bluuebunny/crossref_metadata_2025 huggingface dataset:
The ‘system of the world’ and the scientific culture of early modern France
Authors: Rabinovitch Oded
Published: January 2023

Historians have long debated the origins of modern science in early modern Europe. Recently, however, scholars pointed to our need to understand how the ‘new philosophy’ became a sustained movement, which did not dissipate over the course of a few generations, as had previous scientific renaissances in other civilizations. This article suggests that the mediations of the printed book allowed a broader public to engage with the astronomical ideas at the core of scientific transformations. This article examines the interactions that the world of the book generated between authors at the ‘core’ of early modern science and ‘amateurs’ who were interested in recent cosmological discussion around the notion of the ‘system of the world’. It argues that this concept served simultaneously to discuss mathematico-physical problems, to make claims for authorship and to provide cultural orientation, which made it amenable to appropriation and dialogue across a range of genres. The new social interactions around the ‘system of the world’ allowed a heavily mathematical science to become a viable and sustainable cultural phenomenon, a veritable building-block of a new scientific culture at the heart of European modernity.
Quantitative genetic-by-soil microbiome interactions in a perennial grass affect functional traits
Authors: Khasanova Albina , Edwards Joseph , Bonnette Jason , Singer Esther , Haque Taslima , Juenger Thomas E.
Published: January 2023

Plants interact with diverse microbiomes that can impact plant growth and performance. Recent studies highlight the potential beneficial aspects of plant microbiomes, including the possibility that microbes facilitate the process of local adaptation in their host plants. Microbially mediated local adaptation in plants occurs when local host genotypes have higher fitness than foreign genotypes because of their affiliation with locally beneficial microbes. Here, plant adaptation results from genetic interactions of the host with locally beneficial microbes (e.g. host genotype-by-microbiome interactions). We used a recombinant inbred line (RIL) mapping population derived from upland and lowland ecotypes of the diploid C4 perennial bunch grassPanicum halliito explore quantitative genetic responses to soil microbiomes focusing on functional root and shoot traits involved in ecotypic divergence. We show that the growth and development of ecotypes and their trait divergence depends on soil microbiomes. Moreover, we find that the genetic architecture is modified by soil microbiomes, revealing important plant genotype-by-microbiome interactions for quantitative traits. We detected a number of quantitative trait loci (QTL) that interact with the soil microbiome. Our results highlight the importance of microbial interactions in ecotypic divergence and trait genetic architecture in C4 perennial grasses.
Marine heatwaves and upwelling shape stress responses in a keystone predator
Authors: Rühmkorff Sarah , Wolf Fabian , Vajedsamiei Jahangir , Barboza Francisco Rafael , Hiebenthal Claas , Pansch Christian
Published: January 2023

Climate change increases the frequency and intensifies the magnitude and duration of extreme events in the sea, particularly so in coastal habitats. However, the interplay of multiple extremes and the consequences for species and ecosystems remain unknown. We experimentally tested the impacts of summer heatwaves of differing intensities and durations, and a subsequent upwelling event on a temperate keystone predator, the starfish
Asterias rubens.
We recorded mussel consumption throughout the experiment and assessed activity and growth at strategically chosen time points. The upwelling event overall impaired starfish feeding and activity, likely driven by the acidification and low oxygen concentrations in the upwelled seawater. Prior exposure to a present-day heatwave (+5°C above climatology) alleviated upwelling-induced stress, indicating cross-stress tolerance. Heatwaves of present-day intensity decreased starfish feeding and growth. While the imposed heatwaves of limited duration (9 days) caused slight impacts but allowed for recovery, the prolonged (13 days) heatwave impaired overall growth. Projected future heatwaves (+8°C above climatology) caused 100% mortality of starfish. Our findings indicate a positive ecological memory imposed by successive stress events. Yet, starfish populations may still suffer extensive mortality during intensified end-of-century heatwave conditions.
Legionella maioricensis sp. nov., a new species isolated from the hot water distribution systems of a hospital and a shopping center during routine sampling
Authors: Crespi Sebastian , Drašar Vladimír , Salvà-Serra Francisco , Jaén-Luchoro Daniel , Piñeiro-Iglesias Beatriz , Lindemann Paul Christoffer , Aliaga-Lozano Francisco , Fernández-Juárez Victor , Coll-García Guillem , Moore Edward R. B. , Bennasar-Figueras Antoni
Published: January 2023

Two

Legionella

-like strains isolated from hot water distribution systems in 2012 have been characterized phenotypically, biochemically and genomically in terms of DNA relatedness. Both strains, HCPI-6T and EUR-108, exhibited biochemical phenotypic profiles typical of

Legionella

species. Cells were Gram-negative motile rods which grew on BCYEα agar but not on blood agar and displayed phenotypic characteristics typical of the family

Legionellaceae

, including a requirement for l-cysteine and testing catalase positive. Both strains were negative for oxidase, urease, nitrate reduction and hippurate negative, and non-fermentative. The major ubiquinone was Q12 (59.4 % HCPI-6T) and the dominant fatty acids were C16 : 1 ω7c (28.4 % HCPI-6T, ≈16 % EUR-108), C16 : 0 iso (≈22.5 % and ≈13 %) and C15 : 0 anteiso (19.5 % and ≈23.5 %, respectively). The percent G+C content of genomic DNA was determined to be 39.3 mol %. The 16S rRNA gene, mip sequence and comparative genome sequence-based analyses (average nucleotide identity, ANI; digital DNA–DNA hybridization, dDDH; and phylogenomic treeing) demonstrated that the strains represent a new species of the genus

