bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole genome analysis of hepatitis B virus before and during long-term therapy in chronic infected patients: Molecular characterization, impact on treatment and liver disease progression
Authors: Belaiba Zeineb , Ayouni Kaouther , Gdoura Mariem , Kammoun Rebai Wafa , Touzi Henda , Sadraoui Amel , Hammemi Walid , Yacoubi Lamia , Abdelati Salwa , Hamzaoui Lamine , Msaddak Azzouz Mohamed , Chouikha Anissa , Triki Henda
Published: October 2022

Hepatitis B virus (HBV) infection remains a serious public health concern worldwide despite the availability of an efficient vaccine and the major improvements in antiviral treatments. The aim of the present study is to analyze the mutational profile of the HBV whole genome in ETV non-responder chronic HBV patients, in order to investigate antiviral drug resistance, immune escape, and liver disease progression to Liver Cirrhosis (LC) or Hepatocellular Carcinoma (HCC). Blood samples were collected from five chronic hepatitis B patients. For each patient, two plasma samples were collected, before and during the treatment. Whole genome sequencing was performed using Sanger technology. Phylogenetic analysis comparing the studied sequences with reference ones was used for genotyping. The mutational profile was analyzed by comparison with the reference sequence M32138. Genotyping showed that the studied strains belong to subgenotypes D1, D7, and D8. The mutational analysis showed high genetic variability. In the RT region of the polymerase gene, 28 amino acid (aa) mutations were detected. The most significant mutations were the pattern rtL180M + rtS202G + rtM204V, which confer treatment resistance. In the S gene, 35 mutations were detected namely sP120T, sT126S, sG130R, sY134F, sS193L, sI195M, and sL216stop were previously described to lead to vaccine, immunotherapy, and/or diagnosis escape. In the C gene, 34 mutations were found. In particular, cG1764A, cC1766G/T, cT1768A, and cC1773T in the BCP; cG1896A and cG1899A in the precore region and cT12S, cE64D, cA80T, and cP130Q in the core region were associated with disease progression to LC and/or HCC. Other mutations were associated with viral replication increase including cT1753V, cG1764A/T, cC1766G/T, cT1768A, and cC1788G in the BCP as well as cG1896A and cG1899A in the precore region. In the X gene, 30 aa substitutions were detected, of which substitutions xT36D, xP46S, xA47T, xI88F, xA102V, xI127T, xK130M, xV131I, and xF132Y were previously described to lead to LC and/or HCC disease progression. In conclusion, our results show high genetic variability in the long-term treatment of chronic HBV patients causing several effects. This could contribute to guiding national efforts to optimize relevant HBV treatment management in order to achieve the global hepatitis elimination goal by 2030.
Full-length transcriptome analysis of the bloom-forming dinoflagellate Akashiwo sanguinea by single-molecule real-time sequencing
Authors: Chen Tiantian , Liu Yun , Song Shuqun , Bai Jie , Li Caiwen
Published: October 2022

The dinoflagellate Akashiwo sanguinea is a harmful algal species and commonly observed in estuarine and coastal waters around the world. Harmful algal blooms (HABs) caused by this species lead to serious environmental impacts in the coastal waters of China since 1998 followed by huge economic losses. However, the full-length transcriptome information of A. sanguinea is still not fully explored, which hampers basic genetic and functional studies. Herein, single-molecule real-time (SMRT) sequencing technology was performed to characterize the full-length transcript in A. sanguinea. Totally, 83.03 Gb SMRT sequencing clean reads were generated, 983,960 circular consensus sequences (CCS) with average lengths of 3,061 bp were obtained, and 81.71% (804,016) of CCS were full-length non-chimeric reads (FLNC). Furthermore, 26,461 contigs were obtained after being corrected with Illumina library sequencing, with 20,037 (75.72%) successfully annotated in the five public databases. A total of 13,441 long non-coding RNA (lncRNA) transcripts, 3,137 alternative splicing (AS) events, 514 putative transcription factors (TFs) members from 23 TF families, and 4,397 simple sequence repeats (SSRs) were predicted, respectively. Our findings provided a sizable insights into gene sequence characteristics of A. sanguinea, which can be used as a reference sequence resource for A. sanguinea draft genome annotation, and will contribute to further molecular biology research on this harmful bloom algae.
Insight into genomic organization of pathogenic coronaviruses, SARS-CoV-2: Implication for emergence of new variants, laboratory diagnosis and treatment options
Authors: Bedada Fikru B. , Gorfu Gezahegn , Teng Shaolei , Neita Marguerite E.
Published: October 2022

