bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical observation of Gofried positive buttress reduction in the treatment of young femoral neck fracture: A systematic review and meta-analysis
Authors: Li Huankun , Chen Hongjun , She Ruihao , Li Yanhong , Qin Gang , Gan Fukai , Liang Huahui , Hu Baijun
Published: December 2023

Background:

Femoral neck fractures in young adults(<65 years), have always been a difficult problem, characterized by high rates of nonunion and avascular necrosis (AVN). The clinical efficacy of anatomical reduction and non-anatomical reduction methods needs to be supported by clinical data. Therefore, we conduct a meta-analysis on the clinical efficacy of different reduction methods to better guide clinical practice.

Methods:

Relevant studies published using internal fixation to treat femoral neck fracture in several databases were searched. The outcomes sought included Harris score and the rate of AVN, nonunion and femoral neck shortening (<5 mm). Included studies were assessed for methodological bias and estimates of effect were calculated. Potential reasons for heterogeneity were explored.

Results:

The clinical results showed that compared with the anatomical reduction and positive buttress, there is no significant difference in the rate of AVN (OR = 0.87, 95%CI: 0.55–1.37, P = .55), nonunion (OR = 0.54, 95%CI: 0.21–1.41, P = .21), femoral neck shortening (<5 mm) (OR = 1.03,95%CI: 0.57–1.86, P = .92), the Harris score (MD = −0.28, 95%CI: −1.36–0.80, P = .61) and the excellent and good rate of Harris score (OR = 1.73, 95%CI: 0.84–3.56, P = .61). However, compared with negative buttress, the rate of AVN (OR = 0.62, 95%CI: 0.38–1.01, P = .05), nonunion (OR = 0.34, 95%CI: 0.12–1.00, P = .05) and femoral neck shortening (<5 mm) (OR = 0.27, 95%CI: 0.16–0.45, P < .00001) were significantly lower, and the Harris score (MD = 6.53, 95%CI: 2.55 ~ 10.51, P = .001) was significantly better in positive buttress.

Conclusions:

In the case of difficult to achieve anatomical reduction, for young patients (< 65 years) with femoral neck fracture, reduction with positive buttress can be an excellent alternative and negative buttress should be avoided as much as possible.
Patient delay in chronic kidney disease: A qualitative study
Authors: Zheng Jie , Xue Bo-Wen , Guo Ao-Han , Feng Sheng-Ya , Gao Rong , Wu Shu-Yan , Liu Rong , Zhai Lin-Jun
Published: December 2023

This study aimed to investigate the reasons for patient delay in chronic kidney disease (CKD) and provide a scientific basis for implementing effective interventions. With the adoption of the phenomenological method in qualitative research, semi-structured, face-to-face interviews were conducted with 14 cases, and the Colaizzi seven-step analysis method was used to analyze the interview data and refine the themes. A total of 4 themes were obtained, namely, a cognitive explanation of illness, negative psychological emotions, socioeconomic levels, and limited medical resources. The current status of patient delay in chronic kidney disease is serious, and there are various reasons for it. Health management departments and healthcare providers at all levels should pay attention to this situation and provide targeted supportive interventions and health education to help patients establish the correct awareness of medical consultation and effectively improve their quality of survival.
Effectiveness of whole-body vibration in patients with cerebral palsy: A systematic review and meta-analysis
Authors: Han Yong-Gu , Kim Myoung-Kwon
Published: December 2023

Background:

This study examined the effects of systemic vibration exercises on cerebral palsy patients.

Methods:

Literature published in Cumulated Index to Nursing and Allied Health Literature (CINAHL), Cochrane library, Embase, Physiotherapy Evidence Database (PEDro), and PubMed was reviewed. A total of 2978 studies were initially retrieved. After further reading of the full texts 17 articles were finally included. A quality assessment of the included studies was conducted using the risk of bias (RoB) 2.0, and the Funnel plot and the Egger test were conducted to confirm the publication bias. Subgroup analysis was carried out according to the dependent variables, the international classification of functioning, disability, and health (ICF), frequency, treatment period and age.

Results:

The overall effect size of homogeneity was 0.474 (CI = 0.148–0.801). The analysis of the dependent variables showed the following order of the effect size: balance, muscle strength, spasticity, bone density, range of motion of the joint, gait function, and motor function. In the ICF classification, the effect size was observed to follow the order of body structure and function, activity, and participation. The effect size in the intervention according to the treatment period showed the following order: 7 to 12 weeks, 1 to 6 weeks, and 14 to 24 weeks. The age-dependent classification showed the following order in the effect size: school age, adolescent and adult, and infant and school age.

