bluuebunny/crossref_metadata_2025 huggingface dataset:
Synergistic impact of three complement polymorphisms in the donor, not the recipient, on long-term kidney allograft survival
Authors: Poppelaars Felix , Gaya da Costa Mariana , Faria Bernardo , Eskandari Siawosh K. , Petr Vojtech , Holers V. Michael , Daha Mohamed R. , Berger Stefan P. , Damman Jeffrey , Seelen Marc A. , Thurman Joshua M.
Published: October 2023

Background

Genetic analysis in transplantation offers potential for personalized medicine. Given the crucial role of the complement system in renal allograft injury, we investigated in kidney transplant pairs the impact of complement polymorphisms on long-term outcomes.

Methods

In this observational cohort study, we analyzed polymorphisms in C3 (C3R102G), factor B (CFBR32Q), and factor H (CFHV62I) genes of 1,271 donor-recipient kidney transplant pairs and assessed their association with 15-year death-censored allograft survival.

Results

Individually, only the presence of theCFB32Qvariant in the donor and the combined presence in donor-recipient pairs were associated with better graft survival (P=0.027 andP=0.045, respectively). In the combined analysis, theC3R102G,CFBR32Q, andCFHV62Ivariants in the donor independently associated with the risk of graft loss (HR 1.32; 95%-CI, 1.08– 1.58;P=0.005). Thus, donor kidneys carrying the genetic variants that promote the highest complement activity exhibited the worst graft survival, whereas those with the genetic variants causing the lowest complement activity showed the best graft survival (15-year death-censored allograft survival: 48.8% vs 87.8%,P=0.001).

Conclusion

Our study demonstrates that the combination of complement polymorphisms in the donor strongly associates with long-term allograft survival following kidney transplantation. These findings hold significance for therapeutic strategies involving complement inhibition in kidney transplantation.
Prediction of response to transcranial magnetic stimulation treatment for depression using electroencephalography and statistical learning methods, including an out-of-sample validation
Authors: Bailey Neil W , Fulcher Ben D. , Arns Martijn , Fitzgerald Paul B , Fitzgibbon Bernadette , van Dijk Hanneke
Published: October 2023

Background

Repetitive transcranial magnetic stimulation (rTMS) has shown efficacy for treating depression, but not for all patients. Accurate treatment response prediction could lower treatment burden. Research suggests machine learning trained with electroencephalographic (EEG) data may predict response, but only a limited range of measures have been tested.

Objectives

We used >7000 time-series features to comprehensively test whether rTMS treatment response could be predicted in a discovery dataset and an independent dataset.

Methods

Baseline EEG from 188 patients with depression treated with rTMS (125 responders) were decomposed into the top five principal components (PCs). Thehctsatoolbox was used to extract 7304 time-series features from each participant and PC. A classification algorithm was trained to predict responders from the feature matrix separately for each PC. The classifier was applied to an independent dataset (N= 58) to test generalizability on an unseen sample.

Results

Within the discovery dataset, the third PC (which showed a posterior-maximum and prominent alpha power) showed above-chance classification accuracy (68%,pFDR= 0.005, normalised positive predictive value = 114%). Other PCs did not outperform chance. The model generalized to the independent dataset with above-chance balanced accuracy (60%,p= 0.046, normalised positive predictive value = 114%). Analysis of feature-clusters suggested responders showed more high frequency power relative to total power, and a more negative skew in the distribution of their time-series values.

Conclusion

The dynamical properties of PC3 predicted treatment response with moderate accuracy, which generalized to an independent dataset. Results suggest treatment stratification from pre-treatment EEG may be possible, potentially enabling better outcomes than ‘one-size-fits-all’ treatment approaches.
Upadacitinib and Cardiovascular Adverse Events in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis
Authors: Omidi Fatemeh , Delkash Parisa , Sarmastzadeh Tala , Nasiri Mohammad Javad
Published: October 2023

Background

The safety of Upadacitinib, a Janus kinase inhibitor, in the context of rheumatoid arthritis management has raised concerns regarding potential cardiovascular adverse events, but the evidence remains inconclusive.

Methods

Our study involved a systematic search for articles conducted up to October 1, 2023, encompassing databases such as PubMed/Medline, Embase, and Cochrane CENTRAL. We employed meta-analysis to calculate pooled odds ratios (OR) and their 95% confidence intervals (CI). We assessed potential publication bias through the application of Begg’s and Egger’s tests.

Results

Six studies involving 4202 patients were included. The analysis of the 15 mg dosage revealed a pooled OR of 1.20 (95% CI: 0.3-4.3), indicating a small increase in cardiovascular adverse event likelihood without statistical significance. The 30 mg dosage analysis yielded a combined OR of 2.37 (95% CI: 0.6-9.1), suggesting a potential risk increase but lacking statistical significance. Begg’s and Egger’s tests indicated no publication bias.

