bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased AR expression in castration-resistant prostate cancer rapidly induces AR signaling reprogramming with the collaboration of EZH2
Authors: Labaf Maryam , Li Muqing , Ting Lily , Karno Breelyn , Zhang Songqi , Gao Shuai , Patalano Susan , Macoska Jill A. , Zarringhalam Kourosh , Han Dong , Cai Changmeng
Published: November 2022

Elevated androgen receptor (AR) expression is a hallmark of castration-resistant prostate cancer (CRPC) and contributes to the restoration of AR signaling under the conditions of androgen deprivation. However, whether overexpressed AR alone with the stimulation of castrate levels of androgens can be sufficient to induce the reprogramming of AR signaling for the adaptation of prostate cancer (PCa) cells remains unclear. In this study, we used a PCa model with inducible overexpression of AR to examine the acute effects of AR overexpression on its cistrome and transcriptome. Our results show that overexpression of AR alone in conjunction with lower androgen levels can rapidly redistribute AR chromatin binding and activates a distinct transcription program that is enriched for DNA damage repair pathways. Moreover, using a recently developed bioinformatic tool, we predicted the involvement of EZH2 in this AR reprogramming and subsequently identified a subset of AR/EZH2 co-targeting genes, which are overexpressed in CRPC and associated with worse patient outcomes. Mechanistically, we found that AR-EZH2 interaction is impaired by the pre-castration level of androgens but can be recovered by the post-castration level of androgens. Overall, our study provides new molecular insights into AR signaling reprogramming with the engagement of specific epigenetic factors.
Development and validation of an autophagy-related long non-coding RNA prognostic signature for cervical squamous cell carcinoma and endocervical adenocarcinoma
Authors: Zhou Shuguang , Zhang Weiyu , Cao Wujun , Jin Qinqin , Jiang Xiya , Jiang Xiaomin , Yang Yinting , Yao Hui , Chen Guo , Gao Wei , Zhu Yuting , Qi Jian , Tong Zhuting
Published: November 2022

Background

In this study, we aimed to investigate the signature of the autophagy-related lncRNAs (ARLs) and perform integrated analysis with immune infiltration in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC).

Methods and results

The UCSC Xena and HADb databases provided the corresponding data. The ARLs were selected via constructing a co-expression network of autophagy-related genes (ARGs) and lncRNAs. Univariate Cox regression analysis combined with LASSO regression and multivariate Cox regression analysis were utilized to screen lncRNAs. The ARL risk signature was established by Cox regression and tested if it was an independent element bound up with patient prognosis. We used the xCell algorithm and ssGSEA to clarify the pertinence between immune infiltration and the expression of ARLs. Finally, we predicted the sensitivity of drug treatment as well as the immune response. Results indicated that the three prognostic ARLs (SMURF2P1, MIR9-3HG, and AC005332.4) possessed significant diversity and constituted the ARL signature. Risk score was an individual element (HR = 2.82, 95% CI = 1.87–4.30; p < 0.001). Immune infiltration analysis revealed significant increases in central memory CD8+ T cells, endothelial cells, CD8+ naive T cells, and preadipocytes in the high-risk group (p < 0.05). There were 10 therapeutic agents that varied significantly in their estimated half-maximal inhibitory concentrations in the two groups. According to the experimental validation, we found that SMURF2P1 belongs to the co-stimulatory genes and might assume greater importance in the development of cervical adenocarcinoma. MIR9-3HG and AC005332.4 belonged to the tumor-suppressor genes and they may play a more positive role in cervical squamous cell carcinoma.

Conclusions

This research explored and validated a novel signature of the ARLs, which can be applied to forecast the prognosis of patients with CESC and is closely associated with immune infiltration.
Efficacy and safety of brigatinib in ALK-positive non-small cell lung cancer treatment: A systematic review and meta-analysis
Authors: Xing Puyuan , Hao Xuezhi , Zhang Xin , Li Junling
Published: November 2022

Background

Brigatinib is a central nervous system-active second-generation anaplastic lymphoma kinase (ALK) inhibitor that targets a broad range of ALK rearrangements in patients with non-small cell lung cancer (NSCLC). The current study aimed to analyze the pooled effects and adverse events of brigatinib in patients with ALK-positive NSCLC.

Methods

The pooled estimates and 95% confidence intervals (CI) were calculated with DerSimonian-Laird method and the random effect model.

Results

The pooled objective response rate (ORR) and disease control rate (DCR) of brigatinib were 64% (95% CI 45%-83%) and 88% (95% CI 80%-96%), respectively. The pooled mPFS was 10.52 months (95% CI 7.66-13.37). In the subgroup analyses by treatment line, the highest mPFS was reached in first-line treatment (24.00 months, 95% CI 18.40-43.20), followed by post-crizotinib second-line treatment (mPFS=16.26 months, 95% CI 12.87-19.65), and second-line with any prior ALK tyrosine kinase inhibitors (mPFS=12.96 months, 95% CI 11.14-14.78). Among patients with any baseline brain metastases, the pooled intracranial ORR (iORR) was estimated as 54% (95% CI 35%-73%) for any treatment line, and 60% (95% CI 39%-81%) for first-line treatment. Intracranial PFS (iPFS) reached 19.26 months (95% CI 14.82-23.70) in patients with any baseline brain metastases. Creatine phosphokinase (CPK) increased (44%, 95% CI 26%-63%), diarrhea (37%, 95% CI 27%-48%), and nausea (28%, 95% CI 17%-39%) of any grade were the most common adverse events.

