bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain Volumes, Thicknesses, and Surface Areas as Mediators of Genetic Factors and Childhood Adversity on Intelligence
Authors: Williams Camille M. , Peyre Hugo , Ramus Franck 
Published: September 2022

AbstractAlthough genetic and environmental factors influence general intelligence (g-factor), few studies examined the neuroanatomical measures mediating environmental and genetic effects on intelligence. Therefore, we investigate the brain volumes, cortical mean thicknesses, and cortical surface areas mediating the effects of the g-factor polygenic score (gPGS) and childhood adversity on the g-factor in the UK Biobank.We first identified the global and regional brain measures for the mediation models that contribute to the g-factor independently of global brain size and regional associations. Most regions contributed to the g-factor through global brain size. Parieto-Frontal Integration Theory (P-FIT) regions were not more associated with the g-factor than non-PFIT regions. Adjusting for global brain size and regional associations, only a few regions, such as the right olfactory sulcus and the right mediodorsal thalamic nuclei volumes, the right orbital inferior frontal gyrus surface area, and the anterior cingulate gyrus mean thicknesses, predicted intelligence and were included in the mediation analyses.We conducted mediation analyses on global measures, regional volumes, mean thicknesses, and surface areas, separately. Total brain volume mediated 7.04% of the gPGS’ effect on the g-factor and 2.50% of childhood adversity’s effect on the g-factor. In comparison, the fraction of the gPGS and childhood adversity’s effects mediated by individual regional volumes, surfaces, and mean thicknesses was 10-15 times smaller. Our findings suggest that genetic and environmental effects on general intelligence must be mediated to a larger extent by other structural brain properties.Significance StatementGenes and environmental factors, such as childhood adversity, influence our cognitive abilities via the brain. Our results show that genetic and environmental effects on intelligence are mediated to some extent by neuroanatomical properties. However, we find that global brain measures (e.g., total brain volume) are the largest mediators and that regional volumes, surfaces, and mean thicknesses only mediated a fraction of a person’s genetic predisposition to intelligence and childhood adversity’s effect on intelligence. This suggests that genetic and environmental effects on general intelligence are to a large extent mediated by other kinds of brain structural properties.
Environmental selection influences the microbiome of subsurface petroleum reservoirs
Authors: Gittins Daniel A. , Bhatnagar Srijak , Hubert Casey R. J. 
Published: September 2022

AbstractPetroleum reservoirs within the deep biosphere are extreme environments inhabited by diverse microbial communities creating biogeochemical hotspots in the subsurface. Despite their ecological and industrial importance, systematic studies of core microbial taxa and associated genomic attributes of the oil reservoir microbiome are limited. This study compiles and compares 343 16S rRNA gene amplicon libraries and 25 shotgun metagenomic libraries from oil reservoirs in different parts of the world. Taxonomic composition varies among reservoirs with different physicochemical characteristics, and with geographic distance. Despite oil reservoirs lacking a taxonomic core microbiome in these datasets, gene-centric metagenomic analysis reveals a functional core featuring carbon acquisition and energy conservation strategies consistent with other deep biosphere environments. Genes for anaerobic hydrocarbon degradation are observed in a subset of the samples and are therefore not considered to represent core biogeochemical functions in oil reservoirs. Metabolic redundancy within the petroleum reservoir microbiome reveals these to be deep biosphere systems poised to respond to changes in redox biogeochemistry. This highlights the potential to use microbial genomics for predicting microbial responses to (bio)engineering perturbations to these subsurface habitats.
A systematic review and comparison of automated tools for quantification of fibrous networks
Authors: de Vries Judith J. , Laan Daphne M. , Frey Felix , Koenderink Gijsje H. , de Maat Moniek P.M. 
Published: September 2022

AbstractFibrous networks are essential structural components of biological and engineered materials. Accordingly, many approaches have been developed to quantify their structural properties, which define their material properties. However, a comprehensive overview and comparison of methods is lacking. Therefore, we systematically searched for automated tools quantifying network characteristics in confocal, stimulated emission depletion (STED) or scanning electron microscopy (SEM) images and compared these tools by applying them to fibrin, a prototypical fibrous network in thrombi. Structural properties of fibrin such as fiber diameter and alignment are clinically relevant, since they influence the risk of thrombosis. Based on a systematic comparison of the automated tools with each other, manual measurements, and simulated networks, we provide guidance to choose appropriate tools for fibrous network quantification depending on imaging modality and structural parameter. These tools are often able to reliably measure relative changes in network characteristics, but absolute numbers should be interpreted with care.
High-resolution structures map the metal import pathway in an Nramp transporter
Authors: Ray Shamayeeta , Berry Samuel P. , Wilson Eric A. , Zhang Casey H. , Shekhar Mrinal , Singharoy Abhishek , Gaudet Rachelle 
Published: September 2022

