bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of P21-activated kinases 1 and 4 synergistically suppresses the growth of pancreatic cancer by stimulating anti-tumour immunity
Authors: Ma Yi , Dumesny Chelsea , Dong Li , Ang Ching-Seng , Asadi Khashayar , Zhan Yifan , Nikfarjam Mehrdad , He Hong
Published: May 2024

Background

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal types of cancer, and KRAS oncogene occurs in over 90% of cases. P21-activated kinases (PAK), containing six members (PAK1 to 6), function downstream of KRAS. PAK1 and PAK4 play important roles in carcinogenesis, but their combinational effect remains unknown. In this study, we have determined the effect of dual inhibition of PAK1 and PAK4 in PDA progression using knockout (KO) cancer cell lines.

Methods

Murine wild-type (WT) and PAK1KO pancreatic cancer cell lines were isolated from PAK1+/+ and PAK1−/− KPC (LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx-1-Cre) mice. KPC PAK4KO and KPC PAK1&4 KO cell lines were generated from KPC WT and KPC PAK1KO cell lines respectively using the CRISPR-CAS9 gene knockout technique. PAK WT and KO cell lines were used in mouse models of pancreatic tumours. Cells and tumour tissue were also used in flow cytometry and proteomic studies. A human PDA tissue microarray was stained by immunohistochemistry.

Results

Double knock out of PAK1 and PAK4 caused complete regression of tumour in a syngeneic mouse model. PAK4KO inhibited tumour growth by stimulating a rapid increase of cytotoxic CD8+ T cell infiltration. PAK1KO synergistically with PAK4KO increased cytotoxic CD8+ T cell infiltration and stimulated a sustained infiltration of CD8+ T cells at a later phase to overcome the immune evasion in the PAK4KO tumour. The human PDA tissue microarray study showed the important role of PAK1 and PAK4 in intra-tumoral T-cell function.

Conclusion

Our results demonstrated that dual inhibition of PAK1 and PAK4 synergistically suppressed PDA progression by stimulating cytotoxic CD8 + T cell response.
All-trans retinoic acid pretreatment of mesenchymal stem cells enhances the therapeutic effect on acute kidney injury
Authors: Zhang Yifan , Wang Xiaochen , Ji Yuwei , Hong Haijuan , Geng Xiaodong , Zhang Keying , Fu Zhangning , Cai Guangyan , Chen Xiangmei , Li Ping , Hong Quan
Published: May 2024

A promising new therapy option for acute kidney injury (AKI) is mesenchymal stem cells (MSCs). However, there are several limitations to the use of MSCs, such as low rates of survival, limited homing capacity, and unclear differentiation. In search of better therapeutic strategies, we explored all-trans retinoic acid (ATRA) pretreatment of MSCs to observe whether it could improve the therapeutic efficacy of AKI. We established a renal ischemia/reperfusion injury model and treated mice with ATRA-pretreated MSCs via tail vein injection. We found that AKI mice treated with ATRA-MSCs significantly improved renal function compared with DMSO-MSCs treatment. RNA sequencing screened that hyaluronic acid (HA) production from MSCs promoted by ATRA. Further validation by chromatin immunoprecipitation experiments verified that retinoic acid receptor RARα/RXRγ was a potential transcription factor for hyaluronic acid synthase 2. Additionally, an in vitro hypoxia/reoxygenation model was established using human proximal tubular epithelial cells (HK-2). After co-culturing HK-2 cells with ATRA-pretreated MSCs, we observed that HA binds to cluster determinant 44 (CD44) and activates the PI3K/AKT pathway, which enhances the anti-inflammatory, anti-apoptotic, and proliferative repair effects of MSCs in AKI. Inhibition of the HA/CD44 axis effectively reverses the renal repair effect of ATRA-pretreated MSCs. Taken together, our study suggests that ATRA pretreatment promotes HA production by MSCs and activates the PI3K/AKT pathway in renal tubular epithelial cells, thereby enhancing the efficacy of MSCs against AKI.
Endothelial cell-derived extracellular vesicles modulate the therapeutic efficacy of mesenchymal stem cells through IDH2/TET pathway in ARDS
Authors: Wu Xiao , Tang Ying , Lu Xinxing , Liu Yigao , Liu Xu , Sun Qin , Wang Lu , Huang Wei , Liu Airan , Liu Ling , Chao Jie , Zhang Xiwen , Qiu Haibo
Published: May 2024

Background

Acute respiratory distress syndrome (ARDS) is a severe and fatal disease. Although mesenchymal stem cell (MSC)-based therapy has shown remarkable efficacy in treating ARDS in animal experiments, clinical outcomes have been unsatisfactory, which may be attributed to the influence of the lung microenvironment during MSC administration. Extracellular vesicles (EVs) derived from endothelial cells (EC-EVs) are important components of the lung microenvironment and play a crucial role in ARDS. However, the effect of EC-EVs on MSC therapy is still unclear. In this study, we established lipopolysaccharide (LPS) - induced acute lung injury model to evaluate the impact of EC-EVs on the reparative effects of bone marrow-derived MSC (BM-MSC) transplantation on lung injury and to unravel the underlying mechanisms.

Methods

EVs were isolated from bronchoalveolar lavage fluid of mice with LPS - induced acute lung injury and patients with ARDS using ultracentrifugation. and the changes of EC-EVs were analysed using nanoflow cytometry analysis. In vitro assays were performed to establish the impact of EC-EVs on MSC functions, including cell viability and migration, while in vivo studies were performed to validate the therapeutic effect of EC-EVs on MSCs. RNA-Seq analysis, small interfering RNA (siRNA), and a recombinant lentivirus were used to investigate the underlying mechanisms.

