bluuebunny/crossref_metadata_2025 huggingface dataset:
Identifying novel proteins for suicide attempt by integrating proteomes from brain and blood with genome-wide association data
Authors: Zhao Hao , Liu Yifeng , Zhang Xuening , Liao Yuhua , Zhang Huimin , Han Xue , Guo Lan , Fan Beifang , Wang Wanxin , Lu Ciyong
Published: February 2024

Genome-wide association studies (GWASs) have identified risk loci for suicide attempt (SA), but deciphering how they confer risk for SA remains largely unknown. This study aims to identify the key proteins and gain insights into SA pathogenesis. We integrated data from the brain proteome (N = 376) and blood proteome (N = 35,559) and combined it with the largest SA GWAS summary statistics to date (N = 518,612). A comprehensive set of methods was employed, including Mendelian randomization (MR), Steiger filtering, Bayesian colocalization, proteome‑wide association studies (PWAS), transcript-levels, cell-type specificity, correlation, and protein-protein interaction (PPI) network analysis. Validation was performed using other protein datasets and the SA dataset from FinnGen study. We identified ten proteins (GLRX5, GMPPB, B3GALTL, FUCA2, TTLL12, ADCK1, MMAA, HIBADH, ACP1, DOC2A) associated with SA in brain proteomics. GLRX5, GMPPB, and FUCA2 showed strong colocalization evidence and were supported by PWAS and transcript-level analysis, and were predominantly expressed in glutamatergic neuronal cells. In blood proteomics, one significant protein (PEAR1) and three near-significant proteins (NDE1, EVA1C, B4GALT2) were identified, but lacked colocalization evidence. Moreover, despite the limited correlation between the same protein in brain and blood, the PPI network analysis provided new insights into the interaction between brain and blood in SA. Furthermore, GLRX5 was associated with the GSTP1, the target of Clozapine. The comprehensive analysis provides strong evidence supporting a causal association between three genetically determined brain proteins (GLRX5, GMPPB, and FUCA2) with SA. These findings offer valuable insights into SA’s underlying mechanisms and potential therapeutic approaches.
Extracellular vesicles as tools and targets in therapy for diseases
Authors: Kumar Mudasir A. , Baba Sadaf K. , Sadida Hana Q. , Marzooqi Sara Al. , Jerobin Jayakumar , Altemani Faisal H. , Algehainy Naseh , Alanazi Mohammad A. , Abou-Samra Abdul-Badi , Kumar Rakesh , Al-Shabeeb Akil Ammira S. , Macha Muzafar A. , Mir Rashid , Bhat Ajaz A.
Published: February 2024

Extracellular vesicles (EVs) are nano-sized, membranous structures secreted into the extracellular space. They exhibit diverse sizes, contents, and surface markers and are ubiquitously released from cells under normal and pathological conditions. Human serum is a rich source of these EVs, though their isolation from serum proteins and non-EV lipid particles poses challenges. These vesicles transport various cellular components such as proteins, mRNAs, miRNAs, DNA, and lipids across distances, influencing numerous physiological and pathological events, including those within the tumor microenvironment (TME). Their pivotal roles in cellular communication make EVs promising candidates for therapeutic agents, drug delivery systems, and disease biomarkers. Especially in cancer diagnostics, EV detection can pave the way for early identification and offers potential as diagnostic biomarkers. Moreover, various EV subtypes are emerging as targeted drug delivery tools, highlighting their potential clinical significance. The need for non-invasive biomarkers to monitor biological processes for diagnostic and therapeutic purposes remains unfulfilled. Tapping into the unique composition of EVs could unlock advanced diagnostic and therapeutic avenues in the future. In this review, we discuss in detail the roles of EVs across various conditions, including cancers (encompassing head and neck, lung, gastric, breast, and hepatocellular carcinoma), neurodegenerative disorders, diabetes, viral infections, autoimmune and renal diseases, emphasizing the potential advancements in molecular diagnostics and drug delivery.
Long-term activation of anti-tumor immunity in pancreatic cancer by a p53-expressing telomerase-specific oncolytic adenovirus
Authors: Hashimoto Masashi , Kuroda Shinji , Kanaya Nobuhiko , Kadowaki Daisuke , Yoshida Yusuke , Sakamoto Masaki , Hamada Yuki , Sugimoto Ryoma , Yagi Chiaki , Ohtani Tomoko , Kumon Kento , Kakiuchi Yoshihiko , Yasui Kazuya , Kikuchi Satoru , Yoshida Ryuichi , Tazawa Hiroshi , Kagawa Shunsuke , Yagi Takahito , Urata Yasuo , Fujiwara Toshiyoshi
Published: February 2024

Background

Pancreatic cancer is an aggressive, immunologically “cold” tumor. Oncolytic virotherapy is a promising treatment to overcome this problem. We developed a telomerase-specific oncolytic adenovirus armed with p53 gene (OBP-702).

Methods

We investigated the efficacy of OBP-702 for pancreatic cancer, focusing on its long-term effects via long-lived memory CD8 + T cells including tissue-resident memory T cells (TRMs) and effector memory T cells (TEMs) differentiated from effector memory precursor cells (TEMps).

Results

First, in vitro, OBP-702 significantly induced adenosine triphosphate (ATP), which is important for memory T cell establishment. Next, in vivo, OBP-702 local treatment to murine pancreatic PAN02 tumors increased TEMps via ATP induction from tumors and IL-15Rα induction from macrophages, leading to TRM and TEM induction. Activation of these memory T cells by OBP-702 was also maintained in combination with gemcitabine+nab-paclitaxel (GN) in a PAN02 bilateral tumor model, and GN + OBP-702 showed significant anti-tumor effects and increased TRMs in OBP-702-uninjected tumors. Finally, in a neoadjuvant model, in which PAN02 cells were re-inoculated after resection of treated-PAN02 tumors, GN + OBP-702 provided long-term anti-tumor effects even after tumor resection.

