bluuebunny/crossref_metadata_2025 huggingface dataset:
Computational insights into the cross-talk between medin and Aβ: implications for age-related vascular risk factors in Alzheimer’s disease
Authors: Huang Fengjuan , Fan Xinjie , Wang Ying , Zou Yu , Lian Jiangfang , Wang Chuang , Ding Feng , Sun Yunxiang
Published: January 2024

The aggregation of medin forming aortic medial amyloid is linked to arterial wall degeneration and cerebrovascular dysfunction. Elevated levels of arteriolar medin are correlated with an increased presence of vascular amyloid-β (Aβ) aggregates, a hallmark of Alzheimer’s disease (AD) and vascular dementia. The cross-interaction between medin and Aβ results in the formation of heterologous fibrils through co-aggregation and cross-seeding processes both in vitro and in vivo. However, a comprehensive molecular understanding of the cross-interaction between medin and Aβ—two intrinsically disordered proteins—is critically lacking. Here, we employed atomistic discrete molecular dynamics simulations to systematically investigate the self-association, co-aggregation and also the phenomenon of cross-seeding between these two proteins. Our results demonstrated that both Aβ and medin were aggregation prone and their mixture tended to form β-sheet-rich hetero-aggregates. The formation of Aβ-medin hetero-aggregates did not hinder Aβ and medin from recruiting additional Aβ and medin peptides to grow into larger β-sheet-rich aggregates. The β-barrel oligomer intermediates observed in the self-aggregations of Aβ and medin were also present during their co-aggregation. In cross-seeding simulations, preformed Aβ fibrils could recruit isolated medin monomers to form elongated β-sheets. Overall, our comprehensive simulations suggested that the cross-interaction between Aβ and medin may contribute to their pathological aggregation, given the inherent amyloidogenic tendencies of both medin and Aβ. Targeting medin, therefore, could offer a novel therapeutic approach to preserving brain function during aging and AD by improving vascular health.
MyoV: a deep learning-based tool for the automated quantification of muscle fibers
Authors: Gu Shuang , Wen Chaoliang , Xiao Zhen , Huang Qiang , Jiang Zheyi , Liu Honghong , Gao Jia , Li Junying , Sun Congjiao , Yang Ning
Published: January 2024

Accurate approaches for quantifying muscle fibers are essential in biomedical research and meat production. In this study, we address the limitations of existing approaches for hematoxylin and eosin-stained muscle fibers by manually and semiautomatically labeling over 660 000 muscle fibers to create a large dataset. Subsequently, an automated image segmentation and quantification tool named MyoV is designed using mask regions with convolutional neural networks and a residual network and feature pyramid network as the backbone network. This design enables the tool to allow muscle fiber processing with different sizes and ages. MyoV, which achieves impressive detection rates of 0.93–0.96 and precision levels of 0.91–0.97, exhibits a superior performance in quantification, surpassing both manual methods and commonly employed algorithms and software, particularly for whole slide images (WSIs). Moreover, MyoV is proven as a powerful and suitable tool for various species with different muscle development, including mice, which are a crucial model for muscle disease diagnosis, and agricultural animals, which are a significant meat source for humans. Finally, we integrate this tool into visualization software with functions, such as segmentation, area determination and automatic labeling, allowing seamless processing for over 400 000 muscle fibers within a WSI, eliminating the model adjustment and providing researchers with an easy-to-use visual interface to browse functional options and realize muscle fiber quantification from WSIs.
Multi-scale topology and position feature learning and relationship-aware graph reasoning for prediction of drug-related microbes
Authors: Xuan Ping , Gu Jing , Cui Hui , Wang Shuai , Toshiya Nakaguchi , Liu Cheng , Zhang Tiangang
Published: January 2024

Motivation

The human microbiome may impact the effectiveness of drugs by modulating their activities and toxicities. Predicting candidate microbes for drugs can facilitate the exploration of the therapeutic effects of drugs. Most recent methods concentrate on constructing of the prediction models based on graph reasoning. They fail to sufficiently exploit the topology and position information, the heterogeneity of multiple types of nodes and connections, and the long-distance correlations among nodes in microbe–drug heterogeneous graph.

Results

We propose a new microbe–drug association prediction model, NGMDA, to encode the position and topological features of microbe (drug) nodes, and fuse the different types of features from neighbors and the whole heterogeneous graph. First, we formulate the position and topology features of microbe (drug) nodes by t-step random walks, and the features reveal the topological neighborhoods at multiple scales and the position of each node. Second, as the features of nodes are high-dimensional and sparse, we designed an embedding enhancement strategy based on supervised fully connected autoencoders to form the embeddings with representative features and the more discriminative node distributions. Third, we propose an adaptive neighbor feature fusion module, which fuses features of neighbors by the constructed position- and topology-sensitive heterogeneous graph neural networks. A novel self-attention mechanism is developed to estimate the importance of the position and topology of each neighbor to a target node. Finally, a heterogeneous graph feature fusion module is constructed to learn the long-distance correlations among the nodes in the whole heterogeneous graph by a relationship-aware graph transformer. Relationship-aware graph transformer contains the strategy for encoding the connection relationship types among the nodes, which is helpful for integrating the diverse semantics of these connections. The extensive comparison experimental results demonstrate NGMDA’s superior performance over five state-of-the-art prediction methods. The ablation experiment shows the contributions of the multi-scale topology and position feature learning, the embedding enhancement strategy, the neighbor feature fusion, and the heterogeneous graph feature fusion. Case studies over three drugs further indicate that NGMDA has ability in discovering the potential drug-related microbes.

