bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of admission cortisol levels with outcomes and treatment response in patients at nutritional risk
Authors: Durmisi Mirsada , Kaegi-Braun Nina , Müller Natasha A. , Wunderle Carla , Tribolet Pascal , Stanga Zeno , Mueller Beat , Schuetz Philipp
Published: November 2023

Introduction

Cortisol is a metabolically active stress hormone that may play a role in the pathogenesis of malnutrition. We studied the association between admission cortisol levels and nutritional parameters, disease severity, and response to nutritional support among medical inpatients at nutritional risk.

Methods

Admission cortisol was measured in a subset of 764 patients participating in the Effect of Early Nutritional Support on Frailty, Functional Outcomes, and Recovery of Malnourished Medical Inpatients Trial (EFFORT), a multicentre, randomized-controlled trial that compared individualized nutritional support with usual nutritional care.

Results

Overall, mean cortisol levels were 570 (± 293) nmol/L and significantly higher in patients with high nutritional risk (NRS ≥ 5) and in patients reporting loss of appetite. Cortisol levels in the highest quartile (> 723 nmol/l) were associated with adverse outcomes including mortality at 30 days and 5 years (adjusted HR 2.31, [95%CI 1.47 to 3.62], p = 0.001 and 1.51, [95%CI 1.23 to 1.87], p < 0.001). Nutritional treatment tended to be more effective regarding mortality reduction in patients with high vs. low cortisol levels (adjusted OR of nutritional support 0.54, [95%CI 0.24 to 1.24] vs. OR 1.11, [95%CI 0.6 to 2.04], p for interaction = 0.134). This effect was most pronounced in the subgroup of patients with severe malnutrition (NRS 2002 ≥ 5, p for interaction = 0.047).

Conclusion

This secondary analysis of a randomized nutritional trial suggests that cortisol levels are linked to nutritional and clinical outcome among multimorbid medical patients at nutritional risk and may help to improve risk assessment, as well as response to nutritional treatment.

Trial Registration

ClinicalTrials.gov Identifier: NCT02517476.
Iron and copper: critical executioners of ferroptosis, cuproptosis and other forms of cell death
Authors: Li Yu , Du Yuhui , Zhou Yujie , Chen Qianhui , Luo Zhijie , Ren Yufan , Chen Xudan , Chen Guoan
Published: November 2023

Regulated cell death (RCD) is a regulable cell death that involves well-organized signaling cascades and molecular mechanisms. RCD is implicated in fundamental processes such as organ production and tissue remodeling, removing superfluous structures or cells, and regulating cell numbers. Previous studies have not been able to reveal the complete mechanisms, and novel methods of RCD are constantly being proposed. Two metal ions, iron (Fe) and copper (Cu) are essential factors leading to RCDs that not only induce ferroptosis and cuproptosis, respectively but also lead to cell impairment and eventually diverse cell death. This review summarizes the direct and indirect mechanisms by which Fe and Cu impede cell growth and the various forms of RCD mediated by these two metals. Moreover, we aimed to delineate the interrelationships between these RCDs with the distinct pathways of ferroptosis and cuproptosis, shedding light on the complex and intricate mechanisms that govern cellular survival and death. Finally, the prospects outlined in this review suggest a novel approach for investigating cell death, which may involve integrating current therapeutic strategies and offer a promising solution to overcome drug resistance in certain diseases.
PKCδ regulates the vascular biology in diabetic atherosclerosis
Authors: Qin Peiliang , He Changhuai , Ye Pin , Li Qin , Cai Chuanqi , Li Yiqing
Published: November 2023

Diabetes mellitus, known for its complications, especially vascular complications, is becoming a globally serious social problem. Atherosclerosis has been recognized as a common vascular complication mechanism in diabetes. The diacylglycerol (DAG)–protein kinase C (PKC) pathway plays an important role in atherosclerosis. PKCs can be divided into three subgroups: conventional PKCs (cPKCs), novel PKCs (nPKCs), and atypical PKCs (aPKCs). The aim of this review is to provide a comprehensive overview of the role of the PKCδ pathway, an isoform of nPKC, in regulating the function of endothelial cells, vascular smooth muscle cells, and macrophages in diabetic atherosclerosis. In addition, potential therapeutic targets regarding the PKCδ pathway are summarized.
Macrophage metabolism, phenotype, function, and therapy in hepatocellular carcinoma (HCC)
Authors: Huang Jingquan , Wu Qiulin , Geller David A. , Yan Yihe
Published: November 2023

The pivotal role of the tumor microenvironment (TME) in the initiation and advancement of hepatocellular carcinoma (HCC) is widely acknowledged, as it fosters the proliferation and metastasis of HCC cells. Within the intricate TME of HCC, tumor-associated macrophages (TAMs) represent a significant constituent of non-malignant cells. TAMs engage in direct communication with cancer cells in HCC, while also exerting influence on other immune cells to adopt a tumor-supportive phenotype that facilitates tumor progression. Among the multifaceted mechanisms at play, the metabolic reprogramming of both tumor cells and macrophages leads to phenotypic alterations and functional modifications in macrophages. This comprehensive review elucidates the intricate interplay between cellular metabolism and macrophage phenotype/polarization, while also providing an overview of the associated signaling molecules and potential therapeutic strategies for HCC.
The analysis of the genotype of Sapovirus outbreaks in Zhejiang Province
Authors: Su Lingxuan , Mao Haiyan , Sun Yi , Yan Hao , Ge Qiong , Gong Liming , Zhang Yanjun
Published: November 2023

Background

Sapovirus (SaV) infection is increasing globally. Concurrently, several SaV-outbreaks were observed in children of Zhejiang province, China, in recent years, In this study, the genotypes of Sapovirus from seven outbreaks in the Zhejiang province were analysed.

