bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of caffeine consumption behavior with plasma caffeine levels as exposure measures in drug-target mendelian randomization
Authors: Woolf Benjamin , Cronjé Héléne T , Zagkos Loukas , Larsson Susanna C , Gill Dipender , Burgess Stephen
Published: June 2024

Mendelian randomization is an epidemiologic technique that can explore the potential effect of perturbing a pharmacological target. Plasma caffeine levels can be used as a biomarker to measure the pharmacological effects of caffeine. Alternatively, this can be assessed using a behavioral proxy, such as average number of caffeinated drinks consumed per day. Either variable can be used as the exposure in a Mendelian randomization investigation, and to select which genetic variants to use as instrumental variables. Another possibility is to choose variants in gene regions with known biological relevance to caffeine level regulation. These choices affect the causal question that is being addressed by the analysis, and the validity of the analysis assumptions. Further, even when using the same genetic variants, the sign of Mendelian randomization estimates (positive or negative) can change depending on the choice of exposure. Some genetic variants that decrease caffeine metabolism associate with higher levels of plasma caffeine, but lower levels of caffeine consumption, as individuals with these variants require less caffeine consumption for the same physiological effect. We explore Mendelian randomization estimates for the effect of caffeine on body mass index, and discuss implications for variant and exposure choice in drug target Mendelian randomization investigations.
Simple graphical rules for assessing selection bias in general-population and selected-sample treatment effects
Authors: Mathur Maya B , Shpitser Ilya
Published: June 2024

When analyzing a selected sample from a general population, selection bias can arise relative to the causal average treatment effect (ATE) for the general population, and also relative to the ATE for the selected sample itself. In this paper, we provide simple graphical rules that indicate (1) whether a selected-sample analysis will be unbiased for each ATE and (2) whether adjusting for certain covariates could eliminate selection bias. The rules can easily be checked in a standard single-world intervention graph. When the treatment could affect selection, a third estimand of potential scientific interest is the “net treatment difference”—namely the net change in outcomes that would occur for the selected sample if all members of the general population were treated versus not treated, including any effects of the treatment on which individuals are in the selected sample. We provide graphical rules for this estimand as well. We decompose bias in a selected-sample analysis relative to the general-population ATE into (1) “internal bias” relative to the net treatment difference and (2) “net-external bias,” a discrepancy between the net treatment difference and the general-population ATE. Each bias can be assessed unambiguously via a distinct graphical rule, providing new conceptual insight into the mechanisms by which certain causal structures produce selection bias.
Making proteomics accessible: Rokai
Xplorer for interactive analysis of phospho-proteomic data
Authors: Yılmaz Serhan , Blasco Tavares Pereira Lopes Filipa , Schlatzer Daniela , Ayati Marzieh , Chance Mark R , Koyutürk Mehmet
Published: June 2024

We present RokaiXplorer, an intuitive web tool designed to address the scarcity of user-friendly solutions for proteomics and phospho-proteomics data analysis and visualization. RokaiXplorer streamlines data processing, analysis, and visualization through an interactive online interface, making it accessible to researchers without specialized training in proteomics or data science. With its comprehensive suite of modules, RokaiXplorer facilitates phospho-proteomic analysis at the level of phosphosites, proteins, kinases, biological processes, and pathways. The tool offers functionalities such as data normalization, statistical testing, activity inference, pathway enrichment, subgroup analysis, automated report generation, and multiple visualizations, including volcano plots, bar plots, heat maps, and network views. As a unique feature, RokaiXplorer allows researchers to effortlessly deploy their own data browsers, enabling interactive sharing of research data and findings. Overall, RokaiXplorer fills an important gap in phospho-proteomic data analysis by providing the ability to comprehensively analyze data at multiple levels within a single application.

Availability and implementation

Access RokaiXplorer at: http://explorer.rokai.io.
DDN3.0: determining significant rewiring of biological network structure with differential dependency networks
Authors: Fu Yi , Lu Yingzhou , Wang Yizhi , Zhang Bai , Zhang Zhen , Yu Guoqiang , Liu Chunyu , Clarke Robert , Herrington David M , Wang Yue
Published: June 2024

Motivation

Complex diseases are often caused and characterized by misregulation of multiple biological pathways. Differential network analysis aims to detect significant rewiring of biological network structures under different conditions and has become an important tool for understanding the molecular etiology of disease progression and therapeutic response. With few exceptions, most existing differential network analysis tools perform differential tests on separately learned network structures that are computationally expensive and prone to collapse when grouped samples are limited or less consistent.

Results

We previously developed an accurate differential network analysis method—differential dependency networks (DDN), that enables joint learning of common and rewired network structures under different conditions. We now introduce the DDN3.0 tool that improves this framework with three new and highly efficient algorithms, namely, unbiased model estimation with a weighted error measure applicable to imbalance sample groups, multiple acceleration strategies to improve learning efficiency, and data-driven determination of proper hyperparameters. The comparative experimental results obtained from both realistic simulations and case studies show that DDN3.0 can help biologists more accurately identify, in a study-specific and often unknown conserved regulatory circuitry, a network of significantly rewired molecular players potentially responsible for phenotypic transitions.

