bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk Prediction In Long Term Kidney Transplant Recipients – Model Development Using Apelinergic Markers And Machine Learning Tools
Authors: Batko Krzysztof , Sączek Anna , Banaszkiewicz Małgorzata , Małyszko Jolanta , Koc-Żórawska Ewa , Żórawski Marcin , Niezabitowska Karolina , Siek Katarzyna , Bętkowska-Prokop Alina , Krzanowski Marcin , Krzanowska Katarzyna
Published: May 2024

Introduction

Limited tools exist for predicting kidney function in long-term kidney transplant recipients (KTRs). Elabela and apelin are APJ receptor agonists that constitute the apelinergic axis, which is a recently discovered system regulating vascular and cardiac tissue, in opposition to renin-angiotensin-aldosterone.

Methods

Longitudinal, observational cohort of 102 KTRs who maintained graft function ≥24 months, with no acute rejection history or current active or chronic infection. Serum apelin, elabela, fibroblast growth factor 23 (FGF-23) and α-Klotho were tested using enzyme-linked immunoassay and compared with a control group of 32 healthy volunteers.

Results

Median (IQR) follow-up time was 83 (42, 85) months. Higher serum FGF-23 and elabela, but lower α Klotho concentrations were observed in KTRs. Most KTRs had stable trajectories of renal function. All candidate markers were significantly associated with mean two-year eGFR over follow-up, which itself was validated respective to ‘death with functioning graft’ censored dialysis requirement. Using a cross-validation approach, we demonstrated eGFR at initial visit as the most salient predictor of future renal function. Machine learning models incorporating both clinical and biochemical (candidate markers) assessments were estimated to explain 15% of variance in future eGFR when considering eGFR-independent predictions.

Conclusions

Utilization of machine learning tools that incorporate clinical information and biochemical assessments, including serum amrkers of the apelinergic axis, may help stratify risk and aid decision making in the care of long term KTRs.
Impact of long-lasting insecticidal nets onPlasmodium falciparuminfection among women attending antenatal clinic at the Bonassama District Hospital, Littoral Region of Cameroon
Authors: Ajonina Marcelus U. , Ajonina-Ekoti Irene U. , Ngulefac John , Ade Nicholas , Awambeng Derick N. , Nfor Carine K. , Ayim Martin , Apinjoh Tobias O.
Published: May 2024

Malaria during pregnancy continues to be a significant cause of morbidity and mortality for both infants and mothers, particularly in sub-Saharan African (SSA) countries, despite increased efforts to control it. The utilization of long-lasting insecticide-treated nets (LLINs) during pregnancy is a well-established strategy to reduce the prevalence of malaria. Nonetheless, inadequate adherence remains a persistent challenge in certain regions with high malaria endemicity. This research aimed to assess the effectiveness of long-lasting insecticidal nets in preventing asymptomatic malaria infections among pregnant women attending antenatal care at the Bonassama District Hospital in the Littoral Region of Cameroon. A hospital-based cross-sectional study was conducted from March to June 2022. Data on sociodemographic characteristics and LLIN usage were collected through a structured questionnaire, while asymptomatic malaria infections were identified using a PfHRP2/pLDH malaria qualitative rapid diagnostic kit. The relationship between categorical variables was analyzed using the chi-square test and logistic regression at a significance level of 5%. Out of the 411 pregnant women included in the study, 156 (35.4%) were diagnosed with malaria. The LLIN utilization rate was 65.1% (287). The risk of malaria infection was 2.7 times higher (AOR = 2.75, 95% CI = 1.83-4.14, p < 0.001) among women who did not consistently use LLINs compared to those who did. The majority (65.1%) of pregnant women always used LLINs, while 34.9% did not consistently use them. Pregnant women aged 20-29 were 3.5 times more likely to use LLINs (AOR = 3.53, 95% CI = 1.61-7.75, p = 0.002) compared to those in the 30-39 and >39 age groups. Furthermore, women practicing Christianity were 1.7 times more likely (AOR = 1.72, 95% CI = 1.01-2.96, p = 0.047) to consistently use LLINs than those of the Islamic faith. Pregnant women in their first trimester (AOR = 3.40, 95% CI = 1.24-4.64, p = 0.010) and second trimester (AOR = 1.90, 95%CI = 0.99 -3.62, p = 0.055) were more likely to sleep under net when compared to those in the third trimester. Among the reasons reported by participants for not frequently using LLINs were heat [55.2% (85)], suffocation [13.6% (21)] and the smell of nets [8.4% (13)]. The use of LLIN was moderately high among the participants in this study, though still below national target. Age group, occupation, religion and gestation period were the major factors determining the use of LLINs. Considering the proven effectiveness of LLINs in reducing malaria morbidity and mortality, it is imperative for the National Malaria Control Programme (NMCP) to remain focused in promoting both LLIN ownership and utilization to achieve the national target of 100% and 80%, respectively.
Function and interactions of a protein bridge between the inner membrane complex and subpellicular microtubules inToxoplasma gondii
Authors: Cheng Emily S. , Moon Andy S. , Barshop William D. , Wohlschlegel James A. , Bradley Peter J.
Published: May 2024