Conclusion

Brigatinib is effective in the treatment of patients with ALK-positive NSCLC, particularly showing robust intracranial PFS. Brigatinib used as first-line treatment yielded superior PFS compared with brigatinib used as other treatment lines. These results suggested a benefit of using brigatinib earlier in the patient’s management. All adverse events are manageable, with CPK increased and gastrointestinal reactions found to be the most common types.

Systematic Review Registration

https://inplasy.com/inplasy-2022-3-0142/, identifier (INPLASY202230141).
Dosimetric impact of mechanical movements of the Linac gantry during treatments with small fields
Authors: McCallum-Hee Broderick Ivan , Milan Thomas , White Rohen , Rowshanfarzad Pejman
Published: November 2022

Objective

Current accepted linac Quality Assurance (QA) guidelines used for Volumetric Modulated Arc Therapy (VMAT) suggest a mechanical isocentre tolerance level of 1 mm. However, this tolerance level has not been well-established for the specific case of small field stereotactic VMAT. This study aims to evaluate the clinical impact of mechanical uncertainty on this treatment modality by modelling systematic gantry sag derived isocentre variance in the Treatment Planning System (TPS).

Approach

A previously reported dataset of gantry sag values in the literature served as a starting point for this study. Using an in-house developed VMAT arc splitting algorithm, isocentre shifts were applied at a Control Point (CP) level to DICOM-RT treatment plans. Dose distributions for varying isocentre shift magnitudes were calculated for a set of 29 stereotactic VMAT plans using the Eclipse Acuros XB dose algorithm. These plans had a range of Planning Target Volume (PTV) sizes. A quantitative comparison of each plan was conducted by evaluating five Dose Volume Histogram (DVH)-derived plan quality metrics.

Results

All metrics exhibited a deterioration in plan quality with increasing magnitudes of isocentre shift. At small PTV sizes, these effects were amplified, exhibiting significant changes at 1 mm of average shift when typical targets and tolerances were considered. For plans with PTVs between 0 and 5 cm3, a 1 mm shift reduced PTV coverage by 6.6 ± 2.2% and caused a 12.1 ± 3.8% deterioration in the conformity index. Based on the results of this study, the prevalent tolerance of 1 mm may not be suitable for treatments of small PTVs with small fields.

Significance

In contrast to commonly accepted values, an absolute mechanical isocentre of 0.5 mm with action level at 0.75 mm is recommended for stereotactic VMAT of PTV sizes below 10 cm3.
Where are we going with sentinel nodes mapping in ovarian cancer?
Authors: Kampan Nirmala Chandralega , Teik Chew Kah , Shafiee Mohammed Nasir
Published: November 2022

Lymph node involvement is a major predictive indicator in early-stage epithelial ovarian cancer (EOC). There is presently no effective way to determine lymph node involvement other than surgical staging. As a result, traditional ovarian cancer surgery still includes pelvic and paraaortic lymphadenectomy. However, it might be linked to higher blood loss, lengthier operations, and longer hospital stays. The creation of a technique for accurately predicting nodal status without significant lymphadenectomy is thus the subject of ongoing research. Sentinel lymph nodes (SLN) mapping is a routine procedure in oncological surgery and has been proven to be effective and safe in cervical, vulvar, and uterine cancer. On the other hand, SLN mapping is not yet widely accepted and recognized in EOC. A thorough search of the literature was conducted between January 1995 to March 2022, using PubMed and Embase. This review included studies on lymphatic outflow of the ovaries and the sentinel lymph node method. A total of 13 studies involving 212 patients who underwent sentinel lymph node mapping for ovaries were included. Both open and laparoscopic approach are used. The most popular injection site is the ovarian ligaments, and a variety of agents are utilized, although the main markers were, technetium-99m radiocolloid (Tc-99m) or indocyanine green, either alone or in combination. Overall detection rate for SLN in ovaries is 84.5% (interquartile range: 27-100%). We suggest a standardized method for sentinel lymph node mapping in ovarian cancer. The detection rates, characterization and true positive rates of the approach in investigations support further study. The use of ultra-staging is essential for lower-volume metastasis and reproducibility. To ascertain the clinical utility of sentinel node in early ovarian cancer, larger collaborative prospective clinical trials are necessary.
Treatment adherence and associated factors among glaucoma patients attending Ophthalmic units of referral hospitals in North West Ethiopia, 2019
Authors: Birhanie Setarg Ayenew , Getie Girma Alem , Tesfa Mulugeta , Mulugeta Henok , Gedfew Mihretie , Mekete Yeshimareg Shita , Liknaw Tiliksew , Teshale Mikiyas Muche , Tilahun Melkamu , Amlak Baye Tsegaye , Yitayew Fentahun Minwuyelet , Ayenew Temesgen , Bewket Bekalu , Tsegaye Dejen
Published: November 2022

Objective

Glaucoma is one of the common eye disorders resulting from optic neuropathy, which leads to irreversible blindness if left untreated. Poor adherence to glaucoma medical treatments typically leads to some serious consequences, such as progressive visual impairment and blindness. The aim of this study was to assess adherence to treatment and associated factors among patients with glaucoma attending at Northwest Ethiopia referral hospitals.