Availability and implementation

The Python package of DDN3.0 is freely available at https://github.com/cbil-vt/DDN3. A user’s guide and a vignette are provided at https://ddn-30.readthedocs.io/.
GENTANGLE: integrated computational design of gene entanglements
Authors: Martí Jose Manuel , Hsu Chloe , Rochereau Charlotte , Xu Chenling , Blazejewski Tomasz , Nisonoff Hunter , Leonard Sean P , Kang-Yun Christina S , Chlebek Jennifer , Ricci Dante P , Park Dan , Wang Harris , Listgarten Jennifer , Jiao Yongqin , Allen Jonathan E
Published: June 2024

The design of two overlapping genes in a microbial genome is an emerging technique for adding more reliable control mechanisms in engineered organisms for increased stability. The design of functional overlapping gene pairs is a challenging procedure, and computational design tools are used to improve the efficiency to deploy successful designs in genetically engineered systems. GENTANGLE (Gene Tuples ArraNGed in overLapping Elements) is a high-performance containerized pipeline for the computational design of two overlapping genes translated in different reading frames of the genome. This new software package can be used to design and test gene entanglements for microbial engineering projects using arbitrary sets of user-specified gene pairs.

Availability and implementation

The GENTANGLE source code and its submodules are freely available on GitHub at https://github.com/BiosecSFA/gentangle. The DATANGLE (DATA for genTANGLE) repository contains related data and results and is freely available on GitHub at https://github.com/BiosecSFA/datangle. The GENTANGLE container is freely available on Singularity Cloud Library at https://cloud.sylabs.io/library/khyox/gentangle/gentangle.sif. The GENTANGLE repository wiki (https://github.com/BiosecSFA/gentangle/wiki), website (https://biosecsfa.github.io/gentangle/), and user manual contain detailed instructions on how to use the different components of software and data, including examples and reproducing the results. The code is licensed under the GNU Affero General Public License version 3 (https://www.gnu.org/licenses/agpl.html).
Surface-based multimodal protein–ligand binding affinity prediction
Authors: Xu Shiyu , Shen Lian , Zhang Menglong , Jiang Changzhi , Zhang Xinyi , Xu Yanni , Liu Juan , Liu Xiangrong
Published: June 2024

Motivation

In the field of drug discovery, accurately and effectively predicting the binding affinity between proteins and ligands is crucial for drug screening and optimization. However, current research primarily utilizes representations based on sequence or structure to predict protein–ligand binding affinity, with relatively less study on protein surface information, which is crucial for protein–ligand interactions. Moreover, when dealing with multimodal information of proteins, traditional approaches typically concatenate features from different modalities in a straightforward manner without considering the heterogeneity among them, which results in an inability to effectively exploit the complementary between modalities.

Results

We introduce a novel multimodal feature extraction (MFE) framework that, for the first time, incorporates information from protein surfaces, 3D structures, and sequences, and uses cross-attention mechanism for feature alignment between different modalities. Experimental results show that our method achieves state-of-the-art performance in predicting protein–ligand binding affinity. Furthermore, we conduct ablation studies that demonstrate the effectiveness and necessity of protein surface information and multimodal feature alignment within the framework.

Availability and implementation

The source code and data are available at https://github.com/Sultans0fSwing/MFE.
Conceptus estrogen and prostaglandins provide the maternal recognition of pregnancy signal to prevent luteolysis during early pregnancy in the pig
Authors: Sullivan Riley M , Lucas Caroline G , Sponchiado Mariana , Eitel Emily K , Spate Lee D , Lucy Matthew C , Smith Michael F , Wells Kevin D , Prather Randall S , Geisert Rodney D
Published: June 2024

Conceptus estrogens and prostaglandins have long been considered the primary signals for maternal recognition of pregnancy (MRP) in the pig. However, loss-of-function studies targeting conceptus aromatase genes (CYP19A1 and CYP19A2) and prostaglandin–endoperoxide synthase 2 (PTGS2) indicated that conceptuses can not only signal MRP without estrogens or prostaglandins but can maintain early pregnancy. However, complete loss of estrogen production leads to abortion after day 25 of gestation. Although neither conceptus estrogens nor prostaglandins had a significant effect on early maintenance of corpora lutea (CL) function alone, the two conceptus factors have a biological relationship. To investigate the role that both conceptus estrogens and prostaglandins have on MRP and maintenance of pregnancy, a triple loss-of function model (TKO) was generated for conceptus CYP19A1, CYP19A2, and PTGS2. In addition, a conceptus CYP19A2−/− model (A2KO) was established to determine the role of placental estrogen during later pregnancy. Estrogen and prostaglandin synthesis were greatly reduced in TKO concept uses which resulted in a failure to inhibit luteolysis after day 15 of pregnancy despite the presence of conceptuses in the uterine lumen. However, A2KO placentae not only maintained functional CL but were able to maintain pregnancy to day 32 of gestation. Despite the loss of placental CYP19A2 expression, the allantois fluid content of estrogen was not affected as the placenta compensated by expressing CYP19A1 and CYP19A3, which are normally absent in controls. Results suggest conceptuses can signal MRP through production of conceptus PGE or stimulating PGE synthesis from the endometrium through conceptus estrogen. Failure of conceptuses to produce both factors results in failure of MRP and loss of pregnancy.
The impact of pollinator functional traits on pollination effectiveness is shaped by floral morphs in distylous plant species
Authors: Liu Ruirui , Chen Delai , Xu Shujuan , Zou Yi
Published: June 2024