Conclusions:

Systemic vibration is the most effective intervention to improve the balance and gait in patients with cerebral palsy and improve the body structure and function according to the ICF.
Global knowledge mapping and emerging trends in Helicobacter pylori-related precancerous lesions of gastric cancer research: A bibliometric analysis from 2013 to 2023
Authors: Xiong Meng , Yu Chang , Ren Baoping , Zhong Meiqi , Peng Qinghua , Zeng Meiyan , Song Houpan
Published: December 2023

Helicobacter pylori (H pylori) infection is a crucial element in chronic gastritis progression towards precancerous lesions of gastric cancer (PLGC) formation and, potentially, gastric cancer; however, screening for and eliminating H pylori has several challenges. This study aimed to assess the present research status, prominent themes, and frontiers of H pylori-related PLGC and to provide impartial evaluations of the developmental trends in this domain. This study extracted articles and review papers concerning H pylori-related PLGC published from 2013 to 2023 from the Web of Science Core Collection. The data was analyzed and visualized using VOSviewer and CiteSpace. The study encompassed 1426 papers, with a discernible upward trend in publications between 2013 and 2023. China emerged as the most productive country, whereas the United States exerted the greatest influence. Baylor College of Medicine was the most prolific institution. World Journal of Gastroenterology featured the highest number of published papers, whereas Gastroenterology was the most frequently cited journal. Kim N. from South Korea was the most prolific author. Co-cited literature pertained to various aspects such as gastritis classification, H pylori infection management, gastric cancer prevention, and managing patients with PLGC. Future research will focus on the Kyoto classification, cancer incidence, and gastric intestinal metaplasia. The results of this study indicate a persistent increase in attention directed toward H pylori-associated PLGC. The research emphasis has transitioned from molecular mechanisms, epidemiology, monitoring, and diagnosis to clinical prevention and treatment methodologies. The forthcoming research direction in this area will concentrate on controlling and preventing malignant PLGC transformation.
A nomogram for the prediction of survival for colorectal signet ring cell carcinoma after surgery: A population-based study
Authors: Zhou Di , Yang Yong-Jing , Han Leng , Yu Yong-Jiang , Diao Jian-Dong
Published: December 2023

The aim was to construct and verify a nomogram-based assessment of cancer-specific survival (CSS) in patients with colorectal signet ring cell carcinoma after surgery. Patients were collected from Surveillance, Epidemiology, and End Results program between 2004 and 2015. Independent prognostic indicators were determined in the training cohort by Cox regression model. We identified 2217 eligible patients, who were further categorized into the training set (n = 1693) as well as the validation set (n = 524). Multivariate analysis revealed that age at diagnosis, gender, grade, tumor size, T stage, N stage, and M stage were independent predictive indicators. Then, the above 7 predictive factors were incorporated into a nomogram model to assess CSS, which showed good calibration and discrimination capacities in both sets. Both internal and external calibration plot diagrams revealed that the actual results were consistent with the predicted outcomes. The time-independent area under the curves for 3-year and 5-year CSS in the nomogram were larger than American Joint Committee on Cancer and Surveillance, Epidemiology, and End Results summary stage system. Moreover, decision curve analysis indicated the clinical utility of the nomogram. The nomogram demonstrated favorable predictive accuracy of survival in colorectal signet ring cell carcinoma patients after surgery, which should be further confirmed before clinical implementation.
Nosocomial infections in sickle cell anemia patients: Prevention through multi-disciplinary approach: A review
Authors: Obeagu Emmanuel Ifeanyi , Obeagu Getrude Uzoma , Akinleye Callistus Akinleye , Igwe Matthew Chibunna
Published: December 2023

Sickle cell anemia (SCA), a hereditary blood disorder characterized by the presence of abnormal hemoglobin, poses a unique set of challenges for both patients and healthcare providers. One of the most pressing issues in the care of these individuals is the persistent threat of nosocomial infections, which are infections acquired during hospitalization. This abstract provides a concise overview of the ongoing challenge of nosocomial infections in SCA patients, highlighting the factors contributing to their vulnerability and the preventive measures in place. SCA patients face increased susceptibility to nosocomial infections due to their compromised immune systems, frequent hospitalizations, prolonged stays, and the need for invasive medical interventions. The emergence of multidrug-resistant pathogens further complicates the management of these infections. To address this challenge, healthcare facilities have implemented infection control protocols, vaccination strategies, and antimicrobial stewardship, emphasizing the importance of patient education. Recognizing the gravity of this issue and adopting comprehensive preventive measures is crucial to improving the quality of care and patient outcomes in this vulnerable population. Further research and ongoing efforts are essential to reducing the burden of nosocomial infections in SCA patients and enhancing their overall healthcare experience.
Intraoperative hypotension affects postoperative acute kidney injury depending on the invasiveness of abdominal surgery: A retrospective cohort study
Authors: Fujii Tasuku , Takakura Masashi , Taniguchi Tomoya , Tamura Takahiro , Nishiwaki Kimitoshi
Published: December 2023