Availability and implementation

Source codes and Supplementary Material are available at https://github.com/pingxuan-hlju/NGMDA.
MAGE: metafounders-assisted genomic estimation of breeding value, a novel additive-dominance single-step model in crossbreeding systems
Authors: Zhuo Yue , Du Heng , Diao ChenGuang , Li WeiNing , Zhou Lei , Jiang Li , Jiang JiCai , Liu JianFeng
Published: January 2024

Motivation

Utilizing both purebred and crossbred data in animal genetics is widely recognized as an optimal strategy for enhancing the predictive accuracy of breeding values. Practically, the different genetic background among several purebred populations and their crossbred offspring populations limits the application of traditional prediction methods. Several studies endeavor to predict the crossbred performance via the partial relationship, which divides the data into distinct sub-populations based on the common genetic background, such as one single purebred population and its corresponding crossbred descendant. However, this strategy makes prediction inaccurate due to ignoring half of the parental information of crossbreed animals. Furthermore, dominance effects, although playing a significant role in crossbreeding systems, cannot be modeled under such a prediction model.

Results

To overcome this weakness, we developed a novel multi-breed single-step model using metafounders to assess ancestral relationships across diverse breeds under a unified framework. We proposed to use multi-breed dominance combined relationship matrices to model additive and dominance effects simultaneously. Our method provides a straightforward way to evaluate the heterosis of crossbreeds and the breeding values of purebred parents efficiently and accurately. We performed simulation and real data analyses to verify the potential of our proposed method. Our proposed model improved prediction accuracy under all scenarios considered compared to commonly used methods.

Availability and implementation

The software for implementing our method is available at https://github.com/CAU-TeamLiuJF/MAGE.
LRRC52 is likely a functional component of human KSper
Authors: Zhang Jiali , Zheng Liping , Chen Ying , Luo Tao , Zeng Xuhui , Kang Hang
Published: January 2024

Completion of fertilization is orchestrated by various ion channels in sperm membrane. Hyperpolarization of membrane potential, an indispensable event during the capacitation process, is dominated by sperm potassium channel (KSper). In addition to sperm-specific SLO3, which forms the channel pore, the auxiliary subunit leucine-rich-repeat-containing protein 52 (LRRC52) is required to form mKSper to function under physiological conditions. However, in human sperm, although most evidence supports that hSLO3 is the pore-forming subunit, whether hLRRC52 contributes to hKSper conductance and modulates sperm function remains to be understood. Here, using an extracellular segment that is homologous between mice and humans as an antigen, we developed a polyclonal antibody designed as LID1 that specifically detected mLRRC52 and performed co-immunoprecipitation with mSLO3. Additionally, patch-clamp recordings of mouse sperm showed that, physiological activation of mKSper and sperm functions were dramatically attenuated after treatment with LID1, indicating that LID1 functionally disrupted the regulation of mLRRC52 on mKSper. Next, LID1 was used to investigate the significance of hLRRC52 for hKSper activation. As a result, hLRRC52 was expressed in human sperm and might be assembled with hSLO3. More importantly, LID1 inhibited hKSper currents and depolarized sperm membrane potential, supporting essential modulation of hLRRC52 in hKSper. Ca2+ signaling of human sperm was also compromised in the presence of LID1, which impaired sperm motility and acrosome reaction. Because LID1 specifically inhibited both mKSper and hKSper but not mCatSper or hCatSper, our results suggest that hLRRC52 functions as an important component of hKSper and regulates sperm physiological functions.
Role of miRNAs in glucose metabolism of mouse cumulus cells
Authors: Ma Rui-Jie , Zhang Min , Wu Jia-Shun , Wang Zhi-Peng , Wang Guo-Liang , He Nan , Luo Ming-Jiu , Tan Jing-He
Published: January 2024

It is known that the oocyte has a limited capacity to acquire and metabolize glucose, and it must rely on cumulus cells (CCs) to take up glucose and produce pyruvate for use to produce ATP through oxidative phosphorylation. We therefore propose that miRNAs might regulate glucose metabolism (GM) in CCs and might be used as markers for oocyte quality assessment. Here, mouse CC models with impaired glycolysis or pentose phosphate pathway (PPP) were established, and miRNAs targeting the key enzymes in glycolysis/PPP were predicted using the miRNA target prediction databases. Expression of the predicted miRNAs was compared between CCs with normal and impaired glycolysis/PPP to identify candidate miRNAs. Function of the candidate miRNAs was validated by transfecting CCs or cumulus-oocyte-complexes (COCs) with miRNA inhibitors and observing effects on glucose metabolites of CCs and on competence of oocytes. The results validated that miR-23b-3p, let-7b-5p, 34b-5p and 145a-5p inhibited glycolysis, and miR-24-3p, 3078-3p,183-5p and 7001-5p inhibited PPP of CCs. Our observation using a more physiologically relevant model (intact cultured COCs) further validated the four glycolysis-targeting miRNAs we identified. Furthermore, miR-let-7b-5p, 34b-5p and 145a-5p may also inhibit PPP, as they decreased the production of glucose-6-phosphate. In conclusion, miRNAs play critical roles in GM of CCs and may be used as markers for oocyte quality assessment.