Results

Compared with that in non-ARDS patients, the quantity of EC-EVs in the lung microenvironment was significantly greater in patients with ARDS. EVs derived from lipopolysaccharide-stimulated endothelial cells (LPS-EVs) significantly decreased the viability and migration of BM-MSCs. Furthermore, engrafting BM-MSCs pretreated with LPS-EVs promoted the release of inflammatory cytokines and increased pulmonary microvascular permeability, aggravating lung injury. Mechanistically, LPS-EVs reduced the expression level of isocitrate dehydrogenase 2 (IDH2), which catalyses the formation of α-ketoglutarate (α-KG), an intermediate product of the tricarboxylic acid (TCA) cycle, in BM-MSCs. α-KG is a cofactor for ten-eleven translocation (TET) enzymes, which catalyse DNA hydroxymethylation in BM-MSCs.

Conclusions

This study revealed that EC-EVs in the lung microenvironment during ARDS can affect the therapeutic efficacy of BM-MSCs through the IDH2/TET pathway, providing potential strategies for improving the therapeutic efficacy of MSC-based therapy in the clinic.
Diverse functions and pathogenetic role of Crumbs in retinopathy
Authors: Zhou Xuebin , Zhao Liangliang , Wang Chenguang , Sun Wei , Jia Bo , Li Dan , Fu Jinling
Published: May 2024

The Crumbs protein (CRB) family plays a crucial role in maintaining the apical–basal polarity and integrity of embryonic epithelia. The family comprises different isoforms in different animals and possesses diverse structural, localization, and functional characteristics. Mutations in the human CRB1 or CRB2 gene may lead to a broad spectrum of retinal dystrophies. Various CRB-associated experimental models have recently provided mechanistic insights into human CRB-associated retinopathies. The knowledge obtained from these models corroborates the importance of CRB in retinal development and maintenance. Therefore, complete elucidation of these models can provide excellent therapeutic prospects for human CRB-associated retinopathies. In this review, we summarize the current animal models and human-derived models of different CRB family members and describe the main characteristics of their retinal phenotypes.
A novel protein FNDC3B-267aa encoded by circ0003692 inhibits gastric cancer metastasis via promoting proteasomal degradation of c-Myc
Authors: Liu Yu-Ying , Zhang Yu-Ying , Ran Ling-Yu , Huang Bo , Ren Jun-Wu , Ma Qiang , Pan Xiao-Juan , Yang Fei-Fei , Liang Ce , Wang Xiao-Lin , Wang Shi-Min , Ran Ai , Ning Hao , Jiang Yan , Qin Chang-Hong , Xiao Bin
Published: May 2024

Background

Gastric cancer (GC) ranks fifth in global cancer incidence and third in mortality rate among all cancer types. Circular RNAs (circRNAs) have been extensively demonstrated to regulate multiple malignant biological behaviors in GC. Emerging evidence suggests that several circRNAs derived from FNDC3B play pivotal roles in cancer. However, the role of circFNDC3B in GC remains elusive.

Methods

We initially screened circFNDC3B with translation potential via bioinformatics algorithm prediction. Subsequently, Sanger sequencing, qRT-PCR, RNase R, RNA-FISH and nuclear-cytoplasmic fractionation assays were explored to assess the identification and localization of circ0003692, a circRNA derived from FNDC3B. qRT-PCR and ISH were performed to quantify expression of circ0003692 in human GC tissues and adjacent normal tissues. The protein-encoding ability of circ0003692 was investigated through dual-luciferase reporter assay and LC/MS. The biological behavior of circ0003692 in GC was confirmed via in vivo and in vitro experiments. Additionally, Co-IP and rescue experiments were performed to elucidate the interaction between the encoded protein and c-Myc.

Results

We found that circ0003692 was significantly downregulated in GC tissues. Circ0003692 had the potential to encode a novel protein FNDC3B-267aa, which was downregulated in GC cells. We verified that FNDC3B-267aa, rather than circ0003692, inhibited GC migration in vitro and in vivo. Mechanistically, FNDC3B-267aa directly interacted with c-Myc and promoted proteasomal degradation of c-Myc, resulting in the downregulation of c-Myc-Snail/Slug axis.

Conclusions

Our study revealed that the novel protein FNDC3B-267aa encoded by circ0003692 suppressed GC metastasis through binding to c-Myc and enhancing proteasome-mediated degradation of c-Myc. The study offers the potential applications of circ0003692 or FNDC3B-267aa as therapeutic targets for GC.

Graphical abstract

The mechanism of circ0003692 in suppressing metastasis of GC. FNDC3B-267aa encoded by circ0003692 interacted with c-Myc and promoted the proteasomal degradation of c-Myc, thereby down-regulated c-Myc-Snail/Slug axis and EMT pathway.
Identification of epigenetic silencing of the SFRP2 gene in colorectal cancer as a clinical biomarker and molecular significance
Authors: Boughanem Hatim , pilo Jesús , García-Flores Libia Alejandra , Arranz Isabel , Ramos-Fernandez María , Ortega-Castan María , Crujeiras Ana B. , Sandoval Juan , Macias-Gonzalez Manuel
Published: May 2024

Background

Several studies have suggested secreted frizzled-related protein 2 (SFRP2) gene as a potential clinical biomarker in colorectal cancer (CRC). However, its diagnostic role remains unclear. In this study, we aimed to investigate the significance of SFRP2 methylation levels in a large cohort of biological specimens (including blood, adipose and colonic tissues) from patients with CRC, thereby potentially identifying new biomarker utility.

