bluuebunny/crossref_metadata_2025 huggingface dataset:
Working together: why language policies of international schools must evolve to incorporate collaborative strategies between EAL and the mainstream
Authors: Spencer James
Published: November 2023

This article arises from a research study that aimed to contribute to a better understanding of the essential nature of collaborative relationships between English as an Additional Language (EAL) and mainstream subject teachers at an international secondary school in Ukraine. The research focuses on how EAL teachers support EAL learners in the mainstream classroom through collaborative practices. The article draws on qualitative data from interviews and field notes with Language & Literature, Science and EAL teachers. The interviews investigated how EAL and mainstream collaboration help support EAL learners in the mainstream classroom, and which co-planning strategies most effectively encourage collaboration, as well as EAL and mainstream teachers’ views and experiences about co-planning and working collaboratively. Arising from these data, discussion focuses on the disconnect between collaboration in theory and in practice. The article concludes that although effective collaborative strategies often exist, school language policies need to include scheduled collaborative planning time between EAL and the mainstream, and that professional development for mainstream teachers should be led by EAL teachers in order to foster more balanced content and language classroom teaching.
Exploring predictors of perceived stress: a cross-sectional study among nursing students during their clinical practice
Authors: Sarfika Rika , Wenny Bunga Permata , Muliantino Mulyanti Roberto , Novrianda Dwi , Saifudin I Made Moh. Yanuar
Published: November 2023

Background:

Clinical practice is a demanding academic activity for nursing students, and a variety of factors can affect this perception. This study aimed to investigate the predictors of perceived stress among Indonesian nursing students during their clinical practice.

Methods:

From September to November 2022, this cross-sectional investigation was carried out. Five questionnaires, including the socio-demographic, the PSS, the GHQ, the CBI, the MSPSS and the RSES, were completed by 208 participants. With significance set to p < 0.05, the Pearson correlation and multiple linear regression analysis were carried out.

Results:

Coping strategies ( r = 0.20, p < 0.01), overall health ( r = 0.50, p < 0.01), social support ( r = −0.34, p < 0.01) and self-esteem ( r = −0.51, p < 0.01) were all substantially linked with perceived stress. Furthermore, age (β = −0.22, p < 0.001), coping style (β = 0.22, p < 0.001) and self-esteem (β = −0.42, p < 0.001) substantially predicted perceived stress among nursing students.

Conclusion:

The study’s findings revealed strong relationships between perceived stress and general health, coping mechanisms, self-esteem and social support. These results can be utilised as evidence to help educators and other stakeholders develop programmes that effectively manage stress among nursing students during their clinical rotations.
Strategic interaction between wholesale and ancillary service markets
Authors: Brown David P. , Eckert Andrew , Silveira Douglas
Published: November 2023

In electricity markets, ancillary services (AS) are vital to ensuring system reliability through the instantaneous balancing of supply and demand. An important current policy question is whether AS markets clear simultaneously or sequentially with wholesale markets. We develop a model to study the strategic implications of market timing. We demonstrate that a strategic incentive to reduce AS and, consequently, lower marginal cost in the wholesale market arises when markets clear sequentially. Using data from Alberta, we find that the strategic effect has a small impact on wholesale outcomes but a large impact on the AS market.
Surgical versus medical castration in the treatment of metastatic prostate cancer: A systematic review and meta-analysis
Authors: O’Sullivan Niall J , Temperley Hugo C , Davey Matthew G , Naughton Ailish , Casey Rowan G
Published: November 2023

Introduction:

Metastatic disease is found in up to 20% of prostate cancer (PCa) cases at diagnosis. Since their introduction in the 1980s, long acting gonadotropin-releasing hormone (GnRH) analogues, administered subcutaneously or intramuscularly every 1–6 months have widely replaced bilateral orchidectomy as the method of castration for this cohort of patients. Recent evidence suggests that surgical castration confers a superior side-effect profile and cost. We aimed to perform a systematic review and meta-analysis to compare these two treatment methods particularly in terms of survival, side-effect profile and cost-effectiveness.

