bluuebunny/crossref_metadata_2025 huggingface dataset:
The toxins of vertically transmitted Spiroplasma
Authors: Moore Logan D. , Ballinger Matthew J.
Published: May 2023

Vertically transmitted (VT) microbial symbionts play a vital role in the evolution of their insect hosts. A longstanding question in symbiont research is what genes help promote long-term stability of vertically transmitted lifestyles. Symbiont success in insect hosts is due in part to expression of beneficial or manipulative phenotypes that favor symbiont persistence in host populations. In Spiroplasma, these phenotypes have been linked to toxin and virulence domains among a few related strains. However, these domains also appear frequently in phylogenetically distant Spiroplasma, and little is known about their distribution across the Spiroplasma genus. In this study, we present the complete genome sequence of the Spiroplasma symbiont of Drosophila atripex, a non-manipulating member of the Ixodetis clade of Spiroplasma, for which genomic data are still limited. We perform a genus-wide comparative analysis of toxin domains implicated in defensive and reproductive phenotypes. From 12 VT and 31 non-VT Spiroplasma genomes, ribosome-inactivating proteins (RIPs), OTU-like cysteine proteases (OTUs), ankyrins, and ETX/MTX2 domains show high propensity for VT Spiroplasma compared to non-VT Spiroplasma. Specifically, OTU and ankyrin domains can be found only in VT-Spiroplasma, and RIP domains are found in all VT Spiroplasma and three non-VT Spiroplasma. These domains are frequently associated with Spiroplasma plasmids, suggesting a possible mechanism for dispersal and maintenance among heritable strains. Searching insect genome assemblies available on public databases uncovered uncharacterized Spiroplasma genomes from which we identified several spaid-like genes encoding RIP, OTU, and ankyrin domains, suggesting functional interactions among those domain types. Our results suggest a conserved core of symbiont domains play an important role in the evolution and persistence of VT Spiroplasma in insects.
Evaluation and development of deep neural networks for RNA 5-Methyluridine classifications using autoBioSeqpy
Authors: Yu Lezheng , Zhang Yonglin , Xue Li , Liu Fengjuan , Jing Runyu , Luo Jiesi
Published: May 2023

Post-transcriptionally RNA modifications, also known as the epitranscriptome, play crucial roles in the regulation of gene expression during development. Recently, deep learning (DL) has been employed for RNA modification site prediction and has shown promising results. However, due to the lack of relevant studies, it is unclear which DL architecture is best suited for some pyrimidine modifications, such as 5-methyluridine (m5U). To fill this knowledge gap, we first performed a comparative evaluation of various commonly used DL models for epigenetic studies with the help of autoBioSeqpy. We identified optimal architectural variations for m5U site classification, optimizing the layer depth and neuron width. Second, we used this knowledge to develop Deepm5U, an improved convolutional-recurrent neural network that accurately predicts m5U sites from RNA sequences. We successfully applied Deepm5U to transcriptomewide m5U profiling data across different sequencing technologies and cell types. Third, we showed that the techniques for interpreting deep neural networks, including LayerUMAP and DeepSHAP, can provide important insights into the internal operation and behavior of models. Overall, we offered practical guidance for the development, benchmark, and analysis of deep learning models when designing new algorithms for RNA modifications.
Isolation and characterization of porcine epidemic diarrhea virus with a novel continuous mutation in the S10 domain
Authors: Han Xueying , Liu Yangkun , Wang Yan , Wang Tiejun , Li Ning , Hao Feng , Yao Lunguang , Guo Kangkang
Published: May 2023

Porcine epidemic diarrhea virus (PEDV), which re-emerged in China in 2010, has caused severe economic losses to the global pig industry. In this study, a PEDV strain, designated PEDV WMB, was isolated from piglets with severe diarrhea on a pig farm in Henan Province of China. Whole-genome sequencing and analysis revealed that the PEDV WMB strain belongs to subtype G2c and has a unique continuous mutation in the S10 antigenic epitope of the S protein. Moreover, the virus-neutralization (VN) test indicated that polyclonal antibodies against the S10 protein of other G1 and G2 strains showed reduced VN reactivity to PEDV WMB. The pathogenicity of PEDV WMB was further investigated in 3 day-old piglets. PEDV infection-related clinical symptoms and morphological lesions were observed and confirmed by histopathological and immunohistochemical examination (IHC). These results illustrated that continuous mutation of the S10 epitope might affect the immunogenicity or pathogenicity of PEDV, providing evidence of the need to monitor the genetic diversity of the virus and develop effective measures to prevent and control PEDV.
Aging brain shows joint declines in brain within-network connectivity and between-network connectivity: a large-sample study (N > 6,000)
Authors: Du Yuhui , Guo Yating , Calhoun Vince D.
Published: May 2023

Introduction

Numerous studies have shown that aging has important effects on specific functional networks of the brain and leads to brain functional connectivity decline. However, no studies have addressed the effect of aging at the whole-brain level by studying both brain functional networks (i.e., within-network connectivity) and their interaction (i.e., between-network connectivity) as well as their joint changes.

Methods

In this work, based on a large sample size of neuroimaging data including 6300 healthy adults aged between 49 and 73 years from the UK Biobank project, we first use our previously proposed priori-driven independent component analysis (ICA) method, called NeuroMark, to extract the whole-brain functional networks (FNs) and the functional network connectivity (FNC) matrix. Next, we perform a two-level statistical analysis method to identify robust aging-related changes in FNs and FNCs, respectively. Finally, we propose a combined approach to explore the synergistic and paradoxical changes between FNs and FNCs.

