bluuebunny/crossref_metadata_2025 huggingface dataset:
A composition–decomposition based federated learning
Authors: Sun Chaoli , Wang Xiaojun , Ma Junwei , Xie Gang
Published: August 2023

Federated learning has been shown to be efficient for training a global model without needing to collect all data from multiple entities to the centralized server. However, the model performance, communication traffic, and data privacy and security are still the focus of federated learning after it has been developed. In this paper, a composition–decomposition based federated learning, denoted as CD-FL, is proposed. In the CD-FL approach, the global model, composed of K sub-models with the same framework, will be decomposed and broadcast to all clients. Each client will randomly choose a sub-model, update its parameters using its own dataset, and upload this sub-model to the server. All sub-models, including the sub-models before and after updating, will be clustered into K clusters to form the global model of the next round. Experimental results on Fashion-MNIST, CIFAR-10, EMNIST, and Tiny-IMAGENET datasets show the efficiency of the model performance and communication traffic of the proposed method.
Artificially applied late-terminal drought stress in the field differentially affects Ramularia leaf spot disease in winter barley
Authors: Hoheneder Felix , Groth Jennifer , Herz Markus , Hückelhoven Ralph
Published: August 2023

Ramularia leaf spot disease (RLS) is one of the most dominating fungal diseases in barley. The disease typically appears late in the season after flowering and results in a rapid loss of photosynthetic leaf area. A recent decline in fungicide efficacy and a lack of RLS-resistant cultivars hamper effective control. Global warming will provoke increasing droughts which influence host plant physiology and probably affect outbreak and severity of RLS. Relatively little is known about genetic resistance to RLS in winter barley and about the influence of various weather conditions and climate change on RLS pathogenesis. Hence, we evaluated severity of RLS on 15 winter barley genotypes under persistent late-terminal drought stress or controlled irrigation, respectively, in a field rainout shelter. Over three consecutive years, we observed reproducible differences in quantitative RLS field resistance of the used cultivars and variable suppression of RLS under drought. Our results support a function of drought in suppression of RLS in winter barley, but also reveal strong year effects even under semi-controlled rainout shelter conditions. Data may be relevant for genotype selection in breeding programmes for RLS resistance and for farmers in the frame of integrated disease management under a changing climate.

Graphical abstract
Die prämature Ovarialinsuffizienz
Authors: Anthon Christiane , Kohl Schwartz Alexandra
Published: August 2023

Die prämature Ovarialinsuffizienz (POI) bedeutet für die Patientin einen frühzeitigen Verlust der ovariellen Funktion mit den kurz- und langfristigen Folgen des Östrogenmangels sowie niedrigen Schwangerschaftschancen. Mit einer Prävalenz von 1 % tritt dieses Krankheitsbild selten auf, hat jedoch fatale Auswirkungen für die Betroffenen. Oft stellt sich anfangs die Erkenntnis um die schwierige Situation bezüglich des Kinderwunschs als sehr belastend dar. Im Verlauf haben die Patientinnen dann zunehmend mit den Langzeitfolgen des Östrogenmangels für die kardiovaskuläre, kognitive sowie Knochengesundheit zu kämpfen. Umso wichtiger ist es, die Erkrankung frühzeitig zu diagnostizieren und die Patientinnen adäquat zu behandeln.
Biological control of the fire blight pathogen Erwinia amylovora using bacteriophages
Authors: Gayder Steven , Kammerecker Sandrine , Fieseler Lars
Published: August 2023

Bacteriophages offer unique benefits for the specific control of Erwinia amylovora, the causative agent of fire blight in pome fruit. Unfortunately, the majority of described phages were tested for efficacy in vitro only. Data from infection assays using pear slices or detached blossoms is rare and field trials are barely reported. It remains to be studied if bacteriophages could control fire blight in the open field. This review summarizes current knowledge of different phages infecting E. amylovora. In addition, the requirements for a phage to optimally function as a biological antimicrobial agent in agriculture are discussed together with the ideal setup of field trials and the formulation of phages for best results.
Laparoscopic subtotal cholecystectomy by linear stapler: A simple and feasible technique for difficult cases with severe cholecystitis. A case series
Authors: Noda Keisuke , Kuroki Tamotsu
Published: August 2023

Abstract

Introduction

Laparoscopic subtotal cholecystectomy (LSC) is recognized as a safe, feasible alternative method for avoiding common bile duct injuries in ’difficult’ gallbladders. We describe the details of an LSC technique that uses a linear stapler with the reconstituting method for severe cholecystitis.

Methods

We retrospectively analyzed the cases of 19 Japanese patients diagnosed with acute cholecystitis who underwent LSC (Jan. 2017–Dec. 2020). In each patient, we first attempted to perform a standard laparoscopic cholecystectomy. Four trocars were inserted in all patients. When it was extremely difficult to expose and dissect the triangle of Calot or the neck of the gallbladder due to severe inflammation and fibrosis, an LSC was performed. The gallbladder was divided downward from the gallbladder fundus to the neck. We opened the gallbladder wall at the fundus and removed all gallstones with suction and saline flushing. The gallbladder was transected by a laparoscopic linear stapler.

Results

The median operation time was 166 min; intraoperative blood loss was 35 mL. One patient (5.3%) had minor bile leakage that promptly resolved after the transpapillary approach. The median postoperative hospital stay was 7 days.