Methods:

A systematic review of the literature was performed for studies comparing medical and surgical castration for metastatic PCa. Outcome measurements included overall survival, side-effect profile and cost.

Results:

Fifteen studies on 63,682 participants ( n = 59,045 for medical and n = 4637 for surgical) met inclusion criteria. Our analysis demonstrated a trend towards significance in overall survival rates in favour of surgical castration (hazard ratio = 0.89, 95% confidence interval (CI) = 0.79 to 1.01, p = 0.06), a trend towards significance in cardiovascular complications in favour of the surgical group (odds ratio (OR) = 0.79, 95% CI = 0.62 to 1.00, p = 0.05) and a significantly lower nadir prostate-specific antigen (PSA) level in favour of medical castration (MD PSA 1.17 less in medical castration group, 95% CI = 0.67 to 1.67, p < 0.01).

Conclusion:

Surgical castration appears to be a safe, feasible and efficacious alternative to medical castration, with evidence to suggest a potential survival benefit and limited evidence of a financial benefit in the treatment of men with metastatic PCa. Further studies are required to further quantify the financial burden of one method over another, as well as to identify which subgroup of patients respond best to each method of castration.

Level of evidence:

Level 1
Comparative Analysis of Move-Specific Lexical Bundles in Linguistics Dissertation Abstracts: A Study of Students from China and the United States
Authors: Bao Kai , Liu Meihua
Published: November 2023

This article compared three-word move-specific lexical bundles (MLBs) in dissertation abstracts authored by linguistics doctoral students from China and the United States. Two separate corpora were constructed for analysis: (1) The China Linguistics PhD Abstracts Corpus (CLC), consisting of 700 abstracts totaling 613,713 words generated by doctoral students from China specializing in linguistics, and (2) the America Linguistics PhD Abstracts Corpus (ALC), comprising 700 abstracts totaling 247,359 words written by American doctoral students in linguistics. The identification of MLBs was based on log-likelihood values, indicating a notably higher number of instances within a specific move in contrast to the overall corpus. The study then proceeded to compare the structures, functions, and communicative purposes of MLBs in the two corpora. The findings of the analysis are as follows: (1) Chinese students employed a higher percentage of NP- and PP-based MLBs but a lower proportion of VP-based MLBs, and both groups used different words within similar structures; (2) Chinese students employed a higher percentage of research- and participant-oriented MLBs but a lower proportion of text-oriented MLBs, and the two groups used dissimilar MLBs to fulfill similar functions; and (3) the two groups employed distinct MLBs to achieve identical communicative purposes, with Chinese students utilizing MLBs specific to the CLC corpus. These findings highlight the pedagogical significance of MLBs and underscore the importance of corpus linguistics in identifying and teaching essential move-specific vocabulary to second/foreign language learners.
Atypical Presentation of the Classical Form of Locked-In Syndrome in a Young Patient
Authors: Manongi Ngoda , Clough Jana , Mirchin Ryan , Byrns Kory A. , Tversky Steven
Published: November 2023

Locked-in syndrome (LIS) is an uncommon neurologic disorder that manifests in quadriplegia and anarthria with preserved cognition and self-awareness. Generally, patients with LIS may live for years with preserved quality of life and cognitive function, but with severe disability. There are 3 types of LIS: classic, partial, and total. The classical form is defined by total immobility, with preservation of the ability to perform vertical eye movements, blink, and maintain a normal level of consciousness. We present an unusual case of classical LIS in a 54-year-old man who presented initially with acute-onset left lower extremity weakness and dysarthria with radiographic evidence of extensive, acute right paramedian pontine infarction and high-grade vertebral artery stenosis. However, a week later, the patient developed sudden-onset aphonia, bilateral facial palsy, and quadriplegia with repeat magnetic resonance imaging of the brain showing expansion of right paramedian pontine stroke to also involve the left paramedian pons, without significant change to the vertebral stenosis and basilar artery patency.
Effect of the Copenhagen Achilles Rupture Treatment Algorithm (CARTA) on Calf Muscle Volume and Tendon Elongation After Acute Achilles Tendon Rupture: A Predefined Secondary Analysis of the First 60 Patients in a Randomized Controlled Trial
Authors: Barfod Kristoffer Weisskirchner , Overgård Anders Brøgger , Hansen Maria Swennergren , Haddouchi Ibrahim El , Toft Marianne , Hölmich Per
Published: November 2023