Results

Results showed that the enhanced FNCs mainly occur between different functional domains, involving the default mode and cognitive control networks, while the reduced FNCs come from not only between different domains but also within the same domain, primarily relating to the visual network, cognitive control network, and cerebellum. Aging also greatly affects the connectivity within FNs, and the increased within-network connectivity along with aging are mainly within the sensorimotor network, while the decreased within-network connectivity significantly involves the default mode network. More importantly, many significant joint changes between FNs and FNCs involve default mode and sub-cortical networks. Furthermore, most synergistic changes are present between the FNCs with reduced amplitude and their linked FNs, and most paradoxical changes are present in the FNCs with enhanced amplitude and their linked FNs.

Discussion

In summary, our study emphasizes the diversity of brain aging and provides new evidence via novel exploratory perspectives for non-pathological aging of the whole brain.
Following nanoparticle uptake by cells using high-throughput microscopy and the deep-learning based cell identification algorithm Cellpose
Authors: Yang Boxuan , Richards Ceri J. , Gandek Timea B. , de Boer Isa , Aguirre-Zuazo Itxaso , Niemeijer Else , Åberg Christoffer
Published: May 2023

How many nanoparticles are taken up by human cells is a key question for many applications, both within medicine and safety. While many methods have been developed and applied to this question, microscopy-based methods present some unique advantages. However, the laborious nature of microscopy, in particular the consequent image analysis, remains a bottleneck. Automated image analysis has been pursued to remedy this situation, but offers its own challenges. Here we tested the recently developed deep-learning based cell identification algorithm Cellpose on fluorescence microscopy images of HeLa cells. We found that the algorithm performed very well, and hence developed a workflow that allowed us to acquire, and analyse, thousands of cells in a relatively modest amount of time, without sacrificing cell identification accuracy. We subsequently tested the workflow on images of cells exposed to fluorescently-labelled polystyrene nanoparticles. This dataset was then used to study the relationship between cell size and nanoparticle uptake, a subject where high-throughput microscopy is of particular utility.
Resveratrol ameliorates maternal separation-induced anxiety- and depression-like behaviors and reduces Sirt1-NF-kB signaling-mediated neuroinflammation
Authors: Wei Ru-Meng , Zhang Yue-Ming , Feng Yi-Zhou , Zhang Kai-Xuan , Zhang Jing-Ya , Chen Jing , Luo Bao-Ling , Li Xue-Yan , Chen Gui-Hai
Published: May 2023

Maternal separation in early life has a detrimental effect on the physiological and biochemical functions of the brains of offspring and can lead to anxiety- and depression-like behaviors later in life. Resveratrol possesses a variety of pharmacological properties, including anti-inflammatory, anxiolytic, and anti-depressive effects. In rodents, resveratrol can attenuate anxiety- and depression-like behaviors induced by chronic unpredictable mild stress, estrogen deficiency, and lipopolysaccharide. However, whether resveratrol administration during adolescence can counteract these behaviors when they result from maternal separation is unknown. In this study, male C57BL/6J mice were separated from their mothers for 4 h per day from postnatal day 2 (PND 2) to PND 21; starting on PND 61, resveratrol was administered intraperitoneally at 40 mg/(kg/day–1) for 4 weeks. At 3 months of age, anxiety and depression-like behaviors were assessed in the male offspring using a series of tasks consisting of an open field test, an elevated plus maze test, a forced swimming test, and a tail suspension test. The hippocampal levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) were measured by ELISA, while those of sirtuin 1 (Sirt1) and nuclear factor kappa B (NF-κB) p65 were determined by western blotting and PCR. The results showed that maternal separation led to increased anxiety- and depression-like behaviors, enhanced the levels of pro-inflammatory cytokines, and downregulated the Sirt1/NF-κB signaling pathway in the male offspring; however, these effects could be reversed by treatment with resveratrol. Our findings suggested that resveratrol can ameliorate inflammation and anxiety- and depression-like behaviors induced by maternal separation via the activation of the Sirt1/NF-κB pathway.
Multiple genetic variants involved in both autoimmunity and autoinflammation detected in Chinese patients with sporadic Meniere's disease: a preliminary study
Authors: Zou Jing , Zhang Guoping , Li Hongbin , Zhao Zikai , Zhang Qing , Pyykkö Ilmari , Mäkitie Antti
Published: May 2023

Background

The mechanisms of Meniere's disease (MD) remain largely unknown. The purpose of this study was to identify possible genetic variants associated with immune regulation in MD.

Methods

The whole immune genome of 16 Chinese patients diagnosed with sporadic MD was sequenced using next-generation sequencing.

Results

Definite pathological variants of MEFV (c.1223G>A, c.1105C>T), COL7A1 (c.5287C>T), and ADA (c.445C>T) contributing to the clinical phenotype were found in three patients. Limited and likely pathological variants of TLR3 (c.2228G>A) and RAB27A (c.560G>A) were detected in one patient each. The following definite pathological variants impairing the structure and function of translated proteins were detected in 10 patients, and multigene variants occurred in five patients: PRF1 (c.710C>A), UNC13D (c.1228A>C), COLEC11 (c.169C>T), RAG2 (c.200G>C), BLM (c.1937G>T), RNF31 (c.2533G>A), FAT4 (c.11498A>G), PEPD (c.788A>G), TNFSF12 (c.470G>A), VPS13B (c.11972A>T), TNFRSF13B (c.226G>A), ERCC6L2 (c.4613A>G), TLR3 (c.2228G>A), ADA (c.445C>T), PEPD (c.151G>A), and MOGS (c.2470G>A). The following limited pathological variants impairing the structure and function of translated proteins were detected in five patients, with double gene variants identified in one patient: EXTL3 (c.1396G>A), MTHFD1 (c.2057G>A), FANCA (c.2039T>C), LPIN2 (c.1814C>T), NBAS (c.4049T>C), and FCN3 (c.734G>A).