Conclusion

Using a linear stapler to divide the gallbladder neck is a simple, feasible strategy for LSCs in difficult gallbladders.

Highlights
Economic Analysis of Property Rights
Authors: Barzel Yoram , Allen Douglas W.
Published: August 2023

The standard neoclassical model of economics is incapable of explaining why one form of organization arises over another. It is a model where transaction costs are implicitly assumed to not exist; however, transaction costs are here defined as the costs of strengthening a given distribution of economic property rights, and they always exist. Economic Analysis of Property Rights is a study of how individuals organise resources to maximise the value of their economic rights over these resources. It offers a unified theoretical structure to deal with exchange, rights formation, and organisation that traditional economic theory often ignores. It explains how transaction costs can be reduced through reorganization and, in the end, how the distribution of property rights that exists is the one that maximizes wealth net of these transaction costs. This necessary hypothesis explains much of the puzzling organizations and institutions that exist now and have existed in the past.
Limited evidence for structural balance in the family
Authors: Stein Jonas , Mandemakers Jornt , van de Rijt Arnout
Published: August 2023

Previous studies have shown that relationship sentiments in families follow a pattern wherein either all maintain positive relationships or there are two antagonistic factions. This result is consistent with the network theory of structural balance that individuals befriend their friends’ friend and become enemies with their friends’ enemies. Fault lines in families would then endogenously emerge through the same kinds of interactional processes that organize nations into axis and allies. We argue that observed patterns may instead exogenously come about as the result of personal characteristics or homophilous partitions of family members. Disentangling these alternate theoretical possibilities requires longitudinal data. The present study tracks the sentiment dynamics of 1,710 families in a longitudinal panel study. Results show the same static patterns suggestive of balancing processes identified in earlier research, yet dynamic analysis reveals that conflict in families is not generated or resolved in accordance with balance theory.
Does issue importance attenuate partisan cue-taking?
Authors: Barber Michael , Pope Jeremy C.
Published: August 2023

Are cues from party leaders so important that they can cause individuals to change their own issue positions to align with the party's position? Recent work on the importance of party cues suggests they do, especially given the literature on partisanship as a strong and persistent group identity. However, in this paper we test the limits of those partisan cues. Using a unique two-wave panel survey design we find that the effect of party cues is moderated by the prior level of importance individuals place on an issue. We find that when a person believes an issue area to be more important, party cues are less likely to move that citizen's position, particularly when the cue goes against partisan ideological norms. Our results show evidence that an individual's own issue positions—at least the important ones—can be resilient in the face of party cues.
Prevalence and predictors of vitamin D insufficiency in Brazilian children under 5 years of age: Brazilian National Survey on Child Nutrition (ENANI-2019)
Authors: Normando Paula , de Castro Inês Rugani Ribeiro , Bezerra Flávia Fioruci , Berti Talita Lelis , Bertoni Neilane , Lacerda Elisa Maria de Aquino , Alves-Santos Nadya Helena , de Freitas Maiara Brusco , Kac Gilberto
Published: August 2023

To analyse the association of socio-demographic and health factors with vitamin D insufficiency and 25-hydroxyvitamin D (25(OH)D) concentration in Brazilian children aged 6–59 months. Data from 8145 children from the Brazilian National Survey on Child Nutrition (ENANI-2019) were analysed. The serum concentration of 25(OHD)D was measured using a chemiluminescent immunoassay. The prevalence of vitamin D insufficiency (25(OH)D < 50 nmol/l) and 95 % CI was calculated. Logistic and linear regression models were used to identify the variables associated with vitamin D insufficiency and serum 25(OH)D concentrations, respectively. The mean 25(OH)D concentration was 98·6 ± 36·0 nmol/l, and 4·3 % of the children presented vitamin D insufficiency. Children aged 6–23 months (OR = 2·23; 95 % CI 1·52, 3·26); belonging to Southeast (OR = 5·55; 95 % CI 2·34, 13·17) and South (OR = 4·57; 95 % CI 1·77, 11·84) regions; the second tertile of the National Wealth Score (OR = 2·14; 95 % CI 1·16, 3·91) and winter (OR = 5·82; 95 % CI 2·67, 12·71) and spring (OR = 4·84; 95 % CI 2·17, 10·80) seasons of blood collection were associated with a higher chance of vitamin D insufficiency. Female sex (β = −5·66, 95 % CI − 7·81, −3·51), urban location (β = −14·19, 95 % CI −21·0, −7·22) and no vitamin D supplement use (β = −6·01, 95 % CI −9·64, −2·39) were inversely associated with serum 25(OH)D concentration. The age of children and the Brazilian geographical region of household location were the main predictors of vitamin D insufficiency. In Brazil, vitamin D insufficiency among children aged 6–59 months is low and is not a relevant public health problem.
Cultural Change and Philosophy
Authors: Keum Tae-Yeoun
Published: August 2023

The Shadow of God is a magisterial achievement. In that vein, readers may find it especially opportune that this is a book about the concept of immortality—though, in line with the more dynamic picture it presents of our ideas about immortality in shifting cultural landscapes, I make the more modest, though no less impressive, suggestion that this book will stay with students of German Idealism and of political theory at large for a very long time to come.
The “Black sheep” of the early Daoxue community: the making of Xing Shu's historical image
Authors: Cheung Hiu Yu
Published: August 2023