Methods

A total of 105 faecal samples were collected from children aged between 4 and 17 years from the Zhejiang Provincial Center for Disease Control and Prevention between October 2021 and February 2023. Genotypes were processed using reverse transcription polymerase chain reaction and Sanger sequencing, while next-generation sequencing was used to generate a complete viral genome. Deduced amino acid sequences were analysed to detect VP1 gene mutations.

Results

In total, 60 SaV-positive patients were detected at a 57.14% (60/105) positivity rate. Positive rates in the seven outbreaks were: 22.22% (2/9), 15.00% (3/20), 93.10% (27/29), 84.21% (16/19), 28.57% (2/7), 53.33% (8/15) and 33.33% (2/6), respectively. Four genotypes were identified in the seven outbreaks, of which, GI.1 accounted for 14.29% (1/7), GI.2 accounted for 14.29% (1/7), GI.6 and GII.5 accounted for 14.29% (1/7), and GI.6 accounted for 57.14% (4/7). All patients were children and outbreaks predominantly occurred in primary schools and during cold seasons. Additionally, the complete sequence from the GI.6 outbreak strain showed high homology (identity: 99.99%) with few common substitutions (Y300S, N302S and L8M) in VP1 protein.

Conclusions

SaV genotype diversity was observed in the seven outbreaks, with GI.6 being the main SaV genotype in Zhejiang province. It demonstrated high homology and may provide a platform for SaV prevention and control measures.
Learning from COVID-19: government leaders’ perspectives to improve emergency risk communication
Authors: Savoia Elena , Piltch-Loeb Rachael , Stanton Eva H. , Koh Howard K.
Published: November 2023

Background

The coronavirus disease 2019 (COVID-19) pandemic highlighted the challenges of effective emergency risk communication (ERC) to protect public health, including the difficulty in tackling the spread of inaccurate information. This study aimed to understand those challenges and potential solutions by interviewing leading government spokespersons and their advisors from around the world with experience during large scale emergencies. Interviews were conducted with 27 individuals representing governments from 19 countries across five continents. Thematic analysis, using both a deductive and inductive approach, organized and identified salient themes and patterns that emerged from the interview data.

Results

The thematic analysis of the interviews’ data led to the identification of 9 principles of communication: 1) Timeliness, 2) Transparency, 3) Coordination, 4) Accuracy and Consistency, 5) Accountability and Integrity, 6) Independence from politics, 7) Responsiveness, 8) Equity, 9) Trust and Empathy. We also developed 36 recommendations actionable by government agencies to enhance the practice of the 9 principles. Examples include the need for: proactive communication strategies, permanent communication task forces integrated into preparedness and response efforts, robust processes to enhance open discussion of controversial topics within government agencies, clarification of how various branches of government coordinate to oversee specific aspects of the overall communication, and development of relationships across public and private entities ahead of a crisis.

Conclusions

Our findings suggest key practical recommendations for leaders of government agencies to enhance ERC capabilities going forward. Before a crisis, they must constantly review internal processes and integrate ERC functions into overall communication planning efforts. During a crisis, they must coordinate roles and responsibilities across branches of governments, strive to communicate to a range of populations to uphold equity, maintain transparency by avoiding information voids on controversial issues and build trust by building relationships with a variety of community leaders. After a crisis, government agencies should continue the practice of social listening to hear more about the public’s informational needs, strengthen civic participation processes, and understand how an always evolving information environment can best be leveraged during future crises.
A non-invasive method to predict drought survival in Arabidopsis using quantum yield under light conditions
Authors: Rico-Cambron Thelma Y. , Bello-Bello Elohim , Martínez Octavio , Herrera-Estrella Luis
Published: November 2023

Background

Survival rate (SR) is frequently used to compare drought tolerance among plant genotypes. While a variety of techniques for evaluating the stress status of plants under drought stress conditions have been developed, determining the critical point for the recovery irrigation to evaluate plant SR often relies directly on a qualitative inspection by the researcher or on the employment of complex and invasive techniques that invalidate the subsequent use of the tested individuals.

Results

Here, we present a simple, instantaneous, and non-invasive method to estimate the survival probability of Arabidopsis thaliana plants after severe drought treatments. The quantum yield (QY), or efficiency of photosystem II, was monitored in darkness (Fv/Fm) and light (Fv’/Fm’) conditions in the last phase of the drought treatment before recovery irrigation. We found a high correlation between a plant’s Fv’/Fm’ value before recovery irrigation and its survival phenotype seven days after, allowing us to establish a threshold between alive and dead plants in a calibration stage. This correlation was maintained in the Arabidopsis accessions Col-0, Ler-0, C24, and Kondara under the same conditions. Fv’/Fm’ was then applied as a survival predictor to compare the drought tolerance of transgenic lines overexpressing the transcription factors ATAF1 and PLATZ1 with the Col-0 control.