Toxoplasma gondiiis an obligate intracellular parasite that utilizes peripheral membrane and cytoskeletal structures for critical functions such as host cell invasion, replication, and maintaining cellular morphology. These structures include the inner membrane complex (IMC) as well as the underlying longitudinal subpellicular microtubules (SPMTs) that provide support for the IMC and give the parasite its distinctive crescent shape. While the IMC and SPMTs have been studied on their own, the mechanisms linking these adjacent structures remain largely unknown. This study identifies aT. gondiiprotein named IMT1 that localizes to the maternal IMC and SPMTs and thus appears to tether the IMC to the microtubules. We disrupt the IMT1 gene to assess function and then use deletion analyses and mutagenesis to reveal regions of the protein that are necessary for binding to the IMC cytoskeleton or SPMTs. Using proximity labelling with IMT1 as bait, we identify a series of candidate interactors in the IMC or SPMTs. Exploration of two of these candidates reveals that IMT1 regulates the levels of the microtubule associated protein TLAP2 and binds directly to the cytoskeletal IMC protein IMC1. Taken together, these interactions unveil the specific interactions linking two key cytoskeletal structures of the parasite and provides new insight into the organization of the structural backbone ofT. gondii.
Temporal dynamics and metagenomics of phosphorothioate epigenomes in the human gut microbiome
Authors: Byrne Shane R , DeMott Michael S , Yuan Yifeng , Ghanegolmohammadi Farzan , Kaiser Stefanie , Fox James G. , Alm Eric J. , Dedon Peter C
Published: May 2024

Background

Epigenetic regulation of gene expression and host defense is well established in microbial communities, with dozens of DNA modifications comprising the epigenomes of prokaryotes and bacteriophage. Phosphorothioation (PT) of DNA, in which a chemically-reactive sulfur atom replaces a non-bridging oxygen in the sugar-phosphate backbone, is catalyzed bydndandsspgene families widespread in bacteria and archaea. However, little is known about the role of PTs or other microbial epigenetic modifications in the human microbiome. Here we optimized and applied fecal DNA extraction, mass spectrometric, and metagenomics technologies to characterize the landscape and temporal dynamics of gut microbes possessing PT modifications.

Results

Exploiting the nuclease-resistance of PTs, mass spectrometric analysis of limit digests of PT-containing DNA reveals PT dinucleotides as part of genomic consensus sequences, with 16 possible dinucleotide combinations. Analysis of mouse fecal DNA revealed a highly uniform spectrum of 11 PT dinucleotides in all littermates, with PTs estimated to occur in 5-10% of gut microbes. Though at similar levels, PT dinucleotides in fecal DNA from 11 healthy humans possessed signature combinations and levels of individual PTs. Comparison with a widely distributed microbial epigenetic mark, m6dA, suggested temporal dynamics consistent with expectations for gut microbial communities based on Taylor’s Power Law. Application of PT-seq for site-specific metagenomic analysis of PT-containing bacteria in one fecal donor revealed the larger consensus sequences for the PT dinucleotides in Bacteroidota, Firmicutes, Actinobacteria, and Proteobacteria, which differed from unbiased metagenomics and suggested that the abundance of PT-containing bacteria did not simply mirror the spectrum of gut bacteria. PT-seq further revealed low abundance PT sites not detected as dinucleotides by mass spectrometry, attesting to the complementarity of the technologies.

Conclusions

The results of our studies provide a benchmark for understanding the behavior of an abundant and chemically-reactive epigenetic mark in the human gut microbiome, with implications for inflammatory conditions of the gut.
Impact of variants and vaccination on nasal immunity across three waves of SARS-CoV-2
Authors: Long Jaclyn M. , Miao Vincent N. , Owings Anna H. , Tang Ying , Bromley Joshua D. , Kazer Samuel W. , Kimler Kyle , Asare Chelsea , Ziegler Carly G. K. , Ibrahim Samira , Jivanjee Tasneem , George Micayla , Navia Andrew W. , Drake Riley S. , Parker Adam , Billingsley Benjamin C. , Dotherow Paul , Tarugu Spurthi , Kota Sai K. , Laird Hannah , Wichman T. Grant , Davis Yesenia T. , Dhaliwal Neha S. , Pride Yilianys , Guo Yanglin , Senitko Michal , Harvey Jessie , Bates John T. , Diamond Gill , Garrett Michael R. , Robinson D. Ashley , Frame I.J. , Lyons Jonathan J. , Robinson Tanya O. , Shalek Alex K. , Horwitz Bruce H. , Glover Sarah C. , Ordovas-Montanes Jose
Published: May 2024

SARS-CoV-2 infection and COVID-19 disease vary with respect to viral variant and host vaccination status. However, how vaccines, emergent variants, and their intersection shift host responses in the human nasal mucosa remains uncharacterized. We and others have shown during the first SARS-CoV-2 wave that a muted nasal epithelial interferon response at the site of infection underlies severe COVID-19. We sought to further understand how upper airway cell subsets and states associate with COVID-19 phenotypes across viral variants and vaccination. Here, we integrated new single-cell RNA-sequencing (scRNA-seq) data from nasopharyngeal swabs collected from 67 adult participants during the Delta and Omicron waves with data from 45 participants collected during the original (Ancestral) wave in our prior study. By characterizing detailed cellular states during infection, we identified changes in epithelial and immune cells that are both unique and shared across variants and vaccination status. By defining SARS-CoV-2 RNA+ cells for each variant, we found that Delta samples had a marked increase in the abundance of viral RNA+ cells. Despite this dramatic increase in viral RNA+ cells in Delta cases, the nasal cellular compositions of Delta and Omicron exhibit greater similarity, driven partly by myeloid subsets, than the Ancestral landscapes associated with specialized epithelial subsets. We found that vaccination prior to infection was surprisingly associated with nasal macrophage recruitment and activation rather than adaptive immune cell signatures. While patients with severe disease caused by Ancestral or Delta variants had muted interferon responses, Omicron-infected patients had equivalent interferon responses regardless of disease severity. Our study defines the evolution of cellular targets and signatures of disease severity in the upper respiratory tract across SARS-CoV-2 variants, and suggests that intramuscular vaccines shape myeloid responses in the nasal mucosa upon SARS-CoV-2 infection.
Cardiolipin remodeling maintains the inner mitochondrial membrane in cells with saturated lipidomes
Authors: Venkatraman Kailash , Budin Itay
Published: May 2024