Insect pollinators provide essential ecosystem services, and pollination effectiveness is a key factor in evaluating the relative importance of different insect species. While single-visit deposition (SVD) of pollen on virgin stigmas by insects is usually used to measure pollination effectiveness, how SVD is correlated with species behavioural and morphological traits is poorly understood for different floral morphs. Here, we used distylous common buckwheat (Fagopyrum esculentum Moench) as a model to understand the relationship between SVD and pollen load, key morphological and behavioural traits of pollinators, and how such relationships differ between different floral morphs. We quantified SVD for 16 insect species and measured the body length, proboscis length, pollen load on different parts of the body, and average visit duration for each species. The results showed that SVD is generally positively correlated with pollen load. SVD is significantly positively associated with species body length but negatively associated with proboscis length for thrum flowers but not for pin flowers. Similarly, positive relationships between SVD and visit duration were observed for thrum flowers, but no significant relationship was observed for pin flowers, while flower visit duration was negatively associated with proboscis length. This study also indicates trait-matching between flowers and pollinators, i.e. the short proboscis length is well matched with the short stamen (pin flower) and short style (thrum flower) and hence promotes compatible pollen deposition on thrum flowers. Our study suggests that morphological trait-matching between flowers and pollinators influences the outcome of plant–pollinator interactions, contributing to variations in pollination effectiveness among different pollinators.
The potential of ChatGPT in medicine: an example analysis of nephrology specialty exams in Poland
Authors: Nicikowski Jan , Szczepański Mikołaj , Miedziaszczyk Miłosz , Kudliński Bartosz
Published: June 2024

Background

In November 2022, OpenAI released a chatbot named ChatGPT, a product capable of processing natural language to create human-like conversational dialogue. It has generated a lot of interest, including from the scientific community and the medical science community. Recent publications have shown that ChatGPT can correctly answer questions from medical exams such as the United States Medical Licensing Examination and other specialty exams. To date, there have been no studies in which ChatGPT has been tested on specialty questions in the field of nephrology anywhere in the world.

Methods

Using the ChatGPT-3.5 and -4.0 algorithms in this comparative cross-sectional study, we analysed 1560 single-answer questions from the national specialty exam in nephrology from 2017 to 2023 that were available in the Polish Medical Examination Center's question database along with answer keys.

Results

Of the 1556 questions posed to ChatGPT-4.0, correct answers were obtained with an accuracy of 69.84%, compared with ChatGPT-3.5 (45.70%, P = .0001) and with the top results of medical doctors (85.73%, P = .0001). Of the 13 tests, ChatGPT-4.0 exceeded the required ≥60% pass rate in 11 tests passed, and scored higher than the average of the human exam results.

Conclusion

ChatGPT-3.5 was not spectacularly successful in nephrology exams. The ChatGPT-4.0 algorithm was able to pass most of the analysed nephrology specialty exams. New generations of ChatGPT achieve similar results to humans. The best results of humans are better than those of ChatGPT-4.0.
Does Timing of Ileal Pouch-Anal Anastomosis Matter in Patients With Primary Sclerosing Cholangitis and Orthotopic Liver Transplantation? A Systematic Review and Meta-analysis
Authors: Alsakarneh Saqr , Ahmed Mohamed , Jaber Fouad , Zulqarnain Mir , Karagozian Raffi , Francis Fadi , Farraye Francis A , Hashash Jana G
Published: June 2024

Introduction

Pouchitis is the most common complication in patients with ileal pouch-anal anastomosis (IPAA), which can develop in up to 66% of patients. There is limited data on the effect of orthoptic liver transplantation (OLT) on the risk of developing pouchitis. We aimed to objectively assess whether OLT itself significantly modifies the risk of developing pouchitis in patients with overlap PSC and inflammatory bowel disease (IBD).

Method

We searched Medline, Scopus, and Embase databases from inception through September 2023 for studies that describe the outcomes of IPAA in patients with PSC and IBD who also have a history of OLT. Pooled proportions, Odds Ratio (OR), and 95% confidence intervals (CI) for data were calculated utilizing a random effects model. Using the Freeman-Turkey double arcsine transformation (FTT) method, the pooled weight-adjusted estimate of event rates for clinical outcomes in each group was also calculated. Heterogeneity between studies was assessed using the Cochrane Q statistic (I2).

Results

Seven studies with a total of 291 patients with a history of PSC, IBD, and OLT were identified. The pooled overall risk of pouchitis in PSC/IBD patients with a history of OLT was 65% (95% CI: 0.57–0.72), with no heterogeneity observed in the analysis (I2 = 0%). In a subgroup analysis of patients who had IPAA followed by OLT, 3 studies with 28 patients were included; the pooled risk of pouchitis after IPAA and OLT was 83% (95% CI: 0.71–0.94; I2 = 0%), which was significantly higher (P < .001) than the OLT followed by IPAA group (59%; 95 CI: 0.48–0.71; I2 = 0%). There was no difference in the risk of pouchitis between OLT and non-OLT groups (OR = 1.36; 95% CI: 0.37–5.0).