Conclusions

The results obtained in this work demonstrate that the chlorophyll a fluorescence parameter Fv’/Fm’ can be used as a survival predictor that gives a numerical estimate of the Arabidopsis drought SR before recovery irrigation. The procedure employed to get the Fv’/Fm’ measurements is fast, non-destructive, and requires inexpensive and easy-to-handle equipment. Fv’/Fm’ as a survival predictor can be used to offer an overview of the photosynthetic state of the tested plants and determine more accurately the best timing for rewatering to assess the SR, especially when the symptoms of severe dehydration between genotypes are not contrasting enough to identify a difference visually.
Neurodevelopmental status and adaptive behavior of pediatric patients with mucopolysaccharidosis II: a longitudinal observational study
Authors: Muenzer Joseph , Burton Barbara K. , Amartino Hernan M. , Harmatz Paul R. , Gutiérrez-Solana Luis González , Ruiz-Garcia Matilde , Wu Yuna , Merberg David , Alexanderian David , Jones Simon A.
Published: November 2023

Background

Mucopolysaccharidosis (MPS) II is a rare, X-linked lysosomal storage disease. Approximately two-thirds of patients have central nervous system involvement with some demonstrating progressive cognitive impairment (neuronopathic disease). The natural history of cognitive and adaptive function in patients with MPS II is not well-defined. This 2-year, prospective, observational study evaluated the neurodevelopmental trajectories of boys with MPS II aged ≥ 2 years and < 18 years.

Results

Overall, 55 patients were enrolled. At baseline, mean (standard deviation [SD]) age was 5.60 (3.32) years; all patients were receiving intravenous idursulfase. Cognitive and adaptive function were assessed using the Differential Ability Scales, Second Edition (DAS-II) General Conceptual Ability (GCA) and the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Adaptive Behavior Composite (ABC) scores, respectively. Baseline mean (SD) DAS-II GCA and VABS-II ABC scores were 78.4 (19.11) and 83.7 (14.22), respectively, indicating low cognitive function and moderately low adaptive behavior. Over 24 months, modest deteriorations in mean (SD) scores were observed for DAS-II GCA (−3.8 [12.7]) and VABS-II ABC (−2.0 [8.07]). Changes in DAS-II GCA scores varied considerably, and data suggested the existence of four potential patient subgroups: (1) patients with marked early impairment and rapid subsequent decline, (2) patients with marked early impairment then stabilization, (3) patients with mild early impairment then stabilization, and (4) patients without impairment who remained stable. Subgroup analyses revealed numerically greater DAS-II GCA score reductions from baseline in patients aged < 7 years at baseline (vs. those aged ≥ 7 years) and in patients with DAS-II GCA scores ≤ 70 at baseline (vs. those with scores > 70); between-group differences were nonsignificant. No clear subgroups or patterns were identified for individual changes in VABS-II ABC scores. In total, 49 patients (89.1%) reported ≥ 1 adverse event (AE) and nine patients (16.4%) reported serious AEs.

Conclusions

Some patients with MPS II had rapid declines in cognitive ability, whereas others remained relatively stable after an initial decline. These insights provide a basis for more detailed analyses of different patient subgroups, which may enhance the definition and understanding of factors that influence cognitive and adaptive function in MPS II.

Trial registration

ClinicalTrials.gov, NCT01822184. Registered retrospectively: April 2, 2013.
Clinical features, imaging findings and molecular data of limb-girdle muscular dystrophies in a cohort of Chinese patients
Authors: Lin Feng , Yang Kang , Lin Xin , Jin Ming , Chen Long , Zheng Fu-ze , Qiu Liang-liang , Ye Zhi-xian , Chen Hai-zhu , Lin Min-ting , Wang Ning , Wang Zhi-qiang
Published: November 2023

Background

Limb-girdle muscular dystrophies (LGMDs) are a group of heterogeneous inherited diseases predominantly characterized by limb-girdle muscle weakness and dystrophic changes on histological analysis. The frequency of LGMD subtypes varies among regions in China and ethnic populations worldwide. Here, we analyzed the prevalence of LGMD subtypes, their corresponding clinical manifestations, and molecular data in a cohort of LGMD patients in Southeast China.

Methods

A total of 81 consecutive patients with clinically suspected LGMDs from 62 unrelated families across Southeast China were recruited for targeted next-generation sequencing and whole-exome sequencing from July 2017 to February 2020.

Results

Among 50 patients (41 families) with LGMDs, the most common subtypes were LGMD-R2/LGMD2B (36.6%) and LGMD-R1/LGMD2A (29.3%). Dystroglycanopathies (including LGMD-R9/LGMD2I, LGMD-R11/LGMD2K, LGMD-R14/LGMD2N and LGMD-R20/LGMD2U) were the most common childhood-onset subtypes and were found in 12.2% of the families. A total of 14.6% of the families had the LGMD-R7/LGMD2G subtype, and the mutation c.26_33dupAGGTGTCG in TCAP was the most frequent (83.3%). The only patient with the rare subtype LGMD-R18/LGMD2S had TRAPPC11 mutations; had a later onset than those previously reported, and presented with proximal‒distal muscle weakness, walking aid dependency, fatty liver disease and diabetes at 33 years of age. A total of 22.0% of the patients had cardiac abnormalities, and one patient with LMNA-related muscular dystrophy/LGMD1B experienced sudden cardiac death at 37 years of age. A total of 15.4% of the patients had restrictive respiratory insufficiency. Muscle imaging in patients with LGMD-R1/LGMD2A and LGMD-R2/LGMD2B showed subtle differences, including more severe fatty infiltration of the posterior thigh muscles in those with LGMD-R1/LGMD2A and edema in the lower leg muscles in those with LGMD-R2/LGMD2B.