By focusing on a controversial figure in Northern Song China (960–1127), namely Xing Shu 邢恕, this paper traces the historiographical construction of particular scholar-officials in Chinese historical accounts. Xing Shu, one of the best students of the Daoxue 道學 master Cheng Yi 程頤 (1033–1107), was depicted in most historical writings as a betrayer of his teacher and a political opportunist, including in his biography in the official Song dynastic history. This article demonstrates how the testimonies of Xing Shu's contemporaries offered rich materials for the construction of his treacherous character in later written records. Through a careful examination of these testimonies, the article reveals various historiographical operations through which contemporary testimonies were modified and transformed into seemingly reliable documents of historical figures and thus passed to later generations.
THE THOMAS ASHBY PHOTOGRAPHIC ARCHIVE: A PRIVATE ARCHIVE NOW IN THE PUBLIC DOMAIN
Authors: Giovenco Alessandra , Wade Janet
Published: August 2023

The prints, negatives and albums in the British School at Rome's Thomas Ashby Photographic Archive are a rich assortment of materials created by Ashby and his colleagues, such as Agnes and Dora Bulwer. The archive was the natural and spontaneous product of Ashby's personal and working life and it was not until after his death that it was transferred into the public institutional domain. This article investigates the original intention of Ashby's archive, its transfer from a private to public context, and its subsequent evolution and reception. Building on the work of previous BSR staff and scholars, the article looks at Ashby's archive from a fresh perspective, emphasizing the need to consider the archive's original non-public authorial intent, its polyphonic elements, and the diachronic nature of its formation and reception from Ashby's time to the present. Given that images within photographic archives are now regularly viewed as digital objects, this is a timely discussion of the nature of private photographic archives that have been moved into the public domain. It is now more important than ever that archives like Ashby's are acknowledged as entities with detailed and complex histories, and that these histories are taken into account when viewing the individual photographs within the archive.
Does exposure to democracy decrease health inequality?
Authors: Costa-Font Joan , Knust Niklas
Published: August 2023

Exposure to (a liberal) democracy can have an impact on both the political attention and visibility of the needs of marginalized populations, as well as the design of health policies that can influence the distribution of population health. This paper investigates the effect of exposure to democracy, that is, the number of years spent in a democracy as measured by democracy indexes, on various measures of inequality in self-reported health across European countries. We use an instrumental variable strategy to leverage the potential endogeneity of a country’s exposure to democracy, drawing on both bivariate (socioeconomic) and univariate health inequality measures. Our estimates provide evidence that an additional year in a democracy reduces both bivariate (income-related) health inequality and overall (univariate) health inequality. Our preferred specification suggests a two-point rank reduction in inequality with an additional year under a democracy. The effect is mainly driven by a reduction of “health poverty” alongside other effects.
A knowledge-enabled approach for user experience-driven product improvement at the conceptual design stage
Authors: Li Jun , Guo Xin , Zhang Kai , Zhao Wu
Published: August 2023

Improving existing products plays a vital role in enhancing customer satisfaction and coping with changes in the market. Analyzing user experience (UX) to find the deficiencies of existing products and establishing improved schemes is the key to UX-driven product improvement, especially at the conceptual design stage. Although some tools used in conceptual design, such as requirements analysis and knowledge reasoning, have advanced recently, they lack targeted goals and sufficient efficiency in identifying insufficient product attributes and improving existing functions and structures. The challenge lies in considering the influence imposed on design activities by the original product features (including attributes, functions, and structure). In this study, a knowledge-enabled approach and framework that integrates the conceptual design process, online reviews for UX, and knowledge is proposed to support product improvement. Specifically, a decision-making algorithm based on UX analysis is proposed to identify to-be-improved product attributes. Then, through optimizing the previous knowledge application model from knowledge requirement transformation, knowledge modeling, and knowledge reasoning, a smart knowledge reasoning model is established to push knowledge for functional solving of the to-be-improved attributes. A knowledge configuration method is used to modify product features to generate an improved scheme. To demonstrate the feasibility of the proposed approach, a case study of improving an agricultural sprayer is conducted. Through discussion, this study can help to regulate design activities for product improvement, enhance data and knowledge application, and promote divergent thinking during scheme modification.
Transboundary Rainfall Estimation Using Commercial Microwave Links
Authors: Blettner Nico , Fencl Martin , Bareš Vojtěch , Kunstmann Harald , Chwala Christian
Published: August 2023

Unlike actual rainfall, the spatial extent of rainfall maps is often determined by administrative and political boundaries. Similarly, data from commercial microwave links (CMLs) is usually acquired on a national basis and exchange among countries is limited. Up to now, this has prohibited the generation of transboundary CML‐based rainfall maps despite the great extension of networks across the world. We present CML based transboundary rainfall maps for the first time, using independent CML data sets from Germany and the Czech Republic. We show that straightforward algorithms used for quality control strongly reduce anomalies in the results. We find that, after quality control, CML‐based rainfall maps can be generated via joint and consistent processing, and that these maps allow to seamlessly visualize rainfall events traversing the German‐Czech border. This demonstrates that quality control represents a crucial step for large‐scale (e.g., continental) CML‐based rainfall estimation.
The Art of Promoting Scientific Results
Authors: Micucci Chris , Wooden Paige , Lunn Jenny
Published: August 2023