Method

From March 1st to April 30th, 2019, an institution-based cross-sectional study was conducted on 382 consecutive glaucoma patients attending at Northwest Ethiopia referral hospitals. Data about adherence to glaucoma treatment was collected by using a standardized tool, the Morisky Medication Adherence Scale-8, through an interviewer-administered questionnaire. Each collected data set was coded and entered into Epi-Data version 4.2, and analysis was done by using STATA version 14.0 statistical software. A logistic regression model was fitted to assess the effect of an independent variable on the dependent variable. A p-value < 0.05 was considered to declare a statistically significant association. The study proposal was approved by the Debre Markos University ethical review committee.

Results

Among the study participants, 189 (49.5%) were adherent to glaucoma treatment. In this study, occupation (farmer), good knowledge, favorable attitude, a short distance from patients’ homes to hospitals, and scheduling problems for glaucoma medical follow-up visits were significant factors associated with adherence to glaucoma treatments.

Conclusion

The study has identified the adherence level as being low. Patient related factors and health care system related factors were significantly associated with adherence to glaucoma treatments. Appropriate patient education and planning a patient follow-up strategy might improve patients’ adherence to glaucoma treatment. Care providers should place emphasis on the importance of adherence.
Mechanisms of sympathoexcitation via P2Y6 receptors
Authors: Mosshammer Anna , Zou Lifang , Boehm Stefan , Schicker Klaus
Published: November 2022

Many drugs used in cardiovascular therapy, such as angiotensin receptor antagonists and beta-blockers, may exert at least some of their actions through effects on the sympathetic nervous system, and this also holds true for e.g., P2Y12 antagonists. A new target at the horizon of cardiovascular drugs is the P2Y6 receptor which contributes to the development of arteriosclerosis and hypertension. To learn whether P2Y6 receptors in the sympathetic nervous system might contribute to actions of respective receptor ligands, responses of sympathetic neurons to P2Y6 receptor activation were analyzed in primary cell culture. UDP in a concentration dependent manner caused membrane depolarization and enhanced numbers of action potentials fired in response to current injections. The excitatory action was antagonized by the P2Y6 receptor antagonist MRS2578, but not by the P2Y2 antagonist AR-C118925XX. UDP raised intracellular Ca2+ in the same range of concentrations as it enhanced excitability and elicited inward currents under conditions that favor Cl− conductances, and these were reduced by a blocker of Ca2+-activated Cl− channels, CaCCInh-A01. In addition, UDP inhibited currents through KV7 channels. The increase in numbers of action potentials caused by UDP was not altered by the KV7 channel blocker linopirdine, but was enhanced in low extracellular Cl− and was reduced by CaCCInh-A01 and by an inhibitor of phospholipase C. Moreover, UDP enhanced release of previously incorporated [3H] noradrenaline, and this was augmented in low extracellular Cl− and by linopirdine, but attenuated by CaCCInh-A01. Together, these results reveal sympathoexcitatory actions of P2Y6 receptor activation involving Ca2+-activated Cl− channels.
Evaluation of the effectiveness and efficiency of the East African community joint assessment procedure by pharmaceutical companies: Opportunities for improvement
Authors: Ngum Nancy , Mashingia Jane , Ndomondo-Sigonda Margareth , Walker Stuart , Salek Sam
Published: November 2022

Background: A 2021 study to determine the viewpoints among the seven member countries regarding the effectiveness (i.e., achieving the intended outcomes) and efficiency (i.e., achieving the intended outcomes in timely manner with the resources available) of the East African Community Medicine Regulatory Harmonisation (EAC-MRH) Joint Assessment Procedure recommended the conduct of a similar study among pharmaceutical company applicants. The aim of this study then was to evaluate the effectiveness and efficiency of the current EAC-MRH operating model from the applicants’ perspective, including the challenges and opportunities for improvement.

Methods: Using the Process Effectiveness and Efficiency Rating for Industry questionnaire developed by the authors, data were collected from company representatives responsible for EAC joint procedure submissions.

Results: Responses from 14 study participants underlined the support of pharmaceutical companies for the EAC-MRH initiative, which has facilitated the harmonisation of registration requirements across the EAC region leading to one registration for all countries and a reduction of the workload for both applicants and assessors. In addition, it is expected that shorter timelines for approval will lead to improved access to quality-assured essential medicines in the region. Access to various markets at the same time was also noted as an important benefit to pharmaceutical companies. Noted challenges include a lack of process information, a lack of centralised submission and tracking process and a lack of mandated central registration. A key strategy proposed by participants is the establishment of a regional administrative body to centrally receive and track EAC applications and the eventual establishment of a Regional EAC Medicines Authority.

Conclusion: This is the first study evaluating the performance of the EAC work-sharing initiative from the point of view of the applicants. In general, the applicants believe that the system performs efficiently and fulfils its promise. However, some participants indicated that in some countries an EAC positive recommendation does not directly result in an individual country approvals. Following the recommendations listed in this report may mitigate identified areas for improvement and facilitate the overall goal of the EAC-MRH initiative to expedite the availability of needed quality-assured medicines to patients in the region.
The effects of levosimendan in patients undergoing transcatheter aortic valve replacement- a retrospective analysis
Authors: Zhao Zhenyan , Meng Zhen , Song Guangyuan , Wang Chunrong , Shi Sheng , Zhao Jie , Zhang Hongliang , Wang Moyang , Niu Guannan , Zhou Zheng , Wang Jianhui , Wu Yongjian
Published: November 2022

Background: Aortic stenosis (AS) increases left ventricular afterload, leading to cardiac damage and heart failure (HF). Transcatheter aortic valve replacement (TAVR) is an effective therapy for AS. No inotropic agents including levosimendan have been evaluated in patients undergoing TAVR.