AbstractTransporters of the Nramp (Natural resistance-associated macrophage protein) family import divalent transition metal ions into cells of most organisms. By supporting metal homeostasis, Nramps prevent disorders related to metal insufficiency or overload. Previous studies revealed that Nramps take on a LeuT fold and identified the metal-binding site. We present high- resolution structures ofDeinococcus radioduransNramp in three stable conformations of the transport cycle revealing that global conformational changes are supported by distinct coordination geometries of its physiological substrate, Mn2+, across conformations and conserved networks of polar residues lining the inner and outer gates. A Cd2+-bound structure highlights differences in coordination geometry for Mn2+and Cd2+. Measurements of metal binding using isothermal titration calorimetry indicate that the thermodynamic landscape for binding and transporting physiological metals like Mn2+is different and more robust to perturbation than for transporting the toxic Cd2+metal.
Effectiveness of incentivized peer referral to increase enrollment in a community-based chlamydia screening and treatment study among young Black men
Authors: Campbell Mary Beth , Ratnayake Aneeka , Gomes Gérard , Stoecker Charles , Kissinger Patricia 
Published: September 2022

AbstractPurposeIncentivized peer referral (IPR) has been shown to be an effective method of recruitment for men who have sex with men but has not been studied extensively in men who have sex with women (MSW), particularly among Black MSW. We aimed to determine if IPR was more effective than uncompensated peer referral for recruiting young Black men into a community STI screening study.MethodsWe used data from the Check It study, a chlamydia (Ct) screening and treatment program for young Black men ages 15-26 in New Orleans, LA. Enrollment was compared before and after IPR was implemented using Multiple Series Analysis (MTSA). IPR was introduced to increase recruitment that had been severely diminished because of the COVID-19 shutdown.ResultsOf 1527 men enrolled, 1399 (91.6%) were enrolled pre-IPR and 128 (8.4%) were enrolled post-IPR. The percentage of men referred by a friend or peer was higher in the post-IPR period than in the pre-IPR period (45.7% vs. 19.7%, p<0.001). Post-pandemic, we observed a statistically significant increase of 2.007 more recruitments (p=0.044, 95% CI (0.0515, 3.964)) at the start of the post-IPR era, compared to the pre-IPR era. Overall, we also observed a trending increase in recruitments in the IPR era relative to the pre-IPR era (0.0174 recruitments/week, p=0.285, 95% CI (−0.0146, 0.0493)) with less recruitment decay in the post-IPR compared to pre-IPR.ConclusionsIPR may be an effective means of engaging young Black men in community based STI research and prevention programs, particularly when clinic access is limited.
CURE: A Pre-training Framework on Large-scale Patient Data for Treatment Effect Estimation
Authors: Liu Ruoqi , Chen Pin-Yu , Zhang Ping 
Published: September 2022

AbstractTreatment effect estimation (TEE) refers to the estimation of causal effects, and it aims to compare the difference among treatment strategies on important outcomes. Current machine learning based methods are mainly trained on labeled data with specific treatments or outcomes of interest, which can be sub-optimal if the labeled data are limited. In this paper, we propose a novel transformer-based pre-training and fine-tuning framework called CURE for TEE from observational data. CURE is pre-trained on large-scale unlabeled patient data to learn representative contextual patient representations, and then fine-tuned on labeled patient data for TEE. We design a new sequence encoding for longitudinal (or structured) patient data and we incorporate structure and time into patient embeddings. Evaluated on 4 downstream TEE tasks, CURE outperforms the state-of-the-art methods in terms of an average of 3.8% and 6.9% absolute improvement in Area under the ROC Curve (AUC) and Area under the Precision-Recall Curve (AUPR), and 15.7% absolute improvement in Influence function-based Precision of Estimating Heterogeneous Effects (IF-PEHE). We further demonstrate the data scalability of CURE and verify the results with corresponding randomized clinical trials. Our proposed method provides a new machine learning paradigm for TEE based on observational data.
SARS-CoV-2 Serosurveys: How antigen, isotype and threshold choices affect the outcome
Authors: Binder Raquel A. , Fujimori Gavin F. , Forconi Catherine S. , Reed George W. , Silva Leandro S. , Lakshmi Priya Saikumar , Higgins Amanda , Cincotta Lindsey , Dutta Protiva , Salive Marie-Claire , Mangolds Virginia , Anya Otuwe , Calle J. Mauricio Calvo , Nixon Thomas , Tang Qiushi , Wessolossky Mireya , Wang Yang , Ritacco Dominic A. , Bly Courtney S. , Fischinger Stephanie , Atyeo Caroline , Oluoch Peter O. , Odwar Boaz , Bailey Jeffrey A. , Maldonado-Contreras Ana , Haran John P. , Schmidt Aaron G. , Cavacini Lisa , Alter Galit , Moormann Ann M. 
Published: September 2022