SARS-CoV-2 is a novel zoonotic positive-sense RNA virus (ssRNA+) belonging to the genus beta coronaviruses (CoVs) in the Coronaviridae family. It is the causative agent for the outbreak of the disease, COVID-19. It is the third CoV causing pneumonia around the world in the past 2 decades. To date, it has caused significant deaths worldwide. Notably, the emergence of new genetic variants conferring efficient transmission and immune evasion remained a challenge, despite the reduction in the number of death cases, owing to effective vaccination regimen (boosting) and safety protocols. Thus, information harnessed from SARS-CoV-2 genomic organization is indispensable for seeking laboratory diagnosis and treatment options. Here in, we review previously circulating variants of SARS-CoV-2 designated variant of concern (VOC) including the Alpha (United Kingdom), Beta (South Africa), Gamma (Brazil), Delta (India), and recently circulating VOC, Omicron (South Africa) and its divergent subvariants (BA.1, BA.2, BA.3, BA.2.12.1, BA.4 and BA.5) with BA.5 currently becoming dominant and prolonging the COVID pandemic. In addition, we address the role of computational models for mutagenesis analysis which can predict important residues that contribute to transmissibility, virulence, immune evasion, and molecular detections of SARS-CoV-2. Concomitantly, the importance of harnessing the immunobiology of SARS‐CoV‐2 and host interaction for therapeutic purpose; and use of an in slilico based biocomputational approaches to achieve this purpose via predicting novel therapeutic agents targeting PRR such as toll like receptor, design of universal vaccine and chimeric antibodies tailored to the emergent variant have been highlighted.
Association of lower liver function with cognitive impairment in the Shenzhen ageing-related disorder cohort in China
Authors: Wu Kaiyu , Xu Chunyan , Qiu Guozhen , Guo Qiwen , Chen Chunchun , Liu Wei , Liu Jianjun , Liu Kangding , Zhu Feiqi
Published: October 2022

Background

Accumulating evidence suggests that alterations in liver function may play an important role in the pathogenesis of Alzheimer’s disease (AD). However, it remains unclear whether there is any relationship between lower liver function and cognitive impairment among the elderly.

Methods

From 2017 to 2018, we recruited 7,201 older people (over 60 years old) from 51 community health centers in the Luohu District of Shenzhen City. According to the Mini-Mental State Examination (MMSE) score and education level, participants were divided into a cognitive impairment group (n = 372) and a normal cognitive function group (n = 6,829). Nonparametric test, chi-square tests, and binary logistic regression were used to analyze the data.

Results

Cognitive impairment group exhibits older age, more female sex, lower education level, and lower levels of albumin and triglyceride. Additionally, the aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio was mainly distributed in the range of 1.17 to 1.3 in the cognitive impairment group, and 0.85 to 1.00 in the normal cognitive function group (χ2 = 10.02, p = 0.04). Binary logistic regression showed that cognitive impairment was significantly associated with age (OR = 0.934, 95%CI: 0.886–0.985, p = 0.017), female sex (OR = 2.255, 95%CI: 1.761–2.888, p < 0.001), lower education level (less than senior high school) (OR = 11.509, 95%CI: 9.064–14.613, p < 0.001), and lower albumin (OR = 1.023, 95%CI: 1.004–1.043, p = 0.011).

Conclusion

Except for age, female sex, and lower education level, lower level of albumin and elevated AST to ALT ratio correlate with cognitive impairment. Whether lower liver function plays a role in AD needs to be further studied.
The emerging role of autophagy and mitophagy in tauopathies: From pathogenesis to translational implications in Alzheimer’s disease
Authors: Liu Xiaolan , Ye Meng , Ma Liang
Published: October 2022

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease, affecting more than 55 million individuals worldwide in 2021. In addition to the “amyloid hypothesis,” an increasing number of studies have demonstrated that phosphorylated tau plays an important role in AD pathogenesis. Both soluble tau oligomers and insoluble tau aggregates in the brain can induce structural and functional neuronal damage through multiple pathways, eventually leading to memory deficits and neurodegeneration. Autophagy is an important cellular response to various stress stimuli and can generally be categorized into non-selective and selective autophagy. Recent studies have indicated that both types of autophagy are involved in AD pathology. Among the several subtypes of selective autophagy, mitophagy, which mediates the selective removal of mitochondria, has attracted increasing attention because dysfunctional mitochondria have been suggested to contribute to tauopathies. In this review, we summarize the latest findings on the bidirectional association between abnormal tau proteins and defective autophagy, as well as mitophagy, which might constitute a vicious cycle in the induction of neurodegeneration. Neuroinflammation, another important feature in the pathogenesis and progression of AD, has been shown to crosstalk with autophagy and mitophagy. Additionally, we comprehensively discuss the relationship between neuroinflammation, autophagy, and mitophagy. By elucidating the underlying molecular mechanisms governing these pathologies, we highlight novel therapeutic strategies targeting autophagy, mitophagy and neuroinflammation, such as those using rapamycin, urolithin, spermidine, curcumin, nicotinamide, and actinonin, for the prevention and treatment of AD.
Subdural hematoma expansion in relation to measured mean and peak systolic blood pressure: A retrospective analysis
Authors: Plowman Keegan , Lindner David , Valle-Giler Edison , Ashkin Alex , Bass Jessica , Ruthman Carl
Published: October 2022

Objective

Subdural hematomas (SDH) account for an estimated 5 to 25% of intracranial hemorrhages. Acute SDH occur secondary to rupture of the bridging veins leading to blood collecting within the dural space. Risk factors associated with SDH expansion are well documented, however, there are no established guidelines regarding blood pressure goals in the management of acute SDH. This study aims to retrospectively evaluate if uncontrolled blood pressure within the first 24 h of hospitalization in patients with acute SDH is linked to hematoma expansion as determined by serial CT imaging.

Methods

A single center, retrospective study looked at 1,083 patients with acute SDH, predominantly above age 65. Of these, 469 patients met the inclusion criteria. Blood pressure was measured during the first 24 h of admission along with PT, INR, platelets, blood alcohol level, anticoagulation use and antiplatelet use. Follow-up CT performed within the first 24 h was compared to the initial CT to determine the presence of hematoma expansion. Mean systolic blood pressure (SBP), peak SBP, discharge disposition, length of stay and in hospital mortality were evaluated.