Conclusion

OBP-702 can be a long-term immunostimulant with sustained anti-tumor effects on immunologically cold pancreatic cancer.
Resolvin T4 enhances macrophage cholesterol efflux to reduce vascular disease
Authors: Walker Mary E. , De Matteis Roberta , Perretti Mauro , Dalli Jesmond
Published: February 2024

While cardiovascular disease (CVD) is one of the major co-morbidities in patients with rheumatoid arthritis (RA), the mechanism(s) that contribute to CVD in patients with RA remain to be fully elucidated. Herein, we observe that plasma concentrations of 13-series resolvin (RvT)4 negatively correlate with vascular lipid load in mouse inflammatory arthritis. Administration of RvT4 to male arthritic mice fed an atherogenic diet significantly reduces atherosclerosis. Assessment of the mechanisms elicited by this mediator demonstrates that RvT4 activates cholesterol efflux in lipid laden macrophages via a Scavenger Receptor class B type 1 (SR-BI)-Neutral Cholesterol Ester Hydrolase-dependent pathway. This leads to the reprogramming of lipid laden macrophages yielding tissue protection. Pharmacological inhibition or knockdown of macrophage SR-BI reverses the vasculo-protective activities of RvT4 in vitro and in male mice in vivo. Together these findings elucidate a RvT4-SR-BI centered mechanism that orchestrates macrophage responses to limit atherosclerosis during inflammatory arthritis.
Health effects associated with chewing tobacco: a Burden of Proof study
Authors: Gil Gabriela F. , Anderson Jason A. , Aravkin Aleksandr , Bhangdia Kayleigh , Carr Sinclair , Dai Xiaochen , Flor Luisa S. , Hay Simon I. , Malloy Matthew J. , McLaughlin Susan A. , Mullany Erin C. , Murray Christopher J. L. , O’Connell Erin M. , Okereke Chukwuma , Sorensen Reed J. D. , Whisnant Joanna , Zheng Peng , Gakidou Emmanuela
Published: February 2024

Chewing tobacco use poses serious health risks; yet it has not received as much attention as other tobacco-related products. This study synthesizes existing evidence regarding the health impacts of chewing tobacco while accounting for various sources of uncertainty. We conducted a systematic review and meta-analysis of chewing tobacco and seven health outcomes, drawing on 103 studies published from 1970 to 2023. We use a Burden of Proof meta-analysis to generate conservative risk estimates and find weak-to-moderate evidence that tobacco chewers have an increased risk of stroke, lip and oral cavity cancer, esophageal cancer, nasopharynx cancer, other pharynx cancer, and laryngeal cancer. We additionally find insufficient evidence of an association between chewing tobacco and ischemic heart disease. Our findings highlight a need for policy makers, researchers, and communities at risk to devote greater attention to chewing tobacco by both advancing tobacco control efforts and investing in strengthening the existing evidence base.
Aneuploid embryonic stem cells drive teratoma metastasis
Authors: Xiao Rong , Xu Deshu , Zhang Meili , Chen Zhanghua , Cheng Li , Du Songjie , Lu Mingfei , Zhou Tonghai , Li Ruoyan , Bai Fan , Huang Yue
Published: February 2024

Aneuploidy, a deviation of the chromosome number from euploidy, is one of the hallmarks of cancer. High levels of aneuploidy are generally correlated with metastasis and poor prognosis in cancer patients. However, the causality of aneuploidy in cancer metastasis remains to be explored. Here we demonstrate that teratomas derived from aneuploid murine embryonic stem cells (ESCs), but not from isogenic diploid ESCs, disseminated to multiple organs, for which no additional copy number variations were required. Notably, no cancer driver gene mutations were identified in any metastases. Aneuploid circulating teratoma cells were successfully isolated from peripheral blood and showed high capacities for migration and organ colonization. Single-cell RNA sequencing of aneuploid primary teratomas and metastases identified a unique cell population with high stemness that was absent in diploid ESCs-derived teratomas. Further investigation revealed that aneuploid cells displayed decreased proteasome activity and overactivated endoplasmic reticulum (ER) stress during differentiation, thereby restricting the degradation of proteins produced from extra chromosomes in the ESC state and causing differentiation deficiencies. Noticeably, both proteasome activator Oleuropein and ER stress inhibitor 4-PBA can effectively inhibit aneuploid teratoma metastasis.
High-efficiency reinforcement learning with hybrid architecture photonic integrated circuit
Authors: Li Xuan-Kun , Ma Jian-Xu , Li Xiang-Yu , Hu Jun-Jie , Ding Chuan-Yang , Han Feng-Kai , Guo Xiao-Min , Tan Xi , Jin Xian-Min
Published: February 2024

Reinforcement learning (RL) stands as one of the three fundamental paradigms within machine learning and has made a substantial leap to build general-purpose learning systems. However, using traditional electrical computers to simulate agent-environment interactions in RL models consumes tremendous computing resources, posing a significant challenge to the efficiency of RL. Here, we propose a universal framework that utilizes a photonic integrated circuit (PIC) to simulate the interactions in RL for improving the algorithm efficiency. High parallelism and precision on-chip optical interaction calculations are implemented with the assistance of link calibration in the hybrid architecture PIC. By introducing similarity information into the reward function of the RL model, PIC-RL successfully accomplishes perovskite materials synthesis task within a 3472-dimensional state space, resulting in a notable 56% improvement in efficiency. Our results validate the effectiveness of simulating RL algorithm interactions on the PIC platform, highlighting its potential to boost computing power in large-scale and sophisticated RL tasks.
Avoiding ecosystem and social impacts of hydropower, wind, and solar in Southern Africa’s low-carbon electricity system
Authors: Wu Grace C. , Deshmukh Ranjit , Trainor Anne , Uppal Anagha , Chowdhury A. F. M. Kamal , Baez Carlos , Martin Erik , Higgins Jonathan , Mileva Ana , Ndhlukula Kudakwashe
Published: February 2024