Methods

We examined the expression (by qPCR) and methylation status (by 450 K DNA array and DNA pyrosequencing) of the SFRP2 gene in healthy participants (N = 110, aged as 53.7 (14.2), 48/62 males/females) and patients with CRC (N = 85, aged 67.7 (10.5), 61/24 males/females), across different biological tissues, and assessing its potential as a biomarker for CRC. Additionally, we investigated the effect of recombinant human SFRP2 (rhSFRP2) as a therapeutic target, on cell proliferation, migration, and the expression of key genes related to carcinogenesis and the Wnt pathway.

Results

Our findings revealed that SFRP2 promoter methylation in whole blood could predict cancer stage (I + II vs. III + IV) (AUC = 0.653), lymph node invasion (AUC = 0.692), and CRC recurrence (AUC = 0.699) in patients with CRC (all with p < 0.05). Furthermore, we observed a global hypomethylation of SFRP2 in tumors compared to the adjacent area (p < 0.001). This observation was validated in the TCGA-COAD and TCGA-READ cohorts, demonstrating overall hypermethylation (both with p < 0.001) and low expression (p < 0.001), as shown in publicly available scRNA-Seq data. Notably, neoadjuvant-treated CRC patients exhibited lower SFRP2 methylation levels compared to untreated patients (p < 0.05) and low promoter SFRP2 methylation in untreated patients was associated with poor overall survival (p < 0.05), when compared to high methylation. Finally, treatment with 5 µg of rhSFRP2 treatment in CRC cells (HCT116 cells) inhibited cell proliferation (p < 0.001) and migration (p < 0.05), and downregulated the expression of AXIN2 (p < 0.01), a gene involved in Wnt signaling pathway.

Conclusions

These findings establish promoter methylation of the SFRP2 gene as a prognostic candidate in CRC when assessed in blood, and as a therapeutic prognostic candidate in tumors, potentially valuable in clinical practice. SFRP2 also emerges as a therapeutic option, providing new clinical and therapeutical avenues.
CCR5-overexpressing mesenchymal stem cells protect against experimental autoimmune uveitis: insights from single-cell transcriptome analysis
Authors: Yuan Fa , Zhang Rong , Li Jiani , Lei Qiannan , Wang Shuyi , Jiang Fanying , Guo Yanan , Xiang Mengqing
Published: May 2024

Autoimmune uveitis is a leading cause of severe vision loss, and animal models provide unique opportunities for studying its pathogenesis and therapeutic strategies. Here we employ scRNA-seq, RNA-seq and various molecular and cellular approaches to characterize mouse models of classical experimental autoimmune uveitis (EAU), revealing that EAU causes broad retinal neuron degeneration and marker downregulation, and that Müller glia may act as antigen-presenting cells. Moreover, EAU immune response is primarily driven by Th1 cells, and results in dramatic upregulation of CC chemokines, especially CCL5, in the EAU retina. Accordingly, overexpression of CCR5, a CCL5 receptor, in mesenchymal stem cells (MSCs) enhances their homing capacity and improves their immunomodulatory outcomes in preventing EAU, by reducing infiltrating T cells and activated microglia and suppressing Nlrp3 inflammasome activation. Taken together, our data not only provide valuable insights into the molecular characteristics of EAU but also open an avenue for innovative MSC-based therapy.
E4bp4-Cyp3a11 axis in high-fat diet-induced obese mice with weight fluctuation
Authors: Sun Shuoshuo , Zhang Ruixiang , Chen Yu , Xu Yijiao , Li Xingjia , Liu Chao , Chen Guofang , Wei Xiao
Published: May 2024

Objective

Weight regain after weight loss is a challenge in obesity management. The metabolic changes and underlying mechanisms in obese people with weight fluctuation remain to be elucidated. In the present study, we aimed to profile the features and clinical significance of liver transcriptome in obese mice with weight regain after weight loss.

Methods

The male C57BL/6J mice were fed with standard chow diet or high-fat diet (HFD). After 9 weeks, the HFD-induced obese mice were randomly divided into weight gain (WG), weight loss (WL) and weight regain (WR) group. After 10 weeks of dietary intervention, body weight, fasting blood glucose (FBG), intraperitoneal glucose tolerance, triglycerides (TG), total cholesterol (T-CHO) and low-density lipoprotein cholesterol (LDL-C) were measured. Morphological structure and lipid droplet accumulation in the liver were observed by H&E staining and oil red O staining, respectively. The liver transcriptome was detected by RNA sequencing. Protein expressions of liver cytochrome P450 3a11 (Cyp3a11) and E4 promoter-binding protein 4 (E4bp4) were determined by Western blot.

Results

After 10 weeks of dietary intervention, the body weight, FBG, glucose area under the curve, T-CHO and LDL-C in WL group were significantly lower than those in WG group (P < 0.05). At 4 weeks of HFD re-feeding, the mice in WR group presented body weight and T-CHO significantly lower than those in WG group, whereas higher than those in WL group (P < 0.05). Hepatic vacuolar degeneration and lipid droplet accumulation in the liver were significantly alleviated in WL group and WR group, compared to those in WG group. The liver transcriptome associated with lipid metabolism was significantly altered during weight fluctuation in obese mice. Compared with those in WG group, Cyp3a11 in the liver was significantly upregulated, and E4bp4 was significantly downregulated in WL and WR groups.