Summary sentence: 

We identified and validated eight new miRNAs that inhibit glycolysis and/or pentose phosphate pathways in cumulus cells (CCs) suggesting that miRNAs play critical roles in glucose metabolism of CCs and may be used for oocyte quality markers.
Radiomics-clinical nomogram for preoperative lymph node metastasis prediction in esophageal carcinoma
Authors: Geng Xiaotao , Zhang Yaping , Li Yang , Cai Yuanyuan , Liu Jie , Geng Tianxiang , Meng Xiangdi , Hao Furong
Published: January 2024

Objectives

This research aimed to develop a radiomics-clinical nomogram based on enhanced thin-section CT radiomics and clinical features for the purpose of predicting the presence or absence of metastasis in lymph nodes among patients with resectable esophageal squamous cell carcinoma (ESCC).

Methods

This study examined the data of 256 patients with ESCC, including 140 cases with lymph node metastasis. Clinical information was gathered for each case, and radiomics features were derived from thin-section contrast-enhanced CT with the help of a 3D slicer. To validate risk factors that are independent of the clinical and radiomics models, least absolute shrinkage and selection operator logistic regression analysis was used. A nomogram pattern was constructed based on the radiomics features and clinical characteristics. The receiver operating characteristic curve and Brier Score were used to evaluate the model's discriminatory ability, the calibration plot to evaluate the model's calibration, and the decision curve analysis to evaluate the model’s clinical utility. The confusion matrix was used to evaluate the applicability of the model. To evaluate the efficacy of the model, 1000 rounds of 5-fold cross-validation were conducted.

Results

The clinical model identified esophageal wall thickness and clinical T (cT) stage as independent risk factors, whereas the radiomics pattern was built based on 4 radiomics features chosen at random. Area under the curve (AUC) values of 0.684 and 0.701 are observed for the radiomics approach and clinical model, respectively. The AUC of nomogram combining radiomics and clinical features was 0.711. The calibration plot showed good agreement between the incidence of lymph node metastasis predicted by the nomogram and the actual probability of occurrence. The nomogram model displayed acceptable levels of performance. After 1000 rounds of 5-fold cross-validation, the AUC and Brier score had median values of 0.702 (IQR: 0.65, 7.49) and 0.21 (IQR: 0.20, 0.23), respectively. High-risk patients (risk point >110) were found to have an increased risk of lymph node metastasis [odds ratio (OR) = 5.15, 95% CI, 2.95-8.99] based on the risk categorization.

Conclusion

A successful preoperative prediction performance for metastasis to the lymph nodes among patients with ESCC was demonstrated by the nomogram that incorporated CT radiomics, wall thickness, and cT stage.

Advances in knowledge

This study demonstrates a novel radiomics-clinical nomogram for lymph node metastasis prediction in ESCC, which helps physicians determine lymph node status preoperatively.
Service implications of the revised 2022 National Institute for Health and Care Excellence (NICE) follow-up guidelines for stage IA–IIC melanoma
Authors: Dobbs Thomas D , Jovic Mathew , Ekakkaravichit Nattawan , Ali Stephen R , Gibson John A G , Ibrahim Nader , Hemington-Gorse Sarah , Whitaker Iain S
Published: January 2024

Background

The 2022 National Institute for Health and Care Excellence melanoma guideline update made significant changes to follow-up. The aim of this study was to assess the impact these changes will have on a national melanoma cohort over a 5-year follow-up interval.

Methods

Anonymized, individual-level, population-scale, linkable primary and secondary care National Health Service data for an 18-year interval (2000–2018) in Wales, UK were analysed. These data were used to predict the number of patients over a 10-year interval (2020–2030) that would be diagnosed with melanoma. Follow-up schedules for the 2015 and 2022 National Institute for Health and Care Excellence melanoma guidelines were then used to calculate the number of clinician-led appointments, the number of radiological investigations, and the total healthcare cost between 2025 and 2030, corresponding to a 5-year patient follow-up interval, for those with stage IA–IIC melanoma.

Results

Between 2025 and 2030 it is predicted that implementation of the 2022 guidelines would lead to 21 122 (range 19 194–23 083) fewer clinician-led appointments for patients with stage IA–IIC melanoma. However, there would be a significant increase in the number of radiological investigations (7812; range 7444–8189). These changes would lead to a €2.74 million (€1.87 million–€3.61 million) reduction in the total cost of follow-up over the interval 2025–2030.

Conclusion

Melanoma follow-up guideline changes will result in a substantial reduction in the number of clinical follow-up appointments, but a significant additional burden to radiological services. The overall cost of follow-up at a national level will be reduced.
‘I really hope this injection works’: living with psoriasis in prison
Authors: Rafferty Siobhan , Carty Kieran , Fleming Sarah , Andrawis Madonna , Byrne Berbie , Granahan Aoife , O’ Mahony Sarah , Drumm Claire , Tobin Anne-Marie
Published: January 2024

We highlight the unique challenges of living with psoriasis while in prison. As dermatologists we need to be cognisant of the barriers for prisoners in both accessing appropriate healthcare and maintaining continuity of care.
Addressing Longevity Inequality: How Retirement Age Differentiation Can Be Implemented
Authors: Jensen Svend E Hougaard , Sveinsson Thorsteinn Sigurdur , Zoega Gylfi
Published: January 2024