Conclusion

Patients with sporadic MD carry multiple genetic variants involved in multiple steps of immune regulation, which might render patients susceptible to developing inflammation via both autoimmune and autoinflammation mechanisms upon internal stress.
Association between hysterectomy status and stroke risk and cause-specific and all-cause mortality: evidence from the 2005–2018 National Health and Nutrition Examination Survey
Authors: Shen Ruihuan , Wang Jia , Tian Yuqing , Wang Rui , Guo Peiyao , Shen Shuhui , Liu Donghao , Zou Tong
Published: May 2023

Background

Prior research on women who had hysterectomies has shown mixed results on whether or not hysterectomies increased the incidence of stroke and cause-specific or all-cause mortality.

Methods

Using information from the Continuous National Health and Nutrition Examination Survey (NHANES) in the United States, including linked mortality follow-up files available for public access, a multicycle cross-sectional design mortality linkage study was performed.

Results

Conducted during the years 2005–2018, the study sample included 14,214 female participants ranging in age from 20 to 85 years. The relationship between the hysterectomy status and the risk of stroke and cause-specific and all-cause mortality was examined using a series of weighted logistic regressions and Cox proportional hazards regressions, respectively. The presence of a hysterectomy was consistently linked to an elevated risk of stroke using weighted logistic regression models. The hysterectomy status, however, consistently showed no effect on survival by adjusted weighted Cox regression analysis.

Conclusion

Our study found a significant association between hysterectomy and stroke, even after adjusting for other factors that could impact risk, such as the American Heart Association (AHA)'s Life's Simple 7 cardiovascular health score and variables of age, ethnicity, marital status, income, education, and depression severity.
Prognostic significance of white blood cell to platelet ratio in delayed cerebral ischemia and long-term clinical outcome after aneurysmal subarachnoid hemorrhage
Authors: Zhang Wanwan , Wang Yifei , Zhang Qingqing , Hou Fandi , Wang Lintao , Zheng Zhanqiang , Guo Yong , Chen Zhongcan , Hernesniemi Juha , Feng Guang , Gu Jianjun
Published: May 2023

Objectives

The ratio of white blood cell to platelet count (WPR) is considered a promising biomarker in some diseases. However, its prediction of delayed cerebral ischemia (DCI) and prognosis after aneurysmal subarachnoid hemorrhage (aSAH) has not been studied. The primary objective of this study was to investigate the predictive value of WPR in DCI after aSAH and its impact on 90-day functional outcome.

Materials and methods

This study retrospectively analyzed the data of blood biochemical parameters in 447 patients with aSAH at early admission. Univariate and multivariate analyses were used to determine the risk factors for DCI. According to multivariate analysis results, a nomogram for predicting DCI is developed and verified by R software. The influence of WPR on 90-day modified Rankin score (mRS) was also analyzed.

Results

Among 447 patients with aSAH, 117 (26.17%) developed DCI during hospitalization. Multivariate logistic regression analysis showed that WPR [OR = 1.236; 95%CI: 1.058–1.444; p = 0.007] was an independent risk factor for DCI. The receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive ability of WPR for DCI, and the cut-off value of 5.26 (AUC 0.804, 95% CI: 0.757–0.851, p < 0.001). The ROC curve (AUC 0.875, 95% CI: 0.836–0.913, p < 0.001) and calibration curve (mean absolute error = 0.017) showed that the nomogram had a good predictive ability for the occurrence of DCI. Finally, we also found that high WPR levels at admission were closely associated with poor prognosis.

Conclusion

WPR level at admission is a novel serum marker for DCI and the poor prognosis after aSAH. A nomogram model containing early WPR will be of great value in predicting DCI after aSAH.
Internal carotid artery stenosis: hemodynamics in the ipsilateral ACA affects CT angiography manifestations
Authors: Li Chun , Meng Jihong , Xu Baoxin , Li Xiaodong , Li Miaomiao , Du Xue , Li Shaoyi , Ma Weining
Published: May 2023

Objective

This study aimed to evaluate whether CT angiography (CTA) manifestations in anterior cerebral artery a1 segment (A1) were related to the hemodynamics in patients with internal carotid artery stenosis (ICAS).

Methods

A total of 97 cases were selected. The degree of ICAS and symmetry of A1 were evaluated by CTA examination. Hemodynamic indexes were detected by transcranial Doppler (TCD). The differences in CTA presentations of A1 and hemodynamics between the vessels on the stenotic and contralateral sides were analyzed according to the different degrees of stenosis. The degree of ICAS according to the different manifestations of A1 and the hemodynamics of A1’s adjacent vessels were also analyzed.

Results

In the case of unilateral ICAS, the difference in Vm of A1 between the stenotic and the contralateral side was the most significant relative to the stenosis degree. When unilateral ICAS was ≥70%, the presentation of A1 on the stenotic side was more slender or non-visualized compared to that on the contralateral side, while in cases with unilateral stenosis <70% or bilateral stenosis with a similar degree of stenosis, A1 were mainly symmetrical. When A1 on the side of ICAS was slender or non-visualized, the Vm of A1 was significantly slower than that on the contralateral side (P < 0.001).