Methods: A total of 285 patients underwent TAVR between 2014 and 2019; 210 were included in the matched analysis and 105 received 0.1 μg/kg body weight/min levosimendan immediately after the prosthesis had been successfully implanted. Medical history, laboratory tests, and echocardiography results were analyzed. Endpoints including 2-year all-cause mortality, stroke, or HF-related hospitalization, and a combination of the above were analyzed by Cox proportional hazard models.

Results: The levosimendan group had no difference in 2-year mortality compared with the control group (hazard ratio [HR]: 0.603, 95% confidence interval [CI]: 0.197–1.844; p = 0.375). However, levosimendan reduced stroke or HF-related hospitalization (HR: 0.346; 95% CI: 0.135–0.884; p = 0.027) and the combined endpoint (HR: 0.459, 95% CI: 0.215–0.980; p = 0.044). After adjusting for multiple variants, levosimendan still reduced stroke or HF-related hospitalization (HR: 0.346, 95% CI: 0.134–0.944; p = 0.038).

Conclusion: Prophylactic levosimendan administration immediately after valve implantation in patients undergoing TAVR can reduce stroke or HF-related hospitalization but does not lower all-cause mortality.
Circulating microparticles are associated with plaque burden and cause eNOS uncoupling in patients with carotid atherosclerosis
Authors: Han Xiaowan , Li Tong , Wang Tieshan , Wang Baofu , Li Yang , Wang Lei , Lu Ziwen , Wu Aiming , Liu Lisong , Pan Guozhong , Zhao Mingjing
Published: November 2022

Aims: The study aimed to evaluate the correlation of different microparticle (MP) phenotypes with plaque burden and their diagnostic value and preliminarily explore the role of MPs in atherosclerosis (AS).

Methods: Carotid intima-media thickness (CIMT) and maximal plaque area in 23 patients with carotid atherosclerosis (CAS) and 22 healthy subjects were measured by ultrasound. Transmission electron microscopy, nanoparticle tracking analysis and western blot were used to identify MPs. Flow cytometry assay measured absolute number of MPs, and receiver operating characteristic (ROC) analysis was used to assess the relationship between plaque burden and MPs. To study the preliminary mechanism of MPs in AS, MPs were administered to 32 male Kunming mice, which were randomly divided into control, CAS, healthy, and tetrahydrobiopterin (BH4) groups. Hematoxylin-eosin staining, immunohistochemistry staining, and Western blot were adopted to detect relevant indexes 24 h after the injection.

Results: The plasma levels of CD45+ leukocyte-derived microparticle (LMP), CD11a+ LMP, CD11a+/CD45+ LMP, and CD31+/CD42b+ platelet-derived microparticle (PMP) in CAS patients were significantly higher than those in healthy subjects, and were positively correlated with the maximal plaque area. Moreover, the levels of CD11a+ LMP, CD11a+/CD45+ LMP were also positively correlated with CIMT. The area under the ROC curve of the four MPs was 0.689, 0.747, 0.741, and 0.701, respectively. Compared with healthy subjects, MPs from CAS patients resulted in a significantly lower expression of endothelial nitric oxide synthase (eNOS) dimer/monomer, and BH4 could improve eNOS uncoupling. Moreover, the level of VCAM-1 in intima in the CAS group was significantly higher than in the other three groups.

Conclusion: CD11a+ LMP and CD11a+/CD45+ LMP might be potential biomarkers for CAS prediction. BH4-related eNOS uncoupling occurs in CAS patients, and circulating MPs from them lead to endothelial dysfunction through eNOS uncoupling.
Changes in peripheral T-lymphocyte subsets and serum cytokines in patients with systemic sclerosis
Authors: Guo Rong-Hong , Cheng Hao , Zhang Xiao-Ying , Yu Zhen , Wang Guang-Hui , Hao Shu-Ya , Gao Xiao-Peng , Wen Hong-Yan
Published: November 2022

Objective: T cells represent a predominant cell type in autoimmune disease. However, their exact roles are not fully clear in systemic sclerosis (SSc). This study aimed to mainly investigate the alteration in the absolute numbers of T-lymphocyte subsets and the serum levels of cytokines in SSc patients.

Methods: A total of 76 patients with SSc and 76 age- and sex-matched healthy controls (HCs) were enrolled. The levels of circulating T cell subsets and serum cytokines were measured by flow cytometry. T cell subsets or serum cytokines correlations with disease activity and organ involvement were analyzed.