Differences in life expectancy across socioeconomic groups create a serious problem of inequality within the public part of the pension system. This article considers two actuarially sound ways of addressing longevity inequality. The first is to allow low life-expectancy workers to retire earlier and delay the retirement of the high life-expectancy workers so that the two groups receive the same amount, equal to the expected discounted value of future pension benefits received by the average worker under the current system. The second, and more radical, is to delegate to occupational pension funds the task of paying out the public pension benefits to each retiree, based on a lump-sum transfer from the government to the pension funds of an amount for each retiree equivalent to the payout in the first scenario. (JEL codes: E21 and E24)
The Leaders in Epidemiology, Antimicrobial Stewardship, and Public Health (LEAP) Fellowship, a Novel Training Program in Public Health for Infectious Diseases Physicians
Authors: Hsueh Kevin , Teherani Arianne , Guzman-Cottrill Judith A
Published: January 2024

The severe acute respiratory syndrome coronavirus 2 pandemic demonstrated a critical need for partnerships between practicing infectious diseases (ID) physicians and public health departments. The soon-to-launch combined ID and Epidemic Intelligence Service fellowship can only address a fraction of this need, and otherwise US ID training lacks development pathways for physicians aiming to make careers working with public health departments. The Leaders in Epidemiology, Antimicrobial Stewardship, and Public Health (LEAP) fellowship is a model compatible with the current training paradigm with a proven track record of developing careers of long-term collaboration. Established in 2017 by the ID Society of America, Society for Healthcare Epidemiology of America, Pediatric ID Society, and supported by the Centers for Disease Control and Prevention, LEAP is a single-year in-place, structured training for senior trainees and early career ID physicians. In this viewpoint, we describe the LEAP fellowship, its outcomes, and how it could be adapted into ID training.
Success of the US Veterans Health Administration's Hepatitis C Virus Care Continuum in the Direct-acting Antiviral Era
Authors: Varley Cara D , Lowy Elliott , Cartwright Emily J , Morgan Timothy R , Ross David B , Rozenberg-Ben-Dror Karine , Beste Lauren A , Maier Marissa M
Published: January 2024

Background

Estimated hepatitis C prevalence within the Veterans Health Administration is higher than the general population and is a risk factor for advanced liver disease and subsequent complications. We describe the hepatitis C care continuum within the Veterans Health Administration 1 January 2014 to 31 December 2022.

Methods

We included individuals in Veterans Health Administration care 2021–2022 who were eligible for direct-acting antiviral treatment 1 January 2014 to 31 December 2022. We evaluated the proportion of Veterans who progressed through each step of the hepatitis C care continuum, and identified factors associated with initiating direct-acting antivirals, achieving sustained virologic response, and repeat hepatitis C viremia.

Results

We identified 133 732 Veterans with hepatitis C viremia. Hepatitis C treatment was initiated in 107 134 (80.1%), with sustained virologic response achieved in 98 136 (91.6%). In those who achieved sustained virologic response, 1097 (1.1%) had repeat viremia and 579 (52.8%) were retreated for hepatitis C. Veterans of younger ages were less likely to initiate treatment and achieve sustained virologic response, and more likely to have repeat viremia. Stimulant use and unstable housing were negatively associated with each step of the hepatitis C care continuum.

Conclusions

The Veterans Health Administration has treated 80% of Veterans with hepatitis C in care 2021–2022 and achieved sustained virologic response in more than 90% of those treated. Repeat viremia is rare and is associated with younger age, unstable housing, opioid use, and stimulant use. Ongoing efforts are needed to reach younger Veterans, and Veterans with unstable housing or substance use disorders.
Left-behind places in central and eastern Europe—labour productivity aspect
Authors: Dobrzanski Pawel , Bobowski Sebastian , Clare Karenjit
Published: January 2024

In the 21st century, there have already been a series of economic downturns, particularly the Subprime Crisis 2007–2009 and the Covid-19 pandemic in 2020. All those events triggered changes in productivity, economic performance and structure. The main objective of this study is to identify the regions left behind in the Central and Eastern European (CEE) countries and to analyse the structural and productivity changes taking place within them. In our analysis, we aim to verify the research hypothesis that all left-behind regions in CEE have similar economic structures with a high share of agriculture. The research period covers the years from 2010 until 2020 using data from the Eurostat database. In the first phase of our analysis, we analysed employment, Gross Value Added (GVA) and productivity data for 11 CEE countries. Then, we analysed the Nomenclature of Territorial Units for Statistics at level 3 (NUTS3) regions, and Poland, which is a NUTS2 region. Left-behind regions are defined as those with low productivity and low growth rates. We provide a detailed analysis of the best and worst performing regions in terms of productivity for each country using productivity data and shift-share decomposition of productivity growth rate. Left-behind regions for each CEE country have been identified, and these are BG333, BG342, CZ080, EE004, HR023, HU332, LT027, LV005, PL72, RO216, RO312, SI032, SI035, SI038 and SK032. In our analysis, our hypothesis analysing the relationship between agriculture share in total employment and the productivity level of the region was not confirmed.
Microangiopathy associated with poor outcome of immunoglobulin A nephropathy: a cohort study and meta-analysis
Authors: Dong Lei , Hu Yuncan , Yang Dan , Liu Liu , Li Yueqiang , Ge Shuwang , Yao Ying
Published: January 2024

Background

Microangiopathy (MA) lesions are not rare in immunoglobulin A nephropathy (IgAN) and have been suggested to have a potential role in increasing risk in renal function decline. However, this suggestion has not been universally accepted. We aimed to investigate its role in our cohort and in multiple studies through a systematic meta-analysis.