AGU has various avenues for promoting noteworthy research published in our journals and books, which increases visibility, downloads, and citations.
Renaissance for magnetotactic bacteria in astrobiology
Authors: Shen Jianxun , Paterson Greig A , Wang Yinzhao , Kirschvink Joseph L , Pan Yongxin , Lin Wei
Published: August 2023

Capable of forming magnetofossils similar to some magnetite nanocrystals observed in the Martian meteorite ALH84001, magnetotactic bacteria (MTB) once occupied a special position in the field of astrobiology during the 1990s and 2000s. This flourish of interest in putative Martian magnetofossils faded from all but the experts studying magnetosome formation, based on claims that abiotic processes could produce magnetosome-like magnetite crystals. Recently, the rapid growth in our knowledge of the extreme environments in which MTB thrive and their phylogenic heritage, leads us to advocate for a renaissance of MTB in astrobiology. In recent decades, magnetotactic members have been discovered alive in natural extreme environments with wide ranges of salinity (up to 90 g L−1), pH (1–10), and temperature (0–70 °C). Additionally, some MTB populations are found to be able to survive irradiated, desiccated, metal-rich, hypomagnetic, or microgravity conditions, and are capable of utilizing simple inorganic compounds such as sulfate and nitrate. Moreover, MTB likely emerged quite early in Earth’s history, coinciding with a period when the Martian surface was covered with liquid water as well as a strong magnetic field. MTB are commonly discovered in suboxic or oxic-anoxic interfaces in aquatic environments or sediments similar to ancient crater lakes on Mars, such as Gale crater and Jezero crater. Taken together, MTB can be exemplary model microorganisms in astrobiology research, and putative ancient Martian life, if it ever occurred, could plausibly have included magnetotactic microorganisms. Furthermore, we summarize multiple typical biosignatures that can be applied for the detection of ancient MTB on Earth and extraterrestrial MTB-like life. We suggest transporting MTB to space stations and simulation chambers to further investigate their tolerance potential and distinctive biosignatures to aid in understanding the evolutionary history of MTB and the potential of magnetofossils as an extraterrestrial biomarker.
TRIM26 inhibited osteosarcoma progression through destabilizing RACK1 and thus inactivation of MEK/ERK signaling
Authors: Xia Kezhou , Zheng Di , Wei Zhun , Liu Wenda , Guo Weichun
Published: August 2023

Osteosarcoma is a highly aggressive malignant tumor that is common in the pediatric population and has a high rate of disability and mortality. Recent studies have suggested that the tripartite motif-containing family genes (TRIMs) play critical roles in oncogenesis in several cancers. TRIM26, one of the TRIMs family genes, was more frequently reported to exert a tumor-suppressive role, while its detailed functional roles in the osteosarcoma progression were still unknown and require further investigation. Herein, we found that TRIM26 was markedly downregulated in osteosarcoma tissues and cells. Survival analysis revealed that higher expression of TRIM26 was associated with better prognosis and its expression was an independent protective factor in osteosarcoma. Functional analysis demonstrated that overexpression of TRIM26 inhibited osteosarcoma cell proliferation and invasion via inhibiting the EMT process and MEK/ERK signaling. In contrast, the silence of TRIM26 caused the opposite effect. RACK1, a member of the Trp-Asp repeat protein family, was identified as a novel target of TRIM26. TRIM26 could interact with RACK1 and accelerate the degradation of RACK1, thus inactivation of MEK/ERK signaling. Overexpression of RACK1 could attenuate the inhibitory effect of TRIM26 overexpression on p-MEK1/2 and p-ERK1/2, and silence of RACK1 could partly impair the effect of TRIM26 knockdown-induced upregulation of p-MEK1/2 and p-ERK1/2. Further, a series of gain- and loss-of-function experiments showed that decreased malignant behaviors including cell proliferation and invasion in TRIM26-upregulated cells were reversed when RACK1 was overexpressed, whereas RACK1 knockdown diminished the increased malignant phenotypes in TRIM26-silenced osteosarcoma cells. In conclusion, our study indicated that TRIM26 inhibited osteosarcoma progression via promoting proteasomal degradation of RACK1, thereby resulting in inactivation of MEK/ERK signaling, and impeding the EMT process.
MenT nucleotidyltransferase toxins extend tRNA acceptor stems and can be inhibited by asymmetrical antitoxin binding
Authors: Xu Xibing , Usher Ben , Gutierrez Claude , Barriot Roland , Arrowsmith Tom J. , Han Xue , Redder Peter , Neyrolles Olivier , Blower Tim R. , Genevaux Pierre
Published: August 2023