Results

We found that patients with mean SBP <140 in the first 24 h of admission had a lower rate of hematoma expansion than those with SBP > 140. Patients with peak SBP > 200 had an increased frequency of hematoma expansion with the largest effect seen in patients with SBP > 220. Other risk factors did not contribute to hematoma expansion.

Conclusions

These results suggest that blood pressure is an important factor to consider when treating patients with SDH with medical management. Blood pressure management should be considered in addition to serial neurological exams, repeat radiological imaging, seizure prophylaxis and reversal of anticoagulation.
The pros and cons of multiple puncture in percutaneous balloon compression for treatment of trigeminal neuralgia
Authors: Sun Chenglong , Zheng Wenhao , Zhu Qiang , Du Quan , Yu Wenhua
Published: October 2022

Background

Percutaneous balloon compression (PBC) is an effective and well-established surgery for treating trigeminal neuralgia (TN). However, if the initial attempt fails to produce a distinct pear shape, there is no conventional strategy to follow: repeat a few days later or re-puncture?

Aims

This study aimed to analyze the risk and gain of re-puncturation in PBC surgery for TN treatment.

Methods

We reviewed radiographs and medical records from 79 consecutive PBC cases. The complications and surgical outcomes were compared between one-time success pears and multiple re-puncturing pears. Re-puncturing methods included selecting a more appropriate entry point, a more possible entry angle, finding a stretchy spot around the margin of foramen ovale (FO) with a trocar, and exploring the direction with more resistance using a thinner guiding needle.

Results

In 50% of cases, satisfactory pears were obtained after the first puncture, and in 35% of cases, satisfactory pears were obtained following re-puncturation. Except for hemihypogeusia, which was significantly more in multiple punctures cases (p < 0.05), no additional adverse effects were statistically different between the two groups. There are very few rare complications associated with re-puncturation. Log-Rank test of pain-free rate revealed no statistically significant differences between the two groups (p = 0.129).

Conclusion

This study establishes the safety of re-puncturation in PBC surgery for TN treatment. The operation increases pears and does not cause any serious complications. The surgical outcomes of re-puncturation pears are almost identical to those one-time success pears.
Vestibular dysfunction in pediatric patients with cochlear implantation: A systematic review and meta-analysis
Authors: Wu Qiong , Zhang Qin , Xiao Qianwen , Zhang Yuzhong , Chen Zichen , Liu Shuyun , Wang Xueyan , Xu Yong , Xu Xin-Da , Lv Jingrong , Jin Yulian , Yang Jun , Zhang Qing
Published: October 2022

Objective

Vestibular dysfunction may delay the achievement of balance and perception milestones in pediatric patients after cochlear implantation (CIM).

Methods

A strategic literature search was done following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched the PubMed, Medline, Embase, Web of Science, and Cochrane Library databases from inception to July 2022. Studies were included on the otoliths, semicircular canals, and balance function changes in children after CIM. Two reviewers independently assessed the level of evidence, methodological limitations, risk of bias, and characteristics of the cases. Matched pre- and postoperative vestibular functional test data, including ocular and cervical vestibular-evoked myogenic potential (oVEMP and cVEMP), caloric test, video head impulse test (vHIT), and Bruininks-Oseretsky Test 2 (BOT-2), were used to calculate the relative risk of vestibular disorders. Subgroup analyses were performed according to surgical approach, CIM device status, and etiology.

Results

Twenty studies that met the inclusion criteria were selected for the meta-analysis. We observed significant vestibular dysfunction in pediatric patients with CIM. The results showed a statistically significant increase in abnormal cVEMP response (RR = 2.20, 95% CI = 1.87, 2.58, P < 0.0001), abnormal oVEMP response (RR = 2.10, 95% CI = 1.50, 2.94, P < 0.0001), and abnormal caloric test results (RR = 1.62, 95% CI = 1.20, 2.19, P = 0.0018) after implantation. Statistically significant differences were not found in the vHIT test results of all three semicircular canals before and after the operation (P > 0.05). Regarding static and dynamic balance, we found significantly poorer BOT-2 scores in children with CIM than in the normal group (mean difference = −7.26, 95% CI = −10.82, −3.70, P < 0.0001).

Conclusion

The results showed that vestibular dysfunction might occur after CIM in pediatric patients. Some children experience difficulties with postural control and balance. Our results suggest that a comprehensive evaluation of vestibular function should be performed before and after CIM.
Effect of the interaction between alcohol and meat consumption on the hyperlipidaemia risk among elderly individuals: Evidence from Shanghai, China
Authors: Huang Xiaojing , Hui Hong , Zhu Wenqing , Chen Ning , Wei Yan , Wang Zhaoxin , Shi Jianwei
Published: October 2022

Background

Diet and other lifestyle habits may have an increased effect on blood lipids in older people. This study aimed to examine the associations between diet (meat, fish, and egg), alcohol consumption and blood lipids.

Methods

Surveillance data on chronic diseases and their risk factors were collected from Shanghai during 2017–2018. A Kish table was used for sampling 438 older adults, of whom 71 consumed alcohol. Logistic regression was used to test the relationships between diet, alcohol consumption and blood lipid levels in elderly individuals, and the marginal effects (MEs) were estimated.