Background:

Surgical treatment of acute Achilles tendon rupture (ATR) lowers the risk of rerupture and may reduce calf atrophy and elongation of the Achilles tendon. The Copenhagen Achilles Rupture Treatment Algorithm (CARTA) was developed to provide individualized treatment selection based on ultrasonographic evaluation of the rupture.

Purpose:

In a randomized setup, the present study aimed to investigate whether treatment selection using the CARTA could reduce atrophy and tendon elongation compared with (1) patients treated surgically and (2) patients treated nonsurgically.

Study Design:

Randomized controlled trial; Level of evidence, 2.

Methods:

A total of 60 patients with an acute ATR were randomly assigned to receive treatment based on the CARTA (intervention), surgical treatment (control), or nonsurgical treatment (control) in a 1 to 1 to 1 ratio. After 1 year, magnetic resonance imaging of both calves was performed, and muscle volume and Achilles tendon length were measured. Results were presented as the ratio between the affected and the unaffected limbs (ie, limb symmetry index; %).

Results:

A total of 156 patients were assessed for eligibility, 60 patients were randomized, and 54 patients provided data for the study—19 patients received treatment based on the CARTA (intervention group), 17 patients received nonsurgical treatment (control), and 18 patients received surgical treatment (control). No statistically significant differences were found between the intervention group and the 2 control groups regarding muscle volume and tendon length. No statistically significant differences were found between patients treated surgically and patients treated nonsurgically. Comparison between the affected and the unaffected limb showed statistically significant muscle atrophy (24%-30%) and tendon elongation (soleus, 59%-76%; gastrocnemius, 8%-14%) in the affected limb in all 3 groups.

Conclusion:

Individualized treatment of acute ATR using an ultrasonographic selection algorithm did not reduce calf muscle atrophy or tendon elongation when compared with surgical and nonsurgical treatment. Surgical treatment did not reduce calf muscle atrophy or tendon elongation compared with nonsurgical treatment.
Barriers to the Diagnosis, Care, and Management of Pediatric Patients With Ehlers-Danlos Syndrome in the United States: A Qualitative Analysis
Authors: Black William R. , Black Lora L. , Jones Jordan T.
Published: November 2023

Objectives: Ehlers-Danlos Syndromes (EDS) are a family of heritable connective tissue diseases. Primary practitioners are capable of diagnosing and managing EDS; however, few are knowledgeable and comfortable enough to see patients with EDS, resulting in delays in diagnosis and care. This study explores the barriers physicians experience with diagnosing, managing, and caring for patients with EDS, and potential resolutions to those barriers. Methods: As part of a larger online study, providers (n = 107) in the United States were asked to specify “What information would improve (their) comfort” in diagnosing, caring for, and managing EDS via open-ended questions. Results: Providers reported wanting clinical practice guidelines, in formats that were easily accessible and usable, information on their roles in the management of EDS, the best ways to coordinate with specialty care, and available specialty consultation. Conclusions: Providers overall are willing to diagnose and treat EDS; however, additional supports and training are needed.
Endoscopic revision of one-anastomosis gastric bypass (ER-OAGB) for weight recurrence: a case series of 17 adults
Authors: Maselli Daniel B. , Hoff Anna C. , Kucera Ashley , Waseem Areebah , Wooley Chase , Donnangelo Lauren L. , Coan Brian , McGowan Christopher E.
Published: November 2023