Conclusions

Our meta-analysis revelaed that pouchitis is common in patients who underwent OLT for PSC, especially in those who had IPAA before the OLT. OLT before IPAA may reduce the risk of pouchitis. Further larger studies are warranted to reproduce this and investigate the reason behind this difference.
DNA methylation is associated with hair trace elements in female adolescents from two vulnerable populations in the Colombian Caribbean
Authors: Manjarres-Suarez Alejandra , Bozack Anne , Cardenas Andres , Olivero-Verbel Jesus
Published: June 2024

Exposure to trace elements (TEs) influences DNA methylation patterns, which may be associated with disease development. Vulnerable populations, such as adolescents undergoing maturity, are susceptible to the effects of TE exposure. The aim of this study was to analyze the association of hair TE concentration with DNA methylation in a sample from female adolescents living in two communities in the Colombian Caribbean coast. Hair and blood samples were obtained from 45 females, between 13 and 16 years of age. Seventeen TEs were quantified in hair samples. DNA methylation was measured in leukocytes using the Infinium MethylationEPIC BeadChip. Linear models were employed to identify differentially methylated positions (DMPs) adjusting for age, body mass index, mother’s education, and cell type composition. Among the tested elements, vanadium, chromium, nickel, copper, zinc, yttrium, tin, and barium were significantly associated with DMPs (false discovery rate < 0.05), registering 225, 1, 2, 184, 1, 209 189, and 104 hits, respectively. Most of the DMPs were positively associated with TEs and located in open sea regions. The greatest number of DMPs was annotated to the HOXA3 and FOXO3 genes, related to regulation of gene expression and oxidative stress, respectively. These findings suggest that DNA methylation may be involved in linking exposure to TEs among female adolescents to downstream health risks.
PqqF inhibits T6SS secretion by decreasing the pH in Serratia marcescens FS14
Authors: Jia Fengyu , Peng Xuede , Yang Xiaomei , Qiu Shenshen , Jia Shanshan , Ran Tingting , Wang Weiwu , Xu Dongqing
Published: June 2024

Pyrroloquinoline quinone (PQQ) is a redox cofactor with numerous important physiological functions, and the type VI secretion system (T6SS) is commonly found in Gram-negative bacteria and plays important roles in physiological metabolism of the bacteria. In this study, we found that the deletion of pqqF enhanced the secretion of Hcp-1 in Serratia marcesens FS14 in M9 medium. Transcriptional analysis showed that the deletion of pqqF almost had no effect on the expression of T6SS-1. Further study revealed that the increased secretion of Hcp-1 was altered by the pH changes of the culture medium through the reaction catalyzed by the glucose dehydrogenases in FS14. Finally, we demonstrated that decreased pH of culture medium has similar inhibition effects as PQQ induced on the secretion of T6SS-1. This regulation mode on T6SS by pH in FS14 is different from previously reported in other bacteria. Therefore, our results suggest a novel pH regulation mode of T6SS in S. marcesens FS14, and would broaden our knowledge on the regulation of T6SS secretion.
Haplotype-resolved genome assembly for tetraploid Chinese cherry (Prunus pseudocerasus) offers insights into fruit firmness
Authors: Jiu Songtao , Lv Zhengxin , Liu Moyang , Xu Yan , Chen Baozheng , Dong Xiao , Zhang Xinyu , Cao Jun , Manzoor Muhammad Aamir , Xia Mingxu , Li Fangdong , Li Hongwen , Chen Lijuan , Zhang Xu , Wang Shiping , Dong Yang , Zhang Caixi
Published: June 2024

Chinese cherry (Prunus pseudocerasus) holds considerable importance as one of the primary stone fruit crops in China. However, artificially improving its traits and genetic analysis are challenging due to lack of high-quality genomic resources, which mainly result from difficulties associated with resolving its tetraploid and highly heterozygous genome. Herein, we assembled a chromosome-level, haplotype-resolved genome of the cultivar ‘Zhuji Duanbing’, comprising 993.69 Mb assembled into 32 pseudochromosomes using PacBio HiFi, Oxford Nanopore, and Hi-C. Intra-haplotype comparative analyses revealed extensive intra-genomic sequence and expression consistency. Phylogenetic and comparative genomic analyses demonstrated that P. pseudocerasus was a stable autotetraploid species, closely related to wild P. pusilliflora, with the two diverging ~18.34 million years ago. Similar to other Prunus species, P. pseudocerasus underwent a common whole-genome duplication event that occurred ~139.96 million years ago. Because of its low fruit firmness, P. pseudocerasus is unsuitable for long-distance transportation, thereby restricting its rapid development throughout China. At the ripe fruit stage, P. pseudocerasus cv. ‘Zhuji Duanbing’ was significantly less firm than P. avium cv. ‘Heizhenzhu’. The difference in firmness is attributed to the degree of alteration in pectin, cellulose, and hemicellulose contents. In addition, comparative transcriptomic analyses identified GalAK-like and Stv1, two genes involved in pectin biosynthesis, which potentially caused the difference in firmness between ‘Zhuji Duanbing’ and ‘Heizhenzhu’. Transient transformations of PpsGalAK-like and PpsStv1 increase protopectin content and thereby enhance fruit firmness. Our study lays a solid foundation for functional genomic studies and the enhancement of important horticultural traits in Chinese cherries.
BcSRC2 interacts with BcAPX4 to increase ascorbic acid content for responding ABA signaling and drought stress in pak choi
Authors: Yu Zhanghong , Chen Xiaoshan , Chen Zhongwen , Wang Haibin , Shah Sayyed Hamad Ahmad , Bai Aimei , Liu Tongkun , Xiao Dong , Hou Xilin , Li Ying
Published: June 2024