Conclusion

While there is a suggestion of elevated cardiovascular risk, especially with the 30 mg dosage, the absence of statistical significance and wide confidence intervals underscore the need for cautious interpretation. Individualized treatment decisions, vigilant monitoring, and further research are essential to optimize patient care and deepen our understanding of Upadacitinib’s safety profile.
A stagewise response to mitochondrial dysfunction in mitochondrial DNA maintenance disorders
Authors: Vincent Amy E. , Chen Chun , Gomes Tiago Bernadino , Leo Valeria Di , Laalo Tuomas , Pabis Kamil , Capaldi Rodrick , Mauresch Mike , McDonald David , Filby Andrew , Fuller Andrew , Urban Diana Lehmann , Zeirz Stephan , Deschauer Marcus , Turnbull Doug , Reeve Amy K , Lawless Conor
Published: October 2023

Mitochondrial DNA deletions clonally expand in skeletal muscle of patients with mtDNA maintenance disorders, impairing mitochondrial oxidative phosphorylation dysfunction. Previously we have shown that these mtDNA deletions originally arise and accumulate in the perinuclear mitochondria causing localised mitochondrial dysfunction before spreading through the muscle fibre. We believe that mito-nuclear signalling is a key contributor in this process.

To further understand the role of mito-nuclear signalling, we use imaging mass cytometry to characterise the levels of mitochondrial respiratory complexes I-IV and ATP synthase alongside a mitochondrial mass marker, in a cohort of patients with mtDNA maintenance dosirders. We then expanded this panel to include protein markers of key signalling pathways to investigate the cellular response in fibres with different combinations of oxidative phosphorylation dysfunction and in ragged red fibres.

We find CI and CIV deficiency to be most common, with a smaller proportion of cells that are also CIII and/or CV deficient. Interestingly, we also note that in cells deficient for one or more complexes, any complexes which are not deficient are commonly upregulated beyond the increase of mitochondrial mass typically observed in ragged red fibres. We further find that oxidative phosphorylation deficient fibres exhibit an increase in abundance of proteins involved in the proteostasis e.g. HSP60 and LONP1, and mitochondrial protein synthesis e.g. PHB1. Our analysis suggests that the cellular response to mitochondrial dysfunction changes depending on the combination of deficient oxidative phosphorylation complexes in each cell.
Rebalancing the motor circuit restores movement in aCaenorhabditis elegansmodel for TDP-43-toxicity
Authors: Koopman Mandy , Güngördü Lale , Janssen Leen , Seinstra Renée I. , Richmond Janet E. , Okerlund Nathan , Wardenaar René , Islam Priota , Brown Andre E.X. , Jorgensen Erik M. , Nollen Ellen A.A.
Published: October 2023

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia are caused by the abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm of neurons. How TDP-43 accumulation leads to disease symptoms is not well-characterized. Here, we use aC. elegansmodel for TDP-43-induced toxicity to identify the biological mechanisms that lead to disease-related phenotypes. By applying deep behavioral phenotyping, we established a phenotypic fingerprint of TDP-43 worms. This fingerprint was compared to that of 294C. elegansmutants, in which genes were mutated that are important for nervous system and muscle functioning. By using a computational clustering approach, we found that the release of acetylcholine and GABA was the primary defect in TDP-43 worms. We then functionally dissected the neuromuscular circuit to show that GABA transmission was more severely diminished compared to acetylcholine. Whereas the loss of GABA transmission was caused by a profound loss of GABA synapses, acetylcholine neurons appeared to be functionally silenced. Enhancing functional output of repressed acetylcholine neurons at the level of G-protein coupled receptors or through optogenetic stimulation restored neurotransmission, but inefficiently rescued locomotion. Surprisingly, rebalancing the excitatory and inhibitory input by simultaneous stimulation of GABA and acetylcholine input into muscles not only synergized the effects of boosting individual neurotransmitter systems, but instantaneously improved movement. Our results suggest that interventions accounting for the altered connectome may be more efficient in restoring motor function than those solely focusing on diseased neuron populations.
Early viral infection of cyanobacteria drives bacterial chemotaxis in the oceans
Authors: Henshaw Richard J. , Moon Jonathan , Stehnach Michael R. , Bowen Benjamin P. , Kosina Suzanne M. , Northen Trent R. , Guasto Jeffrey S. , Floge Sheri A.
Published: October 2023

Interactions among marine microbes primarily occur through exudation and sensing of dissolved chemical compounds, which ultimately control ecosystem-scale processes such as biomass production, nutrient cycling, carbon fixation, and remineralization. Prior to lysis, viruses alter host metabolism, stimulating the release of dissolved chemical cues from intact plankton. However, the nature and degree of interactions between prelysis, virus-infected cells and neighbouring microbes remain unquantified. Here, we determine the impact of viral infection on dissolved metabolite pools from the marine cyanobacteriumSynechococcusand the subsequent chemotactic response of heterotrophic bacteria using time-resolved metabolomics and microfluidics. Metabolites released from intact, virus-infectedSynechococcuselicited vigorous chemoattractive responses from heterotrophic bacteria (Vibrio alginolyticusandPseudoalteromonas haloplanktis), with the strongest responses occurring in the early infection stages and following cell lysis. We provide the first experimental observations of sustained chemotaxis towards live, infectedSynechococcus, which is contrasted by no discernible chemotaxis toward uninfectedSynechococcus. Finally, metabolite compounds and concentrations driving chemotactic responses were identified using a novel high-throughput microfluidic device. Our findings establish that prior to cell lysis, virus-infected picophytoplankton release compounds that significantly attract motile heterotrophic bacteria, illustrating a viable mechanism for resource transfer to chemotactic bacteria with implications for our understanding of carbon and nutrient flux across trophic levels.
Cyclic peptide inhibitors stabilize Gq/11 heterotrimers
Authors: Mühle Jonas , Rodrigues Matthew J. , Alenfelder Judith , Jürgenliemke Lars , Guixà-González Ramon , Bacchin Arianna , Andres Fabio , Hennig Michael , Schihada Hannes , Crüsemann Max , König Gabriele M. , Kostenis Evi , Schertler Gebhard , Deupi Xavier
Published: October 2023