Cardiolipin (CL) is a unique, four-chain phospholipid synthesized in the inner mitochondrial membrane (IMM). The acyl chain composition of CL is regulated through a remodeling pathway, whose loss causes mitochondrial dysfunction in Barth syndrome. Yeast has been used extensively as a model system to characterize CL metabolism, but mutants lacking its two remodeling enzymes, Cld1p and Taz1p, have not recapitulated the structural and respiratory phenotypes observed in other systems. Here we show the essential role of CL remodeling in the structure and function of the IMM in yeast grown under reduced oxygenation. Microaerobic fermentation, which mimics natural yeast environments, caused the accumulation of saturated fatty acids and, under these conditions, remodeling mutants showed a loss of IMM ultrastructure. We extended this observation to HEK293 cells, where iPLA2inhibition by bromoenol lactone resulted in respiratory dysfunction and cristae loss upon mild treatment with exogenous saturated fatty acids. In microaerobic yeast, remodeling mutants accumulated unremodeled, saturated CL, but also displayed reduced total CL levels, highlighting the interplay between saturation and CL biosynthesis and breakdown. We identified the mitochondrial phospholipase A1Ddl1p as a regulator of CL levels, and those of its precursors phosphatidylglycerol and phosphatidic acid, under these conditions. Loss ofDDL1partially rescued IMM structure in cells unable to initiate CL remodeling and had differing lipidomic effects depending on oxygenation. These results introduce a revised yeast model for investigating CL remodeling and suggest that its structural functions are dependent on the overall lipid environment in the mitochondrion.
Fragmentation of genomic DNA using Covaris g-Tubes prior to library preparation for sequencing
Authors: Crang Nick , Contreras-López Orlando
Published: May 2024

Covaris g-TUBEs can be used to fragment DNA to pre-determined sizes based on the relative centrifugal force that they are run at. They are recommended for use while preparing Oxford Nanopore Technology libraries by the manufacturer. However, the volumes and DNA concentration typically used for ONT libraries are outside the range of the example data provided by Covaris. Here, we ran g-TUBEs at three different relative centrifugal forces and determined the effect on DNA fragmentation in the range 0.5 - 4 µg. This dataset can be used to inform the effective fragmentation of DNA for creating Oxford Nanopore libraries of an optimal size.
Multimodal single-cell profiling reveals neuronal vulnerability and pathological cell states in focal cortical dysplasia
Authors: Galvão Isabella C. , Lemoine Manuela , Messias Lauana A. , Araújo Patrícia A.O.R.A. , Geraldis Jaqueline C. , Yasuda Clarissa L. , Alvim Marina K. M. , Ghizoni Enrico , Tedeschi Helder , Cendes Fernando , Rogerio Fabio , Lopes-Cendes Iscia , Veiga Diogo F. T.
Published: May 2024

Focal Cortical Dysplasia (FCD) is a neurodevelopmental condition characterized by malformations of the cerebral cortex that often cause drug-resistant epilepsy. In this study, we performed multi-omics single-cell profiling to map the chromatin accessibility and transcriptome landscapes of FCD type II, generating a comprehensive multimodal single-cell dataset comprising 61,525 cells from 11 clinical samples of lesions and controls. Our findings revealed profound chromatin, transcriptomic, and cellular alterations affecting neuronal and glial cells in FCD lesions, including the selective loss of upper-layer excitatory neurons, significant expansion of oligodendrocytes and immature astrocytic populations, and a unique neuronal subpopulation harboring dysmorphic neurons. Furthermore, we uncovered activated microglia subsets, particularly in FCD IIb cases. This comprehensive study unveils neuronal and glial cell states driving FCD development and epileptogenicity, enhancing our understanding of FCD and offering new directions for targeted therapy development.
Structural and functional analysis of the Nipah virus polymerase complex
Authors: Hu Side , Kim Heesu , Yang Pan , Yu Zishuo , Ludeke Barbara , Mobilia Shawna , Pan Junhua , Stratton Margaret , Bian Yuemin , Fearns Rachel , Abraham Jonathan
Published: May 2024