The scale at which low-carbon electricity will need to be deployed to meet economic growth, electrification, and climate goals in Africa is unprecedented, yet the potential land use and freshwater impacts from this massive build-out of energy infrastructure is poorly understood. In this study, we characterize low-impact onshore wind, solar photovoltaics, and hydropower potential in Southern Africa and identify the cost-optimal mix of electricity generation technologies under different sets of socio-environmental land use and freshwater constraints and carbon targets. We find substantial wind and solar potential after applying land use protections, but about 40% of planned or proposed hydropower projects face socio-environmental conflicts. Applying land and freshwater protections results in more wind, solar, and battery capacity and less hydropower capacity compared to scenarios without protections. While a carbon target favors hydropower, the amount of cost-competitively selected hydropower is at most 45% of planned or proposed hydropower capacity in any scenario—and is only 25% under socio-environmental protections. Achieving both carbon targets and socio-environmental protections results in system cost increases of 3-6%. In the absence of land and freshwater protections, environmental and social impacts from new hydropower development could be significant.
G-quadruplexes promote the motility in MAZ phase-separated condensates to activate CCND1 expression and contribute to hepatocarcinogenesis
Authors: Wang Wenmeng , Li Dangdang , Xu Qingqing , Cheng Jiahui , Yu Zhiwei , Li Guangyue , Qiao Shiyao , Pan Jiasong , Wang Hao , Shi Jinming , Zheng Tongsen , Sui Guangchao
Published: February 2024

G-quadruplexes (G4s) can recruit transcription factors to activate gene expression, but detailed mechanisms remain enigmatic. Here, we demonstrate that G4s in the CCND1 promoter propel the motility in MAZ phase-separated condensates and subsequently activate CCND1 transcription. Zinc finger (ZF) 2 of MAZ is a responsible for G4 binding, while ZF3-5, but not a highly disordered region, is critical for MAZ condensation. MAZ nuclear puncta overlaps with signals of G4s and various coactivators including BRD4, MED1, CDK9 and active RNA polymerase II, as well as gene activation histone markers. MAZ mutants lacking either G4 binding or phase separation ability did not form nuclear puncta, and showed deficiencies in promoting hepatocellular carcinoma cell proliferation and xenograft tumor formation. Overall, we unveiled that G4s recruit MAZ to the CCND1 promoter and facilitate the motility in MAZ condensates that compartmentalize coactivators to activate CCND1 expression and subsequently exacerbate hepatocarcinogenesis.
Manipulating solvent fluidic dynamics for large-area perovskite film-formation and white light-emitting diodes
Authors: Shi Guangyi , Huang Zongming , Qiao Ran , Chen Wenjing , Li Zhijian , Li Yaping , Mu Kai , Si Ting , Xiao Zhengguo
Published: February 2024

Presynthesized perovskite quantum dots are very promising for making films with different compositions, as they decouple crystallization and film-formation processes. However, fabricating large-area uniform films using perovskite quantum dots is still very challenging due to the complex fluidic dynamics of the solvents. Here, we report a robust film-formation approach using an environmental-friendly binary-solvent strategy. Nonbenzene solvents, n-octane and n-hexane, are mixed to manipulate the fluidic and evaporation dynamics of the perovskite quantum dot inks, resulting in balanced Marangoni flow, enhanced ink spreadability, and uniform solute-redistribution. We can therefore blade-coat large-area uniform perovskite films with different compositions using the same fabrication parameters. White and red perovskite light-emitting diodes incorporating blade-coated films exhibit a decent external quantum efficiency of 10.6% and 15.3% (0.04 cm2), and show a uniform emission up to 28 cm2. This work represents a significant step toward the application of perovskite light-emitting diodes in flat panel solid-state lighting.
SARS-CoV-2 vaccination may mitigate dysregulation of IL-1/IL-18 and gastrointestinal symptoms of the post-COVID-19 condition
Authors: Fischer Claudia , Willscher Edith , Paschold Lisa , Gottschick Cornelia , Klee Bianca , Diexer Sophie , Bosurgi Lidia , Dutzmann Jochen , Sedding Daniel , Frese Thomas , Girndt Matthias , Hoell Jessica I. , Gekle Michael , Addo Marylyn M. , Schulze zur Wiesch Julian , Mikolajczyk Rafael , Binder Mascha , Schultheiß Christoph
Published: February 2024

The rapid development of safe and effective vaccines helped to prevent severe disease courses after SARS-CoV-2 infection and to mitigate the progression of the COVID-19 pandemic. While there is evidence that vaccination may reduce the risk of developing post-COVID-19 conditions (PCC), this effect may depend on the viral variant. Therapeutic effects of post-infection vaccination have been discussed but the data for individuals with PCC remains inconclusive. In addition, extremely rare side effects after SARS-CoV-2 vaccination may resemble the heterogeneous PCC phenotype. Here, we analyze the plasma levels of 25 cytokines and SARS-CoV-2 directed antibodies in 540 individuals with or without PCC relative to one or two mRNA-based COVID-19 vaccinations as well as in 20 uninfected individuals one month after their initial mRNA-based COVID-19 vaccination. While none of the SARS-CoV-2 naïve individuals reported any persisting sequelae or exhibited PCC-like dysregulation of plasma cytokines, we detected lower levels of IL-1β and IL-18 in patients with ongoing PCC who received one or two vaccinations at a median of six months after infection as compared to unvaccinated PCC patients. This reduction correlated with less frequent reporting of persisting gastrointestinal symptoms. These data suggest that post-infection vaccination in patients with PCC might be beneficial in a subgroup of individuals displaying gastrointestinal symptoms.
A metabolite sensor subunit of the Atg1/ULK complex regulates selective autophagy
Authors: Gross A. S. , Ghillebert R. , Schuetter M. , Reinartz E. , Rowland A. , Bishop B. C. , Stumpe M. , Dengjel J. , Graef M.
Published: February 2024