AbstractBackgroundEvaluating the performance of SARS-CoV-2 serological assays and clearly articulating the utility of selected antigen, isotypes and thresholds is crucial to understanding the prevalence of infection within selected communities.MethodsThis cross-sectional study, implemented in 2020, screened PCR-confirmed COVID-19 patients (n=86), banked pre-pandemic and negative donors (n=96), health care workers and family members (n=552), and university employees (n=327) for anti-SARS-CoV-2 receptor-binding domain (RBD), trimeric spike protein (S), and nucleocapsid protein (N) IgG and IgA antibodies with a laboratory developed Enzyme-Linked Immunosorbent Assay (ELISA) and tested how antigen, isotype and threshold choices affected the seroprevalence. The following threshold methods were evaluated: (i) mean + 3 standard deviations of the negative controls; (ii) 100% specificity for each antigen/isotype combination; and (iii) the maximal Youden index.ResultsWe found vastly different seroprevalence estimates depending on selected antigens, isotypes and the applied threshold method, ranging from 0.0% to 85.4%. Subsequently, we maximized specificity and reported a seroprevalence, based on more than one antigen, ranging from 9.3% to 25.9%.ConclusionsThis study revealed the importance of evaluating serosurvey tools for antigen, isotype, and threshold-specific sensitivity and specificity, in order to interpret qualitative serosurvey outcomes reliably and consistently across studies.
Genome analysis of Parmales, a sister group of diatoms, reveals the evolutionary specialization of diatoms from phago-mixotrophs to photoautotrophs
Authors: Ban Hiroki , Sato Shinya , Yoshikawa Shinya , Yamada Kazumasa , Nakamura Yoji , Ichinomiya Mutsuo , Sato Naoki , Blanc-Mathieu Romain , Endo Hisashi , Kuwata Akira , Ogata Hiroyuki 
Published: September 2022

AbstractThe order Parmales (Bolidophyceae) is a minor group of pico-sized eukaryotic marine phytoplankton that contains species with cells surrounded by silica plates. Previous studies revealed that Parmales is a member of ochrophytes and sister to diatoms (Bacillariophyta), the most successful phytoplankton group in the modern ocean. Therefore, parmalean genomes can serve as a reference to elucidate both the evolutionary events that differentiated these two lineages and the genomic basis for the ecological success of diatoms vs. the more cryptic lifestyle of parmaleans. Here, we compared the genomes of eight parmaleans and five diatoms to explore their physiological and evolutionary differences. Parmaleans were predicted to be phago-mixotrophs. By contrast, diatoms have undergone loss of genes related to phagocytosis, indicating the ecological specialization from phago-mixotroph to photoautotroph in the early evolution of diatoms. Furthermore, diatoms showed significant enrichment in gene sets involved in silica metabolism, nutrient uptake capacity, carbon concentrating mechanisms, and iron uptake in comparison with parmaleans. Overall, our results suggest a strong evolutionary link between the loss of phago-mixotrophy and specialization to a silicified photoautotrophic life stage early in diatom evolution after diverging from the Parmales lineage.
Enhanced Golden Gate Assembly: Evaluating Overhang Strength for Improved Ligation Efficiency
Authors: Strzelecki Patryk , Joly Nicolas , Hébraud Pascal , Hoffmann Elise , Cech Grzegorz M. , Kloska Anna , Busi Florent , Grange Wilfried 
Published: September 2022