Nipah virus (NiV) is a bat-borne, zoonotic RNA virus that is among the most pathogenic viruses known to humans. The NiV polymerase, which mediates viral genome replication and mRNA transcription, is a drug target. However, NiV polymerase structures were previously unavailable. We determined the cryo-EM structure of the NiV polymerase complex, comprising the large protein (L) and its associated co-factor (P), and performed structural, biophysical, and functional analyses of the NiV polymerase. The complex assembles with a long P tetrameric coiled-coil that is capped by a bundle of ⍺-helices that we show are likely dynamic in solution. Highly conserved zinc-binding modules in the capping domain and a large insert in the RdRp palm domain that is short or absent in most other non-segmented negative strand RNA viruses are critical for replication and transcription. Our findings have the potential to aid in the rational development of drugs to combat NiV infection.
Maintenance of haematopoietic stem cells by JAK inhibition and increased tyrosine-unphosphorylated STAT5
Authors: Williams Matthew J , Wang Xiaonan , Bastos Hugo P , Grondys-Kotarba Gabriela , Johnson Carys , Mende Nicole , Calderbank Emily F , Wantoch Michelle , Park Hyun Jung , Wu Qin , Jin Shucheng , Mantica Giovanna , Hannah Rebecca , Wilson Nicola K , Pask Dean C , Hamilton Tina L , Kinston Sarah J , Asby Ryan , Sneade Rachel , Baxter Joanna , Campbell Peter , Vassiliou George S , Laurenti Elisa , Li Juan , Göttgens Berthold , Green Anthony R
Published: May 2024

Normal and malignant hematopoietic stem cells (HSCs) are controlled by extracellular cues including cytokine signalling through the JAK/STAT pathway. Here, we show that STAT5-deficient HSCs exhibit an unusual phenotype: while reduced multi-lineage repopulation and reduced self-renewal are commonly associated with overproliferation and exhaustion, they are instead associated with reduced cell-cycle progression and increased differentiation in STAT5-deficient HSCs. Mechanistic studies show that unphosphorylated-STAT5 (uSTAT5) contributes to this phenotype by constraining HSC differentiation, promoting HSC maintenance and upregulating transcriptional programs associated with stemness. The JAK1/2 inhibitor ruxolitinib increases levels of uSTAT5, constrains differentiation and proliferation of murine HSCs, promotes their maintenance and upregulates transcriptional programs associated with stemness. Ruxolitinib also enhances clonogenicity of normal human HSPCs, CALR-mutant murine HSCs and HSPCs from patients with myelofibrosis. Our results therefore reveal a previously unrecognized role for uSTAT5 in controlling HSC function, highlight JAK inhibition as a strategy for enhancing HSC function and provide insights into the failure of JAK inhibitors to eradicate myeloproliferative neoplasms.
Dissecting the ocular impact of SARS-CoV-2 variants: Analysis of eye globe and retina in animal models
Authors: da Silva José Igor Gomes , Kersten Victor , Munhóz Dati Livia M. , Lins Bruna B. , Tozzeto-Mendoza Tania R. , Rodrigues Daniela del R. F. , Barbosa Rodrigo J. V. , Lima Silvia H. , Villas Boas Lucy S. , da Silva Alexandre dos Santos , Chaim Khallil T. , Mendes-Corrêa Maria Cássia , Russo Momtchilo , Mirotti Luciana , Pinto Marcelo A. , Martins Rodrigo A. P.
Published: May 2024

Neurological and ocular manifestations were reported in COVID-19 patients and in SARS-CoV-2 infected animal models. However, the effects of SARS-CoV-2 variants of concern (VoC) on the eyes and the retina remain unclear. Here, we investigate the cellular and molecular consequences of SARS-CoV-2 VoC infection on the eye and retina in mice and hamsters. Infection with the ancestral SARS-CoV-2 and the Gamma VoC induced a subtle increase in the eye volume of K18-hAce2 mice, but no morphological alteration was observed in hamsters’ eyes. Evaluation of the ocular tropism revealed that distinct SARS-CoV-2 VoC reached the eye globe, but not the retina of K18-hAce2 mice. In contrast, SARS-CoV-2 variants are detected in the hamsters’ retina during both acute infection and after disease recovery. Despite the presence of viral RNA, no inflammation was observed in the hamster retina, as evidenced by unchanged microglial cell density and unaltered gene expression of several immune mediators. Altogether, these findings indicate a limited impact of SARS-CoV-2 variants on the eye and retina.
Clubroot disease in soil: An examination of its occurrence in chemical and organic environments
Authors: Islam Zakirul , Tran Quoc Thinh , Kubo Motoki
Published: May 2024

Clubroot is a disease in cruciferous plants caused by the soil-borne pathogenPlasmodiophora brassicae. This pathogen rapidly spreads in soil, and plant growth is inhibited by infection with spores. In this study, the development of clubroot disease inBrassica rapavar. perviridis was investigated in different soil environments (chemical and organic soils). The bacterial biomass and diversity of the soil and roots were also analyzed in both chemical and organic soils. Bacterial biomass and diversity in the organic soil were higher than those in the chemical soil. The disease severity of plants cultivated in organic soil was lower than that in chemical soil. The number of endophytic bacteria in the roots decreased when the plants were infected withP. brassicaein both soil types. Higher bacterial biomass in the soils and roots appeared to reduce the infection ofP. brassicae.