Legionella

. The analysis based on the 16S rRNA gene sequences showed that the sequence similarities for both strains ranged from 98.8–90.1 % to other members of the genus. The core genome-based phylogenomic tree (protein-concatemer tree based on concatenation of 418 proteins present in single copy) revealed that these two strains clearly form a separate cluster within the genus

Legionella

. ANI and dDDH values confirmed the distinctiveness of the strains. Based on the genomic, genotypic and phenotypic findings from a polyphasic study, the isolates are considered to represent a single novel species, for which the name Legionella maioricensis sp. nov. is proposed. The type strain is HCPI-6T (=CCUG 75071T=CECT 30569T).
The impact on mental health of young Asian Americans due to acts of discrimination and hate crimes during COVID-19
Authors: Gawash Ahmed , Lo David F. , Nghiem Brianna , Rofail Priscilla , Basu Sayan
Published: January 2023

This article is an examination of the acts of discriminiation and hate crimes against the Asian American community and how their mental health has been impacted. The historical examination of acts against the Asian American community stem from acts against the Asian American community during both the yellow peril and the Roosevelt Era. Alongside current day institutionalized policies that are propagated by the media, the resurrection of historical tropes further act to seclude Asian Americans from mainstream society. These acts of seclusion further drive mental health inequality in Asian American society that include, but are not limited to: anxiety, depression, and psychological stress. These mental health inequalities are further subdivided into different ethnic groups that worsen as data is collected from older generations. More recently, COVID-19 has brought forth an upsurge in hate crimes that has only worsened the ability of Asian American youth to fully develop a racial identity; the upsurge in hate crimes is also coupled with invalidation of interethnic differences and invalidation of their discriminatory experiences. The synthesis of current day research will aid in the understanding of the mental health inequality in the Asian American community and aid in further studies that can address these plights.

Purpose Statement

The purpose of this paper is to investigate how acts of discrimination and hate crimes against the Asian community have impacted the mental health of young Asian Americans. This review seeks to explore the many effects of race-based discrimiation specifically for Asian Americans during and after the COVID-19 (coronavirus pandemic) such as: general feelings of inclusivity, physiological responses as a result of increasing racist encounters, and incidences of mental health experiences. Overall, the paper highlights how these characteristics manifest within the Asian American population and what measures and interventions can be done to protect Asian American from the negative consequences of hate.
Solving the Variable-Particle Size Quandary of Bone Mills. Development of an Automated Milling System to Generate Graft Particles of Definite Sizes
Authors: Chandra R Viswa
Published: January 2023

There are situations where block grafts have to be milled to convert them into particulate grafts of definite sizes. The objectives of this study were to evaluate the quality of graft particles generated in two sizes from a custom-built automated milling system (AMS) and their biocompatibility in an animal model. A Monetite block was milled in an AMS to generate small (SS group; 0.5-0.8 mm) and medium size (MS group; 1.0-1.2 mm) particles. Measures of particle count, Feret’s diameter (dF), particle distribution and size were recorded. Biocompatibility of particles was tested in a rabbit tibial defect model. The average particle size was significantly smaller in the SS group than the MS group (0.68±0.39vs1.10±0. 79 mm;p≤0.001). There were significant to highly significant differences between SS and MS groups in measures of particle count (p≤0.001), dF(p=0.02)and size (p≤0.001). SS and MS groups had maximum percentage of particles in the 0.6-1mm (71%) and >1mm (70%) ranges respectively. The mineralized tissue volumes across SS, MS when compared to an autogenous block were 68.92±35.66%, 66.29±29.21% and 89.83±19.91% (p=0.003)respectively. The device was able to generate small and medium-size graft particles which were distinct from each other.
Structural insights into ligand-recognition, activation, and signaling-bias at the complement C5a receptor, C5aR1
Authors: Saha Shirsha , Maharana Jagannath , Yadav Manish K. , Sarma Parishmita , Singh Vinay , Mohapatra Samanwita , Soni Chahat , Saha Sayantan , Mishra Sudha , Ganguly Manisankar , Chami Mohamed , Banerjee Ramanuj , Shukla Arun K.
Published: January 2023