Conclusion

Obese mice experience weight regain after weight loss by HFD re-feeding, but their glucose and lipid metabolism disorders are milder than those induced by the persistence of obesity. Downregulated E4bp4 and upregulated Cyp3a11 are detected in obese mice after weight loss, suggesting that the E4bp4-Cyp3a11 axis may involved in metabolic mechanisms underlying weight regulation.

Graphical Abstract
Factors that influence the scope of practice of the chiropractic profession in Australia: a thematic analysis
Authors: Wiggins Desmond , Downie Aron , Engel Roger , Grace Sandra , Brown Benjamin T.
Published: May 2024

Abstract Scope of practice has been defined as the activities that an individual health care practitioner is allowed to undertake within a specific profession. The chiropractic profession in Australia does not currently have a documented scope of practice. Informed discussions around scope of practice are hampered by a paucity of literature in this area. Acknowledging this void in the literature, we chose to investigate the factors that influence scope of practice of the chiropractic profession. A knowledge of the factors will facilitate discussion on the topic and help the profession to work towards establishing a scope of practice.

Aim The aim of this study was to identify the factors that influence scope of practice of chiropractic in Australia from the perspective of 4 stakeholder groups within the profession.

Methods This study employed semi-structured, online-interviews. Open-ended questions, guided by a flexible interview protocol, and augmented by supplemental questions, probes and comments, were used to gather data on the research question. Data were analysed using reflexive thematic analysis.

Results Six factors that influenced scope of practice of chiropractic were identified in this study: education, evidence (research-derived and practice-based), political influence, community expectations, entrepreneurial business models, and geographical location.

Conclusion Knowledge of the factors that influence scope of practice of chiropractic in Australia is important for establishing a scope of practice for the profession. This knowledge is also of value to a range of stakeholders including patients, health care providers (within and outside the profession), professional associations, and policymakers.
Hypofractionated radiotherapy with simultaneous tumor bed boost (Hi-RISE) in breast cancer patients receiving upfront breast-conserving surgery: study protocol for a phase III randomized controlled trial
Authors: Jin Kairui , Luo Jurui , Yu Xiaoli , Guo Xiaomao
Published: May 2024

Background

The effectiveness and safety of moderately hypofractionated radiotherapy (HFRT) in patients undergoing breast-conserving surgery (BCS) has been demonstrated in several pivotal randomized trials. However, the feasibility of applying simultaneous integrated boost (SIB) to the tumor bed and regional node irradiation (RNI) using modern radiotherapy techniques with HFRT needs further evaluation.

Methods

This prospective, multi-center, randomized controlled, non-inferiority phase III trial aims to determine the non-inferiority of HFRT combined with SIB (HFRTsib) compared with conventional fractionated radiotherapy with sequential boost (CFRTseq) in terms of five-year locoregional control rate in breast cancer patients undergoing upfront BCS. A total of 2904 participants will be recruited and randomized in a 1:1 ratio into the HFRTsib and CFRTseq groups. All patients will receive whole breast irradiation, and those with positive axillary nodes will receive additional RNI, including internal mammary irradiation. The prescribed dose for the HFRTsib group will be 40 Gy in 15 fractions, combined with a SIB of 48 Gy in 15 fractions to the tumor bed. The CFRTseq group will receive 50 Gy in 25 fractions, with a sequential boost of 10 Gy in 5 fractions to the tumor bed.

Discussion

This trial intends to assess the effectiveness and safety of SIB combined with HFRT in early breast cancer patients following BCS. The primary endpoint is locoregional control, and the results of this trial are expected to offer crucial evidence for utilizing HFRT in breast cancer patients after BCS.

Trial registration

This trial was registered at ClincalTrials.gov (NCT04025164) on July 18, 2019.
Multi-omics analysis of a case of congenital microtia reveals aldob and oxidative stress associated with microtia etiology
Authors: Liu Wenbo , Wu Yi , Ma Rulan , Zhu Xinxi , Wang Rui , He Lin , Shu Maoguo
Published: May 2024

Background

Microtia is reported to be one of the most common congenital craniofacial malformations. Due to the complex etiology and the ethical barrier of embryonic study, the precise mechanisms of microtia remain unclear. Here we report a rare case of microtia with costal chondrodysplasia based on bioinformatics analysis and further verifications on other sporadic microtia patients.

Results

One hundred fourteen deleterious insert and deletion (InDel) and 646 deleterious SNPs were screened out by WES, candidate genes were ranked in descending order according to their relative impact with microtia. Label-free proteomic analysis showed that proteins significantly different between the groups were related with oxidative stress and energy metabolism. By real-time PCR and immunohistochemistry, we further verified the candidate genes between other sporadic microtia and normal ear chondrocytes, which showed threonine aspartase, cadherin-13, aldolase B and adiponectin were significantly upregulated in mRNA levels but were significantly lower in protein levels. ROS detection and mitochondrial membrane potential (∆ Ψ m) detection proved that oxidative stress exists in microtia chondrocytes.