Heterotrimeric G proteins play a central role in cellular signaling, acting as switchable molecular regulators. Consequently, pharmacological agents to control G protein activity are of utmost importance to advance our understanding of this signal transduction system. The natural depsipeptides FR900359 (FR) and YM-254890 (YM) are two highly specific and widely used inhibitors of heterotrimeric Gq/11 proteins. These compounds have traditionally been understood to inhibit GDP dissociation by preventing the separation of the GTPase and α-helical domains of the Gα subunit. In this work, we have determined the high-resolution crystal structures of FR and YM bound to heterotrimeric G11 and used them to explain the molecular basis underlying their efficient suppression of G protein signaling. Notably, our data show that FR and YM also function as stabilizers of the interface between the Gα and Gβ subunits, acting as ‘molecular adhesives’ that stabilize the entire heterotrimer. Our results reveal unrecognized mechanistic features that explain how FR and YM effectively blunt Gq/11 signaling in living cells.
DetectEV: a functional enzymatic assays to assess integrity and bioactivity of extracellular vesicles
Authors: Adamo Giorgia , Picciotto Sabrina , Gargano Paola , Paterna Angela , Raccosta Samuele , Rao Estella , Romancino Daniele Paolo , Ghersi Giulio , Manno Mauro , Salamone Monica , Bongiovanni Antonella
Published: October 2023

The application of extracellular vesicles (EVs) as therapeutics or nanocarriers in cell-free therapies necessitates meticulous evaluations of different features, including their identity, bioactivity, batch-to-batch reproducibility, and stability. Given the inherent heterogeneity in EV preparations, this assessment demands sensitive functional assays to provide key quality control metrics, complementing established methods to ensure that EV preparations meet the required functionality and quality standards. Here, we introduce the detectEV assay, an enzymatic-based approach for assessing EV luminal cargo bioactivity and membrane integrity. This method is fast, cost-effective, and quantifiable through enzymatic units. Utilizing microalgae-derived EVs, known as nanoalgosomes, as model systems, we optimized the assay parameters and validated its sensitivity and specificity in quantifying the enzymatic activity of esterases within the EV lumen while also evaluating EV membrane integrity. Compared to conventional methods that assess physicochemical features of EVs, our single-step analysis efficiently detects batch-to-batch variations by evaluating changes in luminal cargo bioactivity and integrity across various EV samples, including differences under distinct storage conditions and following diverse isolation and exogenous loading methods, all using small sample sizes. The detectEV assay’s application to various human-derived EV types demonstrated its versatility and potential universality. Additionally, the assay effectively predicted EV functionality, such as the antioxidant activity of different nanoalgosome batches. Our findings underscore the detectEV assay’s utility in comprehensive characterization of EV functionality and integrity, enhancing batch-to-batch reproducibility and facilitating their therapeutic applications.

Graphical Abstract
Methionine oxidation of Carbohydrate-Active enZymes during white-rot wood decay
Authors: Molinelli Lise , Drula Elodie , Gaillard Jean-Charles , Navarro David , Armengaud Jean , Berrin Jean-Guy , Tron Thierry , Tarrago Lionel
Published: October 2023

White-rot fungi employ secreted carbohydrate-active enzymes (CAZymes) along with reactive oxygen species (ROS), like hydrogen peroxide (H2O2), to degrade lignocellulose in wood. H2O2serves as a co-substrate for key oxidoreductases during the initial decay phase. While the degradation of lignocellulose by CAZymes is well-documented, the impact of ROS on the oxidation of the secreted proteins remains unclear and the identity of the oxidized proteins is unknown. Methionine (Met) can be oxidized to Met sulfoxide (MetO) or Met sulfone (MetO2) with potential deleterious, antioxidant, or regulatory effects. Other residues, like proline (Pro), can undergo carbonylation. Using the white-rotPycnoporus cinnabarinusgrown on aspen wood, we analyzed the Met content of the secreted proteins and their susceptibility to oxidation combining H18O with deep shotgun proteomics. Strikingly, their overall Met content was significantly lower (1.4%) compared to intracellular proteins (2.1%), a feature conserved in fungi but not in metazoans or plants. We evidenced that a catalase, widespread in white-rot fungi, protects the secreted proteins from oxidation. Our redox proteomics approach allowed identification of 49 oxidizable Met and 40 oxidizable Pro residues within few secreted proteins, mostly CAZymes. Interestingly, many of them had several oxidized residues localized in hotspots. Some Met, including those in GH7 cellobiohydrolases, were oxidized up to 47%, with a substantial percentage of sulfone (13%). These Met are conserved in fungal homologs, suggesting important functional roles. Our findings reveal that white-rot fungi safeguard their secreted proteins by minimizing their Met content and by scavenging ROS and pinpoint redox-active residues in CAZymes.