Methods

This cohort study included 450 IgAN patients, confirmed by renal biopsy, at Tongji Hospital, China, from January 2012 to December 2016. Clinical data were collected and analysed. We systematically searched PubMed and Web of Science for studies investigating the association between MA lesions and IgAN.

Results

In our cohort, IgAN patients with MA were significantly older and had higher blood pressure, more proteinuria, worse kidney function and increased uric acid levels compared with patients without MA. When comparing pathological features with the non-MA group, the MA group exhibited more global glomerulosclerosis and interstitial fibrosis/tubular atrophy. MA lesions were independently associated with a composite kidney outcome in IgAN patients {adjusted hazard ratio 2.115 [95% confidence interval (CI) 1.035–4.320], P = .040}. Furthermore, this relationship was validated in a meta-analysis involving 2098 individuals from five independent cohorts. The combined data showed a 187% adjusted risk of poor renal outcome in IgAN patients with MA compared with patients without MA [adjusted risk ratio 2.87 (95% CI 2.05–4.02; I2 = 53%).

Conclusion

MA lesions could serve as a valuable predictor for disease progression in patients with IgAN, extending beyond the widely recognized Oxford MEST-C score.
Modelling bus-based substitution capabilities for metro systems using bipartite graphs
Authors: Kopsidas Athanasios , Kepaptsoglou Konstantinos
Published: January 2024

A disruption of metro services can have a negative impact in the performance of a city’s transportation system and hinder mobility needs of travellers. Investigating the vulnerability of metro systems is required for planning mitigation actions, such as bus substitution services. This study develops a model, which consists of a bipartite graph and its projection to represent the bus substitution capabilities for metro networks. The proposed methodology effectively identifies significant substitution elements (bus lines), evaluates the robustness of alternative options in terms of both connectedness and connectivity, and suggests effective strategies for enhancing bus line capacity to improve network robustness. By applying the methodology to a real-world metro network, valuable insights are gained regarding important bus lines and substitution robustness. Study findings suggest that approaches based on the weighted degree exhibit the greatest effectiveness when it comes to connectivity and the overall efficiency of the network. These findings can assist public transport operators in proactively managing disruptions and improving their services.
Towards a semi-local random walk technique through multilayer social networks to improve link prediction
Authors: Chen Suxia , Zhang Jiachen , Zhang Guijie , Rezaeipanah Amin
Published: January 2024

The rapid expansion of social networks has generated a growing need for scalable algorithms capable of effectively predicting links. Link prediction is a crucial area of study within complex networks research. Link prediction aims to predict future connections between nodes from the current snapshot of the network and plays a vital role in estimating the growth of social networks. This article introduces an improved approach to link prediction in social networks by exploiting an extended version of local random walk as semi-local random walk (SLRW) for multilayer social networks. Here, taking into account the connectivity and structural similarity of the involved nodes, we propose the SLRW method to acquire nodes sequence with the highest similarity. Also, SLRW metric includes a distributed technique to identify the nearest neighbours by considering the extended neighbourhood concept. To ensure optimal performance, we conduct extensive studies on various hyperparameters of the proposed metric. The experimental results conducted on different datasets demonstrate that the proposed metric achieves improvements in the field of link prediction compared to the state-of-the-art baselines.
Ecto-CD38-NADase inhibition modulates cardiac metabolism and protects mice against doxorubicin-induced cardiotoxicity
Authors: Peclat Thais R , Agorrody Guillermo , Colman Laura , Kashyap Sonu , Zeidler Julianna D , Chini Claudia C S , Warner Gina M , Thompson Katie L , Dalvi Pranjali , Beckedorff Felipe , Ebtehaj Sanam , Herrmann Joerg , van Schooten Wim , Chini Eduardo Nunes
Published: January 2024

Aims

Doxorubicin (DXR) is a chemotherapeutic agent that causes dose-dependent cardiotoxicity. Recently, it has been proposed that the NADase CD38 may play a role in doxorubicin-induced cardiotoxicity (DIC). CD38 is the main NAD+-catabolizing enzyme in mammalian tissues. Interestingly, in the heart, CD38 is mostly expressed as an ecto-enzyme that can be targeted by specific inhibitory antibodies. The goal of the present study is to characterize the role of CD38 ecto-enzymatic activity in cardiac metabolism and the development of DIC.

Methods and results

Using both a transgenic animal model and a non-cytotoxic enzymatic anti-CD38 antibody, we investigated the role of CD38 and its ecto-NADase activity in DIC in pre-clinical models. First, we observed that DIC was prevented in the CD38 catalytically inactive (CD38-CI) transgenic mice. Both left ventricular systolic function and exercise capacity were decreased in wild-type but not in CD38-CI mice treated with DXR. Second, blocking CD38-NADase activity with the specific antibody 68 (Ab68) likewise protected mice against DIC and decreased DXR-related mortality by 50%. A reduction of DXR-induced mitochondrial dysfunction, energy deficiency, and inflammation gene expression were identified as the main mechanisms mediating the protective effects.