As a reducing substance, ascorbic acid functioned well in abiotic and biotic stress. However, the regulatory mechanism of drought resistance is rarely known in pak choi. Here we found a gene BcSRC2 containing a C2 domain that responds to ABA signal and drought regulation in pak choi. Silencing of BcSRC2 reduces ascorbic acid content and drought resistance of pak choi. In Arabidopsis, BcSRC2 overexpression promotes ascorbic acid accumulation and increases drought tolerance. Meanwhile, transcriptome analysis between WT and BcSRC2-overexpressing pak choi suggests that ascorbic acid-related genes are regulated. BcSRC2 interacts with BcAPX4 and inhibit APX activity in vitro and in vivo, increasing the ascorbic acid content. We also found that drought stress increases ABA content, which reduces the expression of BcMYB30. BcMYB30 bound to the promoter of BcSRC2 and reduced its expression. Overall, our results suggest that a regulatory module, BcMYB30-BcSRC2-BcAPX4, plays a central role in increasing ascorbic acid content for responding ABA-mediated drought regulation in pak choi.
Multicomponent load forecasting of integrated energy system based on deep learning under low-carbon background
Authors: Li Naixin , Tian Xincheng , Lu Zehan , Han Lin
Published: June 2024

In order to support the economic scheduling and optimal operation of integrated energy distribution system, a multiload forecasting method of integrated energy system based on deep learning is proposed. Firstly, Pearson coefficient is used to analyze the correlation between the three loads. Then, Long Short-Term Memory (LSTM) and Gated Recurrent Unit (GRU) model is used to improve the hidden layer of recurrent neural network (RNN). GRU and LSTM adopt gate structure instead of hidden unit in traditional RNN structure, which can selectively remember important information, and then learn historical load parameter information efficiently, making the prediction result more accurate. Finally, the actual data of the integrated energy system is applied to verify the effectiveness of the algorithm. The experimental results show that the prediction accuracy of the LSTM-GRU model proposed in this article is more accurate, and the research results can provide a reference for the comprehensive load prediction of the integrated energy distribution system.
International Society and Its Many Contestations: A Study of the Unrepresented Nations and Peoples Organization
Authors: Kyris George , Brisland Maurice
Published: June 2024

International society debates help us theorize how states or non-state actors matter for the organization of international relations but pay less attention to actors that transcend the state/non-state binary, and especially how contested states that lack recognition and are excluded from international society have engaged with its norms and institutions, particularly in a collective fashion. In order to explore this, we focus on the Unrepresented Nations and Peoples Organization (UNPO), which has been seen as showing a tension between mimicry of the international system and opening new directions and we explore how has the UNPO engaged with international society norms on statehood and to what extent its structures mirror those of other international organizations. We compare the UNPO to other organizations, and we analyze a set of original data, and we find that the UNPO resembles organizations of international society, but it is also a space where international norms are not altogether rejected but “re-imagined,” for example, in ways that seek to strengthen the credentials of contested states. Simultaneously, the purpose of UNPO membership for contested states is to eventually cease to exist, when they join international society, which testifies to the legitimacy that UNPO gives to international society. Thus, our study cross-fertilizes the themes of contested statehood, international society, and the UNPO to offer a missing account of the collective agency of contested states in engaging with international society, which also contributes to debates on international relations from apparently marginal actors.
Hydrogen–independent CO2 reduction dominates methanogenesis in five temperate lakes that differ in trophic states
Authors: Meier Dimitri , van Grinsven Sigrid , Michel Anja , Eickenbusch Philip , Glombitza Clemens , Han Xingguo , Fiskal Annika , Bernasconi Stefano , Schubert Carsten J , Lever Mark A
Published: June 2024

Emissions of microbially produced methane (CH4) from lake sediments are a major source of this potent greenhouse gas to the atmosphere. The rates of CH4 production and emission are believed to be influenced by electron acceptor distributions and organic carbon contents, which in turn are affected by anthropogenic inputs of nutrients leading to eutrophication. Here, we investigate how eutrophication influences the abundance and community structure of CH4 producing Archaea and methanogenesis pathways across time–resolved sedimentary records of five Swiss lakes with well–characterized trophic histories. Despite higher CH4 concentrations which suggest higher methanogenic activity in sediments of eutrophic lakes, abundances of methanogens were highest in oligotrophic lake sediments. Moreover, while the methanogenic community composition differed significantly at the lowest taxonomic levels (OTU), depending on whether sediment layers had been deposited under oligotrophic or eutrophic conditions, it showed no clear trend in relation to in situ distributions of electron acceptors. Remarkably, even though methanogenesis from CO2-reduction was the dominant pathway in all sediments based on carbon isotope fractionation values, taxonomic identities, and genomes of resident methanogens, CO2-reduction with hydrogen (H2) was thermodynamically unfavorable based on measured reactant and product concentrations. Instead, strong correlations between genomic abundances of CO2-reducing methanogens and anaerobic bacteria with potential for extracellular electron transfer suggest that methanogenic CO2-reduction in lake sediments is largely powered by direct electron transfer from syntrophic bacteria without involvement of H2 as an electron shuttle.
State-level factors associated with implementation of prescription drug monitoring program integration and mandatory use policies, United States, 2009–2020
Authors: Johnson Christian E , Chrischilles Elizabeth A , Arndt Stephan , Carnahan Ryan M
Published: June 2024