Results

Dyslipidaemia was more common among drinkers than among nondrinkers (P < 0.01). Alcohol consumption was associated with dyslipidaemia (OR = 2.667, P < 0.01 for TC; OR = 1.919, P < 0.05 for LDL; OR = 3.412, P < 0.01 for TG), and consumption of more than 50 g of meat per day showed similar associations (OR = 3.227, P < 0.01 for TC; OR = 3.263, P < 0.01, for LDL; OR = 2.329, P < 0.01 for TG). The MEs of alcohol drinking and excessive meat consumption on the rate of dyslipidaemia were 0.324 for TC (P < 0.01), 0.255 for LDL (P < 0.05), and 0.174 for TG (P < 0.01).

Discussion

The risk of hyperlipidaemia was increased among elderly individuals with excessive meat and alcohol consumption, which also had an interactive effect.
Bioinformatic analysis of FOXN3 expression and prognostic value in pancreatic cancer
Authors: Yu Wei , Diao Yongkang , Zhang Yi , Shi Ying , Lv Xiangkang , Zhang Chengwu , Zhang Kangjun , Yao Weifeng , Huang Dongsheng , Zhang Jungang
Published: October 2022

In most cancers, forkhead box N3 (FOXN3) acts as a transcriptional inhibitor to suppress tumor proliferation, but in pancreatic cancer, the opposite effect is observed. To confirm and investigate this phenomenon, FOXN3 expression in various carcinomas was determined using GEPIA2 and was found to be highly expressed in pancreatic cancer. Kaplan-Meier plotter was then used for survival analysis, revealing that high FOXN3 expression in pancreatic cancer might be associated with a poor prognosis. Similarly, clinical samples collected for immunohistochemical staining and survival analysis showed consistent results. The RNA-seq data of pancreatic cancer patients from the TCGA were then downloaded, and the differential expression gene set was obtained using R for gene set enrichment analysis (GSEA). The intersection of the above gene sets and FOXN3-related genes was defined as related differentially expressed gene sets (DEGs), and enrichment analysis was performed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Finally, we analyzed the relationship between FOXN3 and immune infiltration in pancreatic cancer. Collectively, our findings reveal that FOXN3 is involved in the occurrence and progression of pancreatic cancer and may be useful as a prognostic tool in pancreatic cancer immunotherapy.
Neutrophils in pancreatic cancer: Potential therapeutic targets
Authors: Jiang Wenkai , Li Xin , Xiang Caifei , Zhou Wence
Published: October 2022

Pancreatic cancer is a digestive system malignancy and poses a high mortality worldwide. Traditionally, neutrophils have been thought to play a role in acute inflammation. In contrast, their importance during tumor diseases has been less well studied. Generally, neutrophils are recruited into the tumor microenvironment and exert inflammation and tumor-promoting effects. As an essential part of the tumor microenvironment, neutrophils play diverse roles in pancreatic cancer, such as angiogenesis, progression, metastasis and immunosuppression. Additionally, neutrophils can be a new potential therapeutic target in cancer. Inhibitors of cytokines, chemokines and neutrophil extracellular traps can exert antitumor effects. In this review, we describe the role of neutrophils in the development and progression of pancreatic cancer, discuss their potential as therapeutic targets, and aim to provide ideas for improving the prognosis of patients with this malignant tumor disease.
Pembrolizumab-combination therapy for previously untreated metastatic nonsquamous NSCLC: Real-world outcomes at US oncology practices
Authors: Liu Stephen V. , Hu Xiaohan , Li Yeran , Zhao Bin , Burke Thomas , Velcheti Vamsidhar
Published: October 2022

Objectives

The availability of immunotherapies has expanded the options for treating metastatic NSCLC, but information is needed regarding outcomes of immunotherapy for patients treated outside of clinical trials. The aim of this retrospective study was to evaluate the outcomes of therapy with first-line pembrolizumab plus pemetrexed and carboplatin (pembrolizumab-combination) for patients with metastatic nonsquamous NSCLC in the real-world setting of oncology clinics in the United States (US).

Methods

Using deidentified, longitudinal patient records from a nationwide, electronic health record-derived US database, we identified patients with metastatic nonsquamous NSCLC, without EGFR/ALK/ROS1 genomic alterations, who had received no previous systemic anticancer therapy. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and initiated first-line pembrolizumab-combination therapy from 11-May-2017 to 31-January-2019; data cutoff was 31-August-2020. Patients treated in a clinical trial were excluded. Manual chart review supplemented technology-enabled abstraction to identify disease progression and tumor response. Time-to-event endpoints from initiation of pembrolizumab-combination therapy were determined using Kaplan-Meier.

Results

Of 377 patients with metastatic nonsquamous NSCLC, 105 (28%), 104 (28%), and 103 (27%) had programmed death-ligand 1 (PD-L1) expression ≥50%, 1–49%, and <1%, respectively; PD-L1 expression was not documented for 65 patients (17%). Median age was 66 years, and 227 patients (60%) were men. Median follow-up time from first-line therapy initiation to data cutoff was 31.2 months (range, 19.0-39.6 months). Median pembrolizumab real-world time on treatment (rwToT) was 5.8 months (95% CI, 5.0-6.7); 12- and 24-month on-treatment rates for pembrolizumab were 28.0% and 14.9%, respectively. Median overall survival (OS) was 17.2 months (95% CI, 13.6-19.9). For patients in PD-L1 expression ≥50%, 1-49%, <1%, and unknown cohorts, the 12-month survival rates were 66.0%, 58.5%, 54.5%, and 58.3%, respectively, and 24-month survival rates were 43.1%, 37.2%, 35.6%, and 42.0%, respectively. Median real-world progression-free survival was 6.2 months (95% CI, 5.5-7.1); and the real-world response rate was 39.3%, with median duration of response of 13.1 months (95% CI, 10.5-16.8).