Intraoperative hypotension (IOH) or highly invasive surgery adversely affects postoperative clinical outcomes. It is, however, unclear whether IOH affects postoperative acute kidney injury (AKI) depending on the invasiveness of abdominal surgery. We speculated that IOH in highly invasive abdominal surgery is a significant risk factor for postoperative AKI. We retrospectively reviewed the data of 448 patients who underwent abdominal surgery. Patients were divided into 3 groups: highly (such as pancreaticoduodenectomy and hepatectomy), moderately (open abdominal surgery), and minimally (laparoscopic surgery) invasive surgeries. The association between the time-weighted average (TWA) of mean arterial pressure (MAP) values (≤60 and ≤ 55 mm Hg) and AKI occurrences in each group was assessed. Postoperative AKI occurred after highly, moderately, and minimally invasive surgeries in 33 of 222 (14.9%), 14 of 110 (12.7%), and 12 of 116 (10.3%) cases, respectively (P = .526). The median [interquartile range] of TWA-MAP ≤ 60 mm Hg, as an IOH parameter, was 0.94 [0.33–2.08] mm Hg in highly, 0.54 [0.16–1.46] mm Hg in moderately, and 0.14 [0.03–0.57] mm Hg in minimally invasive surgeries (P < 0001). In addition, there was a significant association between TWA-MAP and AKI in highly invasive surgery, unlike in moderately and minimally invasive surgery, with adjusted odds ratios (95% confidence interval) for TWA-MAP ≤ 60 and ≤ 55 mm Hg associated with AKI of 1.23 [1.00–1.52] (P = .049) and 1.55 [1.02–2.36] (P = .041), respectively. Intraoperative MAP ≤ 60 mm Hg in highly invasive abdominal surgery is associated with postoperative AKI, compared to moderately and minimally invasive surgeries. Additionally, low MAP thresholds in highly invasive surgery increase postoperative AKI risk.
Correlation analysis of central arterial pressure parameters and the severity of atherosclerotic lesions in coronary arteries: A retrospective study
Authors: Fang Fang , Huang Ying , Liu Zhiyong , Liu Xuemei , Huang Xiaoyun
Published: December 2023

To investigate the correlation between central arterial pressure (CAP) parameters and the severity of atherosclerotic lesions in the coronary arteries, understand the value of CAP in assessing the risk of coronary heart disease (CHD), and provide a theoretical basis for the prevention and treatment of CHD. Between January 2021 and January 2022, 224 patients admitted to our hospital for complete coronary angiography (CAG) were included in this retrospective study. CAP parameters, including central systolic pressure (CSP), diastolic pressure (CDP), and pulse pressure (CPP), and Gensini scores were collected; the association between CAP parameters and the severity of coronary lesions was analyzed using the Pearson correlation coefficient (r) and multivariate regression analysis. CPP was significantly higher in the coronary multi-branch lesion group than in the single-branch lesion group in patients with CHD (P < .05). CSP, CDP, and CPP were significantly higher in the high Gensini score group than in the low Gensini score group for coronary vascular lesions; furthermore, CSP and CPP were significantly higher in the high Gensini score group than in the medium Gensini score group (P < .05). Pearson correlation analysis showed that CSP and CPP were positively and CDP was negatively correlated with the severity of coronary artery lesions in patients with CHD (P < .05). Logistic regression analysis showed that a history of diabetes, CSP, CDP, and CPP were independent risk factors for severe atherosclerotic lesions in the coronary arteries (P < .05). noninvasive CAP-related indices, such as CSP, CDP, and CPP, are independently correlated with and can be used to predict the severity of coronary lesions in patients with CHD, which may be beneficial for guiding clinical diagnosis and treatment.
Anti-Nasopharyngeal carcinoma mechanism of sanguinarine based on network pharmacology and molecular docking
Authors: Fan Jing-Ying , Liu Jie , Zhang Wen-Qing , Lin Ting , Hu Xi-Ran , Zhou Fang-Liang , Tang Le , He Ying-Chun , Shi Hong-Jian
Published: December 2023

Background:

The purpose of this study was to investigate the mechanism of sanguinarine (SAN) against nasopharyngeal carcinoma (NPC) by means of network pharmacology, molecular docking technique, and experimental verification.

Methods:

The SAN action targets were predicted using the Swiss Target Prediction database, the related NPC targets were determined using the GEO database, and the intersection of drug and disease pathway targets were considered to be the potential targets of SAN against NPC. The target-protein interaction network map was constructed using the STRING database, and the core target genes of SAN against NPC were obtained via topological network analysis. “R” language gene ontology (GO) function and Kyoto encyclopedia of genes and genome (KEGG) pathway enrichment analyses were used to dock the core target genes with SAN with the help of AutodockVina. Cell proliferation was detected using MTT and xCELLigence real-time cell analysis. Apoptosis was identified via Hoechst 33342 staining, JC-1 mitochondrial membrane staining, and annexin V-FITC/PI double fluorescence staining, while protein expression was quantified using western blotting.

Results:

A total of 95 SAN against NPC targets were obtained using target intersection, and 8 core targets were obtained by topological analysis and included EGFR, TP53, F2, FN1, PLAU, MMP9, SERPINE1, and CDK1. Gene ontology enrichment analysis identified 530 items, and 42 items were obtained by Kyoto encyclopedia of genes and genome pathway enrichment analysis and were mainly related to the PI3K/AKT, MAPK, and p53 signaling pathways. Molecular docking results showed that SAN had good binding activity to the core target. SAN inhibited the proliferation of NPC cells, induced apoptosis, reduced the expression levels of survivin and Bcl2, and increased the expression levels of Bax and cleaved caspase-8. It also decreased the expression levels of the key proteins p-c-Raf, p-MEK, and p-ERK1/2 in the MAPK/ERK signaling pathway in NPC cells.

Conclusion:

SAN inhibits the proliferation and induces the apoptosis of NPC cells through the MAPK/ERK signaling pathway.
Effect of Liuzijue exercise in different periods on circadian rhythm of blood pressure in patients with essential hypertension: A randomized trial
Authors: Chen Yixiao , Liu Nannan , Guo Yuyan , Zheng Caiping , Fu Dijun , Cai Yugang , Nie Kaidi , Xia Lina
Published: December 2023

Background:

Exercising at different times of the day is a widely employed strategy for treating essential hypertension, aimed at enhancing the circadian rhythm of blood pressure. This study aimed to investigate the effects of Liuzijue exercise in the morning and afternoon on the circadian rhythm of blood pressure in patients with essential hypertension.