Importance

The study of lignocellulose degradation by fungi is critical for understanding the ecological and industrial implications of wood decay. While carbohydrate-active enzymes (CAZymes) play a well-established role in lignocellulose degradation, the impact of hydrogen peroxide (H2O2) on secreted proteins remains unclear. This study aims at evaluating the effect of H2O2on secreted proteins, focusing on the oxidation of methionine (Met). Using the model white-rot modelPycnoporus cinnabarinusgrown on aspen wood, we showed that fungi protect their secreted proteins from oxidation by reducing their Met content and utilizing a secreted catalase to scavenge exogenous H2O2. The research identified key oxidizable Met within secreted CAZymes. Importantly, some Met like those of GH7 cellobiohydrolases, undergone substantial oxidation levels suggesting important roles in lignocellulose degradation. These findings highlight the adaptive mechanisms employed by white-rot fungi to safeguard their secreted proteins during wood decay and emphasize the importance of these processes in lignocellulose breakdown.
Significant roles in RNA-binding for the amino-terminal domains of Drosophila Pumilio and Nanos
Authors: Wharton Tammy H. , Marhabaie Mohammad , Wharton Robin P.
Published: October 2023

The Drosophila Pumilio (Pum) and Nanos (Nos) RNA-binding proteins govern abdominal segmentation in the early embryo, as well as a variety of other events during development. They bind together to a compound Nanos Response Element (NRE) present in thousands of maternal mRNAs in the ovary and embryo, includinghunchback(hb) mRNA, thereby regulating poly-adenylation, translation, and stability. Many studies support a model in which mRNA recognition and effector recruitment are achieved by distinct regions of each protein. The well-ordered Pum and Nos RNA-binding domains (RBDs) are sufficient to specifically recognize NREs; the relatively larger low-complexity N-terminal domains (NTDs) of each protein have been thought to act by recruiting mRNA regulators. Here we use yeast interaction assays to show that the NTDs also play a significant role in recognition of the NRE, acting via two mechanisms. First, the Pum and Nos NTDs interact in trans to promote assembly of the Pum/Nos/NRE ternary complex. Second, the Pum NTD acts via an unknown mechanism in cis, modifying base recognition by its RBD. These activities of the Pum NTD are important for its regulation of maternalhbmRNA in vivo.
A tuneable minimal cell membrane reveals that two lipid species suffice for life
Authors: Justice Isaac , Kiesel Petra , Safronova Nataliya , von Appen Alexander , Saenz James P.
Published: October 2023

All cells are encapsulated by a lipid membrane which facilitates the interaction between life and its environment. How life exploits the diverse mixtures of lipids that dictate membrane property and function has been experimentally challenging to address. We introduce an approach to tune and minimize lipidomes inMycoplasma mycoidesand the Minimal Cell (JCVI-Syn3A) revealing that a 2-component lipidome can support life. Systematically reintroducing phospholipid features demonstrated that acyl chain diversity is more critical for growth than head group diversity. By tuning lipid chirality, we explored the lipid divide between Archaea and the rest of life, showing that ancestral lipidomes could have been heterochiral. Our approach offers a tunable minimal membrane system to explore the fundamental lipidomic requirements for life, thereby extending the concept of minimal life from the genome to the lipidome.
Purine nucleosides replace cAMP in allosteric regulation of PKA in trypanosomatid pathogens
Authors: Ober Veronica , Githure George B. , Santos Yuri Volpato , Becker Sidney , Moya Gabriel , Basquin Jerôme , Schwede Frank , Lorentzen Esben , Boshart Michael
Published: October 2023

Cyclic nucleotide binding domains (CNB) confer allosteric regulation by cAMP or cGMP to many signalling proteins, including PKA and PKG. PKA of phylogenetically distantTrypanosomais the first exception as it is cyclic nucleotide-independent and responsive to nucleoside analogues (Bachmaier et al. 2019). Here we show that natural nucleosides inosine, guanosine and adenosine are nanomolar affinity CNB ligands and activators of PKA orthologs of the important tropical pathogensT. brucei,T. cruziandLeishmania.The sequence and structural determinants of binding affinity, -specificity and kinase activation of PKAR were established by structure-activity relationship (SAR) analysis, co-crystal structures and mutagenesis. Substitution of 2-3 amino acids in the binding sites is sufficient for conversion of CNB domains from nucleoside to cyclic nucleotide specificity. In addition, a trypanosomatid-specific C-terminal helix (αD) is required for high affinity binding to CNB-B. The αD helix functions as a lid of the binding site that shields ligands from solvent. Selectivity of guanosine for CNB-B and of adenosine for CNB-A results in synergistic kinase activation at low nanomolar concentration. PKA pulldown from rapid lysis establishes guanosine as the predominant ligandin vivoinT. bruceibloodstream forms, whereas guanosine and adenosine seem to synergize in the procyclic developmental stage in the insect vector. We discuss the versatile use of CNB domains in evolution and recruitment of PKA for novel nucleoside-mediated signalling.
cSTAR analysis identifies endothelial cell cycle as a key regulator of flow-dependent artery remodeling
Authors: Deng Hanqiang , Rukhlendo Oleksii S. , Joshi Divyesh , Hu Xiaoyue , Junk Philpp , Tuliakova Anna , Kholodenko Boris N. , Schwartz Martin A.
Published: October 2023