Importanc

Clubroot is a major disease of cruciferous plants caused by soil borne pathogenPlasmodiophora brassica.Pesticides are applied in the soil during cultivation for the inhibition of clubroot disease, which demise soil microbiome. Therefore, eco-friendly control methods are required for sustainable cultivation. Soil management is an important strategy to inhibit clubroot disease severity. In this study, the occurrence of clubroot disease inB.rapawere compared in two distinct soil environments (chemical and organic). Results show infection rate increased with the increase of spore number for both chemical and organic soil environments. However, the diseases severity was lower in plants cultivated in organic soil. The higher endophytic bacterial biomass and diversity seems to be linked for the disease inhibition in organic plants. These findings suggest a sustainable soil management process to reduce clubroot disease prevalence. Application of organic fertilizers in commented soils could substantially reduce clubroot disease severity in the plants.
The Cell Division Protein FzlA Performs a Conserved Function in Diverse Alphaproteobacteria
Authors: Payne Isaac P. , Aubry Brody , Barrows Jordan M. , Brown Pamela J.B. , Goley Erin D.
Published: May 2024

In almost all bacteria, the tubulin-like GTPase FtsZ polymerizes to form a “Z-ring” that marks the site of division. FtsZ recruits other proteins, collectively known as the divisome, that together remodel and constrict the envelope. Constriction is driven by peptidoglycan (PG) cell wall synthesis by the glycosyltransferase FtsW and the transpeptidase FtsI (FtsWI), but these enzymes require activation to function. How recruitment of FtsZ to the division site leads to FtsWI activation and constriction remains largely unknown. Previous work in our laboratory demonstrated that an FtsZ-binding protein, FzlA, is essential for activation of FtsWI in the alphaproteobacteriumCaulobacter crescentus. Additionally, we found that FzlA also binds to a DNA translocase called FtsK, suggesting that it may link constriction activation to chromosome segregation. FzlA is conserved throughout alphaproteobacteria but has only been examined in detail inC. crescentus. Here, we explored whether FzlA function is conserved in diverse alphaproteobacteria. We assessed FzlA homologs fromRickettsia parkeriandAgrobacterium tumefaciens, and found that, similar toC. crescentusFzlA, they bind directly to FtsZ and localize to midcell. The FtsZ-FzlA interaction interface is conserved, as we demonstrated that FzlA from each of the three species examined can bind to FtsZ from any of the threein vitro. Additionally, we determined thatA. tumefaciensFzlA can fulfill the essential function of FzlA when produced inC. crescentus, indicating conservation of function. These results suggest that FzlA serves as an important regulator that coordinates chromosome segregation with envelope constriction across diverse alphaproteobacteria.

Importance

Cell division is essential for bacterial replication and must be highly regulated to ensure robust remodeling of the cell wall in coordination with segregation of the genome to daughter cells. InCaulobacter crescentus, FzlA plays a major role in regulating this process by activating cell wall synthesis in a manner that couples constriction to chromosome segregation. FzlA is broadly conserved in alphaproteobacteria suggesting it plays a similar function across this class of bacteria. Here we have shown that, indeed, FzlA biochemical interactions and function are conserved in diverse alphaproteobacteria. Because FzlA is conserved in alphaproteobacterial human pathogens, understanding this protein and its interactome could present therapeutic benefits by identifying potential antibiotic targets to treat infections.
How repeats rearrange chromosomes in deer mice
Authors: Gozashti Landen , Harringmeyer Olivia S. , Hoekstra Hopi E.
Published: May 2024

Large genomic rearrangements, such as chromosomal inversions, can play a key role in evolution and often underlie karyotype variation, but the mechanisms by which these rearrangements arise remain poorly understood. To study the origins of inversions, we generated chromosome-level de novo genome assemblies for four subspecies of deer mice (Peromyscus maniculatus) with known inversion polymorphisms. We identified ~8,000 inversions, including 47 mega-base scale inversions, that together affect ~30% of the genome. Analysis of inversion breakpoints suggests that while most small (<1 Mb) inversions arise via ectopic recombination between retrotransposons, large (>1 Mb) inversions are primarily associated with segmental duplications (SDs). Large inversion breakpoints frequently occur near centromeres, which may be explained by an accumulation of transposable elements in pericentromeric regions driving SD formation. Additionally, multiple large inversions likely arose from ectopic recombination between near-identical centromeric satellite arrays located megabases apart, a previously uncharacterized mechanism of inversion formation. Together, our results illuminate how repeats give rise to massive shifts in chromosome architecture.
A high content imaging assay for identification of specific inhibitors of nativePlasmodiumliver stage protein synthesis
Authors: McLellan James L. , Morales-Hernandez Beatriz , Saeger Sarah , Hanson Kirsten K.
Published: May 2024