Conclusions

Our results not only spot new candidate genes by WES and label-free proteomics, but also speculate for the first time that metabolism and oxidative stress may disturb cartilage development and this might become therapeutic targets and potential biomarkers with clinical usefulness in the future.
Hypothalamic protein profiling from mice subjected to social defeat stress
Authors: Mitra Shiladitya , Sameer Kumar Ghantasala S. , Samanta Anumita , Schmidt Mathias V. , Thakur Suman S.
Published: May 2024

The Hypothalmic-Pituitary-Adrenal axis also known as the HPA axis is central to stress response. It also acts as the relay center between the body and the brain. We analysed hypothalamic proteome from mice subjected to chronic social defeat paradigm using iTRAQ based quantitative proteomics to identify changes associated with stress response. We identified greater than 2000 proteins after processing our samples analysed through Q-Exactive (Thermo) and Orbitrap Velos (Thermo) at 5% FDR. Analysis of data procured from the runs showed that the proteins whose levels were affected belonged primarily to mitochondrial and metabolic processes, translation, complement pathway among others. We also found increased levels of fibrinogen, myelin basic protein (MBP) and neurofilaments (NEFL, NEFM, NEFH) in the hypothalamus from socially defeated mice. Interestingly, research indicates that these proteins are upregulated in blood and CSF of subjects exposed to trauma and stress. Since hypothalamus secreted proteins can be found in blood and CSF, their utility as biomarkers in depression holds an impressive probability and should be validated in clinical samples.
Exploring the lung-gut direction of the gut-lung axis in patients with ARDS
Authors: Ziaka Mairi , Exadaktylos Aristomenis
Published: May 2024

Acute respiratory distress syndrome (ARDS) represents a life-threatening inflammatory reaction marked by refractory hypoxaemia and pulmonary oedema. Despite advancements in treatment perspectives, ARDS still carries a high mortality rate, often due to systemic inflammatory responses leading to multiple organ dysfunction syndrome (MODS). Indeed, the deterioration and associated mortality in patients with acute lung injury (LI)/ARDS is believed to originate alongside respiratory failure mainly from the involvement of extrapulmonary organs, a consequence of the complex interaction between initial inflammatory cascades related to the primary event and ongoing mechanical ventilation-induced injury resulting in multiple organ failure (MOF) and potentially death. Even though recent research has increasingly highlighted the role of the gastrointestinal tract in this process, the pathophysiology of gut dysfunction in patients with ARDS remains mainly underexplored. This review aims to elucidate the complex interplay between lung and gut in patients with LI/ARDS. We will examine various factors, including systemic inflammation, epithelial barrier dysfunction, the effects of mechanical ventilation (MV), hypercapnia, and gut dysbiosis. Understanding these factors and their interaction may provide valuable insights into the pathophysiology of ARDS and potential therapeutic strategies to improve patient outcomes.
Breast cancer patients enrolled in the Swiss mammography screening program “donna” demonstrate prolonged survival
Authors: Kuklinski David , Blum Marcel , Subelack Jonas , Geissler Alexander , Eichenberger Alena , Morant Rudolf
Published: May 2024

Study goal

We compared the survival rates of women with breast cancer (BC) detected within versus outside the mammography screening program (MSP) “donna”.

Methods

We merged data from the MSP with the data from corresponding cancer registries to categorize BC cases as within MSP (screen-detected and interval carcinomas) and outside the MSP. We analyzed the tumor stage distribution, tumor characteristics and the survival of the women. We further estimated hazard ratios using Cox-regressions to account for different characteristics between groups and corrected the survival rates for lead-time bias.

Results

We identified 1057 invasive (ICD-10: C50) and in-situ (D05) BC cases within the MSP and 1501 outside the MSP between 2010 and 2019 in the Swiss cantons of St. Gallen and Grisons. BC within the MSP had a higher share of stage I carcinoma (46.5% vs. 33.0%;p < 0.01), a smaller (mean) tumor size (19.1 mm vs. 24.9 mm,p < 0.01), and fewer recurrences and metastases in the follow-up period (6.7% vs. 15.6%,p < 0.01). The 10-year survival rates were 91.4% for women within and 72.1% for women outside the MSP (p < 0.05). Survival difference persisted but decreased when women within the same tumor stage were compared. Lead-time corrected hazard ratios for the MSP accounted for age, tumor size and Ki-67 proliferation index were 0.550 (95% CI 0.389, 0.778;p < 0.01) for overall survival and 0.469 (95% CI 0.294, 0.749;p < 0.01) for BC related survival.

Conclusion

Women participating in the “donna” MSP had a significantly higher overall and BC related survival rate than women outside the program. Detection of BC at an earlier tumor stage only partially explains the observed differences.
Current status of community resources and priorities for weed genomics research
Authors: Montgomery Jacob , Morran Sarah , MacGregor Dana R. , McElroy J. Scott , Neve Paul , Neto Célia , Vila-Aiub Martin M. , Sandoval Maria Victoria , Menéndez Analia I. , Kreiner Julia M. , Fan Longjiang , Caicedo Ana L. , Maughan Peter J. , Martins Bianca Assis Barbosa , Mika Jagoda , Collavo Alberto , Merotto Aldo , Subramanian Nithya K. , Bagavathiannan Muthukumar V. , Cutti Luan , Islam Md. Mazharul , Gill Bikram S. , Cicchillo Robert , Gast Roger , Soni Neeta , Wright Terry R. , Zastrow-Hayes Gina , May Gregory , Malone Jenna M. , Sehgal Deepmala , Kaundun Shiv Shankhar , Dale Richard P. , Vorster Barend Juan , Peters Bodo , Lerchl Jens , Tranel Patrick J. , Beffa Roland , Fournier-Level Alexandre , Jugulam Mithila , Fengler Kevin , Llaca Victor , Patterson Eric L. , Gaines Todd A.
Published: May 2024