Activation of the complement cascade is a critical part of our innate immune response against invading pathogens, and it operates in a concerted fashion with the antibodies and phagocytic cells towards the clearance of pathogens. The complement peptide C5a, generated during the activation of complement cascade, is a potent inflammatory molecule, and increased levels of C5a are implicated in multiple inflammatory disorders including the advanced stages of COVID-19 pathophysiology. The proximal step in C5a-mediated cellular and physiological responses is its interaction with two different seven transmembrane receptors (7TMRs) known as C5aR1 and C5aR2. Despite a large body of functional data on C5a-C5aR1 interaction, direct visualization of their interaction at high-resolution is still lacking, and it represents a significant knowledge gap in our current understanding of complement receptor activation and signaling. Here, we present cryo-EM structures of C5aR1 activated by its natural agonist C5a, and a G-protein-biased synthetic peptide ligand C5apep, in complex with heterotrimeric G-proteins. The C5a-C5aR1 structure reveals the ligand binding interface involving the N-terminus and extracellular loops of the receptor, and we observe that C5a exhibits a significant conformational change upon its interaction with the receptor compared to the basal conformation. On the other hand, the structural details of C5apep-C5aR1 complex provide a molecular basis to rationalize the ability of peptides, designed based on the carboxyl-terminus sequence of C5a, to act as potent agonists of the receptor, and also the mechanism underlying their biased agonism. In addition, these structural snapshots also reveal activation-associated conformational changes in C5aR1 including outward movement of TM6 and a dramatic rotation of helix 8, and the interaction interface for G-protein-coupling. In summary, this study provides previously lacking molecular basis for the complement C5a recognition and activation of C5aR1, and it should facilitate structure-based discovery of novel lead molecules to target C5aR1 in inflammatory disorders.
HLA allele-calling using whole-exome sequencing identifies 129 novel associations in 11 autoimmune diseases: a multi-ancestry analysis in the UK Biobank
Authors: Butler-Laporte Guillaume , Farjoun Joseph , Nakanishi Tomoko , Lu Tianyuan , Abner Erik , Chen Yiheng , Hultström Michael , Metspalu Andres , Milani Lili , Mägi Reedik , Nelis Mari , Hudjashov Georgi ,   Estonian Biobank Research Team, Yoshiji Satoshi , Ilboudo Yann , Liang Kevin YH , Su Chen-Yang , Willet Julian DS , Esko Tõnu , Zhou Sirui , Forgetta Vincenzo , Taliun Daniel , Richards J Brent
Published: January 2023

The human leukocyte antigen (HLA) region on chromosome 6 is strongly associated with many immune-mediated and infection-related diseases. Due to its highly polymorphic nature and complex linkage disequilibrium patterns, traditional genetic association studies of single nucleotide polymorphisms (SNPs) do not perform well in this region. Instead, the field has adopted the assessment of the association of HLA alleles (i.e., entire HLA gene haplotypes) with disease. Often based on genotyping arrays, these association studies impute HLA alleles, decreasing accuracy and thus statistical power for rare alleles and in non-European ancestries. Here, we use whole-exome sequencing (WES) from 454,824 UK Biobank participants to directly call HLA alleles using the HLA- HD algorithm. We show this method is more accurate than imputing HLA alleles and harness the improved statistical power to identify 360 associations for 11 auto-immune phenotypes (at least 129 likely novel), leading to better insights into the specific coding polymorphisms that underlie these diseases. We show that HLA alleles with synonymous variants, often overlooked in HLA studies, can significantly influence these phenotypes. Lastly, we show that HLA sequencing may improve polygenic risk scores accuracy across ancestries. These findings allow better characterization of the role of the HLA region in human disease.
T492I mutation alters SARS-CoV-2 properties via modulating viral non-structural proteins
Authors: Lin Xiaoyuan , Sha Zhou , Trimpert Jakob , Kunec Dusan , Jiang Chen , Xiong Yan , Xu BinBin , Zhu Zhenglin , Xue Weiwei , Wu Haibo
Published: January 2023

The historically dominant SARS-CoV-2 Delta variants and the currently dominant Omicron variants carry a T492I substitution within the non-structural protein 4 (NSP4). Based on a combination ofin silicoanalyses, we predicted that the T492I mutation increases the transmissibility and adaptability of the virus. We confirmed this hypothesis by performing competition experiments in hamsters and in human airway tissue culture models. Furthermore, we show that the T492I mutation also increases the replication capacity and infectiveness of the virus, and improves its ability to evade antibody neutralization induced by previous variants. Mechanistically, the T492I mutation increases cleavage efficiency of the viral main protease NSP5 by enhancing enzyme-substrate binding, resulting in increased production of nearly all non-structural proteins processed by NSP5. Importantly, T492I mutation suppresses the viral RNA associated chemokines in monocytic macrophages, which may contribute to the attenuated pathogenicity of Omicron variants. Our results highlight the importance of the NSP4 mutation in the evolutionary dynamics of SARS-CoV-2 and identify a novel target for the development of broad-spectrum antiviral agents.
NGS method for parallel processing of high quality, damaged or fragmented input material using target enrichment
Authors: Lyander Anna , Gellerbring Anna , Hägglund Moa , Elhami Keyvan , Wirta Valtteri
Published: January 2023

Next-generation sequencing (NGS) has been increasingly popular in genomics studies over the last decade and is now commonly used in clinical applications for precision diagnostics. Many disease areas typically involve different kinds of sample specimens, sample qualities and quantities. The quality of the DNA can range from intact, high molecular weight molecules to degraded, damaged and very short molecules. The differences in quality and quantity pose challenges for downstream molecular analyses. To overcome the challenge with the need of different molecular methods for different types of samples, we have developed a joint procedure for preparing enriched DNA libraries from high molecular weight DNA and DNA from formalin-fixed, paraffin-embedded tissue, fresh frozen tissue material, as well as cell-free DNA.
Nucleoside Diphosphate Kinases 1 and 2 regulate a protective liver response to a high-fat diet
Authors: Iuso Domenico , Garcia-Saez Isabel , Couté Yohann , Yamaryo-Botté Yoshiki , Erba Elisabetta Boeri , Adrait Annie , Zeaiter Nour , Tokarska-Schlattner Malgorzata , Jilkova Zuzana Macek , Boussouar Fayçal , Barral Sophie , Signor Luca , Couturier Karine , Hajmirza Azadeh , Chuffart Florent , Vitte Anne-Laure , Bargier Lisa , Puthier Denis , Decaens Thomas , Rousseaux Sophie , Botté Cyrille , Schlattner Uwe , Petosa Carlo , Khochbin Saadi
Published: January 2023