Weight recurrence after one-anastomosis gastric bypass (OAGB), the third most common metabolic and bariatric surgery performed worldwide, is observed in a subset of patients due to the chronic, progressive nature of obesity. Endoscopic revision of the OAGB (ER-OAGB) through full-thickness suturing to reduce the gastrojejunal anastomosis and gastric pouch is a potential alternative to surgical revision. Here, we present a case series of ER-OAGB and long-term nutritional support at two international centers with expertise in bariatric endoscopy. Data were retrospectively evaluated from a prospectively maintained database. The primary outcome was total body weight loss (TBWL) at 12 months. Secondary outcomes included TBWL at 3, 6, and 15 months; excess weight loss (EWL) at 3, 6, 12, and 15 months; frequency of new/worsening symptoms of gastroesophageal reflux disease (GERD); and the frequency of serious adverse events. In this series, 17 adults (70.6% female, mean age 46.8 years, mean BMI 39.1 kg/m2) successfully underwent ER-OAGB an average of 8 years (range 2–21 years) after OAGB for a mean weight recurrence of 43.2% (range 10.9–86.9%). TBWL from ER-OAGB was 9.7 ± 1.8% at 3 months, 13.4 ± 3.5% at 6 months, 18.5 ± 2.1% at 12 months, and 18.1 ± 2.2% at 15 months. EWL from ER-OAGB was 30.5 ± 14.7% at 3 months, 42.6 ± 16.2% at 6 months, 54.2 ± 11.3% at 12 months, and 54.2 ± 11.7% at 15 months. There were no instances of new/worsening GERD symptoms or serious adverse events. In this small series of adults who experienced weight recurrence after OAGB, ER-OAGB facilitated safe and clinically meaningful weight loss, without new or worsening GERD symptoms, when performed by experienced bariatric endoscopists in concert with longitudinal nutritional support.
Evaluation of flexural strength, degree of conversion, and demineralization-prevention properties in adjacent tooth structures of an experimental fissure sealant containing nano-calcium-phosphate compounds
Authors: Fallahzadeh Farnoosh , Pirmoradian Maryam , Ghasemi Solmaz Mohammadzadeh , Mortazavi Maryam
Published: November 2023

Background

The present study aimed to evaluate the flexural strength, degree of conversion, and demineralization-prevention ability of an experimental fissure sealant containing nano-calcium-phosphate compounds.

Methods

An experimental sealant was formulated using silica and nano hydroxyapatite filler particles. The control group consisted of the DENU Seal (n = 10, each group). The flexural bond strength was evaluated by UTM. DC was evaluated by FTIR. To evaluate the demineralization-prevention ability, Cl V cavities in 10 third molar teeth restored with two sealant products, followed by an acid challenge then the Vickers microhardness test was carried out.

Results

The mean flexural strength in the commercial group was higher than the experimental group. However, the mean flexural modulus was not significantly different between the two groups. In the experimental group, DC was significantly higher than the commercial group. Adjacent to the interface, the decrease in microhardness in the experimental group was significantly less than the commercial group. However, on the tooth surface, there were no significant differences between the two groups. In the experimental group, the decrease in microhardness at the interface was less than at the tooth surface, however the situation was opposite in the commercial group.

Conclusions

Incorporating hydroxyapatite into the sealant structure might prevent demineralization, without adverse effects on flexural modulus and degree of conversion.
Communication strategies used by medical physicians when delivering bad news at the Maputo Central Hospital, Mozambique: a cross-sectional study
Authors: Schmauch Natália Ubisse , Pinto Emilia , Rego Francisca , Castro Luísa , Sacarlal Jahit , Rego Guilhermina
Published: November 2023

Background

Physicians’ communication with patients and their families is important during both the disease diagnosis and prognosis stages and through the follow-up process. Effective physician communication improves patients’ quality of life and satisfaction with care and helps reduce suffering for those newly diagnosed with advanced progressive illnesses. This study aims to identify the communication strategies physicians use in the transition to palliative care and how these professionals perceive their academic and clinical preparation concerning this task.

Methods

A cross-sectional and quantitative study. Physicians providing palliative care at the Maputo Central Hospital, Mozambique, were invited to complete a 17-question questionnaire. This questionnaire was based on a Brazilian adaptation of the Setting-Perception-Invitation-Knowledge-Emotions-Strategy (SPIKES) tool, the P-A-C-I-E-N-T-E protocol, with additional questions regarding socio-demographic details and the integration of “communication of bad news” into hospital training.