Background

Prescription drug monitoring programs (PDMPs) have been widely adopted as a tool to address the prescription opioid epidemic in the United States. PDMP integration and mandatory use policies are 2 approaches states have implemented to increase use of PDMPs by prescribers. While the effectiveness of these approaches is mixed, it is unclear what factors motivated states to implement them. This study examines whether opioid dispensing, adverse health outcomes, or other non–health-related factors motivated implementation of these PDMP approaches.

Methods

Time-to-event analysis was performed using lagged state-year covariates to reflect values from the year prior. Extended Cox regression estimated the association of states’ rates of opioid dispensing, prescription opioid overdose deaths, and neonatal opioid withdrawal syndrome with implementation of PDMP integration and mandatory use policies from 2009 to 2020, controlling for demographic and economic factors, state government and political factors, and prior opioid policies.

Results

In our main model, prior opioid dispensing (HR 2.31, 95% CI 1.17, 4.57), neonatal opioid withdrawal syndrome hospitalizations (HR 1.55, 95% CI 1.09, 2.19), and number of prior opioid policies (HR 2.13, 95% CI 1.13, 4.00) were associated with mandatory use policies. Prior prescription opioid overdose deaths (HR 1.21, 95% CI 1.08, 1.35) were also associated with mandatory use policies in a model that did not include opioid dispensing or neonatal opioid withdrawal syndrome. No study variables were associated with implementation of PDMP integration.

Conclusion

Understanding state-level factors associated with implementing PDMP approaches can provide insights into factors that motivate the adoption of future public health interventions.
Do flower-colonizing microbes influence floral evolution? A test with fast-cycling Brassica
Authors: Rivest Sébastien , Forrest Jessica R K
Published: June 2024

Pollinators are thought to be the main drivers of floral evolution. Flowers are also colonized by abundant communities of microbes that can affect the interaction between plants and their pollinators. Very little is known, however, about how flower-colonizing microbes influence floral evolution. Here we performed a 6-generation experimental evolution study using fast-cycling Brassica rapa, in which we factorially manipulated the presence of pollinators and flower microbes to determine how pollinators and microbes interact in driving floral evolution. We measured the evolution of 6 morphological traits, as well as the plant mating system and flower attractiveness. Only one of the 6 traits (flower number) evolved in response to pollinators, while microbes did not drive the evolution of any trait, nor did they interact with pollinators in driving the evolution of morphological traits. Moreover, we did not find evidence that pollinators or microbes affected the evolution of flower attractiveness to pollinators. However, we found an interactive effect of pollinators and microbes on the evolution of autonomous selfing, a trait that is expected to evolve in response to pollinator limitations. Overall, we found only weak evidence that microbes mediate floral evolution. However, our ability to detect an interactive effect of pollinators and microbes might have been limited by weak pollinator-mediated selection in our experimental setting. Our results contrast with previous (similar) experimental evolution studies, highlighting the susceptibility of such experiments to drift and to experimental artefacts.
SPC Manufacturing and Stockpiling Waiver—part 2
Authors: Stief Marco
Published: June 2024

This two-part article analyses and discusses the legal requirements of, as well as the opportunities and risks associated with the SPC Manufacturing and Stockpiling Waiver as introduced by EU Regulation 2019/933. The introduction of the SPC Manufacturing/Stockpiling Waiver on 1 July 2019 opened up opportunities for generics and biosimilars companies established in the EU to manufacture and stockpile medicinal products before expiry of the respective SPC, either for export to third countries or for timely Day-1 market entry in the EU. But unlike, for example, the bolar exemption, application of the SPC Waiver is dependent upon compliance with specific notification, due diligence and labelling obligations. Although introduced more than 4 years ago, there is still considerable legal uncertainty surrounding the application of the SPC Waiver, something recent court decisions in Germany and The Netherlands have exacerbated rather than clarified. The first part of the present article, published in the Journal of Intellectual Property Law and Practice, 2024, Vol.(…), issue (…) analysed and discussed the policy background of the Regulation and examined the SPC Waiver with particular focus on the territorial and temporal scope. This second part scrutinizes the material scope and core components of the waiver, with a particular focus on privileged acts and the conditions under which the waiver is applicable. It distinguishes between primary and closely related privileged acts, and dissects various elements, such as the timing, location, and purpose of these privileged acts.
Targeting MAPK14 in microglial cells: neuroimmune implications of Panax ginseng in post-stroke inflammation
Authors: Guan Hongxu , Yang Xiaoting , Yang Mingfeng , Wang Haitao
Published: June 2024

Aim

This study investigates the molecular mechanisms through which Panax ginseng and Panax notoginseng saponin (PNS) mitigate neuroinflammatory damage and promote neural repair postischemic stroke, utilizing bioinformatics, and experimental approaches.