Cells convert complex metabolic information into stress-adapted autophagy responses. Canonically, multilayered protein kinase networks converge on the conserved Atg1/ULK kinase complex (AKC) to induce non-selective and selective forms of autophagy in response to metabolic changes. Here we show that, upon phosphate starvation, the metabolite sensor Pho81 interacts with the adaptor subunit Atg11 at the AKC via an Atg11/FIP200 interaction motif to modulate pexophagy by virtue of its conserved phospho-metabolite sensing SPX domain. Notably, core AKC components Atg13 and Atg17 are dispensable for phosphate starvation-induced autophagy revealing significant compositional and functional plasticity of the AKC. Our data indicate that, instead of functioning as a selective autophagy receptor, Pho81 compensates for partially inactive Atg13 by promoting Atg11 phosphorylation by Atg1 critical for pexophagy during phosphate starvation. Our work shows Atg11/FIP200 adaptor subunits bind not only selective autophagy receptors but also modulator subunits that convey metabolic information directly to the AKC for autophagy regulation.
microbeMASST: a taxonomically informed mass spectrometry search tool for microbial metabolomics data
Authors: Zuffa Simone , Schmid Robin , Bauermeister Anelize , P. Gomes Paulo Wender , Caraballo-Rodriguez Andres M. , El Abiead Yasin , Aron Allegra T. , Gentry Emily C. , Zemlin Jasmine , Meehan Michael J. , Avalon Nicole E. , Cichewicz Robert H. , Buzun Ekaterina , Terrazas Marvic Carrillo , Hsu Chia-Yun , Oles Renee , Ayala Adriana Vasquez , Zhao Jiaqi , Chu Hiutung , Kuijpers Mirte C. M. , Jackrel Sara L. , Tugizimana Fidele , Nephali Lerato Pertunia , Dubery Ian A. , Madala Ntakadzeni Edwin , Moreira Eduarda Antunes , Costa-Lotufo Leticia Veras , Lopes Norberto Peporine , Rezende-Teixeira Paula , Jimenez Paula C. , Rimal Bipin , Patterson Andrew D. , Traxler Matthew F. , Pessotti Rita de Cassia , Alvarado-Villalobos Daniel , Tamayo-Castillo Giselle , Chaverri Priscila , Escudero-Leyva Efrain , Quiros-Guerrero Luis-Manuel , Bory Alexandre Jean , Joubert Juliette , Rutz Adriano , Wolfender Jean-Luc , Allard Pierre-Marie , Sichert Andreas , Pontrelli Sammy , Pullman Benjamin S. , Bandeira Nuno , Gerwick William H. , Gindro Katia , Massana-Codina Josep , Wagner Berenike C. , Forchhammer Karl , Petras Daniel , Aiosa Nicole , Garg Neha , Liebeke Manuel , Bourceau Patric , Kang Kyo Bin , Gadhavi Henna , de Carvalho Luiz Pedro Sorio , Silva dos Santos Mariana , Pérez-Lorente Alicia Isabel , Molina-Santiago Carlos , Romero Diego , Franke Raimo , Brönstrup Mark , Vera Ponce de León Arturo , Pope Phillip Byron , La Rosa Sabina Leanti , La Barbera Giorgia , Roager Henrik M. , Laursen Martin Frederik , Hammerle Fabian , Siewert Bianka , Peintner Ursula , Licona-Cassani Cuauhtemoc , Rodriguez-Orduña Lorena , Rampler Evelyn , Hildebrand Felina , Koellensperger Gunda , Schoeny Harald , Hohenwallner Katharina , Panzenboeck Lisa , Gregor Rachel , O’Neill Ellis Charles , Roxborough Eve Tallulah , Odoi Jane , Bale Nicole J. , Ding Su , Sinninghe Damsté Jaap S. , Guan Xue Li , Cui Jerry J. , Ju Kou-San , Silva Denise Brentan , Silva Fernanda Motta Ribeiro , da Silva Gilvan Ferreira , Koolen Hector H. F. , Grundmann Carlismari , Clement Jason A. , Mohimani Hosein , Broders Kirk , McPhail Kerry L. , Ober-Singleton Sidnee E. , Rath Christopher M. , McDonald Daniel , Knight Rob , Wang Mingxun , Dorrestein Pieter C.
Published: February 2024

microbeMASST, a taxonomically informed mass spectrometry (MS) search tool, tackles limited microbial metabolite annotation in untargeted metabolomics experiments. Leveraging a curated database of >60,000 microbial monocultures, users can search known and unknown MS/MS spectra and link them to their respective microbial producers via MS/MS fragmentation patterns. Identification of microbe-derived metabolites and relative producers without a priori knowledge will vastly enhance the understanding of microorganisms’ role in ecology and human health.
Stepwise assembly and release of Tc toxins from Yersinia entomophaga
Authors: Feldmüller Miki , Ericson Charles F. , Afanasyev Pavel , Lien Yun-Wei , Weiss Gregor L. , Wollweber Florian , Schoof Marion , Hurst Mark , Pilhofer Martin
Published: February 2024