Fluid shear stress (FSS) from blood flow is sensed by vascular endothelial cells (ECs) to determine vessel stability, remodeling and susceptibility to atherosclerosis and other inflammatory diseases but the regulatory networks that govern these behaviors are only partially understood. We used cSTAR, a powerful new computational method, to define EC transcriptomic states under low shear stress (LSS) that triggers vessel inward remodeling, physiological shear stress (PSS) that stabilizes vessels, high shear stress (HSS) that triggers outward remodeling, and oscillatory shear stress (OSS) that confers disease susceptibility, all in comparison to cells under static conditions (STAT). We combined these results with the LINCS database where EC transcriptomic responses to drug treatments to define a preliminary regulatory network in which the cyclin-dependent kinases CDK1/2 play a central role in promoting vessel stability. Experimental analysis showed that PSS induced a strong late G1 cell cycle arrest in which CDK2 was activated. EC deletion of CDK2 in mice resulted in inward artery remodeling and both pulmonary and systemic hypertension. These results validate use of cSTAR to determine EC state and in vivo vessel behavior, reveal unexpected features of EC phenotype under different FSS conditions, and identify CDK2 as a key element within the EC regulatory network that governs artery remodeling.
Unraveling Evolutionary Dynamics: Insights from In Silico Experiments on Selective Mechanisms in Controlled Environments
Authors: Ledda Marco , Pluchino Alessandro , Ragusa Marco
Published: October 2023

In this paper, we present a series ofin silicoexperiments aimed at probing the evolutionary properties of our model. Our investigation encompasses multiple methodologies, beginning with the standard model used in population genetics for measuring natural selection. Next, we employ the Price equation, a well-established formalism known for its effectiveness in tracking how the relationship between parents and offspring evolves over time. In conclusion, we delve into the model results to explain, in the light of evolutionary theory, how the selective mechanism operates. Furthermore, the speculation about the mechanism will be hindered on the agents of the selective process. Even though natural selection can be considered as a statistical phenomenon, sprouting from the change in population frequencies, we argue that in models where there is a elevate control on the environment, it is possible to define the single element responsible for the selective pressure on theunits of selection.
Investigating a role forPUB17andPUB16in the self-incompatibility pathway in transgenicArabidopsis thaliana
Authors: Beronilla Paula K.S. , Goring Daphne R.
Published: October 2023

In Brassicaceae self-incompatibility (SI), self-pollen rejection is initiated by theS-haplotype specific interactions between the pollen SCR/SP11 ligand and the stigma S Receptor kinase (SRK). InBrassicaSI, a member of the Plant U-Box (PUB) E3 ubiquitin ligases, ARC1, is then activated by SRK in this stigma and cellular events downstream of this cause SI pollen rejection by inhibiting pollen hydration and pollen tube growth. During the transition to selfing,Arabidopsis thalianalost the SI components,SCR, SRK, andARC1. However, this trait can be reintroduced intoA. thalianaby adding back functional copies of these genes from closely related SI species. BothSCRandSRKare required for this, though the degree of SI pollen rejection varies between accessions, andARC1is not always needed to produce a strong SI response. ForA. thalianaC24, only transforming withA. lyrata SCRandSRKconfers a strong SI trait, and so here we investigated if ARC1-related PUBs were involved in the SI pathway. Two close ARC1 paralogs,PUB17andPUB16, were selected, and CRISPR/Cas9 technology was used to generatepub17andpub16mutations in the C24 accession. These mutants were then crossed into a transgenicA. thalianaSI-C24 line and their potential impact on SI pollen rejection was investigated. Overall, we did not observe any significant differences to implicatePUB17andPUB16functioning in the transgenicA. thalianaSI-C24 stigma to reject SI pollen.
Cell-type-resolved somatic mosaicism reveals clonal dynamics of the human forebrain
Authors: Chung Changuk , Yang Xiaoxu , Hevner Robert F. , Kennedy Katie , Vong Keng Ioi , Liu Yang , Patel Arzoo , Nedunuri Rahul , Barton Scott T. , Barrows Chelsea , Stanley Valentina , Mittal Swapnil , Breuss Martin W. , Schlachetzki Johannes C. M. , Gleeson Joseph G.
Published: October 2023

Debate remains around anatomic origins of specific brain cell subtypes and lineage relationships within the human forebrain. Thus, direct observation in the mature human brain is critical for a complete understanding of the structural organization and cellular origins. Here, we utilize brain mosaic variation within specific cell types as distinct indicators for clonal dynamics, denoted as cell-type-specific Mosaic Variant Barcode Analysis. From four hemispheres from two different human neurotypical donors, we identified 287 and 780 mosaic variants (MVs), respectively that were used to deconvolve clonal dynamics. Clonal spread and allelic fractions within the brain reveal that local hippocampal excitatory neurons are more lineage-restricted compared with resident neocortical excitatory neurons or resident basal ganglia GABAergic inhibitory neurons. Furthermore, simultaneous genome-transcriptome analysis at both a cell-type-specific and single-cell level suggests a dorsal neocortical origin for a subgroup of DLX1+inhibitory neurons that disperse radially from an origin shared with excitatory neurons. Finally, the distribution of MVs across 17 locations within one parietal lobe reveals restrictions of clonal spread in the anterior-posterior axis precedes that of the dorsal-ventral axis for both excitatory and inhibitory neurons. Thus cell-type resolved somatic mosaicism can uncover lineage relationships governing the development of the human forebrain.
Simulation-Driven Design of Stabilized SARS-CoV-2 Spike S2 Immunogens
Authors: Nuqui Xandra , Casalino Lorenzo , Zhou Ling , Shehata Mohamed , Wang Albert , Tse Alexandra L. , Ojha Anupam , Kearns Fiona L. , Rosenfeld Mia A. , Miller Emily Happy , Acreman Cory M. , Ahn Surl-Hee , Chandran Kartik , McLellan Jason S. , Amaro Rommie E
Published: October 2023