Conclusion

The CTA manifestations of A1 on the side of ICAS embodied the overall changes of the intracranial hemodynamics after ICAS. A combination of TCD and CTA examination of A1 can assist in judging the location and degree of ICAS.
Innovative perspectives in limbic surgery using deep brain stimulation
Authors: Carrillo-Ruiz José Damián , Carrillo-Márquez José Rodrigo , Beltrán Jesús Quetzalcóatl , Jiménez-Ponce Fiacro , García-Muñoz Luis , Navarro-Olvera José Luis , Márquez-Franco René , Velasco Francisco
Published: May 2023

Limbic surgery is one of the most attractive and retaken fields of functional neurosurgery in the last two decades. Psychiatric surgery emerged from the incipient work of Moniz and Lima lesioning the prefrontal cortex in agitated patients. Since the onset of stereotactic and functional neurosurgery with Spiegel and Wycis, the treatment of mental diseases gave attention to refractory illnesses mainly with the use of thalamotomies. Neurosis and some psychotic symptoms were treated by them. Several indications when lesioning the brain were included: obsessive-compulsive disorder, depression, and aggressiveness among others with a diversity of targets. The indiscriminately use of anatomical sites without enough scientific evidence, and uncertainly defined criteria for selecting patients merged with a deficiency in ethical aspects, brought a lack of procedures for a long time: only select clinics allowed this surgery around the world from 1950 to the 1990s. In 1999, Nuttin et al. began a new chapter in limbic surgery with the use of Deep Brain Stimulation, based on the experience of pain, Parkinson’s disease, and epilepsy. The efforts were focused on different targets to treat depression and obsessive-compulsive disorders. Nevertheless, other diseases were added to use neuromodulation. The goal of this article is to show the new opportunities to treat neuropsychiatric diseases.
Case Report: Complete pathologic response to neoadjuvant selpercatinib in a patient with resectable early-stage RET fusion-positive non-small cell lung cancer
Authors: Goldman Jonathan W. , Sholl Lynette M. , Dacic Sanja , Fishbein Michael C. , Murciano-Goroff Yonina R. , Rajaram Ravi , Szymczak Sylwia , Szpurka Anna M. , Chao Bo H. , Drilon Alexander
Published: May 2023

The LIBRETTO-001 trial demonstrated the activity of the selective rearrangement during transfection (RET) inhibitor selpercatinib in advanced RET fusion-positive non-small cell lung cancer (NSCLC) and resulted in the drug’s approval for this indication. A cohort that included neoadjuvant and adjuvant selpercatinib was opened on LIBRETTO-001 for early-stage RET fusion-positive NSCLC with the primary endpoint of major pathologic response. A patient with a stage IB (cT2aN0M0) KIF5B-RET fusion-positive NSCLC received 8 weeks of neoadjuvant selpercatinib at 160 mg twice daily followed by surgery. While moderate regression in the primary tumor (stable disease, Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.1) was observed radiologically, assessment via an Independent Pathologic Review Committee revealed a pathologic complete response (0% viable tumor). This consensus assessment by three independent pathologists was aided by RET fluorescence in situ hybridization testing of a reactive pneumocyte proliferation showing no rearrangement. Neoadjuvant selpercatinib was well-tolerated with only low-grade treatment-emergent adverse events. The activity of prospective preoperative selpercatinib in this case establishes proof of concept of the potential utility of RET inhibitor therapy in early-stage RET fusion-positive NSCLC.
Molecular subtypes and tumor microenvironment infiltration signatures based on cuproptosis-related genes in colon cancer
Authors: Luo Hongwei , Zhang Que , Liu Xiangchu , Luo Yue , Jiang Xing , Wang Chao , Chen Bin , He Qiming , Zhang Yingchun , Shu Ou , Dai Penggao , He Chengcheng
Published: May 2023

Background

Colon cancer is one of the common cancers, and its prognosis remains to be improved. The role of cuproptosis as a newly discovered form of cell death in the development of colon cancer has not been determined.

Methods

Based on 983 colon cancer samples in the TCGA database and the GEO database, we performed a comprehensive genomic analysis to explore the molecular subtypes mediated by cuproptosis-related genes. Single-sample gene set enrichment analysis (ssGSEA) was utilized to quantify the relative abundance of each cell infiltrate in the TME. A risk score was established using least absolute shrinkage and selection operator regression (LASSO), and its predictive ability for colon cancer patients was verified to explore its guiding value for treatment.

Results

We identified two distinct cuproptosis-related molecular subtypes in colon cancer. These two distinct molecular subtypes can predict clinicopathological features, prognosis, TME activity, and immune-infiltrating cells. A risk model was developed and its predictive ability was verified. Compared with patients in the high-risk score group, patients in the low-risk score group were characterized by lower tumor microenvironment score, higher stem cell activity, lower tumor mutational burden, lower microsatellite instability, higher sensitivity to chemotherapeutics, and better immunotherapy efficacy.