Methods:

This clinical randomized trial recruited 36 patients. They were randomly divided into 3 groups: morning exercise, afternoon exercise, and waiting treatment group. Randomization was performed at a ratio of 1:1:1, ensuring an equal distribution of participants among the 3 groups. Based on maintaining routine work and rest and continuing the original drug treatment, the exercise performed Liuzijue exercise for 12 weeks. The exercise time was 9:00 to 10:00 in the morning exercise group and 14:00 to 15:00 in the afternoon exercise group. The waiting treatment group did not perform any form of fitness exercise. The subjects in the 3 groups were monitored by 24-hour ambulatory blood pressure on the day before and after the first day.

Results:

After the 12-week Liuzijue exercise intervention, mean systolic blood pressure during the night significantly decreased in the morning exercise group (P < .01). In contrast, the waiting group experienced substantial increases in 24-hour mean systolic blood pressure (24hSBP), 24-hour mean diastolic blood pressure (24hDBP), mean systolic blood pressure during the daytime (dSBP), and mean diastolic blood pressure during the daytime (dDBP) (P < .01). Further analysis showed that the morning exercise group had significantly lower 24hSBP, 24hDBP, dSBP, dDBP, and mean systolic blood pressure during the night than the waiting group (P < .05). Additionally, the morning exercise group had lower 24hSBP and dSBP levels than the afternoon exercise group (P < .05). In contrast, the afternoon exercise group had lower 24hDBP and dDBP than the waiting treatment group (P < .05).

Conclusions:

The 12-week Liuzijue exercise in the morning regimen demonstrated superior efficacy in reducing 24-hour ambulatory blood pressure levels among patients with essential hypertension. Moreover, it facilitates the transition of non-dipper blood pressure patterns to dippers, thereby rectifying aberrant circadian rhythms.
The relationship between physical activity level and balance parameters, muscle strength, fear of falling in patients with hypertension
Authors: Özler Necati , Malkoç Mehtap , Angin Ender
Published: December 2023

The number of studies investigating the role of physical activity and exercise in hypertension (HT) patients is insufficient in the literature, and reports evaluating the relationship between HT, physical activity, and balance are lacking. This study aims to examine the relationship between physical activity levels and balance parameters, muscle strength, and fear of falling in patients with HT. 78 subjects with HT participated in this study. Demographic and clinical characteristics of all participants were recorded. Blood pressure was evaluated using a sphygmomanometer, physical activity level was assessed using a SenseWear Armband, fear of falling was assessed using the Fall Efficacy Scale, balance was assessed using the Fullerton Advanced Balance Scale, and muscle strength was evaluated using a digital handheld dynamometer. All 78 subjects completed the study as planned. The average age of participants was 57.75 ± 5.82, the mean systolic blood pressure was 133 ± 5.73, and the diastolic blood pressure was 84 ± 6.78. 34.2% of participants used angiotensin-converting enzyme inhibitors, 38% used beta blockers, and 26% used diuretic drugs. A positive correlation between physical activity and balance scores of individuals with HT was found (P < .005). It was also found that low muscle strength was associated with balance and risk of falling (P < .005). There is a positive correlation between decreased physical activity levels and balance in participants with HT. The results suggest that people with HT who have poor balance also have decreased muscle strength against gravity, such as in the quadriceps femoris and gluteus maximus. Overall, we recommend that patients with HT should improve their physical activity levels.
BIOFORMERS: A SCALABLE FRAMEWORK FOR EXPLORING BIOSTATES USING TRANSFORMERS
Authors: Amara-Belgadi Siham , Li Orion , Zhang David Yu , Gopinath Ashwin
Published: December 2023

Abstract

Generative pre-trained models, such as BERT and GPT, have demonstrated remarkable success in natural language processing and computer vision. Leveraging the combination of large-scale, diverse datasets, transformers, and unsupervised learning, these models have emerged as a promising method for understanding complex systems like language. Despite the apparent differences, human language and biological systems share numerous parallels. Biology, like language, is a dynamic, interconnected network where biomolecules interact to create living entities akin to words forming coherent narratives. Inspired by this analogy, we explored the potential of using transformer-based unsupervised model development for analyzing biological systems and proposed a framework that can ingest vast amounts of biological data to create a foundational model of biology using BERT or GPT. This framework focuses on the concept of a ‘biostate,’ defined as a high-dimensional vector encompassing various biological markers such as genomic, proteomic, transcriptomic, physiological, and phenotypical data. We applied this technique to a small dataset of single-cell transcriptomics to demonstrate its ability to capture meaningful biological insights into genes and cells, even without any pre-training. Furthermore, the model can be readily used for gene network inference and genetic perturbation prediction.
EngineeredBacillus subtilisas oral probiotics to enhance clearance of blood lactate
Authors: Yang Mengdi , Hutchinson Noah , Ye Ningyuan , Yin Jianing , Guan Ming , Wang Zongqi , Chen Peiru , Yang Shaobo , Crane Justin D. , Zhang Ke , He Xuesong , Li Jiahe
Published: December 2023