Conclusions

These findings demonstrate the benefits of first-line pembrolizumab-combination therapy for patients with EGFR/ALK-wild-type, metastatic nonsquamous NSCLC and good performance status who are treated at US community oncology clinics.
BCORL1 S878G, GNB1 G116S, SH2B3 A536T, and KMT2D S3708R tetramutation co-contribute to a pediatric acute myeloid leukemia: Case report and literature review
Authors: Wang Liang , Chen Sen , Shen Yongming , Si Ping
Published: October 2022

Acute myeloid leukemia (AML) is a clinically, morphologically, and genetically heterogeneous group of malignancies characterized by a wide range of genomic alterations responsible for defective regulation of the differentiation and self-renewal programs of hematopoietic stem cells. Here, we report a 4-month-old boy who had acute onset with leukocytosis and abdominal mass. The morphological analysis of bone marrow (BM) smear revealed extremely marrow hyperplasia, large quantities of immature cells, and primary and immature monocytic hyperplasia accounting for 57.5% of nucleated cells. The chromosome karyotype of the case was complex, representing 48, XY, +13, +19[12]/48, idem, del (p12)[8]. After RNAs sequencing, a mutation (c.346G > A, p.G116S) of the GNB1 gene was detected and localized to the mutational hotspot in Exon 7. Meanwhile, the other three mutations were identified by next-generation sequencing (NGS) and whole-exome sequencing (WES) of DNA from the BM aspirate and oral swab, including BCORL1 mutation [c.2632A > G, p.S878G, mutation allele frequency (VAF): 99.95%], SH2B3 mutation (c.1606G > A, p.A536T, VAF: 51.17%), and KMT2D mutation (c.11124C > G, p.S3708R, VAF: 48.95%). BCORL1 mutations have been associated with the pathogenesis of AML, whereas other mutations have rarely been previously reported in pediatric AML. The patient did not undergo the combination chemotherapy and eventually died of respiratory failure. In conclusion, the concurrence of BCORL1, GNB1, SH2B3, and KMT2D mutations may be a mutationally detrimental combination and contribute to disease progression.
Caffeine in liver diseases: Pharmacology and toxicology
Authors: Shan Liang , Wang Fengling , Zhai Dandan , Meng Xiangyun , Liu Jianjun , Lv Xiongwen
Published: October 2022

We have previously shown that adenosine A1AR antagonists, adenosine A2aAR antagonists, and caffeine have significant inhibitory effects on the activation and proliferation of hepatic stellate cells in alcoholic liver fibrosis. Many recent studies have found that moderate coffee consumption is beneficial for various liver diseases. The main active ingredient of coffee is caffeine, which is a natural non-selective adenosine receptor antagonist. Moreover, numerous preclinical epidemiological studies and clinical trials have examined the association between frequent coffee consumption and the risk of developing different liver diseases. In this review, we summarize and analyze the prophylactic and therapeutic effects of caffeine on various liver diseases, with an emphasis on cellular assays, animal experiments, and clinical trials. To review the prevention and treatment effects of caffeine on different liver diseases, we searched all literature before 19 July 2022, using “caffeine” and “liver disease” as keywords from the PubMed and ScienceDirect databases. We found that moderate coffee consumption has beneficial effects on various liver diseases, possibly by inhibiting adenosine binding to its receptors. Caffeine is a potential drug for the prevention and treatment of various liver diseases.
Machine learning advances the integration of covariates in population pharmacokinetic models: Valproic acid as an example
Authors: Zhu Xiuqing , Zhang Ming , Wen Yuguan , Shang Dewei
Published: October 2022

Background and Aim: Many studies associated with the combination of machine learning (ML) and pharmacometrics have appeared in recent years. ML can be used as an initial step for fast screening of covariates in population pharmacokinetic (popPK) models. The present study aimed to integrate covariates derived from different popPK models using ML.

Methods: Two published popPK models of valproic acid (VPA) in Chinese epileptic patients were used, where the population parameters were influenced by some covariates. Based on the covariates and a one-compartment model that describes the pharmacokinetics of VPA, a dataset was constructed using Monte Carlo simulation, to develop an XGBoost model to estimate the steady-state concentrations (Css) of VPA. We utilized SHapley Additive exPlanation (SHAP) values to interpret the prediction model, and calculated estimates of VPA exposure in four assumed scenarios involving different combinations of CYP2C19 genotypes and co-administered antiepileptic drugs. To develop an easy-to-use model in the clinic, we built a simplified model by using CYP2C19 genotypes and some noninvasive clinical parameters, and omitting several features that were infrequently measured or whose clinically available values were inaccurate, and verified it on our independent external dataset.