Results

Of the 121 participants, 62 (51.2%) were male, and 110 (90.9%) were general practitioners, with a median age of 36 years old. They had worked in clinical practice for a median of 8 years and in their current department for three years. The majority of the participants considered that they have an acceptable or good level of bad news communication skills and believed that they do it in a clear and empathic way, paying attention to the patient’s requests and doubts; however, most were not aware of the existing tools to assist them in this task and suggested that delivering bad news ought to be integrated into the undergraduate medical course and included in hospital training.

Conclusions

This study adds to our understanding of physicians’ strategies when communicating bad news in the context of palliative care at one Mozambique hospital. As palliative care is not fully implemented in Mozambique, it is important to use protocols suitable to the country’s healthcare level to improve how doctors deal with patients and their family members.
Myrislignan targets extracellular signal-regulated kinase (ERK) and modulates mitochondrial function to dampen osteoclastogenesis and ovariectomy-induced osteoporosis
Authors: Yang Tao , Chen Weiwei , Gan Kai , Wang Chaofeng , Xie Xiaoxiao , Su Yuangang , Lian Haoyu , Xu Jiake , Zhao Jinmin , Liu Qian
Published: November 2023

Background

Activated osteoclasts cause excessive bone resorption, and disrupt bone homeostasis, leading to osteoporosis. The extracellular signal-regulated kinase (ERK) signaling is the classical pathway related to osteoclast differentiation, and mitochondrial reactive oxygen species are closely associated with the differentiation of osteoclasts. Myrislignan (MRL), a natural product derived from nutmeg, has multiple pharmacological activities; however, its therapeutic effect on osteoporosis is unclear. Here, we investigated whether MRL could inhibit osteoclastogenesis and bone mass loss in an ovariectomy mouse model by suppressing mitochondrial function and ERK signaling.

Methods

Tartrate-resistant and phosphatase (TRAP) and bone resorption assays were performed to observe the effect of MRL on osteoclastogenesis of bone marrow macrophages. MitoSOX RED and tetramethyl rhodamine methyl ester (TMRM) staining was performed to evaluate the inhibitory effect of MRL on mitochondria. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay was performed to detect whether MRL suppressed the expression of osteoclast-specific genes. The impact of MRL on the protein involved in the mitogen-activated protein kinase (MAPK) and nuclear factor-κB pathways was evaluated using western blotting. In addition, a specific ERK agonist LM22B-10, was used to revalidate the inhibitory effect of MRL on ERK. Finally, we established an ovariectomy mouse model to assess the therapeutic effect of MRL on osteoporosis in vivo.

Results

MRL inhibited osteoclast differentiation and the associated bone resorption, by significantly decreasing osteoclastic gene expression. Mechanistically, MRL inhibited the phosphorylation of ERK by suppressing the mitochondrial function, thereby downregulating the nuclear factor of activated T cells 1 (NFATc1) signaling. LM22B-10 treatment further verified the targeted inhibition effect of MRL on ERK. Microscopic computed tomographic and histologic analyses of the tibial tissue sections indicated that ovariectomized mice had lower bone mass and higher expression of ERK compared with normal controls. However, MRL treatment significantly reversed these effects, indicating the anti-osteoporosis effect of MRL.

Conclusion

We report for the first time that MRL inhibits ERK signaling by suppressing mitochondrial function, thereby ameliorating ovariectomy-induced osteoporosis. Our findings can provide a basis for the development of a novel therapeutic strategy for osteoporosis.
Relationship between glucocorticoids and viral load during the Omicron wave in mainland China
Authors: Bai Guangxu , Li Yan , Liu Yang , Wang Xinming , Yu Xuezhong , Ren Lili , Xu Jun
Published: November 2023

Background

Coronavirus disease 19 (COVID-19) is a major public health problem that cannot be ignored. As a widely used drug in the treatment of COVID-19, whether glucocorticoids may accelerate the clearance of COVID-19 is still not clear, and the glucocorticoids may improve the prognosis of patients is also controversial. Therefore, to explore the relationship between COVID-19 viral load and the use of glucocorticoids we designed this study.