Elevated lactate concentrations are implicated in various acute and chronic diseases such as sepsis and mitochondrial dysfunction, respectively. Conversely, ineffective lactate clearance is associated with poor clinical prognoses and high mortality in these diseases. While several groups have proposed using small molecule inhibitors and enzyme replacement to reduce circulating lactate, there are few practical and effective ways to manage this condition. Recent evidence suggests that lactate is exchanged between systemic circulation and the gut, allowing bidirectional modulation between the gut microbiota and peripheral tissues. Inspired by these findings, this work seeks to engineer spore-forming probioticB. subtilisstrains to enable intestinal delivery of lactate oxidase as a therapeutic enzyme. After strain optimization, we showed that oral administration of engineeredB. subtilisspores to the gut of mice reduced elevations in blood lactate in two different mouse models involving exogenous challenge or pharmacologic perturbation without disrupting gut microbiota composition, liver function, or immune homeostasis. Taken together, through the oral delivery of engineered probiotic spores to the gastrointestinal tract, our proof-of-concept study offers a practical strategy to aid in the management of disease states with elevated blood lactate and provides a new approach to ‘knocking down’ circulating metabolites to help understand their roles in host physiological and pathological processes.

Significance Statement

This study pioneers the use of engineeredBacillus subtilisspores as an oral probiotic therapy to enhance the clearance of elevated blood lactate, a condition linked to severe health issues like sepsis and metabolic disorders. By genetically modifying these spores to deliver therapeutic enzymes directly to the gut, we demonstrated a practical, effective method to modulate systemic lactate levels. This approach leverages the natural exchange between the gut microbiota and systemic circulation, offering a new strategy for managing diseases associated with lactate dysregulation. The safety and efficacy of this method were validated in mouse models, providing a foundation for future clinical applications.
Constant-pH Molecular Dynamics Simulations of Closed and Open States of a Proton-gated Ion Channel
Authors: Jansen Anton , Bauer Paul , Howard Rebecca J. , Hess Berk , Lindahl Erik
Published: December 2023

Although traditional molecular dynamics simulations successfully capture a variety of different molecular interactions, the protonation states of titratable residues are kept static. A recentconstant-pHmolecular dynamics implementation in the GROMACS package allows pH effects to be captured dynamically, and promises to provide both the accuracy and computational performance required for studying pH-mediated conformational dynamics in large, complex systems containing hundreds of titratable residues. Here, we demonstrate the applicability of this constant-pH implementation by simulating the proton-gated ion channel GLIC at resting and activating pH, starting from closed and open structures. Our simulations identify residues E26 and E35 as especially pH-sensitive, and reveal state-dependent pKashifts at multiple residues, as well as side chain and domain rearrangements in line with the early stages of gating. Our results are consistent with several previous experimental findings, demonstrating the applicability of constant-pH simulations to elucidate pH-mediated activation mechanisms in multidomain membrane proteins, likely extensible to other complex systems.

Significance statement

Electrostatic interactions play important roles in protein structure and function. Since changes in pH will (de)protonate residues and thereby modify such interactions, pH itself is a critical environmental parameter. However, protonation states of titratable residues are static during classical molecular dynamics simulations. Recently, aconstant-pHalgorithm was implemented in the GROMACS package, allowing pH effects to be captured dynamically. Here, we used this implementation to perform constant-pH simulations of the proton-gated ion channel GLIC, providing insight into its activation mechanism by revealing state-dependent shifts in protonation as well as pH-dependent side chain and domain-level rearrangements. The results show that constant-pH simulations are both accurate and capable of modeling dozens of titratable sites, with important implications for e.g. drug design.
Somatic Mosaicism in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Reveals Widespread Degeneration from Focal Mutations
Authors: Zhou Zinan , Kim Junho , Huang August Yue , Nolan Matthew , Park Junseok , Doan Ryan , Shin Taehwan , Miller Michael B. , Chhouk Brian , Morillo Katherine , Yeh Rebecca C. , Kenny Connor , Neil Jennifer E. , Lee Chao-Zong , Ohkubo Takuya , Ravits John , Ansorge Olaf , Ostrow Lyle W. , Lagier-Tourenne Clotilde , Lee Eunjung Alice , Walsh Christopher A.
Published: December 2023

Although mutations in dozens of genes have been implicated in familial forms of amyotrophic lateral sclerosis (fALS) and frontotemporal degeneration (fFTD), most cases of these conditions are sporadic (sALS and sFTD), with no family history, and their etiology remains obscure. We tested the hypothesis that somatic mosaic mutations, present in some but not all cells, might contribute in these cases, by performing ultra-deep, targeted sequencing of 88 genes associated with neurodegenerative diseases in postmortem brain and spinal cord samples from 404 individuals with sALS or sFTD and 144 controls. Known pathogenic germline mutations were found in 20.6% of ALS, and 26.5% of FTD cases. Predicted pathogenic somatic mutations in ALS/FTD genes were observed in 2.7% of sALS and sFTD cases that did not carry known pathogenic or novel germline mutations. Somatic mutations showed low variant allele fraction (typically <2%) and were often restricted to the region of initial discovery, preventing detection through genetic screening in peripheral tissues. Damaging somatic mutations were preferentially enriched in primary motor cortex of sALS and prefrontal cortex of sFTD, mirroring regions most severely affected in each disease. Somatic mutation analysis of bulk RNA-seq data from brain and spinal cord from an additional 143 sALS cases and 23 controls confirmed an overall enrichment of somatic mutations in sALS. Two adult sALS cases were identified bearing pathogenic somatic mutations inDYNC1H1andLMNA,two genes associated with pediatric motor neuron degeneration. Our study suggests that somatic mutations in fALS/fFTD genes, and in genes associated with more severe diseases in the germline state, contribute to sALS and sFTD, and that mosaic mutations in a small fraction of cells in focal regions of the nervous system can ultimately result in widespread degeneration.
Profiling Expression Strategies for a Type III Polyketide Synthase in a Lysate-Based, Cell-free System
Authors: Sword Tien T. , Dinglasan Jaime Lorenzo N. , Abbas Ghaeath S. K. , Barker J. William , Spradley Madeline E. , Greene Elijah R. , Gooden Damian S. , Emrich Scott J. , Gilchrist Michael A. , Doktycz Mitchel J. , Bailey Constance B.
Published: December 2023