The full-length prefusion-stabilized SARS-CoV-2 spike (S) is the principal antigen of COVID-19 vaccines. Vaccine efficacy has been impacted by emerging variants of concern that accumulate most of the sequence modifications in the immunodominant S1 subunit. S2, in contrast, is the most evolutionarily conserved region of the spike and can elicit broadly neutralizing and protective antibodies. Yet, S2s usage as an alternative vaccine strategy is hampered by its general instability. Here, we use a simulation-driven approach to design S2-only immunogens stabilized in a closed prefusion conformation. Molecular simulations provide a mechanistic characterization of the S2 trimers opening, informing the design of tryptophan substitutions that impart kinetic and thermodynamic stabilization. Structural characterization via cryo-EM shows the molecular basis of S2 stabilization in the closed prefusion conformation. Informed by molecular simulations and corroborated by experiments, we report an engineered S2 immunogen that exhibits increased protein expression, superior thermostability, and preserved immunogenicity against sarbecoviruses.
A novel glycosyltransferase organizes fungal glycogen and cell wall glucans
Authors: Loza Liza , Doering Tamara L.
Published: October 2023

Glycogen is a glucose storage molecule comprised of branched α-1,4-glucan chains, best known as an energy reserve that can be broken down to fuel central metabolism. Because fungal cells have a specialized need for glucose in building cell wall glucans, we investigated whether glycogen is used for this process. For these studies we focused on the pathogenic yeastCryptococcus neoformans, which causes over 112,000 deaths per year worldwide. We identified two enzymes that influence formation of both glycogen and the cell wall: Gly-cogenin (Glg1), which initiates glycogen synthesis, and a novel protein that we callGlucanorganizingenzyme 1 (Goe1). We discovered that cells missing Glg1 lack α-1,4-glucan in their walls, indicating that this material is derived from glycogen. Without Goe1, glycogen rosettes are mislocalized and β-1,3-glucan in the cell wall is reduced. Altogether, our results provide mechanisms for a close association between glycogen and cell wall.
Cross-platform comparison of highly-sensitive immunoassays for inflammatory markers in a COVID-19 cohort1
Authors: Abe Koji , Beer Joanne C. , Nguyen Tran , Ariyapala Ishara S. , Holmes Tyson H. , Feng Wei , Zhang Bingqing , Kuo Dwight , Luo Yuling , Ma Xiao-Jun , Maecker Holden T.
Published: October 2023

A variety of commercial platforms are available for the simultaneous detection of multiple cytokines and associated proteins, often employing antibody pairs to capture and detect target proteins. In this study, we comprehensively evaluated the performance of three distinct platforms: the fluorescent bead-based Luminex assay, the proximity extension-based Olink assay, and a novel proximity ligation assay platform known as Alamar NULISAseq. These assessments were conducted on serum samples from the NIH IMPACC study, with a focus on three essential performance metrics: detectability, correlation, and differential expression. Our results reveal several key findings. Firstly, the Alamar platform demonstrated the highest overall detectability, followed by Olink and then Luminex. Secondly, the correlation of protein measurements between the Alamar and Olink platforms tended to be stronger than the correlation of either of these platforms with Luminex. Thirdly, we observed that detectability differences across the platforms often translated to differences in differential expression findings, although high detectability did not guarantee the ability to identify meaningful biological differences. Our study provides valuable insights into the comparative performance of these assays, enhancing our understanding of their strengths and limitations when assessing complex biological samples, as exemplified by the sera from this COVID-19 cohort.
Fc-dependent functional activity of ChAdOx1-S and CoronaVac vaccine-induced antibodies to the SARS-CoV-2 spike protein
Authors: Harris Alexander W. , Kurtovic Liriye , Nogueira Jeane , Bouzas Isabel , Herbert Opi D. , Wines Bruce D. , Mark Hogarth P. , Poumbourios Pantelis , Drummer Heidi E. , Valim Clarissa , Porto Luís Cristóvão , Beeson James G.
Published: October 2023

Ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission and COVID-19 disease severity is influenced by immunity acquired by natural exposure and/or vaccination, whereby most vaccines are formulated on the Ancestral strain. However, population-level immunity is complicated by the emergence of variants of concern (VOCs), such as Omicron that is the dominant variant currently in circulation. Antibody Fc-dependent effector functions are being increasingly recognised as important mediators in immunity, especially against VOCs. However, induction of these functions in populations with diverse infection and/or vaccination histories, remains poorly defined. Here, we evaluated Fc-dependent functional antibodies following vaccination with two widely used vaccines: AstraZeneca (AZ; ChAdOx1-S) and Sinovac (SV). We quantified FcγR-binding and C1q-fixing antibodies against Ancestral and variant spike (S) proteins in Brazilian adults vaccinated with AZ or SV (n=222), some of which were previously exposed to SARS-CoV-2. AZ induced greater FcγR-binding responses to Ancestral S than the SV vaccine. Previously exposed individuals had significantly greater vaccine-induced responses compared to their naïve counterparts, with notably high C1q-fixation levels, irrespective of vaccine type. FcγR-binding was highest among AZ vaccinated individuals with a prior exposure, and these responses were well retained against the Omicron S protein. Overall, these findings contribute to our understanding of vaccine-induced immunity and its effectiveness against evolving variants.
Comparison Of Low-Density Lipoprotein Cholesterol (Ldl-C), Atherogenic Index In Plasma (Aip) And Apolipoprotein B/Apolipoprotein A1 Ratio In Patients Sent For Routine Lipid Profile Testing At Biochemistry Laboratory - Kenyatta National Hospital
Authors: Kiptim Peter Kibet , Kariuki Rahab Wangari , Kimonge Damaris
Published: October 2023