Results: After data preprocessing, the finally generated combined dataset was divided into a derivation cohort and a validation cohort (8:2). The XGBoost model was developed in the derivation cohort and yielded excellent performance in the validation cohort with a mean absolute error of 2.4 mg/L, root-mean-squared error of 3.3 mg/L, mean relative error of 0%, and percentages within ±20% of actual values of 98.85%. The SHAP analysis revealed that daily dose, time, CYP2C19*2 and/or *3 variants, albumin, body weight, single dose, and CYP2C19*1*1 genotype were the top seven confounding factors influencing the Css of VPA. Under the simulated dosage regimen of 500 mg/bid, the VPA exposure in patients who had CYP2C19*2 and/or *3 variants and no carbamazepine, phenytoin, or phenobarbital treatment, was approximately 1.74-fold compared to those with CYP2C19*1/*1 genotype and co-administered carbamazepine + phenytoin + phenobarbital. The feasibility of the simplified model was fully illustrated by its performance in our external dataset.

Conclusion: This study highlighted the bridging role of ML in big data and pharmacometrics, by integrating covariates derived from different popPK models.
Failure quantitative assessment approach to MOSFET power device by detecting parasitic parameters
Authors: Yun Minghui , Yang Daoguo , He Siliang , Cai Miao , Xiao Jing , Zhang Kailin , Zhang Guo-Qi
Published: October 2022

With the emerging wide bandgap (WBG) semiconductor development, the increasing power density and efficiency of power electronic converters may cause more switching oscillation, electromagnetic interference noise, and additional power loss, further increasing the probability of device failure. Therefore, determining and quantifying the failure of a metal-oxide-semiconductor-field-effect transistor (MOSFET), which assembled using WBG semiconductor in some applications, is crucial to improving the reliability of a power converter. This study proposes a novel failure quantitative assessment approach based on MOSFET parasitic parameters. According to the two-port network theory, MOSFET is equivalent to some second-order RLC circuits composed of independent inductances, capacitances, and resistances in series. Then, the frequency-domain impedance associated with the physical failure of MOSFET is identified through frequency domain reflectometry. Accelerated aging and bond wires cut-off experiments are employed to obtain various quality states of the MOSFET device. Result shows that the MOSFET quality level and its number of bond wire lift-offs can be quantified effectively. Drain-to-source on-resistance (RDS(on)) that normally represents the MOSFET quality shows a positive linear function relationship on drain-to-source parasitic resistance (RD + RS) during the quality degradation proceeding. This finding matches with the correlation established between RDS (on) and RD + RS in theory. Meanwhile, source parasitic inductance (LS) increases with the severity of bond wires faults, and even the slight fault shows a high sensitivity. The proposed approach would be an effective quality screening technology for power semiconductor devices without power on treatment, which can effectively avoid the impact of junction temperature and test conditions (current and voltage) on test results, and does not need to design additional test circuits. The test frequency range we used in this approach was 10–300 MHz, which to some extent is suitable for providing an on-line quality monitoring technology for high-frequency WBG power devices manufacturing.
The impact of an exercise intervention using low-cost equipment on functional fitness in the community-dwelling older adults: A pilot study
Authors: Rodrigues Filipe , Amaro Nuno , Matos Rui , Mendes Diogo , Monteiro Diogo , Morouço Pedro
Published: October 2022

Exercise interventions have shown significant improvements in the older adult population regarding functional and cognitive capacity. However, much research has applied exercise protocols that are expensive both for research and participation. Thus, high investments that are made are currently not ecologically efficient. The aim of the study was to determine whether the impact of a 20-week multicomponent exercise intervention using low-cost material could improve physical fitness in community-dwelling older adults. We tested the feasibility of this three times per week exercise protocol using an inclusive approach. Eligibility criteria included age ≥65 years, the ability to stand and walk with or without assistive devices, being physically inactive; medical clearance, and living in the community. Outcomes were muscle resistance measured using the chair-stand test for lower limbs, cardiorespiratory capacity measured using the 6-min walk test, and agility and balance using the Timed-up and Go test. Flexibility was measured using the chair sit and reach for lower limbs and the back scratch for upper limbs using the dominant leg and arm, respectively. Hand grip strength was measured using a dynamometer. Thirty participants (n = 30) were recruited and included in the intention-to-treat analysis. The mean age of participants was 70 years (±3.62 years), 100% were Caucasians, and 50% were female. There was a significant trend toward a clinically important improvement in the chair-stand (t = −5.23; p < 0.001; d = 0.36), arm curl (t = −5.21; p < 0.001; d = 0.74), 6-min walk test (t = −4.69; p = <0.001; d = 0.77), timed-up and go test (t = 8.788; p < 0.001; d = 1.18), and hand grip strength (t = 2.846; p = 0.009; d = 0.23). There were also differences in the back scratch (t = 2.243; p = 0.035; d = 0.29) and chair sit and reach test (t = −3.380; p < 0.001; d = 0.15). This pilot study has provided preliminary evidence that a 20-week community-based low-cost exercise program may be effective in improving overall functional fitness in older people. The pilot trial has provided the necessary data to design future randomized-controlled trials that can be implemented in the community in an ecological feasible manner.
The Arabidopsis ATP-Binding Cassette E protein ABCE2 is a conserved component of the translation machinery
Authors: Navarro-Quiles Carla , Mateo-Bonmatí Eduardo , Candela Héctor , Robles Pedro , Martínez-Laborda Antonio , Fernández Yolanda , Šimura Jan , Ljung Karin , Rubio Vicente , Ponce María Rosa , Micol José Luis
Published: October 2022