Tc toxins are virulence factors of bacterial pathogens. Although their structure and intoxication mechanism are well understood, it remains elusive where this large macromolecular complex is assembled and how it is released. Here we show by an integrative multiscale imaging approach that Yersinia entomophaga Tc (YenTc) toxin components are expressed only in a subpopulation of cells that are ‘primed’ with several other potential virulence factors, including filaments of the protease M66/StcE. A phage-like lysis cassette is required for YenTc release; however, before resulting in complete cell lysis, the lysis cassette generates intermediate ‘ghost’ cells, which may serve as assembly compartments and become packed with assembled YenTc holotoxins. We hypothesize that this stepwise mechanism evolved to minimize the number of cells that need to be killed. The occurrence of similar lysis cassettes in diverse organisms indicates a conserved mechanism for Tc toxin release that may apply to other extracellular macromolecular machines.
Deep learning-aided decision support for diagnosis of skin disease across skin tones
Authors: Groh Matthew , Badri Omar , Daneshjou Roxana , Koochek Arash , Harris Caleb , Soenksen Luis R. , Doraiswamy P. Murali , Picard Rosalind
Published: February 2024

Although advances in deep learning systems for image-based medical diagnosis demonstrate their potential to augment clinical decision-making, the effectiveness of physician–machine partnerships remains an open question, in part because physicians and algorithms are both susceptible to systematic errors, especially for diagnosis of underrepresented populations. Here we present results from a large-scale digital experiment involving board-certified dermatologists (n = 389) and primary-care physicians (n = 459) from 39 countries to evaluate the accuracy of diagnoses submitted by physicians in a store-and-forward teledermatology simulation. In this experiment, physicians were presented with 364 images spanning 46 skin diseases and asked to submit up to four differential diagnoses. Specialists and generalists achieved diagnostic accuracies of 38% and 19%, respectively, but both specialists and generalists were four percentage points less accurate for the diagnosis of images of dark skin as compared to light skin. Fair deep learning system decision support improved the diagnostic accuracy of both specialists and generalists by more than 33%, but exacerbated the gap in the diagnostic accuracy of generalists across skin tones. These results demonstrate that well-designed physician–machine partnerships can enhance the diagnostic accuracy of physicians, illustrating that success in improving overall diagnostic accuracy does not necessarily address bias.
The palisade layer of the poxvirus core is composed of flexible A10 trimers
Authors: Liu Jiasui , Corroyer-Dulmont Simon , Pražák Vojtěch , Khusainov Iskander , Bahrami Karola , Welsch Sonja , Vasishtan Daven , Obarska-Kosińska Agnieszka , Thorkelsson Sigurdur R. , Grünewald Kay , Quemin Emmanuelle R. J. , Turoňová Beata , Locker Jacomina Krijnse
Published: February 2024

Due to its asymmetric shape, size and compactness, the structure of the infectious mature virus (MV) of vaccinia virus (VACV), the best-studied poxvirus, remains poorly understood. Instead, subviral particles, in particular membrane-free viral cores, have been studied with cryo-electron microscopy. Here, we compared viral cores obtained by detergent stripping of MVs with cores in the cellular cytoplasm, early in infection. We focused on the prominent palisade layer on the core surface, combining cryo-electron tomography, subtomogram averaging and AlphaFold2 structure prediction. We showed that the palisade is composed of densely packed trimers of the major core protein A10. Trimers display a random order and their classification indicates structural flexibility. A10 on cytoplasmic cores is organized in a similar manner, indicating that the structures obtained in vitro are physiologically relevant. We discuss our results in the context of the VACV replicative cycle, and the assembly and disassembly of the infectious MV.
Diffusing capacity as an independent predictor of acute exacerbations in chronic obstructive pulmonary disease
Authors: Park Heemoon , Lee Hyo Jin , Lee Jung-Kyu , Park Tae Yun , Jin Kwang Nam , Heo Eun Young , Kim Deog Kyeom , Lee Hyun Woo
Published: February 2024

A weak correlation between diffusing capacity of the lung for carbon monoxide (DLCO) and emphysema has been reported. This study investigated whether impaired DLCO in chronic obstructive pulmonary disease (COPD) is associated with increased risk of acute exacerbation independent of the presence or extent of emphysema. This retrospective cohort study included patients with COPD between January 2004 and December 2019. The participants were divided into four groups based on visually detected emphysema and impaired DLCO. Among 597 patients with COPD, 8.5% had no emphysema and impaired DLCO whereas 36.3% had emphysema without impaired DLCO. Among the four groups, patients with impaired DLCO and emphysema showed a higher risk of moderate-to-severe or severe exacerbation than those with normal DLCO. Impaired DLCO was an independent risk factor for severe exacerbation (hazard ratio, 1.524 [95% confidence interval 1.121–2.072]), whereas the presence of emphysema was not. The risk of moderate-to-severe or severe exacerbation increases with the severity of impaired DLCO. After propensity-score matching for the extent of emphysema, impaired DLCO was significantly associated with a higher risk of moderate-to-severe (p = 0.041) or severe exacerbation (p = 0.020). In patients with COPD and heterogeneous parenchymal abnormalities, DLCO can be considered an independent biomarker of acute exacerbation.
Effects of irrigation scheduling on the yield and irrigation water productivity of cucumber in coconut coir culture
Authors: Li You-li , Zhang Si-qi , Guo Wen-zhong , Zheng Wen-gang , Zhao Qian , Yu Wen-ya , Li Jian-she
Published: February 2024