Methods

Patients with COVID-19 infection who were admitted to the emergency department of Peking Union Medical College Hospital from the end of 2022 to early 2023 were enrolled in this study. Characteristics of baseline, clinical and laboratory evaluation especially immunological indicator and daily viral load were carefully collected. Kolmogorov–Smirnov test, Student’s t test, Mann–Whitney U test and proportional-hazards model (Cox model) were chosen as appropriate for comparison of variables.

Results

By comparing the daily COVID-19 viral load and prognosis of patients with and without glucocorticoid therapy, we found that glucocorticoids did not statistically enhance the clearance or replication of COVID-19, nor did it change the 28-days and in-hospital mortality. However, glucocorticoid therapy may be a favorable factor for COVID-19 negative conversion in Cox model. The inflammatory factors in patients with glucocorticoid therapy were significantly decreased.

Conclusions

We believe that the real effect of glucocorticoids may be to improve the destruction of host immune system caused by inflammatory storm through host immune regulation and then achieve the improvement of clinical symptoms.
Long non-coding RNA GAS5 promotes cisplatin-chemosensitivity of osteosarcoma cells via microRNA-26b-5p/TP53INP1 axis
Authors: Li Guowei , Yan Xue
Published: November 2023

Osteosarcoma is a common malignant bone tumor. Cisplatin (DDP) achieves a high response rate in osteosarcoma. Here we aim to study the dysregulation of long non-coding RNA the growth arrest-specific transcript 5 (GAS5), and its roles in DDP-resistance of osteosarcoma. The expression of mRNA and microRNA in osteosarcoma tissues and osteosarcoma cell lines were detected by quantitative reverse-transcription polymerase chain reaction, and protein expression levels were measured by western blotting assay. Cell Counting Kit-8 and 5-Ethynyl-2′-deoxyuridine were used to measure cell proliferation. Flow cytometer assay was used to evaluate cell apoptosis. The interactions between miR-26b-5p and GAS5 or tumor protein p53-induced nuclear protein 1 (TP53INP1) were verified by dual luciferase reporter along with biotin RNA pull-down assays. GAS5 was identified to be significantly lowly expressed in osteosarcoma samples especially in cisplatin-resistant (DDP-resistant) tissues. GAS5 was also downregulated in DDP-resistant cells. Over-expressed GAS5 prominently increased the sensitivity of osteosarcoma cells to DDP in vitro. Furthermore, over-expression of GAS5 suppressed cell proliferation and facilitated apoptosis of DDP-resistant cells. Mechanistically, GAS5 sponged miR-26b-5p, over-expression of which reversed the effects of GAS5 on cell proliferation and apoptosis of DDP-resistant cells. In addition, miR-26b-5p targeted TP53INP1. TP53INP1 abrogated the functions of miR-26b-5p on cell proliferation and apoptosis in DDP-resistant cells. Taken together, GAS5 enhanced the sensitivity of osteosarcoma cells to DDP via GAS5/miR-26b-5p/TP53INP1 axis. Therefore, GAS5 may be a potential indicator for the management of osteosarcoma.
Transcriptomic profiles reveal the characteristics of oocytes and cumulus cells at GV, MI, and MII in follicles before ovulation
Authors: Hu Yena , Zhang Ran , Zhang Shuoping , Ji Yaxing , Zhou Qinwei , Leng Lizhi , Meng Fei , Gong Fei , Lu Guangxiu , Lin Ge , Hu Liang
Published: November 2023

Background

The oocyte and its surrounding cumulus cells (CCs) exist as an inseparable entity. The maturation of the oocyte relies on communication between the oocyte and the surrounding CCs. However, oocyte evaluation is primarily based on morphological parameters currently, which offer limited insight into the quality and competence of the oocyte. Here, we conducted transcriptomic profiling of oocytes and their CCs from 47 patients undergoing preimplantation genetic testing for aneuploidy (PGT-A). We aimed to investigate the molecular events occurring between oocytes and CCs at different stages of oocyte maturation (germinal vesicle [GV], metaphase I [MI], and metaphase II [MII]). Our goal is to provide new insights into in vitro oocyte maturation (IVM).