De novolipogenesis (DNL), the process whereby cells synthesize fatty acids from acetyl-coenzyme A (acetyl-CoA), is deregulated in diverse pathologies, including cancer. Here we report that DNL is negatively regulated by Nucleoside Diphosphate Kinases 1 and 2 (NME1/2), housekeeping enzymes involved in nucleotide homeostasis that were recently discovered to bind co-enzyme A (CoA). We show that NME1 additionally binds acetyl-CoA and that ligand recognition involves a unique binding mode dependent on the CoA/acetyl-CoA 3’ phosphate. We report thatNme2knockout mice fed a high-fat diet (HFD) exhibit excessive triglyceride synthesis and liver steatosis. In liver cells NME2 mediates a gene transcriptional response to HFD leading to DNL repression and activation of a protective gene expression program via targeted histone acetylation. Our findings implicate NME1/2 in the epigenetic regulation of a protective liver response to HFD and suggest a potential role in controlling acetyl-CoA usage between the competing paths of histone acetylation and DNL.
Thor-Ribo-Seq: ribosome profiling tailored for low input with RNA-dependent RNA amplification
Authors: Mito Mari , Shichino Yuichi , Iwasaki Shintaro
Published: January 2023

Translation regulation plays a pivotal role in the diversification of gene expression and the response to intra- and extracellular environmental cues. Ribosome profiling (or Ribo-Seq) serves as a sensitive, quantitative, comprehensive, and data-rich technique to survey ribosome traversal across the cellular transcriptome. However, due to the intricacy of library preparation, applications to low input have presented analytic challenges. To overcome this issue, here we developed Thor-Ribo-Seq, a ribosome profiling method tailored for low input. Thor-Ribo-Seq harnesses RNA-templated RNA transcription to linearly amplify ribosome footprints, assessing ribosome traversal at codon resolution with limited artifacts. This highly sensitized ribosome profiling approach provides a versatile option to investigate the translatome in precious samples.
Linear versus Nonlinear Muscle Networks: A Case Study to Decode Hidden Synergistic Patterns During Dynamic Lower-limb Tasks
Authors: O’Keeffe Rory , Rathod Vaibhavi , Shirazi Seyed Yahya , Mehrdad Sarmad , Edwards Alexis , Rao Smita , Atashzar S. Farokh
Published: January 2023

This paper, for the first time, compares the behaviors of nonlinear versus linear muscle networks in decoding hidden peripheral synergistic neural patterns during dynamic functional tasks. In this paper, we report a case study during which one healthy subject conducts a series of four lower limb repetitive tasks. Specifically, the paper focuses on tasks that involve the right knee joint, including walking, sit-tostand, stepping, and drop-jump. Twelve muscles were recorded using the Delsys Trigno system. The linear muscle network was generated using coherence analysis, and the nonlinear network was generated using Spearman’s correlation. The results show that the degree, clustering coefficient, and global efficiency of the muscle network have the highest value among tasks in the linear domain for the walking task, while a low linear synergistic network behavior for the sit-to-stand is observed. On the other hand, the results show that the nonlinear functional muscle network decodes high connectivity (degree) and clustering coefficient and efficiency for the sit-tostand when compared with other tasks. We have also developed a two-dimensional functional connectivity plane composed of linear and nonlinear features and shown that it can span the lower-limb dynamic task space. The results of this paper for the first time highlight the importance of observing both linear and nonlinear connectivity patterns, especially for complex dynamic tasks. It should also be noted that through a simultaneous EEG recording (using BrainVision System), we have shown that, indeed, cortical activity may indirectly explain highly-connected nonlinear muscle network for the sit-to-stand task, highlighting the importance of nonlinear muscle network as a neurophysiological window of observation beyond the periphery.
Acute Kidney Injury, the Present on Admission indicator (POA) and sex disparities: Observational study of inpatient real world data in a Swiss tertiary health care system
Authors: Triep Karen , Musy Sarah , Simon Michael , Endrich Olga
Published: January 2023

Background

Regarding kidney disease, sex differences in epidemiology and clinical relevance have been reported. Related to absolute and relative changes of baseline creatinine, different criteria for staging may induce under-or over-diagnosis related to sex. At the largest Swiss provider of inpatient acute health care, a clinic decision support algorithm ensures exact staging of kidney disease (2012 KDIGO Clinical Practice Guideline). Coding of the indicator “Present On Admission” was introduced at this institution in 2018 to flag post-admission conditions.

Objective

We hypothesized sex differences in health care associated acute kidney injury. Defined indicators and the distribution of stages in acute kidney injury were analysed using the POA flag. Sex differences were reported.

Methods

Retrospective observational study. Routinely collected health data, Insel Group, Berne, Switzerland, 2019 and 2020 (121’757 cases) on the patient history and intensive care treatment duration, comorbidity levels, coded diagnoses, age and sex. Software and statistic: program R, version 4.1.1, standard deviation; median, interquartile range; prop.test; standardized mean difference.

Results

The reporting of post-admission diagnoses was associated with more interhospital transfers, intensive care stays, scores of severity and treatment intensity, mechanical ventilation, age, number of diagnoses, complexity level of the related cases and mortality. A weaker association could be observed for the female population. However, mortality was higher (stage III acute kidney injury 41.6%).

Conclusion

Using the POA-flag the results reflect the clinical situation of complications and comorbidities evolving unexpectedly. As our results show sex differences, i.e. a lower morbidity of female patients for each stage, but a higher mortality, a deeper evaluation of the implied sex differences in staging of kidney disease should follow.