Optimum irrigation scheduling is important for ensuring high yield and water productivity in substrate-cultivated vegetables and is determined based on information such as substrate water content, meteorological parameters, and crop growth. The aim of this study was to determine a precise irrigation schedule for coconut coir culture in a solar greenhouse by comparing the irrigation, evapotranspiration (ET), substrate water content (VWC), as well as the crop growth indices and yield of cucumber, and irrigation water productivity (IWP) under three irrigation schedules: the soil moisture sensor-based method (T-VWC), the accumulated radiation combined with soil moisture sensor-based method (Rn-VWC), and the crop evapotranspiration estimated method using the hourly PM-ETo equation with an improved calculation of Kc (T-ETc). The results showed that the daily irrigation and evapotranspiration amount were the highest under T-VWC treatment, while the lowest under T-ETc treatment. In different meteorological environments, the change in irrigation amount was more consistent with the ET,and the VWC was relatively stable in T-ETc treatment compared with that under T-VWC or Rn-VWC treatments. The plant height, leaves number, leaf area, and stem diameter of T-VWC and Rn-VWC treatments were higher than those of the T-ETc treatments, but there was no significant difference in cucumber yield. Compared with the T-VWC treatment, total irrigation amount under Rn-VWC and T-ETc treatments significantly decreased by 25.75% and 34.04%, respectively ($$\hbox {P}<0.05$$

P
<
0.05

). The highest IWP values of 25.07 kg m$$^{-3}$$

-
3

was achieved from T-ETc treatment with significantly increasing by 44.33% compared to the T-VWC treatment (17.37 kg m$$^{-3}$$

-
3

). In summary, the T-ETc treatment allowed more reasonable irrigation management and was appropriate for growing cucumber in coconut coir culture.
Static micromechanical measurements of the flexural modulus and strength of micrometre-diameter single fibres using deflecting microcantilever techniques
Authors: Reda Ali , Arscott Steve
Published: February 2024

The mechanical properties of natural and man-made fibres ultimately govern the robustness of products. Examples range from textiles to composite materials for mechanical parts in emerging technological applications. An accurate determination of the mechanical properties of microscopic single fibres is therefore important. Today, macroscopic mechanical techniques, such as tensile testing, are commonly employed to obtain this information. However, a relatively high dispersion of results is often encountered due to a relatively long sample size. As an alternative to tensile methods, we demonstrate here micromechanical techniques to accurately measure the flexural modulus and strength of micrometre-sized diameter fibres without the need of force sensing. To demonstrate our ideas, we use the example of single natural fibres (Linum Usitatissimum). The flexural modulus of the single fibres is first accurately measured in the low deflection regime of an inclined bending cantilever in an original setup. The flexural strength of the single fibres is then measured in the high deflection regime of a bending cantilever. Interestingly, the novel measurements have allowed the authors to quantify the flexural strength of two different failure modes in flax fibre, enabling a contribution to plant mechanics.
Uncontrolled blood pressure and its risk factors among hypertensive patients, Marrakech, Morocco
Authors: Belayachi Safae , Boukhari Fatima Zahra , Essayagh Firdaous , Terkiba Othmane , Marc Ikram , Lambaki Abdellah , Zohoun Alban , Essayagh Meriem , Essayagh Touria , Essayagh Sanah
Published: February 2024

Hypertension is a public health problem. Failure to control blood pressure figures is responsible for morbidity and premature mortality. This study aims to describe the characteristics of hypertensive patients followed at primary health care centers in Marrakech. Between May 2021 and December 2022, a cross-sectional study of 922 hypertension patients attending primary health care centers in Marrakech was done. To gather socio-demographic, behavioral, and clinical data, as well as hypertension treatment features and the care-patient-physician triad, a face-to-face questionnaire was employed. To identify risk factors associated with uncontrolled blood pressure, multivariate logistic regression was used. Uncontrolled blood pressure was found in 73.5% of people. The patients' average age was 63.4 ± 9.4 years (mean ± standard deviation), and 524 (77.3%) were women. Tobacco consumption (Adjusted Odd Ratio of 4.34; 95% CI [1.58–11.9]); lack of self-monitoring of hypertension (AOR of 1.69; 95% CI [1.14–2.52]); a family history of hypertension (AOR of 1.58; 95% CI [1.12–2.22]); overweight or obesity (AOR of 1.73; 95% CI [1.15–2.58]); and nonadherence to antihypertensive medication (AOR of 1.58; 95% CI [1.05–2.38]) were identified as risk factors for uncontrolled blood pressure. In hypertensive individuals, the percentage of uncontrolled blood pressure is considerable. It is essential to provide therapeutic education classes for hypertension patients in order to strengthen their power and autonomy in managing their hypertension.
Advanced strain elastography is a reliable approach for prostate cancer detection in patients with elevated PSA levels
Authors: Almalki Yassir Edrees , Mansour Mohamed Gamal El-Din , Ali Susan Adil , Basha Mohammad Abd Alkhalik , Abdelkawi Moustafa Mahmoud , Alduraibi Sharifa Khalid , Almushayti Ziyad A. , Aldhilan Asim S. , Aboualkheir Mervat , Amin Darine , Metkees Mohamed , Basha Ahmed M. A. , Ebaid Noha Yahia
Published: February 2024

This study aimed to examine the validity and reproducibility of strain elastography (SE) for detecting prostate cancer (PCa) in patients with elevated prostate-specific antigen (PSA) levels. The study included 107 patients with elevated PSA levels. All eligible patients underwent transrectal ultrasound (TRUS) with real-time elastography (RTE) to detect suspicious lesions. Two readers independently evaluated the lesions and assigned a strain ratio and elastography score to each lesion. Histopathology was used as a reference standard to estimate the validity of RTE in predicting malignant lesions. An intraclass correlation (ICC) was performed to detect reliability of the strain ratios and elastography scores. TRUS-guided biopsy detected malignancies in 64 (59.8%) patients. TRUS with RTE revealed 122 lesions. The strain ratio index (SRI) cut-off values to diagnose malignancy were 4.05 and 4.35, with sensitivity, specificity, and accuracy of 94.7%, 91.3%, and 93.4%, respectively. An elastography score > 3 was the best cut-off value for detecting malignancy. According to readers, the sensitivity, specificity, and accuracy were 91.3–94.7%, 89.5–93.4%, and 91.3–90.9%, respectively. Excellent inter-reader agreement was recorded for SRI and elastography scores, with ICC of 0.937 and 0.800, respectively. SE proves to be an efficient tool for detecting PCa with high accuracy in patients with elevated PSA levels.
Diagnostic value of renal biopsy in anti-phospholipase A2 receptor antibody-positive patients with proteinuria in China
Authors: Lu Shan , Xiao Jing , Liu Dong , Zhang Yan , Dong Yijun , Zhao Zhanzheng
Published: February 2024