Conclusion

This study contributes to understanding the molecular characteristics of cuproptosis-related subtypes. We demonstrate a critical role for cuproptosis genes in colon cancer s in the TME. Our study contributes to the development of individualized treatment regimens for colon cancer.
Roles of autophagy-related genes in the therapeutic effects of Xuanfei Pingchuan capsules on chronic obstructive pulmonary disease based on transcriptome sequencing analysis
Authors: Zhang Ye , Xue Xiaoming , Meng Lihong , Li Dian , Qiao Wenxiao , Wang Jinyun , Xie Di
Published: May 2023

Objective: Autophagy plays an important role in the occurrence and development of chronic obstructive pulmonary disease (COPD). We evaluated the effect of Xuanfei Pingchuan capsule (XFPC) on autophagy-related genes of COPD by a bioinformatics analysis and experimental verification.

Methods: The best treatment duration was screened by CCK8 assays. HBE cells were divided into three groups: blank, CSE and XFPC. After intervened by XFPC, HBE cells were collected and sent to Shenzhen Huada Gene Company for transcriptome sequencing. Subsequently, differential expression analyses, target gene prediction, and function enrichment analyses were carried out. Expression changes were verified in HBE cells by real-time Quantitative PCR (RT-qPCR) and western blotting (WB).

Results: The result of differential expression analysis displayed that 125 target genes of HBE cells were mainly related to mitogen-activated protein kinase (MKK) binding, interleukin 33 binding, 1-Pyrroline-5-carboxylate dehydrogenase activity, and the mitogen-activated protein kinase (MAPK) signal pathway. Among the target genes, the core genes related to autophagy obtained by maximum neighborhood component algorithm were CSF1, AREG, MAPK9, MAP3K7, and AKT3. RT-qPCR and WB methods were used to verify the result, it showed similar expression changes in CSF1, MAPK9, MAP3K7, and AKT3 in bronchial epithelial cells to those in the bioinformatics analysis.

Conclusion: Through transcriptome sequencing and validation analysis, we predicted that CSF1, MAPK9, MAP3K7, and AKT3 may be the potential autophagy-related genes that play an important role in the pathogenesis of COPD. XFPC may regulate autophagy by down-regulating the expression of CSF1, MAPK9, MAP3K7, and AKT3, thus achieving the purpose of treating chronic obstructive pulmonary disease.
The identification of metabolism-related subtypes and potential treatments for idiopathic pulmonary fibrosis
Authors: Yang Changqing , Wang Guixin , Zhan Wenyu , Wang Yubao , Feng Jing
Published: May 2023

Background: Idiopathic pulmonary fibrosis (IPF) is caused by aberrant repair because of alveolar epithelial injury and can only be effectively treated with several compounds. Several metabolism-related biomolecular processes were found to be involved in IPF. We aimed to identify IPF subtypes based on metabolism-related pathways and explore potential drugs for each subtype.

Methods: Gene profiles and clinical information were obtained from the Gene Expression Omnibus (GEO) database (GSE70867 and GSE93606). The enrichment scores for 41 metabolism-related pathways, immune cells, and immune pathways were calculated using the Gene Set Variation Analysis (GSVA) package. The ConsensusClusterPlus package was used to cluster samples. Novel modules and hub genes were identified using weighted correlation network analysis (WGCNA). Receiver operating characteristic (ROC) and calibration curves were plotted, and decision curve analysis (DCA) were performed to evaluate the model in the training and validation cohorts. A connectivity map was used as a drug probe.

Results: Two subtypes with significant differences in prognosis were identified based on the metabolism-related pathways. Subtype C1 had a poor prognosis, low metabolic levels, and a unique immune signature. CDS2, LCLAT1, GPD1L, AGPAT1, ALDH3A1, LAP3, ADH5, AHCYL2, and MDH1 were used to distinguish between the two subtypes. Finally, subtype-specific drugs, which can potentially treat IPF, were identified.

Conclusion: The aberrant activation of metabolism-related pathways contributes to differential prognoses in patients with IPF. Collectively, our findings provide novel mechanistic insights into subtyping IPF based on the metabolism-related pathway and potential treatments, which would help clinicians provide subtype-specific individualized therapeutic management to patients.
Drug repurposing for reducing the risk of cataract extraction in patients with diabetes mellitus: integration of artificial intelligence-based drug prediction and clinical corroboration
Authors: Gao Zhenxiang , Gorenflo Maria , Kaelber David C. , Monnier Vincent M. , Xu Rong
Published: May 2023

Diabetes mellitus (DM) increases the incidence of age-related cataracts. Currently, no medication is approved or known to delay clinical cataract progression. Using a novel approach based on AI, we searched for drugs with potential cataract surgery-suppressing effects. We developed a drug discovery strategy that combines AI-based potential candidate prediction among 2650 Food and Drug Administration (FDA)-approved drugs with clinical corroboration leveraging multicenter electronic health records (EHRs) of approximately 800,000 cataract patients from the TriNetX platform. Among the top-10 AI-predicted repurposed candidate drugs, we identified three DM diagnostic ICD code groups, such as cataract patients with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), or hyperglycemia, and conducted retrospective cohort analyses to evaluate the efficacy of these candidate drugs in reducing the risk of cataract extraction. Aspirin, melatonin, and ibuprofen were associated with a reduced 5-, 10-, and 20-year cataract extraction risk in all types of diabetes. Acetylcysteine was associated with a reduced 5-, 10-, and 20-year cataract extraction risk in T2DM and hyperglycemia but not in T1DM patient groups. The suppressive effects of aspirin, acetylcysteine, and ibuprofen waned over time, while those of melatonin became stronger in both genders. Thus, the four repositioned drugs have the potential to delay cataract progression in both genders. All four drugs share the ability to directly or indirectly inhibit cyclooxygenase-2 (COX-2), an enzyme that is increased by multiple cataractogenic stimuli.
Pharmacogenomics in practice: a review and implementation guide
Authors: Kabbani Danya , Akika Reem , Wahid Ahmed , Daly Ann K. , Cascorbi Ingolf , Zgheib Nathalie Khoueiry
Published: May 2023