Conclusion

NAD+-preserving strategies by inactivation of CD38 via a genetic or a pharmacological-based approach improve cardiac energetics and reduce cardiac inflammation and dysfunction otherwise seen in an acute DXR cardiotoxicity model.
Radiographic complicated and uncomplicated descending aortic dissections: aortic morphological differences by CT angiography and risk factor analysis
Authors: Berger Tim , Maier Annika , Kletzer Joseph , Schlett Christopher L , Kondov Stoyan , Czerny Martin , Rylski Bartosz , Kreibich Maximilian
Published: January 2024

Aims

To identify radiographic differences between patients with uncomplicated and complicated descending aortic dissections.

Methods and results

Between April 2009 and July 2021, 209 patients with acute descending aortic dissections were analysed as complicated (malperfusion, rupture, diameter progress, and diameter ≥ 55 mm) or uncomplicated. Detailed CTA measurements (slice thickness ≤ 3 mm) were taken in multiplanar reconstruction. A composite endpoint (early aortic failure) was defined as reoperation, diameter progression, and early mortality. Seventy-seven patients were female (36.8%) [complicated n = 27 (36.5%); uncomplicated n = 50 (37.0%) P = 1.00]. Seventy-four (35%) patients were categorized as morphologically complicated, and 135 (65%) as uncomplicated. In patients with complicated dissections, the dissection extended more frequently to the aortic bifurcation (P = 0.044), the coeliac trunk (P = 0.003), the superior mesenteric artery (P = 0.007), and both iliac arteries (P < 0.001) originated less frequently from the true lumen. The length of the most proximal communication (entry) in type B aortic dissection was longer, 14.0 mm [12.0 mm; 27.0 mm] vs. 6.0 mm [4,0 mm; 13.0 mm] in complicated cases (P = 0.005). Identified risk factors for adverse aortic events were connective tissue disease [HR 8.0 (1.9–33.7 95% CI HR)], length of the aortic arch [HR 4.7 (1.5–15.1 95% CI HR)], a false lumen diameter > 19.38 mm [HR 3.389 (1.1–10.2 95% CI HR)], and origin of the inferior mesenteric artery from the false lumen [HR 4.2 (1.0–5.5 95% CI HR)].

Conclusion

We identified significant morphological differences and predictors for adverse events in patients presenting complicated and uncomplicated descending dissections. Our morphological findings will help guide future aortic therapies, taking a tailored patient approach.
Mortality Risk Information, Survival Expectations and Sexual Behaviours
Authors: Ciancio Alberto , Delavande Adeline , Kohler Hans-Peter , Kohler Iliana V
Published: January 2024

We investigate the impact of a randomised information intervention about population-level mortality on health investment and subjective health expectations. Our focus is on risky sex in a high-HIV-prevalence environment. Treated individuals are less likely to engage in risky sexual practices one year after the intervention, with, for example, an 8% increase in abstinence. We collected detailed data on individuals’ subjective expectations about their own and population survival, as well as other important health outcomes. Our findings emphasise the significance of integrating subjective expectation data in field experiments to identify the pathways that lead to behavioural change.
Collateral Damage: The Legacy of the Secret War in Laos
Authors: Riaño Juan Felipe , Valencia Caicedo Felipe
Published: January 2024

We investigate the long-term impact of conflict on economic development, focusing on the US ‘Secret War’ in Laos (1964–73). Our study employs multiple empirical strategies and data on bombing campaigns, satellite imagery, and development indicators to demonstrate that regions heavily bombed during this period experienced lower economic development almost fifty years after the conflict officially ended. A one-standard-deviation increase in bombing intensity is associated with a 7.1% decrease in GDP per capita. We demonstrate the persistent effects of bombing campaigns on human capital accumulation, structural transformation and migration patterns, stressing the role of unexploded ordnance contamination as the primary mechanism of transmission of these effects.
John Sheppard (c.1514–1558/59) at Oxford and the Chapel Royal: exculpation and clarification
Authors: Bowers Roger
Published: January 2024

The received biography available for the English composer John Sheppard (c.1514 – late 1558 or early 1559) is amenable to clarification at a number of points. He was employed as Master of the Choristers at Magdalen College, Oxford, for just a single spell, September 1543 to early 1548. The available evidence suggests that he proceeded thence directly to admission to the Chapel Royal. He had no further contact with Magdalen College; an instance of kidnap and confinement perpetrated in 1555 that is commonly attributed to him was instead committed by one Richard Sheparde/Sheper/Sheprey, a fellow of the college. Despite being only an imperfect draft, his ‘will’ of 1 December 1558 reveals much about his family circumstances at Westminster. He died between 1 December 1558 and 31 January 1559; the actual date must be reconcilable with expectation of his attendance at Queen Elizabeth’s coronation on 15 January 1559, as recorded on a list compiled not earlier than 15 December 1558.
Area-level excess mortality in times of COVID-19 in Switzerland: geographical, socioeconomic and political determinants
Authors: Riou Julien , Panczak Radoslaw , Konstantinoudis Garyfallos , Egger Matthias
Published: January 2024