Weeds are attractive models for basic and applied research due to their impacts on agricultural systems and capacity to swiftly adapt in response to anthropogenic selection pressures. Currently, a lack of genomic information precludes research to elucidate the genetic basis of rapid adaptation for important traits like herbicide resistance and stress tolerance and the effect of evolutionary mechanisms on wild populations. The International Weed Genomics Consortium is a collaborative group of scientists focused on developing genomic resources to impact research into sustainable, effective weed control methods and to provide insights about stress tolerance and adaptation to assist crop breeding.
Nasal profile changes after LeFort I osteotomy (maxillary advancement) with and without ANS reduction in class III skeletal patients: a study protocol for a randomized clinical trial
Authors: Sezavar Mehdi , Moghaddamshaldoozi Hossein Rastegar , Haraji Afshin , Ghanipour Nima , Salmasi Salar Chaychi
Published: May 2024

Background

Dentofacial malformation is a common condition that affects a significant portion of the population, resulting in functional and aesthetic defects. Orthognathic surgeries, such as LeFort I osteotomy, are performed to correct these abnormalities. However, the impact of these surgeries on nasal profile changes remains unclear. Additionally, the role of anterior nasal spine (ANS) reduction in maxillary advancement surgeries of 3–5 mm range is yet to be determined. This study aims to investigate the effect of ANS reduction on soft tissue profile changes following LeFort I osteotomy with a maxillary advancement range of 3–5 mm in class III skeletal patients. The hypothesis is that the changes in nasolabial angle and upper lip length will not significantly differ between patients who undergo LeFort I osteotomy with and without ANS reduction.

Method and design

This study is designed as a randomized controlled trial. A total of 26 class III skeletal patients with maxillofacial abnormalities will be recruited from the maxillofacial clinic of Bu-Ali and Farahikhtegan Hospitals in Tehran, Iran. Patients meeting the inclusion criteria will be randomly assigned to two groups: one group will undergo LeFort I osteotomy with ANS reduction, and the other group will undergo LeFort I osteotomy without ANS reduction. The soft tissue profile changes, specifically the nasolabial angle and upper lip length, will be evaluated and compared between the two groups.

Discussion

Achieving facial harmony through orthognathic surgery requires careful planning and consideration of the impact on surrounding soft tissue. The primary objective is to predict and plan for the effects on the nasolabial region. LeFort I osteotomy is a common procedure used to correct dentofacial deformities, particularly in class III patients. Maxillary advancement during this surgery can lead to changes in nasal tip position, width, and rotation, potentially due to repositioning of the anterior nasal spine and soft tissue dissection. In this study, soft tissue changes will be assessed in non-growing class III patients using cephalometric radiographs. The impact of reducing the anterior nasal spine (ANS) on nasal profile changes will be investigated for maxillary advancements of 3–5 mm. Objective measurements and patient-reported outcomes will be evaluated to gain insights into the aesthetic outcomes of orthognathic surgery. The findings will provide valuable guidance for treatment decisions and alternative options based on expected nasal profile changes.

Trial registration

This project was registered at The Iranian Registry of Clinical Trials (Identifier No. IRCT20210928052625N1, Website: https://www.irct.ir/trial/59171) and Open Science Framework (OSF) (Registration https://doi.org/10.17605/OSF.IO/X3HD4). 2021-06-09.
Size-dependent enhancement of gene expression by Plasmodium 5’UTR introns
Authors: Lin Lirong , Liu Yanjing , Liang Rui , Guo Yue , Xu Ruixue , Fan Ruoxi , Jiao Zhiwei , Zhao Wenting , Yue Lixia , Lu Mingke , Liu Shengfa , Su Xin-zhuan , Li Jian
Published: May 2024

Background

Eukaryotic genes contain introns that are removed by the spliceosomal machinery during mRNA maturation. Introns impose a huge energetic burden on a cell; therefore, they must play an essential role in maintaining genome stability and/or regulating gene expression. Many genes (> 50%) in Plasmodium parasites contain predicted introns, including introns in 5′ and 3′ untranslated regions (UTR). However, the roles of UTR introns in the gene expression of malaria parasites remain unknown.

Methods

In this study, an episomal dual-luciferase assay was developed to evaluate gene expression driven by promoters with or without a 5′UTR intron from four Plasmodium yoelii genes. To investigate the effect of the 5′UTR intron on endogenous gene expression, the pytctp gene was tagged with 3xHA at the N-terminal of the coding region, and parasites with or without the 5′UTR intron were generated using the CRISPR/Cas9 system.

Results

We showed that promoters with 5′UTR introns had higher activities in driving gene expression than those without 5′UTR introns. The results were confirmed in recombinant parasites expressing an HA-tagged gene (pytctp) driven by promoter with or without 5′UTR intron. The enhancement of gene expression was intron size dependent, but not the DNA sequence, e.g. the longer the intron, the higher levels of expression. Similar results were observed when a promoter from one strain of P. yoelii was introduced into different parasite strains. Finally, the 5′UTR introns were alternatively spliced in different parasite development stages, suggesting an active mechanism employed by the parasites to regulate gene expression in various developmental stages.

Conclusions

Plasmodium 5′UTR introns enhance gene expression in a size-dependent manner; the presence of alternatively spliced mRNAs in different parasite developmental stages suggests that alternative slicing of 5′UTR introns is one of the key mechanisms in regulating parasite gene expression and differentiation.

Graphical Abstract
Impact of squat set configuration on mechanical performance in paired sets of upper-body exercises
Authors: Janicijevic Danica , Miras-Moreno Sergio , Morenas-Aguilar Maria Dolores , Chacon-Ventura Sara , Weakley Jonathon , García-Ramos Amador
Published: May 2024

Background

Paired sets and alternative set configurations (e.g., cluster sets) are frequently employed by strength and conditioning practitioners; however, their synergistic impact remains underexplored in research. This study aimed to elucidate whether the set configuration used in a lower-body exercise affects mechanical performance during paired sets of upper-body exercises.