Considerable efforts have been exerted to implement Pharmacogenomics (PGx), the study of interindividual variations in DNA sequence related to drug response, into routine clinical practice. In this article, we first briefly describe PGx and its role in improving treatment outcomes. We then propose an approach to initiate clinical PGx in the hospital setting. One should first evaluate the available PGx evidence, review the most relevant drugs, and narrow down to the most actionable drug-gene pairs and related variant alleles. This is done based on data curated and evaluated by experts such as the pharmacogenomics knowledge implementation (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC), as well as drug regulatory authorities such as the US Food and Drug Administration (FDA) and European Medicinal Agency (EMA). The next step is to differentiate reactive point of care from preemptive testing and decide on the genotyping strategy being a candidate or panel testing, each of which has its pros and cons, then work out the best way to interpret and report PGx test results with the option of integration into electronic health records and clinical decision support systems. After test authorization or testing requirements by the government or drug regulators, putting the plan into action involves several stakeholders, with the hospital leadership supporting the process and communicating with payers, the pharmacy and therapeutics committee leading the process in collaboration with the hospital laboratory and information technology department, and healthcare providers (HCPs) ordering the test, understanding the results, making the appropriate therapeutic decisions, and explaining them to the patient. We conclude by recommending some strategies to further advance the implementation of PGx in practice, such as the need to educate HCPs and patients, and to push for more tests’ reimbursement. We also guide the reader to available PGx resources and examples of PGx implementation programs and initiatives.
Perspectives of international multi-center clinical trials on traditional Chinese herbal medicine
Authors: Wu Shan , Wang Chuanchi , Bai Dong , Chen Nanjie , Hu Jingqing , Zhang Junhua
Published: May 2023

With the introduction of various subjects, such as clinical epidemiology and evidence-based medicine, the qualities and levels of Traditional Chinese Herbal Medicine (TCHM) in China improved substantially, and the processes of internationalization of Traditional Chinese Medicine (TCM) are further accelerated. Since, a variety of drug products in China have been approved for marketing in other countries, and approximately 10 products have submitted the IND application to FDA of United States, of which various Chinese herbal preparations such as compound Danshen dripping pills, Xingling granules, and HMPL-004 have been approved to be investigated in phase III clinical trials. In general, multi-center studies of TCHM are increasing with years, but most of the studies are performed in some certain country, and the actual international multi-center clinical trials are very rare. Number of SCI literatures on multi-center clinical trials of TCHM that published in the recent decade also showed increasing tendency with years, despite the evident reduction in the past 2 years due to the influence of COVID-19 pandemic. Of the multi-center clinical trials of TCHM that performed by mainland China and other oversees regions, except for Taiwan, China, nearly 70% were focused on classic Chinese medicinal formulae and Chinese patent medicine, while the other 30% were on dietary supplements and plant extracts. Facing the future, the “human experience” has attracted close attentions from researchers throughout the world. Effectively utilizing the historic “human experience” is an important method to vitalize potential of original scientific and technological resources of TCHM. Performing multi-center clinical trials with high qualities is still an essential method for TCHM in accessing the mainstream medicine market. In addition, it is also required to further improve the evaluation techniques and methods that not only meet the international standards but also meet the characteristics of TCHM. Furthermore, we should also focus on the TCHM specific clinical values and scientific reports.
Dual pulse heterodyne distributed acoustic sensor system employing SOA-based fiber ring laser
Authors: Zhang Chunxi , Yang Sufan , Wang Xiaxiao
Published: May 2023

Distributed Acoustic Sensor (DAS) has potential in applications such as hydroacoustic detection. In this paper, a dual-pulse heterodyne distributed acoustic sensor (DAS) system using a semiconductor optical amplifier (SOA)-based fiber ring laser (FRL) is proposed. Unlike the previous DAS system configurations, the SOA-based FRL replaces the narrow linewidth laser (NLL) and pulse modulator, reducing costs and simplifying the system. The system is demonstrated theoretically and validated experimentally. The adaptability of the SOA-based FRL in the heterodyne DAS system has been demonstrated in the experiments. Using the dual-pulse heterodyne detection method, the sensor system responds well to distributed acoustic detection and achieves accurate demodulation and positioning. A high signal-to-noise ratio (SNR) of 42.51 dB at 3 kHz is demonstrated as a demodulation result. The system’s frequency range is 5 Hz to 5 kHz with a spatial resolution of 12 m. The proposed approach shows a broad application prospect for low-cost, large-scale, high-SNR distributed acoustic detection in maritime surveillance.
Increasing maternal age associates with lower placental CPT1B mRNA expression and acylcarnitines, particularly in overweight women
Authors: Yong Hannah E. J. , Watkins Oliver C. , Mah Tania K. L. , Cracknell-Hazra Victoria K. B. , Pillai Reshma Appukuttan , Selvam Preben , Islam Mohammad O. , Sharma Neha , Cazenave-Gassiot Amaury , Bendt Anne K. , Wenk Markus R. , Godfrey Keith M. , Lewis Rohan M. , Chan Shiao-Yng
Published: May 2023