The coronavirus disease 2019 (COVID-19)-related excess mortality in Switzerland is well documented, but no study examined mortality at the small-area level. We analysed excess mortality in 2020 for 2141 Swiss municipalities using a Bayesian spatiotemporal model fitted to 2011–19 data. Areas most affected included the Ticino, the Romandie and the Northeast. Rural areas, municipalities within cross-border labour markets, of lower socioeconomic position and with less support for control measures in the popular vote on the COVID-19 Act had greater excess mortality. Particularly vulnerable municipalities require special efforts to mitigate the impact of pandemics.
Construction of an economical xylose-utilizing Saccharomyces cerevisiae and its ethanol fermentation
Authors: Li Fan , Bai Wenxin , Zhang Yuan , Zhang Zijian , Zhang Deguo , Shen Naidong , Yuan Jingwei , Zhao Guomiao , Wang Xiaoyan
Published: January 2024

Traditional industrial Saccharomyces cerevisiae could not metabolize xylose due to the lack of a specific enzyme system for the reaction from xylose to xylulose. This study aims to metabolically remould industrial S. cerevisiae for the purpose of utilizing both glucose and xylose with high efficiency. Heterologous gene xylA from Piromyces and homologous genes related to xylose utilization were selected to construct expression cassettes and integrated into genome. The engineered strain was domesticated with industrial material under optimizing conditions subsequently to further improve xylose utilization rates. The resulting S. cerevisiae strain ABX0928-0630 exhibits a rapid growth rate and possesses near 100% xylose utilization efficiency to produce ethanol with industrial material. Pilot-scale fermentation indicated the predominant feature of ABX0928-0630 for industrial application, with ethanol yield of 0.48 g/g sugars after 48 hours and volumetric xylose consumption rate of 0.87 g/l/h during the first 24 hours. Transcriptome analysis during the modification and domestication process revealed a significant increase in the expression level of pathways associated with sugar metabolism and sugar sensing. Meanwhile, genes related to glycerol lipid metabolism exhibited a pattern of initial increase followed by a subsequent decrease, providing a valuable reference for the construction of efficient xylose-fermenting strains.
Modeling basal area yield using simultaneous equation systems incorporating uncertainty estimators
Authors: Sandoval Simón , Montes Cristián R , Bullock Bronson P
Published: January 2024

Over the last three decades, many growth and yield systems developed for the southeast USA have incorporated methods to create a compatible basal area (BA) prediction and projection equation. This technique allows practitioners to calibrate BA models using both measurements at a given arbitrary age, as well as the increment in BA when time series panel data are available. As a result, model parameters for either prediction or projection alternatives are compatible. One caveat of this methodology is that pairs of observations used to project forward have the same weight as observations from a single measurement age, regardless of the projection time interval. To address this problem, we introduce a variance–covariance structure giving different weights to predictions with variable intervals. To test this approach, prediction and projection equations were fitted simultaneously using an ad hoc matrix structure. We tested three different error structures in fitting models with (i) homoscedastic errors described by a single parameter (Method 1); (ii) heteroscedastic errors described with a weighting factor ${w}_t$ (Method 2); and (iii) errors including both prediction ($\overset{\smile }{\varepsilon }$) and projection errors ($\tilde{\varepsilon}$) in the weighting factor ${w}_t$ (Method 3). A rotation-age dataset covering nine sites, each including four blocks with four silvicultural treatments per block, was used for model calibration and validation, including explicit terms for each treatment. Fitting using an error structure which incorporated the combined error term ($\overset{\smile }{\varepsilon }$ and $\tilde{\varepsilon}$) into the weighting factor ${w}_t$ (Method 3), generated better results according to the root mean square error with respect to the other two methods evaluated. Also, the system of equations that incorporated silvicultural treatments as dummy variables generated lower root mean square error (RMSE) and Akaike’s index values (AIC) in all methods. Our results show a substantial improvement over the current prediction-projection approach, resulting in consistent estimators for BA.
SlWRKY80-mediated jasmonic acid pathway positively regulates tomato resistance to saline–alkali stress by enhancing spermidine content and stabilizing Na+/K+ homeostasis
Authors: Shang Chunyu , Liu Xiaoyan , Chen Guo , Zheng Hao , Khan Abid , Li Guobin , Hu Xiaohui
Published: January 2024

Saline–alkali is an important abiotic stressor influencing tomato production. Exogenous methyl jasmonate (MeJA) is well known to increase tomato resistance to a variety of stresses, although its exact mechanism is yet unknown. In this study we confirmed that 22.5 μmol/l MeJA could significantly improve the saline–alkali stress resistance of tomato. Saline–alkali (300 mM) stress increased the endogenous MeJA and jasmonic acid (JA) contents of tomato by 18.8 and 13.4%, respectively. Exogenous application of 22.5 μmol/l MeJA increased the endogenous MeJA and JA contents in tomato by 15.2 and 15.9%, respectively. Furthermore, we found an important transcription factor, SlWRKY80, which responded to MeJA, and constructed its overexpressing and knockout lines through genetic transformation. It was found that SlWRKY80 actively regulated tomato resistance to saline–alkali stress, and the spraying of exogenous MeJA (22.5 μmol/l) reduced the sensitivity of SlWRKY80 knockout lines to saline–alkali stress. The SlWRKY80 protein directly combines with the promoter of SlSPDS2 and SlNHX4 to positively regulate the transcription of SlSPDS2 and SlNHX4, thereby promoting the synthesis of spermidine and Na+/K+ homeostasis, actively regulating saline–alkali stress. The augmentation of JA content led to a notable reduction of 70.6% in the expression of SlJAZ1, and the release of the SlWRKY80 protein interacting with SlJAZ1. In conclusion, we revealed the mechanism of exogenous MeJA in tomato stress resistance through multiple metabolic pathways, elucidated that exogenous MeJA further promotes spermidine synthesis and Na+/K+ homeostasis by activating the expression of SlWRKY80, which provides a new theoretical basis for the study of the JA stress resistance mechanism and the production of tomato.
Risk of Common Neurological Disorders in Adult Patients with Inflammatory Bowel Disease: A Systematic Review and Meta-analysis
Authors: Zamani Mohammad , Ebrahimtabar Forough , Alizadeh-Tabari Shaghayegh , Kasner Scott E , Elkind Mitchell S V , Ananthakrishnan Ashwin N , Choden Tenzin , Rubin David T , Malekzadeh Reza
Published: January 2024