Results: The absolute numbers of Th2 and Treg cells in SSc patients were lower than those in HCs (p < 0.05), resulting in the ratios of Th1/Th2 [25.01 (12.24, 38.61) vs. 11.64 (6.38, 20.34)] and Th17/Treg [0.42 (0.17, 0.66) vs. 0.17 (0.13, 0.29)] were increased significantly (p < 0.001). The absolute numbers of total T, Th, and Treg cells were negatively correlated with CRP (r = -0.406, p = 0.002; r = -0.263, p < 0.05; r = -0.367 p < 0.01). The serum levels of IL-2, SIL-2R, IL-6, IL-10, INF-γ, and TNF-α were significantly higher than those in HCs (p < 0.001). Increasing IL-2 in the wake of the augment of ESR (r = 0.671, p = 0.004), so did IL-6 (r = 0.378, p < 0.05). The ratio of Th17/Treg in SSc-ILD patients had lower levels than that in other patients [0.35 (0.14, 0.53) vs. 0.64 (0.26, 0.93) p = 0.028]; Treg cells were lessened in patients with Raynaud’s phenomenon relative to controls [3.00 (2.41, 4.28) vs. 3.55 (2.86, 4.53) p < 0.05]. The levels of IL-2, IL-10 and INF-γ [3.32 (1.05,11.73) vs. 2.32 (0.44,6.45), p = 0.045], [8.08 (3.63, 355,77) vs. 4.89 (0.78, 21.44), p = 0.02], [6.31 (2.66, 44.03) vs. 4.03 (0.22, 16.96), p = 0.009] were elevated in patients with arthralgia, while the level of Th17 was decreased [0.62 (0.20,2.16) vs. 1.26 (0.22,10.93), p = 0.026]. ROC curve analysis yielded an optimal cut-off IL-2, IL-10, and INF-γ levels of 2.67, 5.93, and 5.32 pg/ml for the presence of arthralgia.

Conclusion: We exhibited abnormalities in T subsets and the production of their cytokines in SSc, as compared with those in HCs. This may allow the pathogenesis of SSc and the development of novel therapeutic interventions aimed at targeting these cells and the cytokines they produce.
Substrate stiffness engineered to replicate disease conditions influence senescence and fibrotic responses in primary lung fibroblasts
Authors: Blokland Kaj E. C. , Nizamoglu Mehmet , Habibie Habibie , Borghuis Theo , Schuliga Michael , Melgert Barbro N. , Knight Darryl A. , Brandsma Corry-Anke , Pouwels Simon D. , Burgess Janette K.
Published: November 2022

In fibrosis remodelling of ECM leads to changes in composition and stiffness. Such changes can have a major impact on cell functions including proliferation, secretory profile and differentiation. Several studies have reported that fibrosis is characterised by increased senescence and accumulating evidence suggests that changes to the ECM including altered composition and increased stiffness may contribute to premature cellular senescence. This study investigated if increased stiffness could modulate markers of senescence and/or fibrosis in primary human lung fibroblasts. Using hydrogels representing stiffnesses that fall within healthy and fibrotic ranges, we cultured primary fibroblasts from non-diseased lung tissue on top of these hydrogels for up to 7 days before assessing senescence and fibrosis markers. Fibroblasts cultured on stiffer (±15 kPa) hydrogels showed higher Yes-associated protein-1 (YAP) nuclear translocation compared to soft hydrogels. When looking at senescence-associated proteins we also found higher secretion of receptor activator of nuclear factor kappa-B ligand (RANKL) but no change in transforming growth factor-β1 (TGF-β1) or connective tissue growth factor (CTGF) expression and higher decorin protein deposition on stiffer matrices. With respect to genes associated with fibrosis, fibroblasts on stiffer hydrogels compared to soft had higher expression of smooth muscle alpha (α)-2 actin (ACTA2), collagen (COL) 1A1 and fibulin-1 (Fbln1) and higher Fbln1 protein deposition after 7 days. Our results show that exposure of lung fibroblasts to fibrotic stiffness activates genes and secreted factors that are part of fibrotic responses and part of the Senescence-associated secretory phenotype (SASP). This overlap may contribute to the creation of a feedback loop whereby fibroblasts create a perpetuating cycle reinforcing progression of a fibrotic response.
The recommended dosage regimen for caspofungin in patients with higher body weight or hypoalbuminaemia will result in low exposure: Five years of data based on a population pharmacokinetic model and Monte-Carlo simulations
Authors: Yang Qianting , Zhang Tao , Zhang Ying , Sun Dan , Zheng Xiaowei , Du Qian , Wang Xue , Cheng Xiaoliang , Xing Jianfeng , Dong Yalin
Published: November 2022

Background: To develop a population pharmacokinetic (PPK) model for caspofungin, identify parameters influencing caspofungin pharmacokinetics, and assess the required probability of target attainment (PTA) and cumulative fraction of response (CFR) for various dosing regimens of caspofungin in all patients and intensive care unit (ICU)-subgroup patients.

Method: The general PPK model was developed based on data sets from all patients (299 patients). A ICU-subgroup PPK model based on data sets from 136 patients was then analyzed. The effects of demographics, clinical data, laboratory data, and concomitant medications were tested. Monte-Carlo simulations (MCS) were used to evaluate the effectiveness of different caspofungin dosage regimens.

Results: One-compartment model best described the data of all patients and ICU patients. Clearances (CL) were 0.32 L/h and 0.40 L/h and volumes of distribution (V) were 13.31 L and 10.20 L for the general and ICU-subgroup PPK models, respectively. In the general model, CL and V were significantly associated with albumin (ALB) concentration and body weight (WT). In the ICU-subgroup model, CL was associated with WT. The simulated exposure in ICU patients was lower than that in all patients (p < 0.05). MCS indicated that higher caspofungin maintenance doses of 70–150 mg may achieve target CFR of >90% for patients with higher WT (>70 kg) or with C. albicans or C. parapsilosis infections, and especially for ICU patients with hypoalbuminaemia.