Some of the most metabolically diverse species of bacteria (e.g., Actinobacteria) have higher GC content in their DNA, differ substantially in codon usage, and have distinct protein folding environments compared to tractable expression hosts like Escherichia coli. Consequentially, expressing biosynthetic gene clusters (BGCs) from these bacteria in E. coli frequently results in a myriad of unpredictable issues with protein expression and folding, delaying the biochemical characterization of new natural products. Current strategies to achieve soluble, active expression of these enzymes in tractable hosts, such as BGC refactoring, can be a lengthy trial-and-error process. Cell-free expression (CFE) has emerged as 1) a valuable expression platform for enzymes that are challenging to synthesize in vivo, and as 2) a testbed for rapid prototyping that can improve cellular expression. Here, we use a type III polyketide synthase from Streptomyces griseus, RppA, which catalyzes the formation of the red pigment flaviolin, as a reporter to investigate BGC refactoring techniques. We synergistically tune promoter and codon usage to improve flaviolin production from cell-free expressed RppA. We then assess the utility of cell-free systems for prototyping these refactoring tactics prior to their implementation in cells. Overall, codon harmonization improves natural product synthesis more than traditional codon optimization across cell-free and cellular environments. Refactoring promoters and/or coding sequences via CFE can be a valuable strategy to rapidly screen for catalytically functional production of enzymes from BCGs. By showing the coordinators between CFE versus in vivo expression, this work advances CFE as a tool for natural product research.
The exotic thymidine modification 5-hydroxymethyluridine in dinoflagellateAmphidinium carterae
Authors: Li Chongping , Li Ying , Wang Yuci , Meng Ruixiang , Shi Xiaoyan , Zhang Yangyi , Liang Nan , Huang Hongda , Li Yue , Zhou Hui , Xu Jiawei , Xu Wenqi , Chen Hao
Published: December 2023

Dinoflagellate chromosomes are extraordinary, as their organization is independent of architectural nucleosomes unlike typical eukaryotes and shows a cholesteric liquid crystal state. 5-hydroxymethyluridine (5hmU) is present at unusually high levels and its function remains an enigma in dinoflagellates chromosomal DNA. Here, we demonstrate that 5hmU exhibits content variations in different dinoflagellates and is generated at the poly-nucleotide level through hydroxylation of thymidine. Importantly, we identified the enzyme, which is a putative dinoflagellate TET/JBP homologue, catalyzing 5hmU production using eitherin vivoorin vitrobiochemical assay. Based on the near-chromosomal level genome assembly of dinoflagellateAmphidinium carterae, we depicted a comprehensive 5hmU landscape and found that most 5hmU peaks share a conserved TG-rich motif, and are significantly enriched in repeat elements, which mark partially overlapping regions with 5-methylcytosine (5mC) sites. Moreover, inhibition of 5hmU via dioxygenase inhibitor leads to transcriptional activation of 5hmU-marked transposable elements (TEs), implying that 5hmU appears to serve as epigenetic marks for silencing retrotransposon. Together, our results revealed the biogenesis, genome-wide landscape and molecular function of dinoflagellate 5hmU, providing mechanic insight into the function of this enigmatic DNA mark.
Elucidating the Glycan-Binding Specificity and Structure ofCucumis meloAgglutinin, a New R-Type Lectin
Authors: Lundstrøm Jon , Gillon Emilie , Chazalet Valérie , Kerekes Nicole , Di Maio Antonio , Liu Yan , Feizi Ten , Varrot Annabelle , Bojar Daniel
Published: December 2023