Older pregnant women have increased risks of complications including gestational diabetes and stillbirth. Carnitine palmitoyl transferase (CPT) expression declines with age in several tissues and is linked with poorer metabolic health. Mitochondrial CPTs catalyze acylcarnitine synthesis, which facilitates fatty acid oxidization as fuel. We hypothesized that the placenta, containing maternally-inherited mitochondria, shows an age-related CPT decline that lowers placental acylcarnitine synthesis, increasing vulnerability to pregnancy complications. We assessed CPT1A, CPT1B, CPT1C and CPT2 mRNA expression by qPCR in 77 placentas and quantified 10 medium and long-chain acylcarnitines by LC-MS/MS in a subset of 50 placentas. Older maternal age associated with lower expression of placental CPT1B, but not CPT1A, CPT1C or CPT2. CPT1B expression positively associated with eight acylcarnitines and CPT1C with three acylcarnitines, CPT1A negatively associated with nine acylcarnitines, while CPT2 did not associate with any acylcarnitine. Older maternal age associated with reductions in five acylcarnitines, only in those with BMI≥ 25 kg/m2, and not after adjusting for CPT1B expression. Our findings suggest that CPT1B is the main transferase for placental long-chain acylcarnitine synthesis, and age-related CPT1B decline may underlie decreased placental metabolic flexibility, potentially contributing to pregnancy complications in older women, particularly if they are overweight.
Investigation into the importance of using natural PVCs and pathological models for potential-based ECGI validation
Authors: Bear Laura R. , Bergquist Jake A. , Abell Emma , Cochet Hubert , MacLeod Rob S. , Dubois Remi , Serinagaoglu Yesim
Published: May 2023

Introduction: Premature ventricular contractions (PVCs) are one of the most commonly targeted pathologies for ECGI validation, often through ventricular stimulation to mimic the ectopic beat. However, it remains unclear if such stimulated beats faithfully reproduce spontaneously occurring PVCs, particularly in the case of the R-on-T phenomenon. The objective of this study was to determine the differences in ECGI accuracy when reconstructing spontaneous PVCs as compared to ventricular-stimulated beats and to explore the impact of pathophysiological perturbation on this reconstruction accuracy.

Methods: Langendorff-perfused pig hearts (n = 3) were suspended in a human torso-shaped tank, and local hyperkalemia was induced through perfusion of a high-K+ solution (8 mM) into the LAD. Recordings were taken simultaneously from the heart and tank surfaces during ventricular pacing and during spontaneous PVCs (including R-on-T), both at baseline and high K+. Epicardial potentials were reconstructed from torso potentials using ECGI.

Results: Spontaneously occurring PVCs were better reconstructed than stimulated beats at baseline in terms of electrogram morphology [correlation coefficient (CC) = 0.74 ± 0.05 vs. CC = 0.60 ± 0.10], potential maps (CC = 0.61 ± 0.06 vs. CC = 0.51 ± 0.12), and activation time maps (CC = 0.86 ± 0.07 vs. 0.76 ± 0.10), though there was no difference in the localization error (LE) of epicardial origin (LE = 14 ± 6 vs. 15 ± 11 mm). High K+ perfusion reduced the accuracy of ECGI reconstructions in terms of electrogram morphology (CC = 0.68 ± 0.10) and AT maps (CC = 0.70 ± 0.12 and 0.59 ± 0.23) for isolated PVCs and paced beats, respectively. LE trended worse, but the change was not significant (LE = 17 ± 9 and 20 ± 12 mm). Spontaneous PVCs were less well when the R-on-T phenomenon occurred and the activation wavefronts encountered a line of block.

Conclusion: This study demonstrates the differences in ECGI accuracy between spontaneous PVCs and ventricular-paced beats. We also observed a reduction in this accuracy near regions of electrically inactive tissue. These results highlight the need for more physiologically realistic experimental models when evaluating the accuracy of ECGI methods. In particular, reconstruction accuracy needs to be further evaluated in the presence of R-on-T or isolated PVCs, particularly when encountering obstacles (functional or anatomical) which cause line of block and re-entry.
Evaluation of the antioxidant, anti-inflammatory, and anti-tumoral properties of bioactive compounds extracted from murta berries (Ugni molinae T.) dried by different methods
Authors: López Jéssica , Vega-Gálvez Antonio , Ah-Hen Kong S. , Rodríguez Angela , Quispe-Fuentes Issis , Delporte Carla , Valenzuela-Barra Gabriela , Arancibia Yennyfer , Zambrano Angara
Published: May 2023

This study evaluated the effects of different drying methods (freeze drying, vacuum drying, infrared drying, convective drying, and sun drying) on the biological properties of berries from the Chilean murta (Ugni molinae Turcz) shrub. Physical-chemical properties (proximal composition, dietary fiber, sugars) were determined. Total phenolic content through the method of Folin-Ciocalteau, the profile of phenol compounds was determined by HPLC, and antioxidant potential by DPPH and ORAC assays were also evaluated. The topic anti-inflammatory effect was evaluated by mice´s ear edema, and in vitro anti-tumoral activity was tested by MTT assay. The chemical properties of dried berries differed significantly based on the drying method: freeze-dried murta berries showed increased total phenolic content extracted over fresh and dried samples. In addition, this lyophilized extract stood out in its antioxidant potential, in both assays evaluated (DPPH and ORAC), compared to the other drying methods. Notwithstanding, vacuum- and infrared-dried murta also showed a higher ORAC value. Antioxidant potential was significantly associated with phenolic compounds catechin and pyrogallol, which were the most abundant phenolic compounds present in all samples. The anti-inflammatory activity was most effective under freeze-drying and vacuumdrying conditions. Moreover, vacuum drying and infrared drying best preserved the anti-tumoral effect on cancer cells.
Molecular characterization and SNP identification using genotyping-by-sequencing in high-yielding mutants of proso millet
Authors: Francis Neethu , Rajasekaran Ravikesavan , Rajagopalan Veera Ranjani , Bakya S. Vinothini , Muthurajan Raveendran , Kumar Ashwini Girish , Alagarswamy Senthil , Krishnamoorthy Iyanar , Thiyagarajan Chitdeshwari
Published: May 2023