Conclusion

We determined the prevalence of different LGMD subtypes in Southeast China, described the detailed clinical manifestations and distinct muscle MRI patterns of these LGMD subtypes and reported the frequent mutations and the cardiorespiratory involvement frequency in our cohort, all of which might facilitate the differential diagnosis of LGMDs, allowing more timely treatment and guiding future clinical trials.
Provider perceptions of the anticipated benefits, barriers, and facilitators associated with implementing a stepped care model for the delivery of addiction and mental health services in New Brunswick: a mixed-methods observational implementation study
Authors: King Alesha , Harris-Lane Laura M. , Bérubé Stéphane , Burke Katie , Churchill AnnMarie , Cornish Peter , Goguen Bernard , Jaouich Alexia , Rash Joshua A.
Published: November 2023

Background

Providers who work within addiction and mental health (A&MH) services in New Brunswick (NB), Canada completed training in Stepped Care 2.0 and One-at-a-Time (OAAT) therapy as part of a provincial practice change initiative to implement a provincial stepped care model. The present study aimed to identify: (1) the perceived acceptability and feasibility of the SC2.0 model; (2) the perceived benefits, barriers, and facilitators to implement SC2.0 in practice; and (3) perceived impacts on clinical practice.

Methods

This is a mixed-methods observational implementation study. Quantitative surveys were completed after training courses. Open-ended responses were collected after completion of SC2.0 training. A subset of providers who completed surveys were asked to participate in semi-structured interviews. Descriptive statistics were used to describe results from surveys. Open-ended responses and semi-structured interviews were compiled and thematically synthesized in an iterative process using a grounded theory framework. Quantitative and qualitative data were triangulated to build an in-depth understanding of provider perceptions.

Results

316 providers completed surveys and responded to open-ended prompts. Interviews were completed with 28 of those providers. SC2.0 was deemed to be acceptable, a suitable fit, and feasible to implement. Perceived benefits included: (1) timely access to services; (2) increased practice efficiency; and (3) increased availability of services. Perceived barriers included: (1) insufficient availability of resources to populate a SC2.0 continuum of care; (2) provider complacency with their current practice; and (3) difficulty for clients to accept and adjust to change.

Conclusions

Identifying the perceived benefits, facilitators, and barriers to adopting stepped care in practice can lead to targeted implementation strategies and the collection of data that can inform continuous improvement cycles.
Depressive symptoms and anger and aggression in Russian adolescents
Authors: Ruchkin Vladislav , Stickley Andrew , Koposov Roman , Sukhodolsky Denis G. , Isaksson Johan
Published: November 2023

Research among adolescents exploring the association between depressive symptoms and aggression has produced inconsistent findings. This study investigated the prevalence of clinically significant (current major depressive episode) and subthreshold depressive symptoms in a general population sample of adolescents from Northern Russia and explored their association with aggression and anger, while controlling for comorbid mental health problems. The sample consisted of 2600 participants, aged 13–17 years (59.5% female; 95.7% ethnic Russian). Symptoms of a current major depressive episode, types of anger and aggression (anger rumination, trait anger, physical, verbal and social aggression) and comorbid problems (posttraumatic stress, alcohol use, anxiety, and hyperactivity/impulsivity) were assessed by means of self-reports. The prevalence of a clinically significant depressive episode in the past month was 3.5%, while for subthreshold depression it was 21.6%. All anger and aggression variables, as well as comorbid problems increased together with increasing levels of depression. The association between overt aggressive behavior and depression was primarily explained by comorbid mental health problems, whereas anger rumination and social aggression had more direct associations with depression, independent of comorbidity. Among adolescents with depression, boys reported higher levels of social and verbal aggression and of anger rumination than girls. The results of this study suggest that interventions aiming to reduce aggressive behavior in adolescents should consider depression and its comorbid conditions.
Blockage of CacyBP inhibits macrophage recruitment and improves anti-PD-1 therapy in hepatocellular carcinoma
Authors: Wang Jialiang , Zhang Xiaoyu , Ma Xinyi , Chen Dongmei , Cai Meina , Xiao Lexin , Li Jing , Huang Zexuan , Huang Yuehua , Lian Yifan
Published: November 2023

Background

Despite remarkable advancements in cancer immunotherapy, the overall response rate to anti-programmed cell death-1 (anti-PD-1) therapy in hepatocellular carcinoma (HCC) patients remains low. Our previous study has demonstrated the critical role of CacyBP/SIP (Calcyclin-Binding Protein and Siah-1 Interacting Protein) as a regulator of HCC development and progression. However, the possible impact of CacyBP on the tumor immune microenvironment has not yet been clarified.

Methods

The expressions of CacyBP and Myd88 in HCC cell lines and tissues was detected by bioinformatics analysis, real-time quantitative PCR, western blotting and immunohistochemistry. The interaction between CacyBP and Myd88 was measured using co-immunoprecipitation and immunofluorescence. In vitro and in vivo assays were used to investigate the regulation of CacyBP on tumor-associated macrophages (TAMs).