AbstractMolecular cloning, a routine yet essential technique, relies heavily on efficient ligation, which can be significantly improved using Golden Gate Assembly (GGA). A key component of GGA is the use of type IIS enzymes, which uniquely cleave downstream of their recognition sequences to generate various overhangs, including non-palindromic ones. Recent advancements in GGA include the development of newly engineered enzymes with enhanced activity. Additionally, high-throughput GGA assays, which allow for the simultaneous study of all possible overhangs, have identified optimal GGA substrates with high efficiencies and fidelities, greatly facilitating the design of complex assemblies. Interestingly, these assays reveal unexpected correlations between ligation efficiencies and overhang stabilities. One hypothesis for this observation is that newly hydrolyzed DNA fragments with strong overhangs can readily re-ligate, thereby slowing down the overall process. In this paper, we employ a combination of gel electrophoresis and numerical calculations to test this hypothesis, ultimately determining that it does not hold true under the conditions established by conventional GGA assays. Using an assembly of 10 fragments, we demonstrate that strong overhangs yield higher GGA efficiency, while weak overhangs result in lower efficiency. These findings enable us to propose optimal overhangs for efficient GGA assays, significantly increasing yield.
Mechanism of small molecule inhibition of Plasmodium falciparum myosin A informs antimalarial drug design
Authors: Moussaoui Dihia , Robblee James P. , Auguin Daniel , Fisher Fabio , Fagnant Patricia M. , Macfarlane Jill E. , Schaletzky Julia , Wehri Eddie , Mueller-Dieckmann Christoph , Baum Jake , Robert-Paganin Julien , Trybus Kathleen M. , Houdusse Anne 
Published: September 2022

AbstractMalaria is responsible for more than a half million deaths per year. The Plasmodium parasites responsible continue to develop resistance to all known agents, despite treatment with different antimalarial combinations. The atypical Myosin A motor (PfMyoA) is part of a core macromolecular complex called the glideosome, essential for Plasmodium parasite mobility and therefore an attractive drug target. Here, we characterize the interaction of a small molecule (KNX-002) with PfMyoA. KNX-002 inhibits PfMyoA ATPase activity in vitro and blocks asexual blood stage growth of merozoites, one of three motile Plasmodium life-cycle stages. Combining biochemical assays, X-ray crystallography and molecular dynamics, we demonstrate that KNX-002 targets a novel pocket in PfMyoA, sequestering it in a post-rigor state detached from actin. KNX-002 binding affects Mg2+ coordination near ATP, preventing ATP hydrolysis and thus inhibiting motor activity. This first-in-class small-molecule inhibitor of PfMyoA paves the way for developing a new generation of antimalarial treatments.
SARS-CoV-2 polyprotein substrate regulates the stepwise Mpro cleavage reaction
Authors: Narwal Manju , Armache Jean-Paul , Edwards Thomas , Murakami Katsuhiko S. 
Published: September 2022

ABSTRACTProcessing of polyproteins pp1a and pp1ab in Coronaviruses by main protease Mpro is a crucial event in virus replication and a promising target for antiviral drug development. Mpro recognizes multiple recognition sites within polyproteins in a defined order, but its mechanism remains enigmatic due to lack of structural information of the polyprotein substrate bound Mpro complex. Here, we present the cryo-EM structures of the SARS-CoV-2 Mpro in an apo-form and in complex with the nsp7-10 region of pp1a polyprotein. The structure shows that the interaction of Mpro with polyproteins is limited to the recognition site connecting nsp9 and nsp10 proteins without any tight association with the rest of polyprotein structure or sequence. Comparison between the apo-form and the polyprotein bound structures of Mpro highlights the flexible nature of active site region allowing the Mpro to accommodate various recognition sites connecting series of nsp proteins. These observations suggest that the role of Mpro for selecting a preferred cleavage site within the polyprotein is limited and underscore the structure, conformation and/or dynamics of polyprotein determining the sequential polyprotein cleavage by Mpro.
A structural dendrogram of the actinobacteriophage major capsid proteins provides important structural insights into the evolution of capsid stability
Authors: Podgorski Jennifer M. , Freeman Krista , Gosselin Sophia , Huet Alexis , Conway James F. , Bird Mary , Grecco John , Patel Shreya , Jacobs-Sera Deborah , Hatfull Graham , Gogarten Johann Peter , Ravantti Janne , White Simon 
Published: September 2022