Plasmodiumparasite resistance to antimalarial drugs is a serious threat to public health in malaria-endemic areas. Compounds that target core cellular processes like translation are highly desirable, as they should be multistage actives, capable of killing parasites in the liver and blood, regardless of molecular target or mechanism. Assays that can identify these compounds are thus needed. Recently, specific quantification of nativePlasmodium bergheiliver stage protein synthesis as well as that of the hepatoma cells supporting parasite growth, was achieved via automated confocal feedback microscopy of the o-propargyl puromycin (OPP)-labeled nascent proteome, but this imaging modality is limited in throughput. Here, we developed and validated a miniaturized high content imaging (HCI) version of the OPP assay that increases throughput, before deploying this approach to screen the Pathogen Box. We identified only two hits, both of which are parasite-specific quinoline-4-carboxamides, and analogues of the clinical candidate and known inhibitor of blood and liver stage protein synthesis, DDD107498/cabamiquine. We further show that these compounds have strikingly distinct relationships between their antiplasmodial and translation inhibition efficacies. These results demonstrate the utility and reliability of theP. bergheiliver stage OPP HCI assay for specific, single-well quantification ofPlasmodiumand human protein synthesis in the native cellular context, allowing identification of selectivePlasmodiumtranslation inhibitors with the highest potential for multistage activity.
Activation of Heme Metabolism Promotes Tissue Health After Intraarticular Injury or Surgical Exposure
Authors: Liman Suryamin , Gomez-Contreras Piedad C. , Hines Madeline R. , Witt Emily , Fisher Jacob S. , Lu Kevin J. , McNally Lauren D. , Cotoia Alicia T. , Sakyi Maxwell Y. , Wagner Brett A. , Tift Michael S. , Goetz Jessica E. , Byrne James D. , Coleman Mitchell C.
Published: May 2024

Posttraumatic osteoarthritis (PTOA) is a well-recognized public health burden without any disease modifying treatment. This occurs despite noted advances in surgical care in the past 50 years. Mitochondrial oxidative damage pathways initiate PTOA after severe injuries like intraarticular fracture that often require surgery and contribute to PTOA after less severe injuries that may or may not require surgery like meniscal injuries. When considering the mitochondrial and redox environment of the injured joint, we hypothesized that activation of heme metabolism, previously associated with healing in many settings, would cause prototypic mitochondrial reprogramming effects in cartilage ideally suited for use at the time of injury repair. Activation of heme metabolism can be accomplished through the gasotransmitter carbon monoxide (CO), which activates hemeoxygenase-1 (HO1) and subsequent heme metabolism. In this study, we employed unique carbon monoxide (CO)-containing foam (COF) to stimulate heme metabolism and restore chondrocyte oxygen metabolismin vitroandin vivo. Doxycycline-inducible, chondrocyte-specific HO1 overexpressing transgenic mice show similar mitochondrial reprogramming after induction compared to COF. CO is retained at least 24 h after COF injection into stifle joints and induces sustained increases in heme metabolism. Lastly, intraarticular injection of COF causes key redox outcomes without any adverse safety outcomes in rabbit stifle jointsex vivoandin vivo. We propose that activation of heme metabolism is an ideal adjuvant to trauma care that replenishes chondrocyte mitochondrial metabolism and restores redox homeostasis.
Factors shaping the assembly of lichen holobionts in a tropical lichen community
Authors: Kosecka Magdalena , Bourceret Amélia , Perez-Lamarque Benoît , Guzow-Krzemińska Beata , Kukwa Martin , Flakus Adam , Rodriguez-Flakus Pamela , Selosse Marc-André
Published: May 2024

Lichen thalli host complex microbial communities, which may foster the ecological stability and longevity of the lichen symbiosis. Yet, we lack a holistic understanding of the processes contributing to the assembly of the lichen holobiont. This study assessed the diversity and community structure in taxonomically diverse co-occurring lichens associated with Trebouxiophyceae algae from Bolivian forests. We focused on three components of the lichen holobiont: the lichenized fungus (mycobiont) and its associated algae (photobiome) and fungi (mycobiome). We specifically tested the influence of mycobiont identity, thallus morphological type, reproductive strategy, and lichen secondary metabolites on the lichen-associated photobiome and mycobiome. To understand the specialization patterns between holobiont components, we investigated interaction networks.

We observed that co-occurring mycobiont taxa host diverse, taxon-specific, yet overlapping photobiome and mycobiome. In particular, these communities are significantly influenced by the host’s thallus morphological type and its secondary metabolites. Finally, we demonstrated that both photobiome and mycobiome are structured mainly by mycobiont identity, which results in modular networks with strong phylogenetic signals and high levels of specialization. In conclusion, the symbiotic interactions within lichen are structured mainly by the mycobiont, which appears to be the leading architect of the lichen holobiont.
Single Cell Transcriptome Defines Cell Type Repertoire of AdultDaphnia magna
Authors: Krishnan Indira , Yampolsky Lev Y , Petrova Kseniya , Peshkin Leonid
Published: May 2024

Detailed knowledge of transcriptional responses to environmental and developmental cues is impossible without single cell (SC) resolution data. We performed two SC RNAseq experiments surveying transcriptional profiles of females and males ofD. magna, a freshwater plankton crustaceanwhichis both a classic and emerging new model for eco-physiology, toxicology, and evolutionary genomics. We were able to identify over 30 distinct cell types about half of which could be functionally annotated. First, we identified ovaries- and testis-related cell types by focusing on female- and male-specific clusters. Second, we compared markers between SC clusters and bulk RNAseq data on transcriptional profiles of early embryos, circulating hemocytes, midgut, heads (containing brain, eyes, muscles and hepatic caeca), antennae II, and carapace. Finally, we compared transcriptional profiles of Daphnia cell clusters with orthologous markers of 250+ cell types annotated in Drosophila cell atlas. This allowed us to recognize striated muscle cells, gut enterocytes, cuticular cells, as well as 5 different neuron types, including photoreceptors and 3 ovaries-related clusters, one of which tentatively identified as the germ line cells. One well-defined cluster showed a significant enrichment in markers of both hemocytes and fat body ofDrosophila, but not with bulk RNAseq data from circulating hemocytes, allowing us to hypothesize the existence of non-circulating, fat body-associated population of hemocytes inDaphnia. On the other hand, the circulating hemocytes express numerous cuticular proteins suggesting their role, in addition to macrophagy, in wound repair. At the same time numerous cell types remain unidentified, including those that map to FCA groups ambiguously or are characterized byDaphnia-specific markers with no clear orthology in the fruitfly. Likewise, many known or presumed cell types or tissues inDaphniahave not been identified to SC clusters. A detailed in-situ hybridization study would be necessary to match not yet annotated SC clusters to functional cell groups.