Proso millet (Panicummiliaceum L.) is a short-duration C4 crop that is drought tolerant and nutritionally rich and can grow well in marginal lands. Though the crop has many climate-resilient traits like tolerance to drought and heat, its yield is lower than that of common cereals like rice, wheat, and maize. Being an underutilized crop, the molecular resources in the crop are limited. The main aim of the present study was to develop and characterize contrasting mutants for yield and generate functional genomic information for the trait in proso millet. Gamma irradiation-induced mutant population was screened to identify high-yielding mutants, which were evaluated up to M4 generation. One mutant with a dense panicle and high yield (ATL_hy) and one with a lax panicle and low yield (ATL_ly) along with the wild type were sequenced using the genotyping-by-sequencing approach. The variants detected as single nucleotide polymorphisms (SNPs) and insertions–deletions (InDels) were annotated against the reference genome of proso millet. Bioinformatic analyses using the National Center for Biotechnology Information (NCBI) and UniProt databases were performed to elucidate genetic information related to the SNP variations. A total of 25,901, 30,335, and 31,488 SNPs, respectively, were detected in the wild type, ATL_hy mutants, and ATL_ly mutants. The total number of functional SNPs identified in high-yielding and low-yielding mutants was 84 and 171, respectively. Two functional SNPs in the high-yielding mutant (ATL_hy) and one in the low-yielding mutant (ATL_ly) corresponded to the gene coding for “E3 ubiquitin-protein ligase UPL7”. Pathway mapping of the functional SNPs identified that two SNPs in ATL_ly were involved in the starch biosynthetic pathway coding for the starch synthase enzyme. This information can be further used in identifying genes responsible for various metabolic processes in proso millet and in designing useful genetic markers.
Developing and validating a measure of parental knowledge about early math development
Authors: Douglas Ashli-Ann , Msall Camille , Rittle-Johnson Bethany
Published: May 2023

Parents’ knowledge about the math skills that most preschool-aged children can develop might be an important component of the Home Math Environment (HME) as it might shape their math beliefs and efforts to support their preschoolers’ math development. This study aimed to systematically develop measures of parents’ knowledge about two critical early math topics, numeracy, and patterning, across five studies conducted with a total of 616 U.S. parents of 3- to 5-year-olds (66% mothers, 54% sons, 73% White, 60% college-educated). Parents were recruited via CloudResearch or a university database. Study 1 focused on item generation to revise a previous measure to capture a wider set of children’s early math skills and analysis of the psychometric properties of the measure after it was completed by 161 parents via a survey. Study 2 included an analysis of a new sample of parents (n = 21) who responded to the measures twice across two weeks to explore test–retest reliability. The measures were iteratively revised, administered to new samples, and analyzed in Studies 3 (n = 45), 4 (n = 46), and 5 (n = 344). The measures demonstrated adequate internal consistency and validity (construct, convergent, and discriminant) in Study 5 such as being positively related to parents’ numeracy and patterning beliefs about their children. Overall, the newly developed measures satisfy standards for the development of an adequate measure and can be used to better understand what parents know about early math development and how this relates to the HME that they facilitate.
Effects of tailored interventions for anxiety management in choking-susceptible performing artists: a mixed-methods collective case study
Authors: Lubert Veronika J. , Nordin-Bates Sanna M. , Gröpel Peter
Published: May 2023

Introduction

Not being able to manage performance anxiety and subsequently experiencing a decline in performance have been called “choking under pressure”. High trait anxiety and fear of negative evaluation, as well as low self-efficacy or self-confidence, can put performers especially at risk of experiencing choking. This study, therefore, examined the effects of psychological choking interventions tailored to “choking-susceptible” performing artists individually in a coaching setting.

Methods

We conducted a mixed-methods (QUANT + QUAL) collective case study with nine performing artists, who each received five individual coaching sessions. The tailored choking interventions comprised acclimatization training, goal setting, and pre-performance routines, including elements such as imagery, self-talk, and relaxation techniques. Before and after the 10-week intervention phase, they filled in questionnaires on trait performance anxiety, fear of negative evaluation, and self-efficacy, performed in front of a jury, and were interviewed about their experiences. Transcripts of interviews and coaching sessions were analyzed using thematic analysis. Heart rate measurements, weekly performance videos, and expert evaluations were also part of our comprehensive data.

Results

Quantitative data showed reductions in performance anxiety and fear of negative evaluation, and increases in self-efficacy and performance quality, from before to after the intervention phase. Most participants also had a lower heart rate when performing for the jury. Themes from qualitative analysis comprised managing nervousness and feeling more relaxed, becoming more self-confident, satisfaction with artistic and mental performance, feeling good and enjoying performing, and general positive effects.

Conclusion

Tailoring psychological interventions may provide several benefits for choking-susceptible performing artists.