Methods

Twenty-one resistance-trained individuals (14 men and 7 women) randomly completed three experimental sessions that involved four sets of five repetitions at 75%1RM during both the bench press and bench pull exercises. The three experimental sessions varied solely in the activity conducted during the inter-set rest periods of each upper-body exercise: (i) Traditional squat – six squat repetitions without intra-set rest at 65%1RM; (ii) Rest redistribution squat – two clusters of three repetitions of the squat exercise at 65%1RM with 30 s of intra-set rest; and (iii) Passive rest – no exercise.

Results

The rest redistribution set configuration allowed the sets of the squat exercise to be performed at a faster velocity than the traditional set configuration (p = 0.037). However, none of the mechanical variables differed between the exercise protocols neither in the bench press (p ranged from 0.279 to 0.875) nor in the bench pull (p ranged from 0.166 to 0.478).

Conclusions

Although rest redistribution is an effective strategy to alleviate fatigue during the sets in which it is implemented, it does not allow subjects to perform better in subsequent sets of the training session.
In-silico analysis of ribosome inactivating protein (RIP) of the Cucurbitaceae family
Authors: Maqsood Quratulain , Sumrin Aleena , Ali Qurban , Hussain Nazim , Malook Saif Ul , Ali Daoud
Published: May 2024

Ribosome-inactivating proteins (RIPs) are highly active N-glycosidases that depurinate both bacterial and eukaryotic rRNAs, halting protein synthesis during translation. Found in a diverse spectrum of plant species and tissues, RIPs possess antifungal, antibacterial, antiviral, and insecticidal properties linked to plant defense. In this study, we investigated the physiochemical properties of RIP peptides from the Cucurbitaceae family through bioinformatics approaches. Molecular weight, isoelectric point, aliphatic index, extinction coefficient, and secondary structures were analyzed, revealing their hydrophobic nature. The novelty of this work lies in the comprehensive examination of RIPs from the Cucurbitaceae family and their potential therapeutic applications. The study also elucidated the binding interactions of Cucurbitaceae RIPs with key biological targets, including Interleukin-6 (IL-6). Strong hydrogen bond interactions between RIPs and these targets suggest potential for innovative insilico drug design and therapeutic applications, particularly in cancer treatment. Comprehensive analysis of bond lengths using Ligpolt + software provides insights for optimizing molecular interactions, offering a valuable tool for drug design and structural biology studies.
Stochastic dynamics of an SIR model for respiratory diseases coupled air pollutant concentration changes
Authors: He Sha , Tan Yiping , Wang Weiming
Published: May 2024

Industrial development has made air pollution increasingly severe, and many respiratory diseases are closely related to air quality in terms of infection and transmission. In this work, we used the classic stochastic susceptible–infectious–recovered (SIR) model to reflect the spread of respiratory disease, coupled with the diffusion process of air pollutants to the infectious disease model, and we investigated the impact of various environmental noises on the process of disease transmission and air pollutant diffusion. The value of this study lies in two aspects. Mathematically, we define threshold $\mathcal{R}_{1}^{s}$

R
1
s

for extinction and threshold $\mathcal{R}_{2}^{s}$

R
2
s

for persistence of the disease in the stochastic model ($\mathcal{R}_{2}^{s}<\mathcal{R}_{1}^{s}$

R
2
s

<

R
1
s

) when the parameters are constant, and we show that (i) when $\mathcal{R}_{1}^{s}$

R
1
s

is less than 1, the disease will go to stochastic extinction; (ii) when $\mathcal{R}_{2}^{s}$

R
2
s

is larger than 1, the disease will persist almost surely and the model has a unique ergodic stationary distribution; (iii) when $\mathcal{R}_{1}^{s}$

R
1
s

is larger than 1 and $\mathcal{R}_{2}^{s}$

R
2
s

is less than 1, the extinction of the disease has randomness, which is demonstrated through numerical experiments. In addition, we derive the exact expression of the probability density function of the stationary distribution by solving the corresponding Fokker–Planck equation under the condition of disease persistence and analyze the effects of random noises on stationary distribution characteristics and the disease extinction. Epidemiologically, the change of the concentration of air pollutants affects the conditions for disease extinction and persistence. The increase in the inflow of pollutants and the increase in the clearance rate have negative and positive impacts on the spread of diseases, respectively. We found that an increase in random noise intensity will increase the variance, reduce the kurtosis of distribution, which is not conducive to predicting and controlling the development status of the disease; however, large random noise intensity can also increase the probability of disease extinction and accelerates disease extinction. We further investigate the dynamic of the stochastic model, assuming that the inflow rate switches between two levels by numerical experiments. The results show that the random noise has a significant impact on disease extinction. The data fitting of the switching model shows that the model can effectively depict the relationship and changes in trends between air pollution and diseases.
Natural variation in tocopherols, B vitamins, and isoflavones in seeds of 13 Korean conventional soybean varieties
Authors: Kim Eun-Ha , Jung Jung-Won , Yu Oh Suk , Lee So-Young , Kim Myeong-Ji , Lee Sang-Gu , Park Hyoun-Min , Jo Yongmin , Joo Yongsung , Oh Seon-Woo
Published: May 2024