Results

We identified that CacyBP was positively correlated with Myd88, a master regulator of innate immunity, and Myd88 was a novel binding substrate downstream of CacyBP in HCC. Additionally, CacyBP protected Myd88 from Siah-1-mediated proteasome-dependent degradation by competitively binding to its Toll/interleukin-1 receptor (TIR) domain. Inhibition of CacyBP-Myd88 signaling subsequently diminished HDAC1-mediated H3K9ac and H3K27ac modifications on the CX3CL1 promoter and reduced its transcription and secretion in HCC cells. Moreover, by using in vitro and in vivo strategies, we demonstrated that depletion of CacyBP impaired the infiltration of TAMs and the immunosuppressive state of the tumor microenvironment, further sensitizing HCC-bearing anti-PD-1 therapy.

Conclusions

Our findings suggest that targeting CacyBP may be a novel treatment strategy for improving the efficacy of anti-PD-1 immunotherapy in HCC.
Targeting FAcilitates Chromatin Transcription complex inhibits pleural mesothelioma and enhances immunotherapy
Authors: Singh Anand , Pruett Nathanael , Dixit Shivani , Gara Sudheer K. , Wang Haitao , Pahwa Roma , Schrump David S. , Hoang Chuong D.
Published: November 2023

Background

Diffuse pleural mesothelioma (DPM) is an aggressive therapy-resistant cancer with unique molecular features. Numerous agents have been tested, but clinically effective ones remain elusive. Herein, we propose to use a small molecule CBL0137 (curaxin) that simultaneously suppresses nuclear factor-κB (NF-κB) and activates tumor suppressor p53 via targeting FAcilitates Chromatin Transcription (FACT) complex, a histone chaperone critical for DNA repair.

Methods

We used DPM cell lines, murine models (xeno- and allo-grafts), plus DPM patient samples to characterize anti-tumor effects of CBL0137 and to delineate specific molecular mechanisms.

Results

We verified that CBL0137 induced cell cycle arrest and apoptosis. We also discovered that DPM is a FACT-dependent cancer with overexpression of both subunits structure-specific recognition protein 1 (SSRP1), a poor prognosis indicator, and suppressor of Ty 16 (SUPT16H). We defined several novel uses of CBL0137 in DPM therapy. In combination with cisplatin, CBL0137 exhibited additive anti-tumor activity compared to monotherapy. Similarly, CBL0137 (systemic) could be combined with other novel agents like microRNA-215 (intrapleural) as a more effective regimen. Importantly, we established that CBL0137 induces immunogenic cell death that contributes to activating immune response pathways in DPM. Therefore, when CBL0137 is combined with dual immune checkpoint inhibitors DPM tumor growth is significantly suppressed.

Conclusions

We identified an unrecognized molecular vulnerability of DPM based on FACT dependency. CBL0137 alone and in several combinations with different therapeutics showed promising efficacy, including that of improved anti-tumor immunity. Overall, these preclinical findings suggest that CBL0137 could be ideally suited for use in DPM clinical trials.
Cytomulate: accurate and efficient simulation of CyTOF data
Authors: Yang Yuqiu , Wang Kaiwen , Lu Zeyu , Wang Tao , Wang Xinlei
Published: November 2023

Recently, many analysis tools have been devised to offer insights into data generated via cytometry by time-of-flight (CyTOF). However, objective evaluations of these methods remain absent as most evaluations are conducted against real data where the ground truth is generally unknown. In this paper, we develop Cytomulate, a reproducible and accurate simulation algorithm of CyTOF data, which could serve as a foundation for future method development and evaluation. We demonstrate that Cytomulate can capture various characteristics of CyTOF data and is superior in learning overall data distributions than single-cell RNA-seq-oriented methods such as scDesign2, Splatter, and generative models like LAMBDA.
N-of-one differential gene expression without control samples using a deep generative model
Authors: Prada-Luengo Iñigo , Schuster Viktoria , Liang Yuhu , Terkelsen Thilde , Sora Valentina , Krogh Anders
Published: November 2023

Differential analysis of bulk RNA-seq data often suffers from lack of good controls. Here, we present a generative model that replaces controls, trained solely on healthy tissues. The unsupervised model learns a low-dimensional representation and can identify the closest normal representation for a given disease sample. This enables control-free, single-sample differential expression analysis. In breast cancer, we demonstrate how our approach selects marker genes and outperforms a state-of-the-art method. Furthermore, significant genes identified by the model are enriched in driver genes across cancers. Our results show that the in silico closest normal provides a more favorable comparison than control samples.
Optimized strategy for schistosomiasis elimination: results from marginal benefit modeling
Authors: Li Qin , Zheng Jin-Xin , Jia Tie-Wu , Feng Xin-Yu , Lv Chao , Zhang Li-Juan , Yang Guo-Jing , Xu Jing , Zhou Xiao-Nong
Published: November 2023

Background

Poverty contributes to the transmission of schistosomiasis via multiple pathways, with the insufficiency of appropriate interventions being a crucial factor. The aim of this article is to provide more economical and feasible intervention measures for endemic areas with varying levels of poverty.

Methods

We collected and analyzed the prevalence patterns along with the cost of control measures in 11 counties over the last 20 years in China. Seven machine learning models, including XGBoost, support vector machine, generalized linear model, regression tree, random forest, gradient boosting machine and neural network, were used for developing model and calculate marginal benefits.