Conclusion: The PPK model and MCS presented in the study demonstrated that the recommended dosage regimen for caspofungin in patients with higher body weight or hypoalbuminaemia will result in low exposure.
Fast color point cloud registration based on virtual viewpoint image
Authors: Hui Zhao , Yong-Jian Zhang , Lei Zhang , Xiao-Xue Jiao , Li-Ying Lang
Published: November 2022

With the increase of point cloud scale, the time required by traditional ICP-related point cloud registration methods increases dramatically, which cannot meet the registration requirements of large-scale point clouds. In this paper, a fast registration technique for large scale point clouds based on virtual viewpoint image generation is studied. Firstly, the projection image of color point cloud is generated by virtual viewpoint. Then, the feature is extracted based on ORB and the rotation and translation matrix is calculated. The experimental results show that the registration time of the proposed method is about 1s when the size of the point cloud is from 300,000 to 2 million, which is improved by 17–258 times compared with the traditional ICP registration method, and the registration error is reduced by 80% from ICP 5.0 to 1.0. This paper provides a new idea and method for large-scale color point cloud registration.
A linear time series analysis of carbon price via a complex network approach
Authors: Hu Yuxia , Chu Chengbin , Wu Peng , Hu Jun
Published: November 2022

Identifying the essential characteristics and forecasting carbon prices is significant in promoting green transformation. This study transforms the time series into networks based on China’s pilots by using the visibility graph, mining more information on the structure features. Then, we calculate nodes’ similarity to forecast the carbon prices by link prediction. To improve the predicted accuracy, we notice the node distance to introduce the weight coefficient, measuring the impact of different nodes on future nodes. Finally, this study divides eight pilots into different communities by hierarchical clustering to study the similarities between these pilots. The results show that eight pilots are the “small world” networks except for Chongqing and Shenzhen pilots, all of which are “scale-free” networks except for Shanghai and Tianjin pilots. Compared with other predicted methods, the proposed method in this study has good predicted performance. Moreover, these eight pilots are divided into three clusters, indicating a higher similarity in their price-setting schemes in the same community. Based on the analysis of China’s pilots, this study provides references for carbon trading and related enterprises.
Rheology of vesicle prototissues: A microfluidic approach
Authors: Layachi Majid , Casas-Ferrer Laura , Massiera Gladys , Casanellas Laura
Published: November 2022

Synthetic biomimetic prototissues with reduced complexity can facilitate the understanding of intricate biological processes, by allowing the role of specific physical or chemical mechanisms to be isolated. The aim of the present work is to provide a rheological description of vesicle prototissues as a biomimetic model for the flow of cellular tissues, which can be relevant for the mechanical comprehension of embryogenesis or tumor metastasis. Prototissue were obtained by the controlled assembly of Giant Unilamellar Vesicles (GUVs) mediated by the biotin-streptavidin pair, using a simple assembly protocol. Prototissues were mechanically probed in a “pipette-aspiration” inspired microfluidic chip, under controlled pressure conditions. A viscoelastic flow behavior was obtained which was well captured by a generalized Kelvin-Voigt fluid model, with inferred rheological parameters that did not show a significant dependence on the GUV-GUV adhesion strength. In addition, the flow of the vesicle prototissues exhibited a strain-stiffening behavior. Complementary flow velocimetry analysis revealed a decrease of prototissue effective permeability with the applied pressure, and enabled to identify vesicle spatial reorganizations taking place within the prototissue. Overall, our microfluidic setup makes possible the simultaneous characterization of the biomimetic prototissue at two different length scales, global and local, bridging the viscoelastic response of the overall prototissue with its structural changes between an ensemble of vesicles.
RNA-seq and qRT-PCR analyses reveal the physiological response to acute hypoxia and reoxygenation in Epinephelus coioides
Authors: Lai Xingxing , Zhong Zhongxuan , Lin Bing , Wu Yuxin , Ma Yonghao , Zhang Cuiping , Yang Yang , Zhang Mingqing , Qin Weijian , Fu Xiaoqin , Shu Hu
Published: November 2022

Hypoxia is a critical problem in intensive Epinephelus coioides aquaculture systems. In the present study, the physiological responses of E. coioides muscle to acute hypoxic stress (DO = 0.6 ± 0.1 mg/L) and reoxygenation (DO = 6.0 ± 0.1 mg/L) were analyzed by transcriptome sequencing (RNA-seq) and quantitative real-time PCR (qRT–PCR). RNA-seq was conducted on the muscle tissues of E. coioides in the hypoxia-tolerant (EMS), hypoxia-sensitive (EMW), and normoxic (CM) groups. Among the three groups, a total of 277 differentially expressed genes (DEGs) were identified. KEGG analysis revealed that the pathways significantly enriched after hypoxic stress are involved in the immune response, glycolysis/gluconeogenesis, energy metabolism, vasodilation and proliferation, cell proliferation, and apoptosis. qRT‒PCR verified that the differentially expressed genes FIH-1, PHD-2, PPARα, BCL-XL, LDH-A, and Flt-1 were significantly upregulated after hypoxic stress and returned to normal levels after reoxygenation, suggesting that these DEGs play important roles in responding to hypoxia treatment. In addition, the HIF-1 signaling pathway was also activated under hypoxic stress, and qRT‒PCR confirmed that the expression level of HIF-1α was significantly elevated under acute hypoxic stress, indicating that the HIF-1 signaling pathway is the central pathway in the E. coioides hypoxic response mechanism and activates other related pathways to adapt to hypoxic stress. These pathways jointly regulate energy metabolism, substance synthesis, blood vessel proliferation, cell proliferation, and differentiation and prolong survival time. These results provide ideas for understanding physiological regulation after hypoxic stress and reoxygenation and provide basic insights for the future breeding of hypoxia-tolerant E. coioides.
Climate change conditions the selection of rust-resistant candidate wild lentil populations for in situ conservation
Authors: Civantos-Gómez Iciar , Rubio Teso María Luisa , Galeano Javier , Rubiales Diego , Iriondo José María , García-Algarra Javier
Published: November 2022