Highlights

First single-cell transcriptomic atlas forDaphnia magna, identifies > 30 distinct cell types.

Novel cell type representing circulating hemocytes may play a role in cuticle regeneration.

Evidence for non-circulating hemocyte-like cells associated with the fat body in Daphnia.

Cuticle/epithelial cells expressing photoreceptors, suggesting light-sensing capabilities.

Subfunctionalization of divergent paralogs across cell types for ecological versatility.
Predicting task-related brain activity from resting-state brain dynamics with fMRI Transformer
Authors: Kwon Junbeom , Seo Jungwoo , Wang Heehwan , Moon Taesup , Yoo Shinjae , Cha Jiook
Published: May 2024

Accurate prediction of the brain's task reactivity from resting-state functional magnetic resonance imaging (fMRI) data remains a significant challenge in neuroscience. Traditional statistical approaches often fail to capture the complex, nonlinear spatiotemporal patterns of brain function. This study introduces SwiFUN (Swin fMRI UNet Transformer), a novel deep-learning framework designed to predict 3D task activation maps directly from resting-state fMRI scans. SwiFUN leverages advanced techniques such as shifted window-based self-attention, which helps to understand complex patterns by focusing on varying parts of the data sequentially, and a contrastive learning strategy to better capture individual differences among subjects. When applied to predicting emotion-related task activation in adults (UK Biobank, n=7,038) and children (ABCD, n=4,944), SwiFUN consistently achieved higher overall prediction accuracy than existing methods across all contrasts; it demonstrated an improvement of up to 27% for the FACES-PLACES contrast in ABCD data. The resulting task activation maps revealed individual differences across cortical and subcortical regions associated with sex, age, and depressive symptoms. This scalable, transformer-based approach potentially reduces the need for task-based fMRI in clinical settings, marking a promising direction for future neuroscience and clinical research that enhances our ability to understand and predict brain function.
Accounting for quantum effects in atomistic spin dynamics
Authors: Berritta M. , Scali S. , Cerisola F. , Anders J.
Published: May 2024

Atomistic spin dynamics (ASD) is a standard tool to model the magnetization dynamics of a variety of materials. The fundamental dynamical model underlying ASD is entirely classical. In this paper, we present two approaches to effectively incorporate quantum effects into ASD simulations, thus enhancing their low-temperature predictions. The first allows to simulate the magnetic behavior of a quantum spin system by solving the equations of motion of a classical spin system at an effective temperature relative to the critical temperature. This effective temperature is determined from the microscopic properties of the system. The second approach is based on a semiclassical model where classical spins interact with an environment with a quantumlike power spectrum. The parameters that characterize this model can be calculated or extracted from experiments. This semiclassical model quantitatively reproduces the absolute temperature behavior of a magnetic system, thus accounting for the quantum mechanical aspects of its dynamics, even at low temperature. The methods presented here can be readily implemented in current ASD simulations with no additional complexity cost.

Published by the American Physical Society
2024
Zero to ultralow magnetic field NMR of
[1−13C]pyruvate
and
[2−13C]pyruvate
enabled by SQUID sensors and hyperpolarization
Authors: Myers John Z. , Bullinger Friedemann , Kempf Nicolas , Plaumann Markus , Ortmeier Adam , Theis Thomas , Povolni Pavel , Romanowski Jannik , Engelmann Jörn , Scheffler Klaus , Hövener Jan-Bernd , Buckenmaier Kai , Körber Rainer , Pravdivtsev Andrey N.
Published: May 2024

Accurately characterizing magnetic resonance of molecules at zero to ultralow magnetic field (nTs-µTs) is challenging, due to vanishingly small sensitivity, which depends on the thermal equilibrium polarization of the nuclear spins and instrumentation. We overcome the former limitation with the parahydrogen-based hyperpolarization method SABRE-SHEATH (signal amplification by reversible exchange in shield enables alignment transfer to heteronuclei). This method allows for the continuous transfer of spin order from parahydrogen to a substrate via chemical exchange, reaching polarization levels of some percent (level equivalent to C13 polarization at 20 kT). We address the latter with our application of a superconducting quantum interference device (SQUID)-based detector setup that allows for broadband detection (dc-MHz) with exquisite sensitivity over its entire range. Here, we present the results of our comprehensive characterization of [1−13C]pyruvate and [2−13C]pyruvate, hyperpolarized via SABRE-SHEATH, from zero field to 100 µT. To this end, we show low-noise, high-resolution spectra for both molecules, detecting how the NMR spectrum changes from the -coupling dominated zero-field spectrum to the strongly coupled spectrum, and then finally to the conventional high-field, otherwise known Zeeman-dominated spectrum. We also analytically derive the evolution of product operators in arbitrary magnetic fields, which aid in the understanding of the differences between spin evolution and spin-coupling regimes. We predict and confirm that the absence of spin precession at zero field can result in observable oscillation of magnetization along one axis with a frequency of the -coupling constant, no observable spin evolution, or observing spin evolution that corresponds to “forbidden” transitions at high field. The zero-field spectra with their near-dc signals reveal different relaxation rates for the different spin states of hyperpolarized C13 pyruvates, demonstrating the utility of SQUID detectors and hyperpolarization for the characterization of magnetic resonance phenomena.

