling into and remaining in poverty.

Design/methodology/approach

The paper introduces a new methodology that integrates the concepts of the well-being gap, individual and indicator-specific weighting, and vulnerability. This approach is simple to apply and accurately measures vulnerability with less susceptibility to measurement error and outliers. The index satisfies all poverty and vulnerability axioms, including transferability and monotonicity. The newly proposed method has been applied to Namibian and Ghanaian data and compared with similar techniques.

Findings

The results showed that Ghana's vulnerability to income and multidimensional poverty was 37.9% and 56%, respectively. Of the 37.9% of vulnerable individuals, 23.4% were at risk of falling into poverty, while 14.57% were at risk of remaining in poverty. These findings demonstrate the effectiveness of VIMPI in accurately estimating vulnerability to poverty and its potential to inform targeted policies to alleviate poverty.

Originality/value

This paper proposes a new methodology to estimate vulnerability to income and multidimensional poverty.