Crop Wild Relatives (CWR) are a valuable source of genetic diversity that can be transferred to commercial crops, so their conservation will become a priority in the face of climate change. Bizarrely, in situ conserved CWR populations and the traits one might wish to preserve in them are themselves vulnerable to climate change. In this study, we used a quantitative machine learning predictive approach to project the resistance of CWR populations of lentils to a common disease, lentil rust, caused by fungus Uromyces viciae-fabae. Resistance is measured through a proxy quantitative value, DSr (Disease Severity relative), quite complex and expensive to get. Therefore, machine learning is a convenient tool to predict this magnitude using a well-curated georeferenced calibration set. Previous works have provided a binary outcome (resistant vs. non-resistant), but that approach is not fine enough to answer three practical questions: which variables are key to predict rust resistance, which CWR populations are resistant to rust under current environmental conditions, and which of them are likely to keep this trait under different climate change scenarios. We first predict rust resistance in present time for crop wild relatives that grow up inside protected areas. Then, we use the same models under future climate IPCC (Intergovernmental Panel on Climate Change) scenarios to predict future DSr values. Populations that are rust-resistant by now and under future conditions are optimal candidates for further evaluation and in situ conservation of this valuable trait. We have found that rust-resistance variation as a result of climate change is not uniform across the geographic scope of the study (the Mediterranean basin), and that candidate populations share some interesting common environmental conditions.
Plastaumatic: Automating plastome assembly and annotation
Authors: Chen Wenyi , Achakkagari Sai Reddy , Strömvik Martina
Published: November 2022

Plastome sequence data is most often extracted from plant whole genome sequencing data and need to be assembled and annotated separately from the nuclear genome sequence. In projects comprising multiple genomes, it is labour intense to individually process the plastomes as it requires many steps and software. This study developed Plastaumatic - an automated pipeline for both assembly and annotation of plastomes, with the scope of the researcher being able to load whole genome sequence data with minimal manual input, and therefore a faster runtime. The main structure of the current automated pipeline includes trimming of adaptor and low-quality sequences using fastp, de novo plastome assembly using NOVOPlasty, standardization and quality checking of the assembled genomes through a custom script utilizing BLAST+ and SAMtools, annotation of the assembled genomes using AnnoPlast, and finally generating the required files for NCBI GenBank submissions. The pipeline is demonstrated with 12 potato accessions and three soybean accessions.
Additive effects of warming and nitrogen addition on the performance and competitiveness of invasive Solidago canadensis L.
Authors: Ren Guangqian , Yang Bin , Cui Miaomiao , Yu Haochen , Fan Xue , Dai Zhicong , Sun Jianfan , Li Guanlin , Zhang Haiyan , Du Daolin
Published: November 2022

Changes in temperature and nitrogen (N) deposition determine the growth and competitive dominance of both invasive and native plants. However, a paucity of experimental evidence limits understanding of how these changes influence plant invasion. Therefore, we conducted a greenhouse experiment in which invasive Solidago canadensis L. was planted in mixed culture with native Artemisia argyi Levl. et Van under combined conditions of warming and N addition. Our results show that due to the strong positive effect of nitrogen addition, the temperature increases and nitrogen deposition interaction resulted in greatly enhanced species performance. Most of the relative change ratios (RCR) of phenotypic traits differences between S. canadensis and A. argyi occur in the low invasion stage, and six of eight traits had higher RCR in response to N addition and/or warming in native A. argyi than in invasive S. canadensis. Our results also demonstrate that the effects of the warming and nitrogen interaction on growth-related traits and competitiveness of S. canadensis and A. argyi were usually additive rather than synergistic or antagonistic. This conclusion suggests that the impact of warming and nitrogen deposition on S. canadensis can be inferred from single factor studies. Further, environmental changes did not modify the competitive relationship between invasive S. canadensis and native A. argyi but the relative yield of S. canadensis was significantly greater than A. argyi. This finding indicated that we can rule out the influence of environmental changes such as N addition and warming which makes S. canadensis successfully invade new habitats through competition. Correlation analysis showed that invasive S. canadensis may be more inclined to mobilize various characteristics to strengthen competition during the invasion process, which will facilitate S. canadensis becoming the superior competitor in S. canadensis-A. argyi interactions. These findings contribute to our understanding of the spreading of invasive plants such as S. canadensis under climate change and help identify potential precautionary measures that could prevent biological invasions.
The gastrodin biosynthetic pathway in Pholidota chinensis Lindl. revealed by transcriptome and metabolome profiling
Authors: Liu Baocai , Chen Jingying , Zhang Wujun , Huang Yingzhen , Zhao Yunqing , Juneidi Seifu , Dekebo Aman , Wang Meijuan , Shi Le , Hu Xuebo
Published: November 2022