Plant lectins have garnered attention for their roles as laboratory probes and potential therapeutics. Here, we report the discovery and characterization ofCucumis meloagglutinin (CMA1), a new R-type lectin from melon. Our findings reveal CMA1’s unique glycan-binding profile, mechanistically explained by its 3D structure, augmenting our understanding of R-type lectins. We expressed CMA1 recombinantly and assessed its binding specificity using multiple glycan arrays, covering 1,046 unique sequences. This resulted in a complex binding profile, strongly preferring C2-substituted, beta-linked galactose (both GalNAc and Fuca1-2Gal), which we contrasted with the established R-type RCA1 lectin. We also report binding of specific glycosaminoglycan subtypes and a general enhancement of binding by sulfation. Further validation using agglutination, thermal shift assays, and surface plasmon resonance confirmed and quantified this binding specificity in solution. Finally, we solved the high-resolution structure of the CMA1 N-terminal domain using X-ray crystallography, supporting our functional findings at the molecular level. Our study provides a comprehensive understanding of CMA1, laying the groundwork for further exploration of its biological and therapeutic potential.
Impact of disruptions in antigen processing and presentation machinery on sarcoma
Authors: Renne Salvatore Lorenzo , Sama’ Laura , Kumar Sonia , Mintemur Omer , Ruspi Laura , Santori Ilaria , Sicoli Federico , Bertuzzi Alexia , Laffi Alice , Bonometti Arturo , Colombo Piergiuseppe , D’amato Vittoria , Bressan Alessandra , Scorsetti Marta , Terracciano Luigi , Navarria Pierina , D’incalci Maurizio , Quagliuolo Vittorio , Pasqualini Fabio , Grizzi Fabio , Cananzi Ferdinando Carlo Maria
Published: December 2023

Background

The antigen processing machinery (APM) plays a critical role in generating tumor-specific antigens that can be recognized and targeted by the immune system. The status of the APM in sarcomas is not well characterized.

Methods

We investigated 126 patients with 8 types of bone and soft tissue sarcoma operated between 2001-2021. Tissue microarrays mapped 11 specific areas in each case. The presence/absence of APM protein was determined through immunohistochemistry. Bayesian networks were used.

Results

All investigated sarcomas had some defects in APM. The least damaged component was HLA Class I subunit β2-microglobulin and HLA Class II. The proteasome LMP10 subunit was defective in leiomyosarcoma (LMS), myxoid liposarcoma (MLPS), and dedifferentiated liposarcoma (DDLPS), while MHC I transporting unit TAP2 was altered in undifferentiated pleomorphic sarcoma (UPS), gastrointestinal stromal tumor (GIST), and chordoma (CH). Among different neoplastic areas, high-grade areas showed different patterns of expression compared to high lymphocytic infiltrate areas. Heterogeneity at the patient level was also observed. Loss of any APM component was prognostic of distant metastasis (DM) for LMS and DDLPS and of overall survival (OS) for LMS.

Conclusion

Sarcomas exhibit a high degree of defects in APM components, with differences among histotypes and tumoral areas. The most commonly altered APM components were HLA Class I subunit β2-microglobulin, HLA Class I subunit α (HC10), and MHC I transporting unit TAP2. The loss of APM components was prognostic of DM and OS and clinically relevant for LMS and DDLPS. This study explores sarcoma molecular mechanisms, enriching personalized therapeutic approaches.
Divergent trends in the incidence and mortality of coronary events, especially in women. Evidence from Finland in 1996-2021
Authors: Kallström Atte , Holopainen Ida , Kambur Oleg , Perola Markus , Salomaa Veikko , Havulinna Aki S. , Ramste Markus , Sinisalo Juha
Published: December 2023

Objective

Acute coronary syndrome (ACS) incidence and case fatality (CF) have declined in the past decades, but some studies have suggested a potential stagnation in this decline. We examined how the ACS burden has evolved among persons aged 35-74 in Finland from 1996 to 2021.

Methods

We used Finnish country-wide Hospital Discharge- and Causes of Death-Registers covering first non-fatal and fatal ACS events, totaling 69 906 442 person-years at risk. We analyzed incidence, mortality, and 28-day CF, and their trends using negative binomial, Poisson, segmented, and logistic regression adjusting for age and sex.

Results

Altogether, the analysis consisted of 186 489 non-fatal and 72 907 fatal ACS events. ACS incidence declined in men (annual percentage change (APC) −2.0% [95% CI −2.2 to −1.8]) and in older women (APC of 55-64 year old −1.5% [−1.7 to −1.2] and 65-74 year old −3.3% [−3.4 to −3.2]), but the incidence decline slowed down over the last decade. In younger women aged 35-54, incidence was unchanged during the study period. ACS mortality and CF declined (APC of the mortality in men - 4.4% [−4.6 to −4.2] and in women −5.0% [−5.2 to −4.7]. APC of CF in men −2.7% [−2.8 to −2.6] and in women −3.3% [−3.6 to −3.1]).

Conclusions

ACS mortality declined in all groups, but the decline in ACS incidence slowed down and even halted in women. In women aged 35-54, the incidence was unchanged during the study period. These results emphasize the need of intensified cardiovascular prevention, particularly in women.

Key messages

What is already known on this topic

During the last decades coronary artery disease treatment and prevention have improved worldwide which has led to a decline in ACS mortality and case fatality. However, recent studies from several countries suggest, that incidence decline has stagnated or even turned to increase, especially in younger age cohorts.

What this study adds

This study showed that incidence has ceased its decline in women aged 35-54 and has slowed down in older age groups. Together with declining mortality this results in a growing number of patients living with cardiovascular disease leading to increased healthcare costs.