Results

Our findings indicate that oocyte maturation is a complex and dynamic process and that MI oocytes can be further classified into two distinct subtypes: GV-like-MI oocytes and MII-like-MI oocytes. Human oocytes and cumulus cells at three different stages of maturation were analyzed using RNA-seq, which revealed unique transcriptional machinery, stage-specific genes and pathways, and transcription factor networks that displayed developmental stage-specific expression patterns. We have also identified that both lipid and cholesterol metabolism in cumulus cells is active during the late stage of oocyte maturation. Lipids may serve as a more efficient energy source for oocytes and even embryogenesis.

Conclusions

Overall, our study provides a relatively comprehensive overview of the transcriptional characteristics and potential interactions between human oocytes and cumulus cells at various stages of maturation before ovulation. This study may offer novel perspectives on IVM and provide a reliable reference data set for understanding the transcriptional regulation of follicular maturation.
Logic-based modeling and drug repurposing for the prediction of novel therapeutic targets and combination regimens against E2F1-driven melanoma progression
Authors: Singh Nivedita , Khan Faiz M , Bala Lakshmi , Vera Julio , Wolkenhauer Olaf , Pützer Brigitte , Logotheti Stella , Gupta Shailendra K.
Published: November 2023

Melanoma presents increasing prevalence and poor outcomes. Progression to aggressive stages is characterized by overexpression of the transcription factor E2F1 and activation of downstream prometastatic gene regulatory networks (GRNs). Appropriate therapeutic manipulation of the E2F1-governed GRNs holds the potential to prevent metastasis however, these networks entail complex feedback and feedforward regulatory motifs among various regulatory layers, which make it difficult to identify druggable components. To this end, computational approaches such as mathematical modeling and virtual screening are important tools to unveil the dynamics of these signaling networks and identify critical components that could be further explored as therapeutic targets. Herein, we integrated a well-established E2F1-mediated epithelial-mesenchymal transition (EMT) map with transcriptomics data from E2F1-expressing melanoma cells to reconstruct a core regulatory network underlying aggressive melanoma. Using logic-based in silico perturbation experiments of a core regulatory network, we identified that simultaneous perturbation of Protein kinase B (AKT1) and oncoprotein murine double minute 2 (MDM2) drastically reduces EMT in melanoma. Using the structures of the two protein signatures, virtual screening strategies were performed with the FDA-approved drug library. Furthermore, by combining drug repurposing and computer-aided drug design techniques, followed by molecular dynamics simulation analysis, we identified two potent drugs (Tadalafil and Finasteride) that can efficiently inhibit AKT1 and MDM2 proteins. We propose that these two drugs could be considered for the development of therapeutic strategies for the management of aggressive melanoma.

Graphical abstract
Trichinella spiralis cathepsin L induces macrophage M1 polarization via the NF-κB pathway and enhances the ADCC killing of newborn larvae
Authors: Liu Ruo Dan , Meng Xiang Yu , Le Li Chen , Xu Qiu Yi , Lin Xin Zhi , Dong Bo Rang , Ye Chu Yan , Miao Tian Tian , Si Xin Yi , Long Shao Rong , Cui Jing , Wang Zhong Quan
Published: November 2023

Background

During the early stages of Trichinella spiralis infection, macrophages predominantly undergo polarization to the M1-like phenotype, causing the host’s inflammatory response and resistance against T. spiralis infection. As the disease progresses, the number of M2-type macrophages gradually increases, contributing to tissue repair processes within the host. While cysteine protease overexpression is typically associated with inflammation, the specific role of T. spiralis cathepsin L (TsCatL) in mediating macrophage polarization remains unknown. The aim of this study was to assess the killing effect of macrophage polarization mediated by recombinant T. spiralis cathepsin L domains (rTsCatL2) on newborn larvae (NBL).