The general results confirm the necessity of a diagnosis-onset reporting in health statistic.
Higher ratio of plasma omega-6/omega-3 fatty acids is associated with greater risk of all-cause, cancer, and cardiovascular mortality: a population-based cohort study in UK Biobank
Authors: Zhang Yuchen , Sun Yitang , Yu Qi , Song Suhang , Brenna J. Thomas , Shen Ye , Ye Kaixiong
Published: January 2023

Background

Circulating omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) have been associated with various chronic diseases and mortality, but results are conflicting. Few studies examined the role of omega-6/omega-3 ratio in mortality.

Methods

We investigated plasma omega-3 and omega-6 PUFAs and their ratio in relation to all-cause and cause-specific mortality in a large prospective cohort, the UK Biobank. Of 85,425 participants who had complete information on circulating PUFAs, 6,461 died during follow-up, including 2,794 from cancer and 1,668 from cardiovascular disease (CVD). Associations were estimated by multivariable Cox proportional hazards regression with adjustment for relevant risk factors.

Results

Risk for all three mortality outcomes increased as the ratio of omega-6/omega-3 PUFAs increased (all Ptrend< 0.05). Comparing the highest to the lowest quintiles, individuals had 26% (95% CI, 15-38%) higher total mortality, 14% (95% CI, 0-31%) higher cancer mortality, and 31% (95% CI, 10-55%) higher CVD mortality. Moreover, omega-3 and omega-6 PUFAs in plasma were all inversely associated with all-cause, cancer, and CVD mortality, with omega-3 showing stronger effects.

Conclusions

Using a population-based cohort in UK Biobank, our study revealed a strong association between the ratio of circulating omega-6/omega-3 PUFAs and the risk of all-cause, cancer, and CVD mortality.
Prediction of Long COVID Based on Severity of Initial COVID-19 Infection: Differences in predictive feature sets between hospitalized versus non-hospitalized index infections
Authors: Socia Damien , Larie Dale , Feuerwerker Sol , An Gary , Cockrell Chase
Published: January 2023

Long COVID is recognized as a significant consequence of SARS-COV2 infection. While the pathogenesis of Long COVID is still a subject of extensive investigation, there is considerable potential benefit in being able to predict which patients will develop Long COVID. We hypothesize that there would be distinct differences in the prediction of Long COVID based on the severity of the index infection, and use whether the index infection required hospitalization or not as a proxy for developing predictive models. We divide a large population of COVID patients drawn from the United States National Institutes of Health (NIH) National COVID Cohort Collaborative (N3C) Data Enclave Repository into two cohorts based on the severity of their initial COVID-19 illness and correspondingly trained two machine learning models: the Long COVID after Severe Disease Model (LCaSDM) and the Long COVID after Mild Disease Model (LCaMDM). The resulting models performed well on internal validation/testing, with a F1 score of 0.94 for the LCaSDM and 0.82 for the LCaMDM. There were distinct differences in the top 10 features used by each model, possibly reflecting the differences in type and amount of pathophysiological data between the hospitalized and non-hospitalized patients and/or reflecting different pathophysiological trajectories in the development of Long COVID. Of particular interest was the importance of Plant Hardiness Zone in the feature set for the LCaMDM, which may point to a role of climate and/or sunlight in the progression to Long COVID. Future work will involve a more detailed investigation of the potential role of climate and sunlight, as well as refinement of the predictive models as Long COVID becomes increasingly parsed into distinct clinical phenotypes.
Specificity Guides Interpretation: On H3K4 Methylation at Enhancers and Broad Promoters
Authors: Shah Rohan N. , Ruthenburg Alexander J.
Published: January 2023

In 2018, we used internally calibrated chromatin immunoprecipitation (ICeChIP) to find that many of the most commonly used antibodies against H3K4 methylforms had significant off-target binding, which compromised the findings of at least eight literature paradigms that used these antibodies for ChIP-seq (Shah et al., 2018). In many cases, we were able to recapitulate the prior findings in K562 cells with the original, low-quality antibody, only to find that the models did not hold up to scrutiny with highly specific reagents and quantitative calibration.

In a recent preprint originally prepared as a Letter to the Editor of Molecular Cell, though they agree with our overarching conclusions, Pekowska and colleagues take issue with analyses presented for two relatively minor points of the paper (Pekowska et al., 2023). We are puzzled by the assertion that these two points constitute the “bulk” of our findings, nor is it clear which components of our “analytical design” they find problematic. We feel their critique, however mild, is misguided.
Corynebacterium diphtheriaecauses keratinocyte-intrinsic ribotoxic stress and NLRP1 inflammasome activation in a model of cutaneous diphtheria
Authors: ROBINSON Kim S. , TOH Gee Ann , FIRDAUS Muhammad Jasrie , THAM Khek Chian , ROZARIO Pritisha , LIM Chrissie , TOH Ying Xiu , LAU Zhi Heng , BINDER Sophie Charlotte , MAYER Jacob , BONNARD Carine , SCHMIDT Florian I. , COMMON John E. A. , ZHONG Franklin L.
Published: January 2023