Pholidota chinensis Lindl. is an epiphytic or lithophytic perennial herb of Orchidaceae family used as a garden flower or medicinal plant to treat high blood pressure, dizziness and headache in traditional Chinese medicine. Gastrodin (GAS) is considered as a main bioactive ingredient of this herb but the biosynthetic pathway remains unclear in P. chinensis. To elucidate the GAS biosynthesis and identify the related genes in P. chinensis, a comprehensive analysis of transcriptome and metabolome of roots, rhizomes, pseudobulbs and leaves were performed by using PacBio SMART, Illumina Hiseq and Ultra Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS). A total of 1,156 metabolites were identified by UPLC-MS/MS, of which 345 differential metabolites were mainly enriched in phenylpropanoid/phenylalanine, flavone and flavonol biosynthesis. The pseudobulbs make up nearly half of the fresh weight of the whole plant, and the GAS content in the pseudobulbs was also the highest in four tissues. Up to 23,105 Unigenes were obtained and 22,029 transcripts were annotated in the transcriptome analysis. Compared to roots, 7,787, 8,376 and 9,146 differentially expressed genes (DEGs) were identified in rhizomes, pseudobulbs and leaves, respectively. And in total, 80 Unigenes encoding eight key enzymes for GAS biosynthesis, were identified. Particularly, glycosyltransferase, the key enzyme of the last step in the GAS biosynthetic pathway had 39 Unigenes candidates, of which, transcript28360/f2p0/1592, was putatively identified as the most likely candidate based on analysis of co-expression, phylogenetic analysis, and homologous searching. The metabolomics and transcriptomics of pseudobulbs versus roots showed that 8,376 DEGs and 345 DEMs had a substantial association based on the Pearson’s correlation. This study notably enriched the metabolomic and transcriptomic data of P. chinensis, and it provides valuable information for GAS biosynthesis in the plant.
Identification of elite fiber quality loci in upland cotton based on the genotyping-by-target-sequencing technology
Authors: Chen Hong , Han Zegang , Ma Qi , Dong Chengguang , Ning Xinzhu , Li Jilian , Lin Hai , Xu Shouzhen , Li Yiqian , Hu Yan , Si Zhanfeng , Song Qingping
Published: November 2022

Genome-wide association studies (GWAS) of fiber quality traits of upland cotton were conducted to identify the single-nucleotide polymorphic (SNP) loci associated with cotton fiber quality, which lays the foundation for the mining of elite] cotton fiber gene resources and its application in molecular breeding. A total of 612 upland cotton accessions were genotyped using the ZJU Cotton Chip No. 1 40K chip array via the liquid-phase probe hybridization-based genotyping-by-target-sequencing (GBTS) technology. In the present study, five fiber quality traits, namely fiber length, fiber strength, micronaire, uniformity and elongation, showed different degrees of variation in different environments. The average coefficient of variation of fiber strength was the greatest, whereas the average coefficient of variation of uniformity was the least. Significant or extremely significant correlations existed among the five fiber quality traits, especially fiber length, strength, uniformity and elongation all being significantly negative correlated with micronaire. Population cluster analysis divided the 612 accessions into four groups: 73 assigned to group I, 226 to group II, 220 to group III and 93 to group IV. Genome-wide association studies of five fiber quality traits in five environments was performed and a total of 42 SNP loci associated with target traits was detected, distributed on 19 chromosomes, with eight loci associated with fiber length, five loci associated with fiber strength, four loci associated with micronaire, twelve loci associated with fiber uniformity and thirteen loci associated with fiber elongation. Of them, seven loci were detected in more than two environments. Nine SNP loci related to fiber length, fiber strength, uniformity and elongation were found on chromosome A07, seven loci related to fiber length, fiber strength, micronaire and elongation were detected on chromosome D01, and five loci associated with fiber length, uniformity and micronaire were detected on chromosome D11. The results from this study could provide more precise molecular markers and genetic resources for cotton breeding for better fiber quality in the future.
The effects of previous summer drought and fertilization on winter non-structural carbon reserves and spring leaf development of downy oak saplings
Authors: Wang Xiaoyu , Schönbeck Leonie , Gessler Arthur , Yang Yue , Rigling Andreas , Yu Dapao , He Peng , Li Maihe
Published: November 2022

It is still unknown whether the previous summer season drought and fertilization will affect the winter non-structural carbohydrate (NSC) reserves, spring leaf development, and mortality of trees in the next year. We, therefore, conducted an experiment with Quercus pubescens (downy oaks) saplings grown under four drought levels from field capacity (well-watered; ~25% volumetric water content) to wilting point (extreme drought; ~6%), in combination with two fertilizer treatments (0 vs. 50 kg/ha/year blended) for one growing season to answer this question. We measured the pre- and post-winter NSC, and calculated the over-winter NSC consumption in storage tissues (i.e. shoots and roots) following drought and fertilization treatment, and recorded the spring leaf phenology, leaf biomass, and mortality next year. The results showed that, irrespective of drought intensity, carbon reserves were abundant in storage tissues, especially in roots. Extreme drought did not significantly alter NSC levels in tissues, but delayed the spring leaf expansion and reduced the leaf biomass. Previous season fertilization promoted shoot NSC use in extreme drought-stressed saplings over winter (showing reduced carbon reserves in shoots after winter), but it also showed positive effects on survival next year. We conclude that: (1) drought-stressed downy oak saplings seem to be able to maintain sufficient mobile carbohydrates for survival, (2) fertilization can alleviate the negative effects of extreme drought on survival and recovery growth of tree saplings.