Results

The XGBoost model had the highest prediction accuracy with an R2 of 0.7308. Results showed that risk surveillance, snail control with molluscicides and treatment were the most effective interventions in controlling schistosomiasis prevalence. The best combination of interventions was interlacing seven interventions, including risk surveillance, treatment, toilet construction, health education, snail control with molluscicides, cattle slaughter and animal chemotherapy. The marginal benefit of risk surveillance is the most effective intervention among nine interventions, which was influenced by the prevalence of schistosomiasis and cost.

Conclusions

In the elimination phase of the national schistosomiasis program, emphasizing risk surveillance holds significant importance in terms of cost-saving.

Graphical Abstract
Association between ultra-processed food consumption and the incidence of type 2 diabetes: the ELSA-Brasil cohort
Authors: Canhada Scheine L. , Vigo Álvaro , Levy Renata , Luft Vivian C. , da Fonseca Maria de Jesus M. , Giatti Luana , Molina Maria del Carmen B. , Duncan Bruce B. , Schmidt Maria Inês
Published: November 2023

Background

Ultra-processed food (UPF) consumption increases the risk of type 2 diabetes in various high-income countries, with some variation in the magnitude across studies. Our objective was to investigate the association of UPF consumption and specific subgroups with incident type 2 diabetes in Brazilian adults.

Methods

The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) is a multicenter cohort study of 15,105 adults (35–74 years) enrolled in public institutions in Brazil (2008–2010). We followed participants with two clinic visits (2012–2014; 2017–2019) and annual telephone surveillance. After excluding those with diabetes at baseline, who died or were lost in the follow-up, with missing data, with implausible energy food intake, or reporting bariatric surgery, there were 10,202 participants. We used the NOVA classification to assess UPF consumption based on a food frequency questionnaire. We defined type 2 diabetes by self-report, medication use, or comprehensive laboratory tests. We estimated relative risks (RR) and 95% confidence intervals (95% CI) using robust Poisson regression.

Results

Median UPF consumption was 372 g/day. Over 8.2 (0.7) years of follow-up, we detected 1799 (17.6%) incident cases. After adjustment for socio-demographics, family history of diabetes, and behavioral risk factors, comparing the fourth (≥ 566 g/day) with the first (< 236 g/day) quartile of UPF distribution, RR was 1.24 (1.10–1.39); every 150 g/day increments in UPF consumption resulted in a RR of 1.05 (1.03–1.07). Reclassifying natural beverages with added sweeteners as UPF increased risk (RR 1.40; 1.25–1.58). Among UPF subgroupings, consumption of processed meats and sweetened beverages increased diabetes risk, while yogurt and dairy sweets decreased the risk (p < 0.05).

Conclusions

UPF consumption increased the incidence of type 2 diabetes in Brazilian adults, with heterogeneity across specific food items. These findings add to previous evidence for the role of UPFs in the development of diabetes and other chronic diseases, supporting recommendations to avoid their intake in diabetes prevention and management.
Long noncoding RNAs emerge from transposon-derived antisense sequences and may contribute to infection stage-specific transposon regulation in a fungal phytopathogen
Authors: Qian Jiangzhao , Ibrahim Heba M. M. , Erz Myriam , Kümmel Florian , Panstruga Ralph , Kusch Stefan
Published: November 2023

Background

The genome of the obligate biotrophic phytopathogenic barley powdery mildew fungus Blumeria hordei is inflated due to highly abundant and possibly active transposable elements (TEs). In the absence of the otherwise common repeat-induced point mutation transposon defense mechanism, noncoding RNAs could be key for regulating the activity of TEs and coding genes during the pathogenic life cycle.

Results

We performed time-course whole-transcriptome shotgun sequencing (RNA-seq) of total RNA derived from infected barley leaf epidermis at various stages of fungal pathogenesis and observed significant transcript accumulation and time point-dependent regulation of TEs in B. hordei. Using a manually curated consensus database of 344 TEs, we discovered phased small RNAs mapping to 104 consensus transposons, suggesting that RNA interference contributes significantly to their regulation. Further, we identified 5,127 long noncoding RNAs (lncRNAs) genome-wide in B. hordei, of which 823 originated from the antisense strand of a TE. Co-expression network analysis of lncRNAs, TEs, and coding genes throughout the asexual life cycle of B. hordei points at extensive positive and negative co-regulation of lncRNAs, subsets of TEs and coding genes.

Conclusions

Our work suggests that similar to mammals and plants, fungal lncRNAs support the dynamic modulation of transcript levels, including TEs, during pivotal stages of host infection. The lncRNAs may support transcriptional diversity and plasticity amid loss of coding genes in powdery mildew fungi and may give rise to novel regulatory elements and virulence peptides, thus representing key drivers of rapid evolutionary adaptation to promote pathogenicity and overcome host defense.
A pangenome-guided manually curated library of transposable elements for Zymoseptoria tritici
Authors: Baril Tobias , Croll Daniel
Published: November 2023

Objectives

High-quality species-specific transposable element (TE) libraries are required for studies to elucidate the evolutionary dynamics of TEs and gain an understanding of their impacts on host genomes. Such high-quality TE resources are severely lacking for species in the fungal kingdom. To facilitate future studies on the putative role of TEs in rapid adaptation observed in the fungal wheat pathogen Zymoseptoria tritici, we produced a manually curated TE library. This was generated by detecting TEs in 19 reference genome assemblies representing the global diversity of the species supplemented by multiple sister species genomes. Improvements over previous TE libraries have been made on TE boundary resolution, detection of ORFs, TE domains, terminal inverted repeats, and class-specific motifs.