Background

Several studies investigated the risks of neurological conditions in patients with inflammatory bowel disease (IBD), with some variability in findings. We aimed to perform a systematic review and meta-analysis of available evidence to elucidate the association between IBD and the risks of common neurological disorders.

Methods

We conducted a literature search through Embase, PubMed, Scopus, and ProQuest databases from inception to June 30, 2023, to identify cohort studies assessing the risk of developing stroke, all-cause dementia, Parkinson’s disease (PD), multiple sclerosis (MS), seizure/epilepsy, and peripheral neuropathy in adult IBD patients compared with non-IBD population. We combined hazard ratios (HRs) with 95% confidence intervals (CIs) to compute pooled estimates using a random-effects model.

Results

In total, 22 cohort studies were included, of which 9 studies reported 7074 stroke events in 202 460 IBD patients, 5 studies reported 3783 all-cause dementia diagnoses in 109 602 IBD patients, 7 studies reported 932 PD diagnoses in 354 792 IBD patients, and 1 study reported 6 MS events in 35 581 IBD patients. We observed increased risks of incident stroke (pooled HR = 1.19; 95% CI, 1.06-1.31), all-cause dementia (pooled HR = 1.22; 95% CI, 1.05-1.38), PD (pooled HR = 1.39; 95% CI, 1.20-1.58), and MS (HR = 2.89; 95% CI, 1.02-8.42). No eligible studies were found on peripheral neuropathy and seizure/epilepsy.

Conclusions

Inflammatory bowel disease may be modestly associated with increased risks of stroke, all-cause dementia, and PD. Further longitudinal studies are warranted to investigate potential links with MS, seizure/epilepsy, and peripheral neuropathy, as well as their clinical significance.
THE MODULATORY EFFECT OF PREBIOTIC INULIN-TYPE FRUCTANS ON THE MICROBIOME PROFILE OF CHILDREN WITH INFLAMMATORY BOWEL DISEASE: A DOUBLE-BLIND RANDOMIZED CONTROLLED TRIAL
Authors: Breton Jessica , Tanes Ceylan , Kyle Bittinger , Kachelries Kelly , Crisci Melissa , Compher Charlene , Baldassano Robert , Albenberg Lindsey
Published: January 2024

OBJECTIVE

The intestinal microbiota plays a pivotal role in the inflammation associated with inflammatory bowel disease (IBD) through their interaction with the mucosal immune system. Prebiotic interventions using inulin-type fructans increase faecal and mucosal bifidobacteria as well as butyrate producing bacteria in healthy volunteers. The aim of this study was to assess the effect of a two-month oligofructose-enriched inulin (OI) supplementation on the microbiome composition, metabolome of children with IBD with subclinical disease activity.

DESIGN

We performed a single-center, double-blind, placebo-controlled trial at the Children’s Hospital of Philadelphia. Participants included children, 6–21 years old, with subclinical active colonic IBD as defined by a fecal calprotectin level between 50 and 500 μg/g and clinical remission. Participants were randomly assigned 1:1 to consume prebiotic OI or maltodextrin placebo for 8 weeks. Fecal and rectal swabs samples were collected at baseline, week 4, 8 and 16 for fecal calprotectin, microbiome profiling (shotgun metagenomic sequencing) and matching metabolomics (liquid chromatography tandem mass spectrometry).

RESULTS

The study randomized 68 patients, and 59 were included in the efficacy analyses. The global fecal and mucosal microbiome composition was significantly altered by prebiotic intake and specific inulin-induced increase in relative abundance of Bifidobacterium and Anaerostipes in the fecal samples were identified at week 4 (Figure 1). Two months after discontinuation of OI, the microbial composition of both groups returned to baseline levels. Fecal metabolite profiles were not altered during the 8-week intervention. A negative correlation was observed between calprotectin levels and the relative abundance of Bifidobacterium [q=0.08] and butyrate producer Anaerostipes [q=0.017] (Figure 2). Outcome analysis of inulin-induced change in calprotectin level during the intervention is pending.

CONCLUSIONS

Dietary intervention with prebiotic OI causes short term alterations in the microbiome of children with IBD characterized by an enrichment of Bifidobacterium and butyrate producer Anaerostipes. These results open new perspectives for development of microbiome-targeted dietary interventions in pediatric IBD.

JB received the Crohn’s and Colitis Foundation Career Development Award # 693867 for this study.

Figure 1 Selective effect of prebiotic supplementation on microbiome composition

Figure 2 Correlation between calprotectin level and inulin-induced microbiome shift

A negative correlation between fecal calprotectin level and inulin-induced change in relative abundance of Bifidobacterium [q= 0.08] and Anaerostipes [q=0.017] was observed during the 8-week intervention.