Mycobacterium tuberculosis, the bacterium responsible for human tuberculosis, has a genome encoding a remarkably high number of toxin-antitoxin systems of largely unknown function. We have recently shown that the M. tuberculosis genome encodes four of a widespread, MenAT family of nucleotidyltransferase toxin-antitoxin systems. In this study we characterize MenAT1, using tRNA sequencing to demonstrate MenT1 tRNA modification activity. MenT1 activity is blocked by MenA1, a short protein antitoxin unrelated to the MenA3 kinase. X-ray crystallographic analysis shows blockage of the conserved MenT fold by asymmetric binding of MenA1 across two MenT1 protomers, forming a heterotrimeric toxin-antitoxin complex. Finally, we also demonstrate tRNA modification by toxin MenT4, indicating conserved activity across the MenT family. Our study highlights variation in tRNA target preferences by MenT toxins, selective use of nucleotide substrates, and diverse modes of MenA antitoxin activity.
Single-cell genomics improves the discovery of risk variants and genes of atrial fibrillation
Authors: Selewa Alan , Luo Kaixuan , Wasney Michael , Smith Linsin , Sun Xiaotong , Tang Chenwei , Eckart Heather , Moskowitz Ivan P. , Basu Anindita , He Xin , Pott Sebastian
Published: August 2023

Genome-wide association studies (GWAS) have linked hundreds of loci to cardiac diseases. However, in most loci the causal variants and their target genes remain unknown. We developed a combined experimental and analytical approach that integrates single cell epigenomics with GWAS to prioritize risk variants and genes. We profiled accessible chromatin in single cells obtained from human hearts and leveraged the data to study genetics of Atrial Fibrillation (AF), the most common cardiac arrhythmia. Enrichment analysis of AF risk variants using cell-type-resolved open chromatin regions (OCRs) implicated cardiomyocytes as the main mediator of AF risk. We then performed statistical fine-mapping, leveraging the information in OCRs, and identified putative causal variants in 122 AF-associated loci. Taking advantage of the fine-mapping results, our novel statistical procedure for gene discovery prioritized 46 high-confidence risk genes, highlighting transcription factors and signal transduction pathways important for heart development. In summary, our analysis provides a comprehensive map of AF risk variants and genes, and a general framework to integrate single-cell genomics with genetic studies of complex traits.
Combinatorial expression of neurexins and LAR-type phosphotyrosine phosphatase receptors instructs assembly of a cerebellar circuit
Authors: Sclip Alessandra , Südhof Thomas C.
Published: August 2023

Synaptic adhesion molecules (SAMs) shape the structural and functional properties of synapses and thereby control the information processing power of neural circuits. SAMs are broadly expressed in the brain, suggesting that they may instruct synapse formation and specification via a combinatorial logic. Here, we generate sextuple conditional knockout mice targeting all members of the two major families of presynaptic SAMs, Neurexins and leukocyte common antigen-related-type receptor phospho-tyrosine phosphatases (LAR-PTPRs), which together account for the majority of known trans-synaptic complexes. Using synapses formed by cerebellar Purkinje cells onto deep cerebellar nuclei as a model system, we confirm that Neurexins and LAR-PTPRs themselves are not essential for synapse assembly. The combinatorial deletion of both neurexins and LAR-PTPRs, however, decreases Purkinje-cell synapses on deep cerebellar nuclei, the major output pathway of cerebellar circuits. Consistent with this finding, combined but not separate deletions of neurexins and LAR-PTPRs impair motor behaviors. Thus, Neurexins and LAR-PTPRs are together required for the assembly of a functional cerebellar circuit.
A deep learning method for replicate-based analysis of chromosome conformation contacts using Siamese neural networks
Authors: Al-jibury Ediem , King James W. D. , Guo Ya , Lenhard Boris , Fisher Amanda G. , Merkenschlager Matthias , Rueckert Daniel
Published: August 2023

The organisation of the genome in nuclear space is an important frontier of biology. Chromosome conformation capture methods such as Hi-C and Micro-C produce genome-wide chromatin contact maps that provide rich data containing quantitative and qualitative information about genome architecture. Most conventional approaches to genome-wide chromosome conformation capture data are limited to the analysis of pre-defined features, and may therefore miss important biological information. One constraint is that biologically important features can be masked by high levels of technical noise in the data. Here we introduce a replicate-based method for deep learning from chromatin conformation contact maps. Using a Siamese network configuration our approach learns to distinguish technical noise from biological variation and outperforms image similarity metrics across a range of biological systems. The features extracted from Hi-C maps after perturbation of cohesin and CTCF reflect the distinct biological functions of cohesin and CTCF in the formation of domains and boundaries, respectively. The learnt distance metrics are biologically meaningful, as they mirror the density of cohesin and CTCF binding. These properties make our method a powerful tool for the exploration of chromosome conformation capture data, such as Hi-C capture Hi-C, and Micro-C.
Gabapentinoid consumption in 65 countries and regions from 2008 to 2018: a longitudinal trend study
Authors: Chan Adrienne Y. L. , Yuen Andrew S. C. , Tsai Daniel H. T. , Lau Wallis C. Y. , Jani Yogini H. , Hsia Yingfen , Osborn David P. J. , Hayes Joseph F. , Besag Frank M. C. , Lai Edward C. C. , Wei Li , Taxis Katja , Wong Ian C. K. , Man Kenneth K. C.
Published: August 2023