How this study might affect research, practice, or policy

The alarming results of this study underline the importance of intensifying prevention, focusing especially on young and middle-aged women.
Assessment of transparency indicators in Space Medicine
Authors: Bellomo Rosa Katia , Zavalis Emmanuel A. , Ioannidis John P. A.
Published: December 2023

Space medicine is a vital discipline with often time-intensive and costly projects and constrained opportunities for studying various elements such as space missions, astronauts, and simulated environments. Moreover, private interests gain increasing influence in this discipline. In scientific disciplines with these features, transparent and rigorous methods are essential. Here, we undertook an evaluation of transparency indicators in publications within the field of space medicine. A meta-epidemiological assessment of PubMed Central Open Access (PMC OA) eligible articles within the field of space medicine was performed for prevalence of code sharing, data sharing, pre-registration, conflicts of interest, and funding. Text mining was performed with the rtransparent text mining algorithms with manual validation of 200 random articles to obtain corrected estimates. Across 1215 included articles, 39 (3%) shared code, 258 (21%) shared data, 10 (1%) were registered, 110 (90%) contained a conflict-of-interest statement, and 1141 (93%) included a funding statement. After manual validation, the corrected estimates for code sharing, data sharing, and registration were 5%, 27%, and 1%, respectively. Data sharing was 32% when limited to original articles and highest in space/parabolic flights (46%). Overall, across space medicine we observed modest rates of data sharing, rare sharing of code and almost non-existent protocol registration. Enhancing transparency in space medicine research is imperative for safeguarding its scientific rigor and reproducibility.
Classification of virologic trajectories during nucleos/tide analogue treatment of hepatitis B virus (HBV) infection
Authors: Wang Tingyan , Campbell Cori , Stockdale Alexander J , Todd Stacy , McIntyre Karl , Frankland Andrew , Jaworski Jakub , Glampson Ben , Papadimitriou Dimitri , Mercuri Luca , Jones Christopher R , Salih Hizni , Roadknight Gail , Little Stephanie , Noble Theresa , Várnai Kinga A , Davis Cai , Heinson Ashley I , George Michael , Borca Florina , English Louise , Romão Luis , Ramlakhan David ,   NIHR HIC Viral Hepatitis and Liver Disease Consortium, Woods Kerrie , Davies Jim , Nastouli Eleni , Khakoo Salim I , Gelson William , Cooke Graham S , Barnes Eleanor , Matthews Philippa C
Published: December 2023

Background & Aims

The dynamics of HBV viral load (VL) in patients with chronic hepatitis B (CHB) on nucleos/tide analogue (NA) treatment and its relationship with liver disease are poorly understood. We aimed to study longitudinal VL patterns and their associations with CHB clinical outcomes.

Methods

Utilising large scale, routinely collected electronic health records from six centres in England, collated by the National Institute for Health and Care Research Health Informatics Collaborative (NIHR HIC), we applied latent class mixed models to investigate VL trajectory patterns in adults receiving NA treatment. We assessed associations of VL trajectory with alanine transaminase (ALT), and with liver fibrosis/cirrhosis.

Results

We retrieved data from 1885 adults on NA treatment (median follow-up 6.2 years, interquartile range (IQR) 3.7-9.3 years), with 21,691 VL measurements (median 10 per patient, IQR 5-17). Five VL classes were identified from the derivation cohort (n=1367, discrimination: 0.93, entropy: 0.90): class 1 ‘long term suppression’ (n=827, 60.5%), class 2 ‘timely virological suppression’ (n=254, 18.6%), class 3 ‘persistent moderate viraemia’ (n=140, 10.2%), class 4 ‘persistent high-level viraemia’ (n=44, 3.2%), and class 5 ‘slow virological suppression’ (n=102, 7.5%). The model demonstrated a discrimination of 0.93 and entropy of 0.88 for the validation cohort (n=518). ALT decreased variably over time in VL-suppressed groups (classes 1, 2, 5; all p<0.001), but did not significantly improve in those with persistent viraemia (classes 3, 4). Patients in class 5 had 2-fold increased hazards of fibrosis/cirrhosis compared to class 1 (adjusted hazard ratio, 2.00; 95% CI, 1.33-3.02).

Conclusions

Heterogeneity exists in virological response to NA therapy in CHB patients, with over 20% showing potentially suboptimal responses. Slow virological suppression is associated with liver disease progression.
Antimicrobial resistance landscape in a metropolitan city context using open drain wastewater-based metagenomic analysis
Authors: Madhukar Manas Kumar , Singh Nirupama , Rajesh Iyer V , Sowpati Divya Tej , Tallapaka Karthik Bharadwaj , Mishra Rakesh Kumar , Moharir Shivranjani Chandrashekhar
Published: December 2023

The One Health concept recognizes the inextricable interactions of the diverse ecosystems and their subsequent effect on human, animal and plant health. Antimicrobial resistance (AMR) is a major One Health concern and is predicted to cause catastrophes if appropriate measures are not implemented. In this study, to understand the AMR landscape in metropolitan city context, we performed metagenomic analysis of open drain wastewater samples. We analysed 17 samples from open drains that receive influx from human, animal, agricultural and industrial wastes. Our data suggests that macrolide antibiotics have developed the highest resistance in the city through mutations in the 23S rRNA gene, which is present in multiple pathogens includingEscherichia coli, Campylobacter jejuni, Acinetobacter baumannii, Streptococcus pneumoniae, Pseudomonas aeruginosa, Neisseria gonorrhoeae, Klebsiella pneumoniaeandHelicobacter pylori. Except for a few geographical locations, most other locations show a similar landscape for AMR. Considering human mobility and other similar anthropogenic activities, we suggest that such an AMR landscape may be common across other regions.