Data description

A TE consensus library for Z. tritici formatted for use with RepeatMasker. This data is relevant to other researchers investigating TE-host evolutionary dynamics in Z. tritici or who are interested in comparative studies of the fungal kingdom. Further, this TE library can be used to improve gene annotation. Finally, this TE library increases the number of manually curated TE datasets, providing resources to further our understanding of TE diversity.
Placental extract suppresses lipid droplet accumulation by autophagy during the differentiation of adipose-derived mesenchymal stromal/stem cells into mature adipocytes
Authors: Ando Yusuke , Odawara Eri , Sakai Hiroyasu , Sato Fumiaki , Kamei Junzo
Published: November 2023

Objective

Placental extract, which contains various bioactive compounds, has been used as traditional medicine. Many studies have demonstrated additional applications of placental extract and provided a scientific basis for the broad spectrum of its effects. We have previously reported that porcine placental extract (PPE) strongly suppresses adipogenesis in a 3T3-L1 preadipocyte cell line, inhibiting differentiation. This study aimed to examine the effect of PPE on the accumulation of lipid droplets (LD) in adipose-derived mesenchymal stromal/stem cells (ASC).

Results

The study findings revealed that PPE decreased the size of LD during the differentiation of ASC into mature adipocytes. RT-qPCR analysis revealed that PPE increased the gene expression of lysosomal acid lipase A (Lipa), a lipolysis-related gene, in ASC-differentiated adipocytes. However, no differences were noted in the adipocyte differentiation markers (Pparg, Cebpa, and Adipoq), or the adipogenesis-related genes (Dgat1, Dgat2, Fasn, Soat1, and Soat2). In addition, PPE promoted autophagosome formation, which was partially co-localized with the LD, indicating that PPE accelerated the degradation of LD by inducing autophagy (termed lipophagy) during the differentiation of ASC into mature adipocytes. These results suggest that the use of PPE may be a potential novel treatment for regulating adipogenesis for the treatment of obesity.
Neuronal transcriptome, tau and synapse loss in Alzheimer’s knock-in mice require prion protein
Authors: Stoner Austin , Fu Li , Nicholson LaShae , Zheng Chao , Toyonaga Takuya , Spurrier Joshua , Laird Will , Cai Zhengxin , Strittmatter Stephen M.
Published: November 2023

Background

Progression of Alzheimer’s disease leads to synapse loss, neural network dysfunction and cognitive failure. Accumulation of protein aggregates and brain immune activation have triggering roles in synaptic failure but the neuronal mechanisms underlying synapse loss are unclear. On the neuronal surface, cellular prion protein (PrPC) is known to be a high-affinity binding site for Amyloid-β oligomers (Aβo). However, PrPC’s dependence in knock-in AD models for tau accumulation, transcriptomic alterations and imaging biomarkers is unknown.

Methods

The necessity of PrPC was examined as a function of age in homozygous AppNL−G−F/hMapt double knock-in mice (DKI). Phenotypes of AppNL−G−F/hMapt mice with a deletion of Prnp expression (DKI; Prnp−/−) were compared with DKI mice with intact Prnp, mice with a targeted deletion of Prnp (Prnp−/−), and mice with intact Prnp (WT). Phenotypes examined included behavioral deficits, synapse loss by PET imaging, synapse loss by immunohistology, tau pathology, gliosis, inflammatory markers, and snRNA-seq transcriptomic profiling.

Results

By 9 months age, DKI mice showed learning and memory impairment, but DKI; Prnp−/− and Prnp−/− groups were indistinguishable from WT. Synapse loss in DKI brain, measured by [18F]SynVesT-1 SV2A PET or anti-SV2A immunohistology, was prevented by Prnp deletion. Accumulation of Tau phosphorylated at aa 217 and 202/205, C1q tagging of synapses, and dystrophic neurites were all increased in DKI mice but each decreased to WT levels with Prnp deletion. In contrast, astrogliosis, microgliosis and Aβ levels were unchanged between DKI and DKI; Prnp−/− groups. Single-nuclei transcriptomics revealed differential expression in neurons and glia of DKI mice relative to WT. For DKI; Prnp−/− mice, the majority of neuronal genes differentially expressed in DKI mice were no longer significantly altered relative to WT, but most glial DKI-dependent gene expression changes persisted. The DKI-dependent neuronal genes corrected by Prnp deletion associated bioinformatically with synaptic function. Additional genes were uniquely altered only in the Prnp−/− or the DKI; Prnp−/− groups.

Conclusions

Thus, PrPC-dependent synapse loss, phospho-tau accumulation and neuronal gene expression in AD mice can be reversed without clearing Aβ plaque or preventing gliotic reaction. This supports targeting the Aβo-PrPC interaction to prevent Aβo-neurotoxicity and pathologic tau accumulation in AD.
Hyperthermia elevates brain temperature and improves behavioural signs in animal models of autism spectrum disorder
Authors: Lopez-Rodriguez Ana Belen , Murray Carol L. , Kealy John , Towns Clodagh , Roche Andrew , Nazmi Arshed , Doran Michelle , Lowry John P. , Cunningham Colm
Published: November 2023

Background

Autism spectrum disorders (ASD) are predominantly neurodevelopmental and largely genetically determined. However, there are human data supporting the idea that fever can improve symptoms in some individuals, but those data are limited and there are almost no data to support this from animal models. We aimed to test the hypothesis that elevated body temperature would improve function in two animal models of ASD.