Recent studies raised concerns about the increasing use of gabapentinoids in different countries. With their potential for misuse and addiction, understanding the global consumption of gabapentinoids will offer us a platform to examine the need for any interventional policies. This longitudinal trend study utilised pharmaceutical sales data from 65 countries and regions across the world to evaluate the global trends in gabapentinoid consumption between 2008-2018. The multinational average annual percentage change of gabapentinoid consumption was +17.20%, increased from 4.17 defined daily dose per ten thousand inhabitants per day (DDD/TID) in 2008 to 18.26 DDD/TID in 2018. High-income countries had the highest pooled gabapentinoid consumption rate (39.92 DDD/TID) in 2018, which was more than six times higher than the lower-middle income countries (6.11 DDD/TID). The study shows that despite differences in healthcare system and culture, a consistent increase in gabapentinoid consumption is observed worldwide, with high-income countries remaining the largest consumers.
Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis
Authors: Mandrioli Jessica , D’Amico Roberto , Zucchi Elisabetta , De Biasi Sara , Banchelli Federico , Martinelli Ilaria , Simonini Cecilia , Lo Tartaro Domenico , Vicini Roberto , Fini Nicola , Gianferrari Giulia , Pinti Marcello , Lunetta Christian , Gerardi Francesca , Tarlarini Claudia , Mazzini Letizia , De Marchi Fabiola , Scognamiglio Ada , Sorarù Gianni , Fortuna Andrea , Lauria Giuseppe , Bella Eleonora Dalla , Caponnetto Claudia , Meo Giuseppe , Chio Adriano , Calvo Andrea , Cossarizza Andrea
Published: August 2023

In preclinical studies rapamycin was found to target neuroinflammation, by expanding regulatory T cells, and affecting autophagy, two pillars of amyotrophic lateral sclerosis (ALS) pathogenesis. Herein we report a multicenter, randomized, double-blind trial, in 63 ALS patients who were randomly assigned in a 1:1:1 ratio to receive rapamycin 2 mg/m2/day,1 mg/m2/day or placebo (EUDRACT 2016-002399-28; NCT03359538). The primary outcome, the number of patients exhibiting an increase >30% in regulatory T cells from baseline to treatment end, was not attained. Secondary outcomes were changes from baseline of T, B, NK cell subpopulations, inflammasome mRNA expression and activation status, S6-ribosomal protein phosphorylation, neurofilaments; clinical outcome measures of disease progression; survival; safety and quality of life. Of the secondary outcomes, rapamycin decreased mRNA relative expression of the pro-inflammatory cytokine IL-18, reduced plasmatic IL-18 protein, and increased the percentage of classical monocytes and memory switched B cells, although no corrections were applied for multiple tests. In conclusion, we show that rapamycin treatment is well tolerated and provides reassuring safety findings in ALS patients, but further trials are necessary to understand the biological and clinical effects of this drug in ALS.
Genomic analysis and clinical correlations of non-small cell lung cancer brain metastasis
Authors: Skakodub Anna , Walch Henry , Tringale Kathryn R. , Eichholz Jordan , Imber Brandon S. , Vasudevan Harish N. , Li Bob T. , Moss Nelson S. , Hei Yu Kenny Kwok , Mueller Boris A. , Powell Simon , Razavi Pedram , Yu Helena A. , Reis-Filho Jorge S. , Gomez Daniel , Schultz Nikolaus , Pike Luke R. G.
Published: August 2023

Up to 50% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), yet the study of BM genomics has been limited by tissue access, incomplete clinical data, and a lack of comparison with paired extracranial specimens. Here we report a cohort of 233 patients with resected and sequenced (MSK-IMPACT) NSCLC BM and comprehensive clinical data. With matched samples (47 primary tumor, 42 extracranial metastatic), we show CDKN2A/B deletions and cell cycle pathway alterations to be enriched in the BM samples. Meaningful clinico-genomic correlations are noted, namely EGFR alterations in leptomeningeal disease (LMD) and MYC amplifications in multifocal regional brain progression. Patients who developed early LMD frequently have had uncommon, multiple, and persistently detectable EGFR driver mutations. The distinct mutational patterns identified in BM specimens compared to other tissue sites suggest specific biologic underpinnings of intracranial progression.
A critical role of a eubiotic microbiota in gating proper immunocompetence in Arabidopsis
Authors: Paasch Bradley C. , Sohrabi Reza , Kremer James M. , Nomura Kinya , Cheng Yu Ti , Martz Jennifer , Kvitko Brian , Tiedje James M. , He Sheng Yang
Published: August 2023

Although many studies have shown that microbes can ectopically stimulate or suppress plant immune responses, the fundamental question of whether the entire preexisting microbiota is indeed required for proper development of plant immune response remains unanswered. Using a recently developed peat-based gnotobiotic plant growth system, we found that Arabidopsis grown in the absence of a natural microbiota lacked age-dependent maturation of plant immune response and were defective in several aspects of pattern-triggered immunity. Axenic plants exhibited hypersusceptibility to infection by the bacterial pathogen Pseudomonas syringae pv. tomato DC3000 and the fungal pathogen Botrytis cinerea. Microbiota-mediated immunocompetence was suppressed by rich nutrient conditions, indicating a tripartite interaction between the host, microbiota and abiotic environment. A synthetic microbiota composed of 48 culturable bacterial strains from the leaf endosphere of healthy Arabidopsis plants was able to substantially restore immunocompetence similar to plants inoculated with a soil-derived community. In contrast, a 52-member dysbiotic synthetic leaf microbiota overstimulated the immune transcriptome. Together, these results provide evidence for a causal role of a eubiotic microbiota in gating proper immunocompetence and age-dependent immunity in plants.
Unconventional room-temperature carriers in the triangular-lattice Mott insulator TbInO3
Authors: Jung Taek Sun , Xu Xianghan , Kim Jaewook , Kim Beom Hyun , Shin Hyun Jun , Choi Young Jai , Moon Eun-Gook , Cheong Sang-Wook , Kim Jae Hoon
Published: August 2023