NLRP1 is an innate immune sensor protein that activates inflammasome-driven pyroptotic cell death. Recent work demonstrates that human NLRP1 has evolved to sense viral infections. Whether and how human NLRP1 responds to other infectious agents is unclear. Here, and in a companion manuscript, we report that human NLRP1, as an integral component of the ribotoxic stress response (RSR), is activated by bacterial exotoxins that target human ribosome elongation factors EEF1 and EEF2, including Diphtheria Toxin (DT) fromCorynebacterium diphtheriae, exotoxin A fromPseudomonas aeruginosaand sidI fromLegionella pneumophila. In human keratinocytes, DT activates RSR kinases ZAKα, p38 and JNKs, upregulates a set of signature RSR transcripts and triggers rapid NLRP1-dependent pyroptosis. Mechanistically, these processes require 1) DtxR-mediated de-repression of DT production in the bacteria, as well as 2) diphthamide synthesis and 3) ZAKα/p38-driven NLRP1 phosphorylation in the host. In 3D human skin cultures,Corynebacterium diphtheriae infection disrupts barrier function and induces IL-1 driven inflammation. Pharmacologic inhibition of p38 and ZAKα suppresses keratinocyte pyroptosis and rescues barrier integrity ofCorynebacterium diphtheriae-treated organotypic skin. In summary, these findings implicate RSR and the NLRP1 inflammasome in antibacterial innate immunity and might explain certain aspects of diphtheria pathogenesis.

KEY POINTS

EEF1/EEF2-targeting bacterial exotoxins activate the human NLRP1 inflammasome.

DT+ve toxigenicCorynebacterium diphtheriaeinduces ZAKα-driven RSR and NLRP1-driven pyroptosis in human keratinocytes.

Identification of transcripts that are induced by multiple RSR agents across multiple cell types.

p38 and ZAKα inhibition rescues epidermal integrity by limiting pyroptosis in 3D skin mode of cutaneous diphtheria.
A controller-peripheral architecture and costly energy principle for learning
Authors: Luo Xiaoliang , Mok Robert M. , Roads Brett D. , Love Bradley C.
Published: January 2023

Complex behavior is supported by the coordination of multiple brain regions. How do brain regions coordinate absent a homunculus? We propose coordination is achieved by a controller-peripheral architecture in which peripherals (e.g., the ventral visual stream) aim to supply needed inputs to their controllers (e.g., the hippocampus and prefrontal cortex) while expending minimal resources. We developed a formal model within this framework to address how multiple brain regions coordinate to support rapid learning from a few example images. The model captured how higher-level activity in the controller shaped lower-level visual representations, affecting their precision and sparsity in a manner that paralleled brain measures. In particular, the peripheral encoded visual information to the extent needed to support the smooth operation of the controller. Alternative models optimized by gradient descent irrespective of architectural constraints could not account for human behavior or brain responses, and, typical of standard deep learning approaches, were unstable trial-by-trial learners. While previous work offered accounts of specific faculties, such as perception, attention, and learning, the controller-peripheral approach is a step toward addressing next generation questions concerning how multiple faculties coordinate.
Discovering dynamic plant enzyme complexes in yeast for novel alkaloid pathway identification from a medicinal plant kratom
Authors: Wu Yinan , Liu Chang , Gong Franklin L. , Li Sijin
Published: January 2023

Discovering natural product biosynthetic pathways from medicinal plants is challenging and laborious, largely due to the complexity of the transcriptomics-driven pathway prediction process. Here we developed a novel approach that captures the protein-level connections between enzymes for pathway discovery with improved accuracy. We proved that heterologous protein-protein interaction screening in yeast enabled the efficient discovery of both dynamic plant enzyme complexes and the pathways they organize. This approach discovered complexes and pathways in the monoterpene indole alkaloid metabolism of a medicinal plant, kratom with high success rate. Screening using a strictosidine β-D-glucosidase (MsSGD1) against 19 medium-chain dehydrogenase/reductases (MsMDRs) identified five MsSGD1-MsMDR complexes. Three out of the five interacting MsMDRs were then proven functional, while the remaining 14 non-interacting candidates did not show obvious activities. The work discovered three branched pathways by combining transcriptomics, metabolomics, and heterologous PPI screening and demonstrated a new plant pathway discovery strategy.
Sequencing ofN6-methyl-deoxyadenosine at single-base resolution across the mammalian genome
Authors: Feng Xinran , Cui Xiaolong , Zhang Li-Sheng , Ye Chang , Wang Pingluan , Zhong Yuhao , Zheng Zhong , He Chuan
Published: January 2023

While DNAN6-methyl-deoxyadenosine (6mA) is abundant in bacteria and protists, its presence and function in mammalian genomes have been less clear. We present Direct-Read 6mA sequencing (DR-6mA-seq), an antibody-independent method to measure 6mA at base-resolution with high sensitivity. DR-6mA-seq employs a unique mutation-based strategy to reveal 6mA sites as misincorporation signatures without any chemical or enzymatic modulation of 6mA. We validated DR-6mA-seq through successful mapping of the well-characterized G(6mA)TC motif in theE. coliDNA and identified 6mA sites in the mammalian mitochondrial DNA. As expected, when applying DR-6mA-seq to mammalian systems, we found that genomic DNA (gDNA) 6mA abundance is in general low in most mammalian tissues and cells; however, we did observe distinct gDNA 6mA sites in mouse testis and glioblastoma cells. DR-6mA-seq provides an enabling tool to detect 6mA at single-base resolution with high sensitivity for a comprehensive understanding of DNA 6mA in eukaryotes.
MultiCOVID: a multi modal Deep Learning approach for COVID-19 diagnosis
Authors: Hardy-Werbin Max , Maiques José Maria , Busto Marcos , Cirera Isabel , Aguirre Alfons , Garcia-Gisbert Nieves , Zuccarino Flavio , Carbullanca Santiago , Del Carpio Luis Alexander , Ramal Didac , Gayete Ángel , Martínez-Roldan Jordi , Marquez-Colome Albert , Bellosillo Beatriz , Gibert Joan
Published: January 2023

The rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to a global overextension of healthcare. Both Chest X-rays (CXR) and blood test have been demonstrated to have predictive value on Coronavirus Disease 2019 (COVID-19) diagnosis on different prevalence scenarios. With the objective of improving and accelerating the diagnosis of COVID-19, a multi modal prediction algorithm (MultiCOVID) based on CXR and blood test was developed, to discriminate between COVID-19, Heart Failure (HF) and Non-Covid Pneumonia (NCP) and healthy (Control) patients. This retrospective single-center study includes CXR and blood test obtained between January 2017 and May 2020. Multi modal prediction models were generated using opensource DL algorithms. Performance of the MultiCOVID algorithm was compared with interpretations from five experienced thoracic radiologists on 300 random test images using the McNemar-Bowker test. A total of 8578 samples from 6123 patients (mean age 66 +/- 18 years of standard deviation, 3523 men) were evaluated across datasets. For the entire test set, the overall accuracy of MultiCOVID was 84%, with a mean AUC of 0.92 (0.89-0.94). For 300 random test images, overall accuracy of MultiCOVID was significantly higher (69.6%) compared with individual radiologists (range, 43.7%- 58.7%) and the consensus of all five radiologists (59.3%, P<.001). Overall, we have developed a multimodal deep learning algorithm, MultiCOVID, that discriminates among COVID-19, heart failure, non-covid pneumonia and healthy patients using both CXR and blood test with a significantly better performance than experienced thoracic radiologists.
Most clinical trials involving American children that violated FDAAA legal reporting requirements had not published outcomes in the scientific literature
Authors: Bruckner Till , Yerunkar Samruddhi , Basegmez Okan , Borana Ronak , Chavarría Belén , Velarde Mayra , DeVito Nicholas J.
Published: January 2023

Non-publication, incomplete publication and excessively slow publication of clinical trial outcomes contribute to research waste and can harm patients. In this cohort study, we used publicClinicalTrials.govregistry records to identify 81 paediatric clinical trials in the United States that appear to have violated the FDA Amendments Act 2007 (FDAAA) reporting requirements. We then searched the literature for the outcomes of these 81 trials and contacted trial sponsors about the status of results.

We found that only 22/81 trials (27.2%) had made their results public in a full-length peer-reviewed publication, and that only 8/81 (9.9%) trials had done so within one year of their primary completion date. Our findings highlight the need for US Food and Drug Administration and the National Institutes of Health to systematically monitor FDAAA compliance and enforce reporting requirements.
Traditional male circumcision and the risk for HIV transmission among men: a systematic review
Authors: Asa Gregorius Abanit , Fauk Nelsensius Klau , Ward Paul Russell
Published: January 2023

Introduction

Although traditional male circumcision (TMC) is still practiced in a number of countries, and its healing process may have a high risk of HIV and other STIs transmission, there have been no published systematic reviews on TMC, HIV risk, and impacts on circumcised men and their families. The aim of this study is to synthesise evidence of how TMC practices contribute to HIV transmission among males and the impacts of HIV on themselves and their families.

Methods

The systematic search started with an initial search following the PICO (Population, Intervention, Comparison and Outcomes) framework. A systematic review was conducted to find literature using databases including PubMed, CINHAL, SCOPUS, ProQuest, Cochrane, and Medline. The search was limited to the English language, and with no year limit in order to capture as many articles as possible about circumcision, traditional male circumcision, HIV, and impact on men and their families. Critical appraisal tools developed by the Joanna Briggs Institute (JBI) for study design were used to assess the methodological quality of included studies.

Result

A total of 18 studies were included: 11 were qualitative studies, 5 were quantitative studies, and 2 were mixed-method studies. All the studies included were conducted in areas where traditional male circumcision was performed (17 in Africa and 1 in Papua New Guinea). The findings of the review were categorized into themes namely TMC as a cultural practice, consequences of not being traditionally circumcised on men and their families, and TMC-related risk of HIV transmission. The review showed that TMC and HIV risk could bring significant and negative challenges for men and their families.

Conclusion

The findings indicated the need for targeted health intervention programs and efforts to address psychological and social challenges in communities practicing TMC.

Prospero Number Registration

CRD42022357788.
Apoptosis recognition receptors regulate skin tissue repair in mice
Authors: Justynski Olivia , Bridges Kate , Krause Will , Forni Maria Fernanda , Phan Quan , Sandoval-Schaefer Teresa , Driskell Ryan , Miller-Jensen Kathryn , Horsley Valerie
Published: January 2023