Methods

We used a 4 h whole-body hyperthermia (WBH) protocol and, separately, systemic inflammation induced by bacterial endotoxin (LPS) at 250 µg/kg, to dissociate temperature and inflammatory elements of fever in two ASD animal models: C58/J and Shank3B- mice. We used one- or two-way ANOVA and t-tests with normally distributed data and Kruskal–Wallis or Mann–Whitney with nonparametric data. Post hoc comparisons were made with a level of significance set at p < 0.05. For correlation analyses, data were adjusted by a linear regression model.

Results

Only LPS induced inflammatory signatures in the brain while only WBH produced fever-range hyperthermia. WBH reduced repetitive behaviours and improved social interaction in C58/J mice and significantly reduced compulsive grooming in Shank3B- mice. LPS significantly suppressed most activities over 5–48 h.

Limitations

We show behavioural, cellular and molecular changes, but provide no specific mechanistic explanation for the observed behavioural improvements.

Conclusions

The data are the first, to our knowledge, to demonstrate that elevated body temperature can improve behavioural signs in 2 distinct ASD models. Given the developmental nature of ASD, evidence that symptoms may be improved by environmental perturbations indicates possibilities for improving function in these individuals. Since experimental hyperthermia in patients would carry significant risks, it is now essential to pursue molecular mechanisms through which hyperthermia might bring about the observed benefits.
Validation of scoring systems for the prediction of complicated appendicitis in adults using clinical and computed tomographic findings
Authors: Kaewlai Rathachai , Tongsai Sasima , Teerasamit Wanwarang , Wongsaengchan Dhanawin , Noppakunsomboon Napakadol , Khamman Pramuk , Chatkaewpaisal Anchisa , Apisarnthanarak Piyaporn
Published: November 2023

Objectives

The study aimed to evaluate scoring systems for predicting complicated appendicitis in adults diagnosed with acute appendicitis on computed tomography.

Methods

Three hundred twenty-five consecutive adult patients (mean age 51.9 ± 19.6 years, 212 women) diagnosed with acute appendicitis on computed tomography were retrospectively included. Clinical and imaging findings were compared between patients with and without complicated appendicitis, and independent associations were identified. As C-reactive protein was not available for most patients, 5 out of 8 scoring systems were modified. They, and a newly proposed system, were compared via area under the receiver operating characteristics (ROC) curve (AUC), Additionally, the latter was internally validated. Pairwise comparison was performed, and diagnostic performance of these scoring systems was obtained.

Results

One hundred twenty-seven patients (36.8%) had complicated appendicitis. Significant independent associations were found between complicated appendicitis and duration of symptoms > 12 h, appendicolith, periappendiceal fat stranding, periappendiceal fluid, and extraluminal air (p values < 0.001 to 0.037; AUCs of 0.824–0.829). AUCs of 9 scoring systems ranged from 0.692 to 0.831. Of these, modified Atema, Kim HY, and proposed scores had similarly high and non-significantly different AUCs (0.793–0.831) on pairwise comparison. Their sensitivities, specificities, and accuracies were 73.0–90.6%, 48.5–70.6%, and 64.3–72.3%, respectively. Internal validity test demonstrated high AUCs (0.826–0.844) with one of the proposed scores using odds ratio having 100% sensitivity and 100% negative predictive value.

Conclusions

Few scoring systems, including proposed ones, had high AUCs, sensitivity, and reasonable specificities, which could potentially aid in safely selecting adult patients with acute appendicitis for nonoperative management.

Critical relevance statement

The study suggests few scoring systems for predicting complicated appendicitis with high AUCs and reasonable sensitivities, potentially aiding in selecting patients for nonoperative management.

Key points

• The study evaluated existing and proposed new scoring systems to predict complicated appendicitis in adults with acute appendicitis on computed tomography.

• Several factors were found to be significantly associated with complicated appendicitis, including duration of symptoms, appendicolith, periappendiceal fat stranding, periappendiceal fluid, and extraluminal air.

• The modified Atema, Kim HY, and newly proposed scoring systems performed well, potentially aiding in nonoperative management selection.

Graphical Abstract
Mycoremediation of lead and cadmium by lignocellulosic enzymes of Pleurotus eryngii
Authors: Goligar N. , Saadatmand S. , Khavarinejad R. A.
Published: November 2023

This study aimed to investigate the ability of Pleurotus eryngii fungus to absorb lead and cadmium from industrial wastewater. After culturing the fungus on a potato dextrose agar (PDA) medium containing 0 (control), 150 mg L−1, 250 mg L−1, and 350 mg L−1 concentrations of lead and cademium for 30 days, the mycelia were isolated from the culture medium and their extracts were used to measure protein content and the activity of antioxidant enzymes. Also, heavy metal contents were analyzed by atomic absorption spectrometry using flame photometry. Results showed that the growth of mycelia was significantly affected by different concentrations of the two heavy metals. High tolerance of heavy metal pollution in the culture media and the ability to accumulate lead and cademium confirmed that Pleurotus eryngii is a favorable option for mycoremediation. Also, molecular studies for fungal sequencing were investigated using the trench method, the sequence of the fungus was recorded in the gene bank, and finally the fungus was identified in the study.