Background

Cardiovascular disease is a rising global concern accounting for one-third of mortalities. Notably, cardiovascular disease risk factors; including dyslipidemia, smoking, obesity, poor diet, and hypertension are modifiable. It has been established through various studies that dyslipidemia is at the core of atherosclerosis observed in cardiovascular diseases making it important in risk assessment and as a therapeutic target as informed by various guidelines. Plasma lipid profile has been key in the diagnosis of dyslipidemia particularly low-density lipoprotein cholesterol that is used in initial risk assessment and treatment monitoring. However, due to clinical and analytical challenges, LDLC is understated or overstated in some patients due to biological variability.

Objective

To compare low-density lipoprotein cholesterol, atherogenic index in plasma, and Apolipoprotein A1 / Apolipoprotein B ratio for cardiovascular risk assessment in patients sent for routine lipid profile testing at biochemistry laboratory - Kenyatta National Hospital

Methodology

This was laboratory-based cross-sectional study, 307 residual samples from patients sent for lipid profile testing were tested for, Apo A1, and Apo B concentrations using Mindray BS 2000M chemistry analyzer using Mindray reagents (Shenzhen Mindray Bio-Medical Electronics Co., Ltd) at biochemistry laboratory KNH. The obtained data was used to calculate the atherogenic index of plasma (AIP) and Apo B/ Apo A ratio.

Results

The median age of the participants was 49 years, 56% were female. The median(range) values were Total cholesterol 4.17 (3.11, 5.20),High-density lipoprotein cholesterol 1.21 (0.88, 1.54)Low-density lipoprotein cholesterol 2.60 (1.84, 3.37)Triglycerides 1.12 (0.83, 1.62),APOA-1 1.38 (1.11, 1.57),APOB 0.95 (0.73, 1.21)Apo B/ApoA-1 ratio 0.75 (0.56, 0.94) and Atherogenic index of plasma 0.09 (−0.14, 0.45). More than a quarter (26.7%) of the participants had LDL-C above 2.35 mmol/l. More than a third of the patients (42%, n=124) were at risk of CVD according to ApoB/ApoA-1 ratio, while 40 %,(n=122) had a high CVD risk according to the atherogenic index stratification.

We observed a positive correlation between LDL-C and ApoA-1, Apo B and Apo B/ApoA-1 ratio. There is a significant agreement between atherogenic index and APOB/APOA-1 ratio in CVD risk identification kW=0.36 (95% CI, 0.27-0.46), p<0.001.

Conclusion

Atherogenic Index of plasma, Apo A and Apo B markers offer additional benefits in CVD risk identification.
Viral and host factors associated with SARS-CoV-2 disease severity in Georgia, USA
Authors: Carmola Ludy R. , Roebling Allison Dorothy , Khosravi Dara , Langsjoen Rose M. , Bombin Andrei , Bixler Bri , Reid Alex , Chen Cara , Wang Ethan , Lu Yang , Zheng Ziduo , Zhang Rebecca , Nguyen Phuong-Vi , Arthur Robert A. , Fitts Eric , Gulick Dalia Arafat , Higginbotham Dustin , Taz Azmain , Ahmed Alaa , Crumpler John Hunter , Kraft Colleen , Lam Wilbur A. , Babiker Ahmed , Waggoner Jesse J. , Openo Kyle P. , Johnson Laura M. , Westbrook Adrianna , Piantadosi Anne
Published: October 2023

While SARS-CoV-2 vaccines have shown strong efficacy, their suboptimal uptake combined with the continued emergence of new viral variants raises concerns about the ongoing and future public health impact of COVID-19. We investigated viral and host factors, including vaccination status, that were associated with SARS-CoV-2 disease severity in a setting with low vaccination rates. We analyzed clinical and demographic data from 1,957 individuals in the state of Georgia, USA, coupled with viral genome sequencing from 1,185 samples. We found no difference in disease severity between individuals infected with Delta and Omicron variants among the participants in this study, after controlling for other factors, and we found no specific mutations associated with disease severity. Compared to those who were unvaccinated, vaccinated individuals experienced less severe SARS-CoV-2 disease, and the effect was similar for both variants. Vaccination within 270 days before infection was associated with decreased odds of moderate and severe outcomes, with the strongest association observed at 91-270 days post-vaccination. Older age and underlying health conditions, especially immunosuppression and renal disease, were associated with increased disease severity. Overall, this study provides insights into the impact of vaccination status, variants/mutations, and clinical factors on disease severity in SARS-CoV-2 infection when vaccination rates are low. Understanding these associations will help refine and reinforce messaging around the crucial importance of vaccination in mitigating the severity of SARS-CoV-2 disease.
Identifying crossovers and shared genetic material in whole genome sequencing data from families
Authors: Paskov Kelley , Chrisman Brianna , Stockham Nathaniel , Washington Peter Yigitcan , Dunlap Kaitlyn , Jung Jae-Yoon , Wall Dennis P.
Published: October 2023