Background

Cerebral infarction significantly contributes to disability worldwide, with chronic neuroinflammation worsening cognitive impairments and leading to neurodegenerative diseases. Addressing neuroimmune interactions is crucial for slowing disease progression and enhancing patient recovery, highlighting the need for advanced research in neuroimmune regulatory mechanisms and therapeutic strategies.

Objective

To elucidate the effects of the traditional Chinese medicine components Panax ginseng and PNS on neuroinflammatory damage following ischemic stroke, focusing on the molecular pathways involved in mitigating inflammation and facilitating neural repair.

Methods

The study employs single-cell sequencing and transcriptomic analysis to investigate gene expression changes associated with cerebral infarction. Gene set enrichment analysis and weighted gene co-expression network analysis are used to identify key molecular markers and core genes. Furthermore, pharmacological profiling, including functional assays, assesses the impact of Ginsenoside-Rc, a PNS derivative, on microglial cell viability, cytokine production, and reactive oxygen species (ROS) levels.

Results

Our analysis revealed that MAPK14 is a critical mediator in the neuroinflammatory response to ischemic stroke. Ginsenoside-Rc potentially targets and modulates MAPK14 activity to suppress inflammation. Experimental validation showed that Ginsenoside-Rc treatment, combined with MAPK14 silencing, significantly alters MAPK14 expression and mitigates neuroinflammatory damage, evidenced by reduced microglial cell death, inflammatory factor secretion, and ROS production.

Conclusion

Ginsenoside-Rc’s modulation of MAPK14 offers a promising therapeutic strategy for reducing neuroinflammation and potentially improving cognitive recovery post-ischemic stroke. This supports the therapeutic application of the traditional Chinese medicine Sanqi in ischemic stroke care, providing a theoretical and experimental foundation for its use.

Others

Future work will focus on extending these findings through clinical trials to evaluate the efficacy and safety of Ginsenoside-Rc in human subjects, aiming to translate these promising preclinical results into practical therapeutic interventions for ischemic stroke recovery.
Leptomeningeal metastases from solid tumors: A Society for Neuro-Oncology and American Society of Clinical Oncology consensus review on clinical management and future directions
Authors: Wilcox Jessica A , Chukwueke Ugonma N , Ahn Myung-Ju , Aizer Ayal A , Bale Tejus A , Brandsma Dieta , Brastianos Priscilla K , Chang Susan , Daras Mariza , Forsyth Peter , Garzia Livia , Glantz Michael , Oliva Isabella C Glitza , Kumthekar Priya , Le Rhun Emilie , Nagpal Seema , O’Brien Barbara , Pentsova Elena , Lee Eudocia Quant , Remsik Jan , Rudà Roberta , Smalley Inna , Taylor Michael D , Weller Michael , Wefel Jeffrey , Yang Jonathan T , Young Robert J , Wen Patrick Y , Boire Adrienne A
Published: June 2024

Leptomeningeal metastases (LM) are increasingly becoming recognized as a treatable, yet generally incurable, complication of advanced cancer. As modern cancer therapeutics have prolonged the lives of patients with metastatic cancer, specifically in patients with parenchymal brain metastases, treatment options, and clinical research protocols for patients with LM from solid tumors have similarly evolved to improve survival within specific populations. Recent expansions in clinical investigation, early diagnosis, and drug development have given rise to new unanswered questions. These include leptomeningeal metastasis biology and preferred animal modeling, epidemiology in the modern cancer population, ensuring validation and accessibility of newer leptomeningeal metastasis diagnostics, best clinical practices with multimodality treatment options, clinical trial design and standardization of response assessments, and avenues worthy of further research. An international group of multi-disciplinary experts in the research and management of LM, supported by the Society for Neuro-Oncology and American Society of Clinical Oncology, were assembled to reach a consensus opinion on these pressing topics and provide a roadmap for future directions. Our hope is that these recommendations will accelerate collaboration and progress in the field of LM and serve as a platform for further discussion and patient advocacy.
Histopathologic and molecular profile of gliomas diagnosed in Lagos, Nigeria
Authors: Odukoya Lateef A , Ida Cristiane M , Eckel-Passow Jeanette E , Kollmeyer Thomas M , Vaubel Rachael , Lachance Daniel H , Fonkem Ekokobe , Badmos Kabir B , Bankole Olufemi B , Llewellyn Henry , Kitange Gasper J , Aldape Kenneth , Daramola Adetola O , Anunobi Charles C , Jenkins Robert B
Published: June 2024

Background

The optimal diagnosis and management of patients with brain tumors currently uses the 2021 WHO integrated diagnosis of histomorphologic and molecular features. However, neuro-oncology practice in resource-limited settings usually relies solely on histomorphology. This study aimed to classify glioma cases diagnosed in the Department of Anatomic and Molecular Pathology, Lagos University Teaching Hospital, using the 2021 WHO CNS tumor classification.

Methods

Fifty-six brain tumors from 55 patients diagnosed with glioma between 2013 and 2021 were reevaluated for morphologic diagnosis. Molecular features were determined from formalin-fixed paraffin-embedded (FFPE) tissue using immunohistochemistry (IHC) for IDH1-R132H, ATRX, BRAF-V600E, p53, Ki67, and H3-K27M, OncoScan chromosomal microarray for copy number, targeted next generation sequencing for mutation and fusion and methylation array profiling.