Renal biopsy remains the gold standard for diagnosing membranous nephropathy (MN). Recent studies have suggested that renal biopsy can be replaced with the serum phospholipase A2 receptor (PLA2R) antibody test for MN diagnosis in patients with nephrotic syndrome. However, this test has not been validated in the Chinese population. In this study, we investigated whether renal biopsy provides additional diagnostic information on patients with proteinuria who are seropositive for PLA2R antibodies (SAb +). We retrospectively reviewed the clinicopathological characteristics of SAb + adult patients (aged ≥ 18 years) with proteinuria (≥ 0.5 g/24 h) assessed at the Department of Nephrology, the First Affiliated Hospital of Zhengzhou University, from June 2021 to March 2022. Among a total of 801 SAb + patients who received renal biopsy, those with incomplete pathological data, diabetes or any potential cause of secondary MN were excluded. Among the 491 remaining patients, 474 had primary MN (PMN), 16 had atypical MN (AMN, 9 patients with “full house” and 2 patients with HBsAg + /HBcAg + immunofluorescence results), and 1 had focal segmental glomerulosclerosis. In patients with an eGFR of ≥ 60 mL/min/1.73 m2 (n = 451), 436 had PMN, and 71 (16.3%) exhibited additional biopsy findings, with obesity-related glomerulopathy being the most common. In patients with an impaired eGFR (n = 40), 38 had PMN, and 31 (81.6%) showed additional findings, with acute tubular injury being the most common. In conclusion, anti-PLA2R antibody positivity is highly predictive of PMN in Chinese adults but often coexists with other pathological diagnoses. The advantages of renal biopsy for detecting other pathologies should be weighed against the potential risks of the biopsy procedure.
Comparison of noninvasive cardiac output and stroke volume measurements using electrical impedance tomography with invasive methods in a swine model
Authors: Chung Chi Ryang , Ko Ryoung Eun , Jang Geuk Young , Lee Kyounghun , Suh Gee Young , Kim Yongmin , Woo Eung Je
Published: February 2024

Pulmonary artery catheterization (PAC) has been used as a clinical standard for cardiac output (CO) measurements on humans. On animals, however, an ultrasonic flow sensor (UFS) placed around the ascending aorta or pulmonary artery can measure CO and stroke volume (SV) more accurately. The objective of this paper is to compare CO and SV measurements using a noninvasive electrical impedance tomography (EIT) device and three invasive devices using UFS, PAC-CCO (continuous CO) and arterial pressure-based CO (APCO). Thirty-two pigs were anesthetized and mechanically ventilated. A UFS was placed around the pulmonary artery through thoracotomy in 11 of them, while the EIT, PAC-CCO and APCO devices were used on all of them. Afterload and contractility were changed pharmacologically, while preload was changed through bleeding and injection of fluid or blood. Twenty-three pigs completed the experiment. Among 23, the UFS was used on 7 pigs around the pulmonary artery. The percentage error (PE) between COUFS and COEIT was 26.1%, and the 10-min concordance was 92.5%. Between SVUFS and SVEIT, the PE was 24.8%, and the 10-min concordance was 94.2%. On analyzing the data from all 23 pigs, the PE between time-delay-adjusted COPAC-CCO and COEIT was 34.6%, and the 10-min concordance was 81.1%. Our results suggest that the performance of the EIT device in measuring dynamic changes of CO and SV on mechanically-ventilated pigs under different cardiac preload, afterload and contractility conditions is at least comparable to that of the PAC-CCO device. Clinical studies are needed to evaluate the utility of the EIT device as a noninvasive hemodynamic monitoring tool.
Preference for diagnosing and treating renal colic during pregnancy: a survey among Chinese urologists
Authors: Deng Shidong , Guo Dayong , Liu Lingzhi , Wang Yurou , Fei Kuilin , Zhang Huihui
Published: February 2024

To explore the preference for diagnosing and treating renal colic during pregnancy among Chinese urologists. A questionnaire was designed using the Sojump® platform. WeChat, the largest social networking platform in China, was used to distribute the questionnaire to urologists at hospitals of all levels in China. In total, 110 responses were included. Of the respondents, 100.0% used ultrasound to diagnose renal colic during pregnancy, followed by magnetic resonance imaging (17.3%) and low-dose CT (3.6%). Phloroglucinol (80.9%) and progesterone (72.7%) were the most commonly used antispasmodics and analgesics. Opioid analgesics were not commonly used (12.7%). Most of the respondents (63.6%) indicated that no more than 20% of the patients needed surgical intervention. If surgery was unavoidable, 95.5% preferred temporary renal drainage, including ureteral stenting (92.7%) and percutaneous nephrostomy (2.7%). However, some respondents still preferred definitive stone treatment, such as ureteroscopy lithotripsy (3.6%) and percutaneous nephrolithotomy (0.9%). Moreover, there were no differences in the choices of urologists with different professional titles regarding diagnostic tools, most therapeutic medications, or surgical methods (p > 0.05). Ultrasound is the preferred tool for diagnosing renal colic during pregnancy. Low-dose CT is still not widely accepted. Pregnant patients with renal colic are initially treated conservatively. Urologists prefer ureteral stenting when there are clinical indications for intervention.
Chemical control of excited-state reactivity of the anionic green fluorescent protein chromophore
Authors: List Nanna H. , Jones Chey M. , Martínez Todd J.
Published: February 2024