Large, whole-genome sequencing (WGS) data sets containing families provide an important opportunity to identify crossovers and shared genetic material in siblings. However, the high variant calling error rates of WGS in some areas of the genome can result in spurious crossover calls, and the special inheritance status of the X Chromosome presents challenges. We have developed a hidden Markov model that addresses these issues by modeling the inheritance of variants in families in the presence of error-prone regions and inherited deletions. We call our method PhasingFamilies. We validate PhasingFamilies using the platinum genome family NA1281 (precision: 0.81; recall: 0.97), as well as simulated genomes with known crossover positions (precision: 0.93; recall: 0.92). Using 1925 quads from the Simons Simplex Collection, we found that PhasingFamilies resolves crossovers to a median resolution of 3527.5 bp. These crossovers recapitulate existing recombination rate maps, including for the X Chromosome; produce sibling pair IBD that matches expected distributions; and are validated by the haplotype estimation tool SHAPEIT. We provide an efficient, open-source implementation of PhasingFamilies that can be used to identify crossovers from family sequencing data.
Localizing unmapped sequences with families to validate the Telomere-to-Telomere assembly and identify new hotspots for genetic diversity
Authors: Chrisman Brianna , He Chloe , Jung Jae-Yoon , Stockham Nate , Paskov Kelley , Washington Peter , Petereit Juli , Wall Dennis P.
Published: October 2023

Although it is ubiquitous in genomics, the current human reference genome (GRCh38) is incomplete: It is missing large sections of heterochromatic sequence, and as a singular, linear reference genome, it does not represent the full spectrum of human genetic diversity. To characterize gaps in GRCh38 and human genetic diversity, we developed an algorithm for sequence location approximation using nuclear families (ASLAN) to identify the region of origin of reads that do not align to GRCh38. Using unmapped reads and variant calls from whole-genome sequences (WGSs), ASLAN uses a maximum likelihood model to identify the most likely region of the genome that a subsequence belongs to given the distribution of the subsequence in the unmapped reads and phasings of families. Validating ASLAN on synthetic data and on reads from the alternative haplotypes in the decoy genome, ASLAN localizes >90% of 100-bp sequences with >92% accuracy and ∼1 Mb of resolution. We then ran ASLAN on 100-mers from unmapped reads from WGS from more than 700 families, and compared ASLAN localizations to alignment of the 100-mers to the recently released T2T-CHM13 assembly. We found that many unmapped reads in GRCh38 originate from telomeres and centromeres that are gaps in GRCh38. ASLAN localizations are in high concordance with T2T-CHM13 alignments, except in the centromeres of the acrocentric chromosomes. Comparing ASLAN localizations and T2T-CHM13 alignments, we identified sequences missing from T2T-CHM13 or sequences with high divergence from their aligned region in T2T-CHM13, highlighting new hotspots for genetic diversity.
The moderating effect of fintech on the relationship between CSR and banks' financial stability: Baron and Kenny's approach analysis
Authors: Salah Mahdi Ines Ben , Bouaziz Mariem , Boujelbène Abbes Mouna
Published: October 2023

Purpose

Corporate social responsibility (CSR) and fintech have emerged as critical megatrends in the banking industry. This study aims to examine the impact of financial technology on the relationship between CSR and banks' financial stability. Specifically, it investigates the moderating effect of fintech on the association between CSR and the financial stability of conventional banks operating in Qatar, UAE, Saudi Arabia, Kuwait, Bahrain, Jordan, Pakistan and Turkey from 2010 to 2021.

Design/methodology/approach

To achieve the authors’ objective, the authors apply Baron and Kenny's three-link model, tested with fixed and random effects regression models.

Findings

The results reveal that the development of fintech decreases banks' financial stability, whereas it promotes banks' involvement in CSR strategies. Furthermore, the findings indicate that fintech plays a moderating role in the relationship between CSR and financial stability. It positively moderates the impact of CSR on financial stability. The robustness analysis highlights the mutual reinforcement of fintech and CSR dimensions in improving the financial stability of banks. Thus, by fostering community and product responsibility, fintech could enhance the financial stability of banks.

Practical implications

Finally, the authors recommend that banks focus more on developing technological and environmentally friendly financial products.

Originality/value

This study contributes significantly by providing valuable insights for managers and policymakers seeking to improve banks' financial stability through the simultaneous adoption of new financial technology products and the strong commitment to CSR practices.
Market power, industry concentration and earnings management: does corporate governance matter
Authors: Banerjee Ameet Kumar , Chatterjee Soumen , Dutta Avijan
Published: October 2023

Purpose

This study examines a link between firms' product market power, industry concentration, the degree of earnings management and the role of governance in curbing earnings management.

Design/methodology/approach

The author uses different panel techniques of feasible generalized least squares (FGLS) and system generalized method of moments (GMM) to show robust study findings.

Findings

The study results reveal that firms lacking product market pricing power engage in earnings management, adding a new dimension to the existing literature. These findings mirror even at the industry level, where the authors document immense competitiveness led to earnings manipulation and stringent corporate governance mechanism has the potency to curb earnings management.

Practical implications

The paper has valuable insights and practical implications for policymakers and market participants. The results indicate robust institutional oversight mechanisms can deter earnings management in a concentrated market.

Originality/value

To the best of the authors’ knowledge, this is among the first paper from India, a growing emerging economy, to look at the various aspects of market characteristics, earnings management and the role of corporate governance.