Results

Of 55 central nervous system tumors, 3 were excluded from histomorphologic reevaluation for not being of glial or neuroepithelial origin. Of the remaining 52 patients, the median age was 20.5 years (range: 1 to 60 years), 38(73%) were males and 14(27%) were females. Seventy-one percent of the gliomas evaluated provided adequate DNA from archival FFPE tissue blocks. After applying the 2021 WHO diagnostic criteria the initial morphologic diagnosis changed for 35% (18/52) of cases. Diagnoses of 5 (9.6%) gliomas were upgraded, and 7 (14%) were downgraded.

Conclusions

This study shows that the incorporation of molecular testing can considerably improve brain tumor diagnoses in Nigeria. Furthermore, this study highlights the diagnostic challenges in resource-limited settings and what is at stake in the global disparities of brain tumor diagnosis.
Strong low-energy rattling modes enabled liquid-like ultralow thermal conductivity in a well-ordered solid
Authors: Liu Peng-Fei , Li Xiyang , Li Jingyu , Zhu Jianbo , Tong Zhen , Kofu Maiko , Nirei Masami , Xu Juping , Yin Wen , Wang Fangwei , Liang Tianjiao , Xie Lin , Zhang Yongsheng , Singh David J , Ma Jie , Lin Hua , Zhang Junrong , He Jiaqing , Wang Bao-Tian
Published: June 2024

Crystalline solids exhibiting inherently low lattice thermal conductivity (κL) are of great importance in applications such as thermoelectrics and thermal barrier coatings. However, κL cannot be arbitrarily low and is limited by the minimum thermal conductivity related to phonon dispersions. In this work, we report the liquid-like thermal transport in a well-ordered crystalline CsAg5Te3, which exhibits an extremely low κL value of ∼0.18 Wm−1K−1. On the basis of first-principles calculations and inelastic neutron scattering measurements, we find that there are lots of low-lying optical phonon modes at ∼3.1 meV hosting the avoided-crossing behavior with acoustic phonons. These strongly localized modes are accompanied by weakly bound rattling Ag atoms with thermally induced large amplitudes of vibrations. Using the two-channel model, we demonstrate that coupling of the particle-like phonon modes and the heat-carrying wave-like phonons is essential for understanding the low κL, which is heavily deviated from the 1/T temperature dependence of the standard Peierls theory. In addition, our analysis indicates that the soft structural framework with liquid-like motions of the fluctuating Ag atoms is the underlying cause that leads to the suppression of the heat conduction in CsAg5Te3. These factors synergistically account for the ultralow κL value. Our results demonstrate that the liquid-like heat transfer could indeed exist in a well-ordered crystal.
The Soviet Union and Eastern Europe
Authors: Libman Alexander
Published: June 2024

The chapter reviews the political science scholarship on Communist regimes in Eastern Europe and in the USSR, their collapse, and their legacies. It identifies key features of Communist regimes and positions them in the overall landscape of comparative authoritarianism studies. It points out the internal contradictions plaguing Communist regimes, but also factors explaining their durability and stability. It discusses main theories explaining the collapse of the Communist regimes in Eastern Europe and in the USSR. Finally, it shows that Communist legacies remain an important obstacle for the democratic consolidation in Eastern Europe and the post-Soviet Eurasia. The focus of the chapter is on both the Communist regimes themselves and the scholarship on Communist regimes and its place in the political science research on authoritarian regimes.
Central Asian Authoritarianisms
Authors: Kassenova Nargis , Frigerio Alessandro
Published: June 2024

The authoritarian trend has dominated in Central Asia since 1991, when its five countries acquired independence after the dissolution of the USSR. Despite their common origins, the political systems in these countries now display considerable differences. We account for these variations, and highlight the complexity of authoritarian politics in Central Asia, in three steps. First, we place them on the dual continuum of anarchy-democracy-dictatorship and libertarianism-liberalism-totalitarianism. Second, we discuss how authoritarianism has become the dominant trend in the region, and define the common trait of all these countries under the general umbrella of neopatrimonial authoritarianism. Third, we illustrate the oscillations of the regimes in the region over the past three decades by focusing on three elements that could explain the variations in authoritarianisms: leaders, elites and societies, and external influences. We conclude with some thoughts on authoritarianism’s prospects in Central Asia, and outline areas for future research.
Policing schools in the USA: An evidence summary and future research agenda
Authors: Petrosino Anthony , Fronius Trevor , Baskerville Trent
Published: June 2024

School-based policing programs started as far back in the USA as the 1950s and became more popular in part as concerns about school safety increased. After the murder of George Floyd in May 2020, the scrutiny of municipal police extended to school policing, and the concerns that policing exacerbates the school-to-prison pipeline, particularly for Black and Brown children, led several districts to remove officers from their schools. However, some of these same districts have reinstated police following widespread reports of fighting and behavioural issues among students after nearly 2 years of sporadic education due to the COVID-19 pandemic. This paper discusses some of the recent trends and highlights evidence from several systematic reviews of evidence on the efforts of school policing, including a large-scale effort for the Campbell Collaboration. A more recent evaluation published since the reviews were done is also discussed. Finally, the article highlights a report to Congress by the National Institute of Justice and concludes with policy implications and a future agenda for research.