Controlling excited-state reactivity is a long-standing challenge in photochemistry, as a desired pathway may be inaccessible or compete with other unwanted channels. An important example is internal conversion of the anionic green fluorescent protein (GFP) chromophore where non-selective progress along two competing torsional modes (P: phenolate and I: imidazolinone) impairs and enables Z-to-E photoisomerization, respectively. Developing strategies to promote photoisomerization could drive new areas of applications of GFP-like proteins. Motivated by the charge-transfer dichotomy of the torsional modes, we explore chemical substitution on the P-ring of the chromophore as a way to control excited-state pathways and improve photoisomerization. As demonstrated by methoxylation, selective P-twisting appears difficult to achieve because the electron-donating potential effects of the substituents are counteracted by inertial effects that directly retard the motion. Conversely, these effects act in concert to promote I-twisting when introducing electron-withdrawing groups. Specifically, 2,3,5-trifluorination leads to both pathway selectivity and a more direct approach to the I-twisted intersection which, in turn, doubles the photoisomerization quantum yield. Our results suggest P-ring engineering as an effective approach to boost photoisomerization of the anionic GFP chromophore.
Effect of vessel compression on blood flow in microvascular networks and its implications for tumour tissue hypoxia
Authors: Enjalbert Romain , Krüger Timm , Bernabeu Miguel O.
Published: February 2024

The tumour microenvironment is abnormal and one of its consequences is that blood vessels are compressed. Vessel compression correlates with reduced survival rates, while decompression of vessels improves tissue oxygenation as well as increases survival rates. Vessel compression contributes, at a single vascular bifurcation, to the increase of heterogeneity of red blood cell (RBC) transport. However, the effect that vessel compression has at a network level is unknown. This work numerically investigates the effect of vessel compression on RBC transport in microvascular networks. The key findings are that vessel compression both reduces the average haematocrit, and increases haematocrit heterogeneity, in vessels in the network. The mechanisms for these changes in haematocrit distribution are unravelled, and a parameter sweep shows that networks with lower inlet haematocrits are more susceptible to haemodilution from vessel compression over a wide range of compressed fraction of a network. These findings provide a theoretical underpinning for the link between vessel compression and tumour tissue hypoxia.
A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings
Authors: Véniant Murielle M. , Lu Shu-Chen , Atangan Larissa , Komorowski Renee , Stanislaus Shanaka , Cheng Yuan , Wu Bin , Falsey James R. , Hager Todd , Thomas Veena A. , Ambhaikar Malhar , Sharpsten Lucie , Zhu Yineng , Kurra Vamsi , Jeswani Rohini , Oberoi Rajneet K. , Parnes Jane R. , Honarpour Narimon , Neutel Joel , Strande Jennifer L.
Published: February 2024

Obesity is a major public health crisis. Multi-specific peptides have emerged as promising therapeutic strategies for clinical weight loss. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are endogenous incretins that regulate weight through their receptors (R). AMG 133 (maridebart cafraglutide) is a bispecific molecule engineered by conjugating a fully human monoclonal anti-human GIPR antagonist antibody to two GLP-1 analogue agonist peptides using amino acid linkers. Here, we confirm the GIPR antagonist and GLP-1R agonist activities in cell-based systems and report the ability of AMG 133 to reduce body weight and improve metabolic markers in male obese mice and cynomolgus monkeys. In a phase 1, randomized, double-blind, placebo-controlled clinical study in participants with obesity (NCT04478708), AMG 133 had an acceptable safety and tolerability profile along with pronounced dose-dependent weight loss. In the multiple ascending dose cohorts, weight loss was maintained for up to 150 days after the last dose. These findings support continued clinical evaluation of AMG 133.
Realtime monitoring of thrombus formation in vivo using a self-reporting vascular access graft
Authors: Hoare Daniel , Kingsmore David , Holsgrove Michael , Russell Ewan , Kirimi Mahmut T. , Czyzewski Jakub , Mirzai Nosrat , Kennedy Simon , Neale Steven L. , Mercer John R.
Published: February 2024

Background

Chronic kidney disease (CKD) affects 10% of the global population costing over a hundred billion dollars per annum and leading to increased risk of cardiovascular disease. Many patients with CKD require regular haemodialyses. Synthetic arteriovenous grafts (AVG) are increasingly used to provide rapid vascular connection for dialysis. Initially, they have excellent patency rates but are critically limited by neointimal hyperplasia at the venous anastomosis, which drives subsequent thrombosis, graft failure and death.

Methods

Here, we describe a system in which electrical impedance spectroscopy sensors are incorporated circumferentially into the wall of a synthetic arteriovenous graft. This is combined with an implantable radiotelemetry system for data transmission outside the patient. The system was tested using monolayers of endothelial and smooth muscle cells as well as swine blood and clots with explanted human carotid artery plaques. Sensor testing was then performed in vitro and the device was implanted in vivo in female swine.

Results

The device can wirelessly report the accumulation of biological material, both cells and blood. Differences are also detected when comparing controls with pathological atheroma. In swine differences between blockage formation in a graft were remotely obtained and wireless reported.

Conclusions

Combining electrical impedance spectroscopy and an implantable radiotelemetry system enables graft surveillance. This has the potential to be used for early detection of venous stenosis and blood clot formation in real-time in vivo. In principle, the concept could apply to other cardiovascular diseases and vascular implantable devices.