ATP-Binding Cassette E (ABCE) proteins dissociate cytoplasmic ribosomes after translation terminates, and contribute to ribosome recycling, thus linking translation termination to initiation. This function has been demonstrated to be essential in animals, fungi, and archaea, but remains unexplored in plants. In most species, ABCE is encoded by a single-copy gene; by contrast, Arabidopsis thaliana has two ABCE paralogs, of which ABCE2 seems to conserve the ancestral function. We isolated apiculata7-1 (api7-1), the first viable, hypomorphic allele of ABCE2, which has a pleiotropic morphological phenotype reminiscent of mutations affecting ribosome biogenesis factors and ribosomal proteins. We also studied api7-2, a null, recessive lethal allele of ABCE2. Co-immunoprecipitation experiments showed that ABCE2 physically interacts with components of the translation machinery. An RNA-seq study of the api7-1 mutant showed increased responses to iron and sulfur starvation. We also found increased transcript levels of genes related to auxin signaling and metabolism. Our results support for the first time a conserved role for ABCE proteins in translation in plants, as previously shown for the animal, fungal, and archaeal lineages. In Arabidopsis, the ABCE2 protein seems important for general growth and vascular development, likely due to an indirect effect through auxin metabolism.
Histological characteristics, cell wall hydrolytic enzyme activity, and transcriptome analysis with seed shattering of Stylosanthes accessions
Authors: Li Xinyong , Zhang Jingwen , Zhang Jingxue , Sheng Wei , Huang Rui , Dong Rongshu , Ding Xipeng , Liu Pandao , Liu Guodao
Published: October 2022

Stylosanthes spp. (stylo) are annual or perennial legume forages that are widely grown as forage and cover crops in tropical and subtropical regions. However, the seed yield of stylo is very low due to serious seed shattering. In the present study, we found that, although seed shattering was common among the stylo accessions, the shattering rates were genetically different. Therefore, we first synthesized the morphological, histological characteristic, physiochemical, and transcriptome analyses to determine the seed shattering mechanism in stylo. In general, the stylo germplasm with shorter lobules and thicker stems had a lower seed shattering rate and a higher seed weight. The seed and seed stalk joint is the abscission zone in stylo. Multiplex histology and hydrolytic enzyme activity analysis showed that the tearing of the abscission zone occurs due to the intense enzymatic degradation of polygalacturonase and cellulase in the seed shattering-susceptible accession TF0275. cDNA libraries from the abscission zone tissues of TF0041 and TF0275 at 14, 21, and 28 days after flowering were constructed and sequenced. A total of 47,606 unigenes were annotated and 18,606 differentially expressed genes (DEGs) were detected, including 9,140 upregulated and 9,446 downregulated unigenes. Furthermore, the 26 candidate DEGs involved in lignin biosynthesis, cellulase synthesis, and plant hormone signal transduction were found at all three developmental stages. This study provides valuable insights for future mechanistic studies of seed shattering in stylo.
Molecular characterization of a novel strain of Bacillus halotolerans protecting wheat from sheath blight disease caused by Rhizoctonia solani Kühn
Authors: Feng Zhibin , Xu Mingzhi , Yang Jin , Zhang Renhong , Geng Zigui , Mao Tingting , Sheng Yuting , Wang Limin , Zhang Juan , Zhang Hongxia
Published: October 2022

Rhizoctonia solani Kühn naturally infects and causes Sheath blight disease in cereal crops such as wheat, rice and maize, leading to severe reduction in grain yield and quality. In this work, a new bacterial strain Bacillus halotolerans LDFZ001 showing efficient antagonistic activity against the pathogenic strain Rhizoctonia solani Kühn sh-1 was isolated. Antagonistic, phylogenetic and whole genome sequencing analyses demonstrate that Bacillus halotolerans LDFZ001 strongly suppressed the growth of Rhizoctonia solani Kühn sh-1, showed a close evolutionary relationship with B. halotolerans F41-3, and possessed a 3,965,118 bp circular chromosome. Bioinformatic analysis demonstrated that the genome of Bacillus halotolerans LDFZ001 contained ten secondary metabolite biosynthetic gene clusters (BGCs) encoding five non-ribosomal peptide synthases, two polyketide synthase, two terpene synthases and one bacteriocin synthase, and a new kijanimicin biosynthetic gene cluster which might be responsible for the biosynthesis of novel compounds. Gene-editing experiments revealed that functional expression of phosphopantetheinyl transferase (SFP) and major facilitator superfamily (MFS) transporter genes in Bacillus halotolerans LDFZ001 was essential for its antifungal activity against R. solani Kühn sh-1. Moreover, the existence of two identical chitosanases may also make contribution to the antipathogen activity of Bacillus halotolerans LDFZ001. Our findings will provide fundamental information for the identification and isolation of new sheath blight resistant genes and bacterial strains which have a great potential to be used for the production of bacterial control agents.