Published by the American Physical Society
2024
Impact of ownership concentration on stock returns: a case of developed economies
Authors: Ali Asif , Masood Omar
Published: May 2024

Purpose

The primary objective of this study is to determine how concentrated ownership affects stock returns by country and scale (by market capitalization), like large, medium, and small-cap firms in selected developed economies of the world.

Design/methodology/approach

Using a dataset comprising 12,751 annual observations from 850 listed companies from developed economies from 2004 to 2018, the study employs panel data models and instrumental variable estimation to mitigate endogeneity bias.

Findings

The findings reveal a significant and positive correlation between ownership concentration and expected returns on corporate equities in developed economies. Furthermore, the study categorizes firms into distinct size categories and finds nuanced differences in the relationship between ownership concentration and stock returns across large, medium, and small-cap enterprises. The results of the study reveal that ownership concentration (by country) and scale (Large, medium, and small) have a significant and positive impact on the stock returns of firms in developed economies.

Practical implications

the practical implications of this study extend to investors, firms, policymakers, regulators, and other stakeholders involved in the financial markets. By considering these implications, stakeholders can make informed decisions to enhance market efficiency, investor protection, and overall market integrity.

Originality/value

To the authors' understanding, this study is the first to examine the impact of concentrated ownership on excessive stock returns across countries and scales, with an explicit focus on large, medium, and small companies in select developed economies worldwide.
Leveraging digital transformation on the path to sustainable development: the role of excellence models
Authors: Morgado Oliveira Joana , F. Gomes Carlos
Published: May 2024

Purpose

This study explores how excellence models can leverage digital transformation on the path to sustainable development in organisations.

Design/methodology/approach

A survey was used to study the different facets of digital capabilities and their impact on sustainable development success of organisations holding an external recognition from the European Foundation for Quality Management (EFQM). Partial Least Squares structural equation modelling (PLS-SEM) combined with Necessary Condition Analysis (NCA) were used to analyse data.

Findings

Internalising excellence practices is decisive in mediating effective digital capabilities to achieve sustainable development. To achieve high levels of sustainable development success, organisations must achieve high levels of excellence practices internalisation, which are much more important than the excellence model external recognition.

Research limitations/implications

This study addresses essential issues with theoretical and practical value but is limited to a sample of organisations with EFQM recognition in two countries. Future studies should address different organisations and cultural environments.

Practical implications

The findings are relevant for organisations facing digital transformation and sustainable development challenges. They are essential for managers leveraging digital capabilities to capitalise on practices and processes and achieve Sustainable Development Goals. Organisations can benefit from a multidimensional approach to digital capabilities when struggling against external challenges.

Originality/value

This study closes a research gap regarding the impact of digital capabilities on sustainable development success. It is the first empirical study to combine sufficiency and necessity conditions analyses to explore the mediating role of excellence practices internalisation and one of the first to address digital capabilities from a multidimensional perspective.
Macroeconomic shocks, market uncertainty and speculative bubbles: a decomposition-based predictive model of Indian stock markets
Authors: Ghosh Indranil , Chaudhuri Tamal Datta , Sarkar Sunita , Mukhopadhyay Somnath , Roy Anol
Published: May 2024

Purpose

Stock markets are essential for households for wealth creation and for firms for raising financial resources for capacity expansion and growth. Market participants, therefore, need an understanding of stock price movements. Stock market indices and individual stock prices reflect the macroeconomic environment and are subject to external and internal shocks. It is important to disentangle the impact of macroeconomic shocks, market uncertainty and speculative elements and examine them separately for prediction. To aid households, firms and policymakers, the paper proposes a granular decomposition-based prediction framework for different time periods in India, characterized by different market states with varying degrees of uncertainty.

Design/methodology/approach

Ensemble empirical mode decomposition (EEMD) and fuzzy-C-means (FCM) clustering algorithms are used to decompose stock prices into short, medium and long-run components. Multiverse optimization (MVO) is used to combine extreme gradient boosting regression (XGBR), Facebook Prophet and support vector regression (SVR) for forecasting. Application of explainable artificial intelligence (XAI) helps identify feature contributions.

Findings

We find that historic volatility, expected market uncertainty, oscillators and macroeconomic variables explain different components of stock prices and their impact varies with the industry and the market state. The proposed framework yields efficient predictions even during the COVID-19 pandemic and the Russia–Ukraine war period. Efficiency measures indicate the robustness of the approach. Findings suggest that large-cap stocks are relatively more predictable.

Research limitations/implications

The paper is on Indian stock markets. Future work will extend it to other stock markets and other financial products.

Practical implications

The proposed methodology will be of practical use for traders, fund managers and financial advisors. Policymakers may find it useful for assessing the impact of macroeconomic shocks and reducing market volatility.

Originality/value

Development of a granular decomposition-based forecasting framework and separating the effects of explanatory variables in different time scales and macroeconomic periods.