Apoptosis and clearance of apoptotic cells via efferocytosis are evolutionarily conserved processes that drive tissue repair. However, the mechanisms by which recognition and clearance of apoptotic cells regulate repair are not fully understood. Here, we use single-cell RNA sequencing to provide a map of the cellular dynamics during early inflammation in mouse skin wounds. We find that apoptotic pathways and efferocytosis receptors are elevated in fibroblasts and immune cells, including resident Lyve1+macrophages, during inflammation. Interestingly, human diabetic foot wounds upregulate mRNAs for apoptotic genes and display increased and altered efferocytosis signaling via the receptor Axl. During early inflammation in mouse wounds, we detect upregulation of Axl in dendritic cells and fibroblasts via TLR3-independent mechanisms. Inhibition studiesin vivoin mice reveal that Axl signaling is required for wound repair but is dispensable for efferocytosis. By contrast, inhibition of another efferocytosis receptor, Timd4, in mouse wounds decreases efferocytosis and abrogates wound repair. These data highlight the distinct mechanisms by which apoptotic cell detection coordinates tissue repair and provides potential therapeutic targets for chronic wounds in diabetic patients.
Higher Angiotensin I Converting Enzyme 2 (ACE2) levels in the brain of individuals with Alzheimer’s disease
Authors: Louise Reveret , Manon Leclerc , Vincent Emond , Andréanne Loiselle , Philippe Bourassa , Cyntia Tremblay , Bennett David A , Sébastien Hébert , Frédéric Calon
Published: January 2023

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major cause of death in the elderly. Cognitive decline due to Alzheimer’s disease (AD) is frequent in the geriatric population disproportionately affected by the COVID-19 pandemic. Interestingly, central nervous system (CNS) manifestations have been reported in SARS-CoV-2-infected patients. In this study, we investigated the levels of Angiotensin I Converting Enzyme 2 (ACE2), the main entry receptor of SARS-COV-2 in cells, inpostmortemparietal cortex samples from two independent AD cohorts, totalling 142 persons. Higher concentrations of ACE2 protein and mRNA were found in individuals with a neuropathological diagnosis of AD compared to age-matched healthy control subjects. Brain levels of soluble ACE2 were inversely associated with cognitive scores (p = 0.02), markers of pericytes (PDGFRβ, p=0.02 and ANPEP, p = 0.007) and caveolin1 (p = 0.03), but positively correlated with soluble amyloid-β peptides (Aβ) concentrations (p = 0.01) and insoluble phospho- tau (S396/404, p = 0.002). No significant differences in ACE2 were observed in the 3xTgAD mouse model of tau and Aβ neuropathology. Results from immunofluorescence and Western blots showed that ACE2 protein is mainly localized in neurons in the human brain but predominantly in microvessels in the mouse brain. The present data show that an AD diagnosis is associated with higher levels of soluble ACE2 in the human brain, which might contribute to a higher risk of CNS SARS-CoV-2 infection.
Peripheral extracellular vesicle-derived miR-150-3p exacerbates acute kidney injury following acute pancreatitis by promoting ferroptosis through FTH1 signaling
Authors: Cui Ji-tao , Wang Guo-sheng , Yan Chang-sheng , Cheng Long , Guo Xiao-yu , Huang Zi-jian , Wang Zi-xin , Tang De-sheng , Ji Liang , Wang Gang
Published: January 2023

Acute kidney injury following acute pancreatitis (AP-AKI) is one of the most fatal complications caused by acute pancreatitis (AP). Extracellular vesicles (EVs) in circulating blood are believed to be crucial to the process of AP-AKI, but the mechanisms are still unclear. In this study, we first constructed an AP-AKI rat model by retrograde sodium taurocholate through the pancreatic duct and then injected circulating blood-derived EVs into AP-AKI rats. Measurements of peripheral blood creatinine and urea nitrogen levels showed that EVs could add to kidney injury in AP-AKI rats. By analyzing the levels of renal Fe2+, cyclooxygenase 2 (COX-2), malondialdehyde (MDA), and glutathione peroxidase 4 (GPX4), we also found that extracted EVs could aggravate renal tubular ferroptosis in AP-AKI rats. Using high-throughput sequencing, we screened for high expression of EV miR-150-3P in AP-AKI patients. In vitro, we found that overexpressed miR-150-3P can influence MDA, Fe2+, lipid peroxide and GSH levels in HK-2 cells and ultimately aggravate ferroptosis. Next, through a dual-luciferase assay, we confirmed that miR-150-3p could exacerbate ferroptosis by directly targeting ferritin heavy chain 1 (FTH1). Finally, in AP-AKI rats, we again demonstrated that overexpression of miR-150-3P exacerbated renal ferroptosis through the miR-150-3P/FTH1 axis. Collectively, these findings provide new avenues to explore the mechanisms of the onset and exacerbation of AP-AKI.
m6A methylated long noncoding RNA regulates proinflammatory response emerging as novel target for IBD
Authors: Olazagoitia-Garmendia Ane , Rojas-Márquez Henar , Sebastian-delaCruz Maialen , Ochoa Anne , Mendoza-Gomez Luis Manuel , Madrigal Alain Huerta , Santin Izortze , Castellanos-Rubio Ainara
Published: January 2023

Cytokine mediated sustained inflammation increases the risk to develop different complex chronic inflammatory diseases, such as inflammatory bowel disease (IBD). Recent studies highlighted the involvement of inflammation associated gene variants in m6A methylation. Moreover, long noncoding RNAs (lncRNAs) participate in the pathogenesis of inflammatory disorders and their function can be influenced by differential methylation. Here we describe the functional implication ofLOC339803lncRNA in the development of IBD. We found that allele-specific m6A methylation affects YTHDC1 mediated protein binding affinity.LOC339803-YTHDC1 interaction dictates chromatin localization ofLOC339803ultimately inducingIL1Band contributing to the development of intestinal inflammation. Our findings were confirmed using human intestinal biopsy samples from IBD and controls.

Overall, our results supportLOC339803lncRNA as an important mediator of intestinal inflammation, presenting this lncRNA as a potential novel therapeutic target for the treatment of IBD.