Importance

A new Bacillus halotolerans strain Bacillus halotolerans LDFZ001 resistant to sheath blight in wheat is isolated. Bacillus halotolerans LDFZ001 harbors a new kijanimicin biosynthetic gene cluster, and the functional expression of SFP and MFS contribute to its antipathogen ability.
Combined analysis of transcriptome and metabolome reveals the molecular mechanism and candidate genes of Haloxylon drought tolerance
Authors: Yang Fang , Lv Guanghui
Published: October 2022

Haloxylon ammodendron and Haloxylon persicum, as typical desert plants, show strong drought tolerance and environmental adaptability. They are ideal model plants for studying the molecular mechanisms of drought tolerance. Transcriptomic and metabolomic analyses were performed to reveal the response mechanisms of H. ammodendron
and H. persicum
to a drought environment at the levels of transcription and physiological metabolism. The results showed that the morphological structures of H. ammodendron
and H. persicum
showed adaptability to drought stress. Under drought conditions, the peroxidase activity, abscisic acid content, auxin content, and gibberellin content of H. ammodendron increased, while the contents of proline and malondialdehyde decreased. The amino acid content of H. persicum was increased, while the contents of proline, malondialdehyde, auxin, and gibberellin were decreased. Under drought conditions, 12,233 and 17,953 differentially expressed genes (DEGs) were identified in H. ammodendron
and H. persicum
, respectively, including members of multiple transcription factor families such as FAR1, AP2/ERF, C2H2, bHLH, MYB, C2C2, and WRKY that were significantly up-regulated under drought stress. In the positive ion mode, 296 and 452 differential metabolites (DEMs) were identified in H. ammodendron
and H. persicum, respectively; in the negative ion mode, 252 and 354 DEMs were identified, primarily in carbohydrate and lipid metabolism. A combined transcriptome and metabolome analysis showed that drought stress promoted the glycolysis/gluconeogenesis pathways of H. ammodendron
and H. persicum
and increased the expression of amino acid synthesis pathways, consistent with the physiological results. In addition, transcriptome and metabolome were jointly used to analyze the expression changes of the genes/metabolites of H. ammodendron
and H. persicum
that were associated with drought tolerance but were regulated differently in the two plants. This study identified drought-tolerance genes and metabolites in H. ammodendron
and H. persicum
and has provided new ideas for studying the drought stress response of Haloxylon.
Compositional analysis in sorghum (Sorghum bicolor) NIR spectral techniques based on mean spectra from single seeds
Authors: Hacisalihoglu Gokhan , Armstrong Paul R. , Mendoza Princess Tiffany D. , Seabourn Bradford W.
Published: October 2022

Sorghum (Sorghum bicolor) is an economically important cereal crop that can be used as human food, animal feed, and for industrial use such as bioenergy. In sorghum breeding programs, development of cultivars with desirable seed quality characteristics is important and development of rapid low-cost screening methods for seed nutritional traits are desired, since most standard methods are destructive, slow, and less environmentally friendly. This study investigates the feasibility of single kernel NIR spectroscopy (SKNIRS) for rapid determination of individual sorghum seed components. We developed successful multivariate prediction models based on partial least squares (PLS) regression for protein, oil, and weight in sorghum. The results showed that for sorghum protein content ranging from 8.92% to 18.7%, the model coefficients of determination obtained were RCAL2=0.95 (RMSEC= 0.44) and RPRED2=0.87 (RMSEP= 0.69). The model coefficients of determination for oil prediction were RCAL2=0.92 (RMSEC= 0.23) and RPRED2=0.71 (RMSEP= 0.41) for oil content ranging from 1.96% to 5.61%. For weight model coefficients of determination were RCAL2=0.81 (RMSEC= 0.007) and RPRED2=0.63 (RMSEP= 0.007) for seeds ranging from 4.40 mg to 77.0 mg. In conclusion, mean spectra SKNIRS can be used to rapidly determine protein, oil, and weight in intact single seeds of sorghum seeds and can provide a nondestructive and quick method for screening sorghum samples for these traits for sorghum breeding and industry use.
Identification of QTNs, QTN-by-environment interactions and genes for yield-related traits in rice using 3VmrMLM
Authors: Zhang Jin , Wang Shengmeng , Wu Xinyi , Han Le , Wang Yuan , Wen Yangjun
Published: October 2022

Rice, which supports more than half the population worldwide, is one of the most important food crops. Thus, potential yield-related quantitative trait nucleotides (QTNs) and QTN-by-environment interactions (QEIs) have been used to develop efficient rice breeding strategies. In this study, a compressed variance component mixed model, 3VmrMLM, in genome-wide association studies was used to detect QTNs for eight yield-related traits of 413 rice accessions with 44,000 single nucleotide polymorphisms. These traits include florets per panicle, panicle fertility, panicle length, panicle number per plant, plant height, primary panicle branch number, seed number per panicle, and flowering time. Meanwhile, QTNs and QEIs were identified for flowering times in three different environments and five subpopulations. In the detections, a total of 7~23 QTNs were detected for each trait, including the three single-environment flowering time traits. In the detection of QEIs for flowering time in the three environments, 21 QTNs and 13 QEIs were identified. In the five subpopulation analyses, 3~9 QTNs and 2~4 QEIs were detected for each subpopulation. Based on previous studies, we identified 87 known genes around the significant/suggested QTNs and QEIs, such as LOC_Os06g06750 (OsMADS5) and LOC_Os07g47330 (FZP). Further differential expression analysis and functional enrichment analysis identified 30 candidate genes. Of these candidate genes, 27 genes had high expression in specific tissues, and 19 of these 27 genes were homologous to known genes in Arabidopsis. Haplotype difference analysis revealed that LOC_Os04g53210 and LOC_Os07g42440 are possibly associated with yield, and LOC_Os04g53210 may be useful around a QEI for flowering time. These results provide insights for future breeding for high quality and yield in rice.