The strong correlations between electrons in Mott insulator materials may produce highly entangled many-body states with unconventional emergent excitations. The signatures of such excitations, if any, are commonly believed to be observable only at low temperatures. Here, we challenge this common belief and show using terahertz time-domain spectroscopy that exotic carriers exist even at room temperature in TbInO3, a candidate material for realizing a low-temperature quantum spin-liquid phase. In particular, over the entire temperature range of 1.5–300 K, we observe a quadratic frequency dependence in the real part of the in-plane optical conductivity as well as Fano asymmetry of an optical phonon mode strongly interacting with the excitation continuum. These features are robust even under external magnetic fields of up to 7 T. Our data confirm the presence of emergent charge carriers within the Mott charge gap of TbInO3, suggesting that it is possible to probe and manipulate highly entangled quantum many-body states at room temperature.
Alignment of spatial genomics data using deep Gaussian processes
Authors: Jones Andrew , Townes F. William , Li Didong , Engelhardt Barbara E.
Published: August 2023

Spatially resolved genomic technologies have allowed us to study the physical organization of cells and tissues, and promise an understanding of local interactions between cells. However, it remains difficult to precisely align spatial observations across slices, samples, scales, individuals and technologies. Here, we propose a probabilistic model that aligns spatially-resolved samples onto a known or unknown common coordinate system (CCS) with respect to phenotypic readouts (for example, gene expression). Our method, Gaussian Process Spatial Alignment (GPSA), consists of a two-layer Gaussian process: the first layer maps observed samples’ spatial locations onto a CCS, and the second layer maps from the CCS to the observed readouts. Our approach enables complex downstream spatially aware analyses that are impossible or inaccurate with unaligned data, including an analysis of variance, creation of a dense three-dimensional (3D) atlas from sparse two-dimensional (2D) slices or association tests across data modalities.
Distortion of Mendelian segregation across the Angus cattle genome uncovering regions affecting reproduction
Authors: Id-Lahoucine S. , Casellas J. , Lu D. , Sargolzaei M. , Miller S. , Cánovas A.
Published: August 2023

Nowadays, the availability of genotyped trios (sire-dam-offspring) in the livestock industry enables the implementation of the transmission ratio distortion (TRD) approach to discover deleterious alleles in the genome. Various biological mechanisms at different stages of the reproductive cycle such as gametogenesis, embryo development and postnatal viability can induce signals of TRD (i.e., deviation from Mendelian inheritance expectations). In this study, TRD was evaluated using both SNP-by-SNP and sliding windows of 2-, 4-, 7-, 10- and 20-SNP across 92,942 autosomal SNPs for 258,140 genotyped Angus cattle including 7,486 sires, 72,688 dams and 205,966 offspring. Transmission ratio distortion was characterized using allelic (specific- and unspecific-parent TRD) and genotypic parameterizations (additive- and dominance-TRD). Across the Angus autosomal chromosomes, 851 regions were clearly found with decisive evidence for TRD. Among these findings, 19 haplotypes with recessive patterns (potential lethality for homozygote individuals) and 52 regions with allelic patterns exhibiting complete or quasi-complete absence for homozygous individuals in addition to under-representation (potentially reduced viability) of the carrier (heterozygous) offspring were found. In addition, 64 (12) and 20 (4) regions showed significant influence on the trait heifer pregnancy at p-value < 0.05 (after chromosome-wise false discovery rate) and 0.01, respectively, reducing the pregnancy rate up to 15%, thus, supporting the biological importance of TRD phenomenon in reproduction.
Investigating the effects of vaccine on COVID-19 disease propagation using a Bayesian approach
Authors: Ling Lu , Ukkusuri Satish V.
Published: August 2023

The causal impact of COVID-19 vaccine coverage on effective reproduction number R(t) under the disease control measures in the real-world scenario is understudied, making the optimal reopening strategy (e.g., when and which control measures are supposed to be conducted) during the recovery phase difficult to design. In this study, we examine the demographic heterogeneity and time variation of the vaccine effect on disease propagation based on the Bayesian structural time series analysis. Furthermore, we explore the role of non-pharmaceutical interventions (NPIs) and the entrance of the Delta variant of COVID-19 in the vaccine effect for U.S. counties. The analysis highlights several important findings: First, vaccine effects vary among the age-specific population and population densities. The vaccine effect for areas with high population density or core airport hubs is 2 times higher than for areas with low population density. Besides, areas with more older people need a high vaccine coverage to help them against the more contagious variants (e.g., the Delta variant). Second, the business restriction policy and mask requirement are more effective in preventing COVID-19 infections than other NPI measures (e.g., bar closure, gather ban, and restaurant restrictions) for areas with high population density and core airport hubs. Furthermore, the mask requirement consistently amplifies the vaccine effects against disease propagation after the presence of contagious variants. Third, areas with a high percentage of older people are suggested to postpone relaxing the restaurant restriction or gather ban since they amplify the vaccine effect against disease infections. Such empirical insights assist recovery phases of the pandemic in designing more efficient reopening strategies, vaccine prioritization, and allocation policies.
Ni2+ and Cu2+ complexes of N-(2,6-dichlorophenyl)-N-mesityl formamidine dithiocarbamate structural and functional properties as CYP3A4 potential substrates
Authors: Oladipo Segun D. , Zamisa Sizwe J. , Badeji Abosede A. , Ejalonibu Murtala A. , Adeleke Adesola A. , Lawal Isiaka A. , Henni Amr , Lawal Monsurat M.
Published: August 2023