AbstractMany double-stranded DNA viruses, including tailed bacteriophages (phages) and herpesviruses, use the HK97-fold in their major capsid protein to make the capsomers of the icosahedral viral capsid. Following the genome packaging at near-crystalline densities, the capsid is subjected to a major expansion and stabilization step that allows it to withstand environmental stresses and internal high pressure. Several different mechanisms for stabilizing the capsid have been structurally characterized, but how these mechanisms have evolved is still not understood. Using cryo-EM structure determination, structural comparisons, phylogenetic analyses, and Alphafold predictions, we have constructed a detailed structural dendrogram describing the evolution of capsid structural stability within the actinobacteriophages. The cryo-EM reconstructions of ten capsids solved to resolutions between 2.2 and 4 Ångstroms revealed that eight of them exhibit major capsid proteins that are linked by a covalent cross-linking (isopeptide bond) between subunits that was first described in the HK97 phage. Those covalent interactions ultimately lead to the formation of mutually interlinked capsomers that has been compared to the structure of chain mail. However, three of the closely related phages do not exhibit such an isopeptide bond as demonstrated by both our cryo-EM maps and the lack of the required residue. This work raises questions about the importance of previously described capsid stabilization mechanisms.
Endogenous Plasmids and Reductive Genome Evolution in Host-Associated Bacteria
Authors: Xiong Qing , Fung Cathy Sin-Hang , Xiao Xiaojun , Wan Angel Tsz-Yau , Wang Mingqiang , Ren Yaning , Yang Kevin Yi , Cui Yubao , Liu Xiaoyu , Tsui Stephen Kwok-Wing 
Published: September 2022

AbstractReductive genome evolution is commonly observed among host-associated bacteria including many important pathogens, such as Mycobacterium leprae but its molecular mechanism is not well understood 1–5. One of the most widely accepted hypotheses to explain bacterial genome reduction is Muller’s ratchet, in which the associated bacteria tend to accumulate deleterious mutations for reduction in the absence of chromosomal recombination inside the eukaryotic host organism 1,2. Cardinium species belong to the family Amoebophilaceae of the CFB group bacteria, which are a group of endosymbiont bacteria widely distributed among arthropods, that along with Wolbachia can cause cytoplasmic incompatibility 6,7. In this study, we explored bacterial reductive evolution within the de novo assembled genomes of Cardinium endosymbionts in two astigmatic mites 8,9. Our results shed light on the reduction mechanism driven by endogenous plasmids and their encoded enzymes.
Conserved intramolecular networks in GDAP1 are closely connected to CMT-linked mutations and protein stability
Authors: Sutinen Aleksi , Paffenholz Dirk , Nguyen Giang Thi Tuyet , Ruskamo Salla , Torda Andrew E. , Kursula Petri 
Published: September 2022

ABSTRACTCharcot-Marie-Tooth disease (CMT) is the most common inherited peripheral polyneuropathy in humans, and its subtypes are linked to mutations in dozens of different genes, including the gene coding for ganglioside-induced differentiation-associated protein 1 (GDAP1). The main GDAP1-linked CMT subtypes are the demyelinating CMT4A and the axonal CMT2K. Over a hundred different missense CMT mutations in the GDAP1 gene have been reported. However, despite implications for mitochondrial fission and fusion, cytoskeletal interactions, and response to reactive oxygen species, the etiology of GDAP1-linked CMT is poorly understood at the protein level. Based on earlier structural data, CMT-linked mutations could affect intramolecular interaction networks within the GDAP1 protein. We carried out structural and biophysical analyses on several CMT-linked GDAP1 protein variants and describe new crystal structures of the autosomal recessive R120Q and the autosomal dominant A247V and R282H GDAP1 variants. These mutations reside in the structurally central helices α3, α7, and α8. In addition, solution properties of the CMT mutants R161H, H256R, R310Q, and R310W were analysed. All disease variant proteins retain close to normal structure and solution behaviour. All mutations, apart from those affecting Arg310 outside the folded GDAP1 core domain, decreased thermal stability. In addition, a bioinformatics analysis was carried out to shed light on the conservation and evolution of GDAP1, which is an outlier member of the GST superfamily. Many CMT mutation sites are highlighted in the bioinformatics analyses focusing on sequence conservation and entropy, and the analyses support the outlier nature of GDAP1 in the GST superfamily. A central role for the α6-α7 loop, within a conserved interaction network, is identified for GDAP1 protein stability. To conclude, we have expanded the structural analysis on GDAP1, strengthening the hypothesis that alterations in conserved intramolecular interactions may alter GDAP1 stability and function, eventually leading to mitochondrial dysfunction, impaired protein-protein interactions, and neuronal degeneration.