Soybean seeds are excellent sources of tocopherols, B vitamins, and isoflavones, which are well known for their health benefits. This study investigated the influence of environment and genotype on these constituents across 13 Korean soybean varieties cultivated in three locations during the 2017–2019 growing seasons. Statistical analyses, employing both univariate and multivariate methods, revealed significant impacts of genetic and environmental factors on the composition of tocopherols, B vitamins, and isoflavones. Through permutational univariate analysis of variance, the primary contributors to each measured component were identified. Genotype strongly influenced the levels of β- and δ-tocopherols, whereas the interaction between location and year predominantly affected α- and γ-tocopherols. Vitamin B1 content was predominantly determined by genotype, whereas B3 and B6 were influenced by annual variations. Vitamin B2 level was primarily affected by the interplay between environmental and genotypic effects. Genotype had a significant effect on isoflavone components, with the exception of daidzein. Furthermore, early maturing varieties and those with black seed coats exhibited low levels of isoflavone components and total isoflavones, suggesting a relationship between maturity group and seed coat color in isoflavone variation. These findings can be used as reference values for compositional equivalence assessment of genetically modified soybeans.
Analysis of urban sprawl dynamics using machine learning, CA-Markov chain, and the Shannon entropy model: a case study in Mbombela City, South Africa
Authors: Mhangara Paidamwoyo , Gidey Eskinder , Manjoo Rabia
Published: May 2024

Over half of the world’s population resides in urban areas. We anticipate that this pattern will become more evident, notably in South Africa. Therefore, research on urban spirals, both past and projected, is necessary for efficient urban land use planning and management. This study aims to assess the spatio-temporal urban sprawl dynamics from 2003 to 2033 in Mbombela, South Africa. We employed robust approaches such as machine learning, the cellular automata-Markov chain, and the Shannon entropy model to look at how urban sprawl changes over time using both the Landsat 4–5 Thematic Mapper and the 8 Operational Land Imagers. We conducted this study to bridge the gaps in existing research, which primarily focuses on past and current urban growth trends rather than future trends. The findings indicated that the coverage of built-up areas and vegetation has expanded by 1.98 km2 and 13.23 km2 between the years 2003 and 2023. On the other hand, the amount of land continues to decrease by -12.56 km2 and − 2.65 km2 annually, respectively. We anticipate an increase in the built-up area and vegetation to a total of 7.60 km2 and 0.57 km2, respectively, by the year 2033. We anticipate a total annual decline of -7.78 km2 and − 0.39 km2 in water bodies and open land coverage, respectively. This work has the potential to assist planners and policymakers in improving sustainable urban land-use planning.
Association between underweight, serum albumin levels, and height loss in the Japanese male population: a retrospective study
Authors: Shimizu Yuji , Honda Eiko , Sasaki Nagisa , Takada Midori , Yoshida Tomokatsu , Motomura Kazushi
Published: May 2024

Background

Previous study has shown that height loss (defined as the highest quartile of height loss per year) was inversely associated with serum albumin levels. Furthermore, comparatively healthy hyponutrition has been linked with being underweight; as such, underweight might be inversely associated with serum albumin levels and positively associated with height loss.

Methods

To clarify the associations between serum albumin level, underweight status, and height loss, we conducted a retrospective study of 8,096 men over 4.0 years (median).

Results

Serum albumin level at baseline was inversely associated with being underweight (body mass index [BMI]: < 18.5 kg/m2) at baseline and height loss. The known cardiovascular risk factor adjusted odds ratio (OR) and 95% confidence interval (CI) of underweight at baseline and of height loss for 1 standard deviation increment of serum albumin (0.28 g/dL) was 0.79 (0.70, 0.90) and 0.84 (0.80, 0.88). Underweight was also shown to be positively associated with height loss: with the reference of normal-low weight (BMI: 18.5–22.9 kg/m2), the adjusted OR (95% CI) was 1.60 (1.21, 2.10).

Conclusion

Comparative healthy hyponutrition, which is related to low serum albumin levels and being underweight, is a significant risk factor for height loss among Japanese men. These results help to clarify the mechanisms underlying height loss.
Evolutionary and functional analyses of LRP5 in archaic and extant modern humans
Authors: Roca-Ayats Neus , Maceda Iago , Bruque Carlos David , Martínez-Gil Núria , Garcia-Giralt Natàlia , Cozar Mónica , Mellibovsky Leonardo , Van Hul Wim , Lao Oscar , Grinberg Daniel , Balcells Susanna
Published: May 2024

Background

The human lineage has undergone a postcranial skeleton gracilization (i.e. lower bone mass and strength relative to body size) compared to other primates and archaic populations such as the Neanderthals. This gracilization has been traditionally explained by differences in the mechanical load that our ancestors exercised. However, there is growing evidence that gracilization could also be genetically influenced.

Results

We have analyzed the LRP5 gene, which is known to be associated with high bone mineral density conditions, from an evolutionary and functional point of view. Taking advantage of the published genomes of archaic Homo populations, our results suggest that this gene has a complex evolutionary history both between archaic and living humans and within living human populations. In particular, we identified the presence of different selective pressures in archaics and extant modern humans, as well as evidence of positive selection in the African and South East Asian populations from the 1000 Genomes Project. Furthermore, we observed a very limited evidence of archaic introgression in this gene (only at three haplotypes of East Asian ancestry out of the 1000 Genomes), compatible with a general erasing of the fingerprint of archaic introgression due to functional differences in archaics compared to extant modern humans. In agreement with this hypothesis, we observed private mutations in the archaic genomes that we experimentally validated as putatively increasing bone mineral density. In particular, four of five archaic missense mutations affecting the first β-propeller of LRP5 displayed enhanced Wnt pathway activation, of which two also displayed reduced negative regulation.

Conclusions

In summary, these data suggest a genetic component contributing to the understanding of skeletal differences between extant modern humans and archaic Homo populations.