Metal compounds continued to attract diverse applications due to their malleability in several capacities. In this study, we present our findings on the crystal structures and functional properties of Ni2+ and Cu2+ complexes of N'-(2,6-dichlorophenyl)-N-mesitylformamidine dithiocarbamate (L) comprising [Ni-(L)2] (1) and [Cu-(L)2] (2) with a four-coordinate metal center. We established the two complex structures through 1H and 13C nuclear magnetic resonance (NMR), elemental, and single-crystal X-ray analysis. The analyses showed that the two complexes are isomorphous, having P21/c as a space group and a unit-cell similarity index (π) of 0.002. The two complexes conform to a distorted square planar geometry around the metal centers. The calculated and experimental data, including bond lengths, angles, and NMR values, are similar. Hirshfeld surface analysis revealed the variational contribution of the different types of intermolecular contacts driven by the crystal lattice of the two solvated complexes. Our knowledge of the potential biological implication of these structures enabled us to probe the compounds as prospective CYP3A4 inhibitors. This approach mimics current trends in pharmaceutical design and biomedicine by incorporating potentially active molecules into various media to predict their biological efficacies. The simulations show appreciable binding of compounds 1 and 2 to CYP3A4 with average interaction energies of –97 and –87 kcal/mol, respectively. The protein attains at least five conformational states in the three studied models using a Gaussian Mixture Model-based clustering and free energy prediction. Electric field analysis shows the crucial residues to substrate binding at the active site, enabling CYP3A4 structure to function prediction. The predicted inhibition with these Ni2+ and Cu2+ complexes indicates that CYP3A4 overexpression in a diseased state like cancer would reduce, thereby increasing the chemotherapeutic compounds' shelf-lives for adsorption. This multidimensional study addresses various aspects of molecular metal electronics, including their application as substrate-mimicking inhibitors. The outcome would enable further research on bio-metal compounds of critical potential.
Improvement in OCD symptoms associated with serotoninergic psychedelics: a retrospective online survey
Authors: Buot Anne , Pallares Cecile , Oganesyan Alina , Dauré Charles , Bonnelle Valérie , Burguière Eric , Dos Santos Joao Flores Alves , N’Diaye Karim , Ljuslin Michael , Smith Pauline , Verroust Vincent , Wyplosz Benjamin , Morgiève Margot , Mallet Luc
Published: August 2023

A renewed interest in the use of psychedelics for treating obsessive compulsive disorder (OCD) has emerged in the last 20 years. But pre-clinical and clinical evidence remain scarce, and little is known about the factor determining the magnitude and persistence of the therapeutic effect. We therefore designed a retrospective online survey to explore, in the general population using psychoactive drugs, their impact on OCD symptoms. We also assessed the attitude of the participants towards the substance in term of frequency of intakes. In a sample of 174 participants, classic psychedelics were reported as the only substances effective at reducing OCD symptoms. In classic psychedelics users, symptoms reduction was associated with the intensity of acute effects, itself correlated to the dose. Reports on the persistence of the therapeutic effect varied from weeks to months, but we could not find any predicting factor. Finally, the occurrence and frequency of subsequent intakes, which seemed to be limited in our sample, were predicted by the magnitude and persistence of the therapeutic effect, respectively. Our observations support the hypothesis of classic psychedelics efficacy in reducing OCD symptoms but a careful evaluation of the persistence of this effect is still needed.
Strength prediction model of fractured dolomite and analysis of mechanical properties based on PFC3D
Authors: Chen Yi , Rao Junying , Zhao Changjie , Xue Yanghao , Liu Chang , Yin Quan
Published: August 2023

To investigate the mechanical properties of fractured dolomite, this study analyzed the fracture characteristics (dip angle, length, position, quantity) using the Pearson coefficient and MIC coefficient. Subsequently, the data pertaining to fracture characteristics is preprocessed using a third-degree polynomial, and a three-classification strategy is implemented to improve the logistic regression algorithm to establish the strength prediction model of fractured dolomite. Furthermore, the significance order of the impact of fracture characteristics on rock strength was determined using the numerical simulation software PFC3D, and the dip angle effect was explained from the perspective of internal fracture propagation within the rock. The results show that: (1) When the regularization coefficient λ = 10,000, the algorithm has the highest prediction accuracy and the strongest model generalization ability. (2) The numerical simulation analysis software PFC3D can accurately invert rock failure process and characteristics, and the order of influence of fracture characteristics on rock strength is dip angle > length > position.