Methods

rTsCatL2 was expressed in Escherichia coli strain BL21. Polarization of the rTsCatL2-induced RAW264.7 cells was analyzed by enzyme-linked immunosorbent assay (ELISA), quantitative PCR (qPCR), western blot, immunofluorescence and flow cytometry. The effect of JSH-23, an inhibitor of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), on rTsCatL2-induced M1 polarization investigated. Cytotoxic effects of polarized macrophages on NBL were observed using in vitro killing assays.

Results

Following the co-incubation of rTsCatL2 with RAW264.7 murine macrophage cells, qPCR and ELISA revealed increased transcription and secretion levels of inducible nitric oxide synthase (iNOS), interleukin (IL)-6, IL-1β and tumor necrosis factor alpha (TNF-α) in macrophages. Western blot analysis showed a significant increase in iNOS protein expression, while the expression level of arginase-1 protein remained unchanged. Flow cytometry revealed a substantial increase in the number of CD86-labeled macrophages. The western blot results also indicated that rTsCatL2 increased the expression levels of phospho-NF-κB and phospho-nuclear factor-κB inhibitor alpha (IκB-α) proteins in a dose-dependent manner, while immunofluorescence revealed that rTsCatL2 induced nuclear translocation of the p65 subunit of NF-κB (NF-κB p65) protein in macrophages. The inhibitory effect of JSH-23 suppressed and abrogated the effect of rTsCatL2 in promoting M1 macrophage polarization. rTsCatL2 mediated polarization of macrophages to the M1-like phenotype and enhanced macrophage adhesion and antibody-dependent cell-mediated cytotoxicity (ADCC) killing of NBL.

Conclusions

The results indicated that rTsCatL2 induces macrophage M1 polarization via the NF-κB pathway and enhances the ADCC killing of NBL. This study provides a further understanding of the interaction mechanism between T. spiralis and the host.

Graphical Abstract
Massive underrepresentation of Arabs in genomic studies of common disease
Authors: Bhattacharya Romit , Chen NingNing , Shim Injeong , Kuwahara Hiroyuki , Gao Xin , Alkuraya Fowzan S. , Fahed Akl C.
Published: November 2023

Arabs represent 5% of the world population and have a high prevalence of common disease, yet remain greatly underrepresented in genome-wide association studies, where only 1 in 600 individuals are Arab. We highlight the persistent and unaddressed underrepresentation of Arabs in genomic databases and discuss its impact on public health genomics and missed opportunities for biological discovery.
Targeting oncogenic TERT promoter variants by allele-specific epigenome editing
Authors: Kouroukli Alexandra G. , Rajaram Nivethika , Bashtrykov Pavel , Kretzmer Helene , Siebert Reiner , Jeltsch Albert , Bens Susanne
Published: November 2023

Background

Activation of dominant oncogenes by small or structural genomic alterations is a common driver mechanism in many cancers. Silencing of such dominantly activated oncogenic alleles, thus, is a promising strategy to treat cancer. Recently, allele-specific epigenome editing (ASEE) has been described as a means to reduce transcription of genes in an allele-specific manner. In cancer, specificity to an oncogenic allele can be reached by either targeting directly a pathogenic single-nucleotide variant or a polymorphic single-nucleotide variant linked to the oncogenic allele. To investigate the potential of ASEE in cancer, we here explored this approach by targeting variants at the TERT promoter region. The TERT promoter region has been described as one of the most frequently mutated non-coding cancer drivers.

Results

Sequencing of the TERT promoter in cancer cell lines showed 53% (41/77) to contain at least one heterozygous sequence variant allowing allele distinction. We chose the hepatoblastoma cell line Hep-G2 and the lung cancer cell line A-549 for this proof-of-principle study, as they contained two different kinds of variants, namely the activating mutation C228T in the TERT core promoter and the common SNP rs2853669 in the THOR region, respectively. These variants were targeted in an allele-specific manner using sgRNA-guided dCas9-DNMT3A-3L complexes. In both cell lines, we successfully introduced DNA methylation specifically to the on-target allele of the TERT promoter with limited background methylation on the off-target allele or an off-target locus (VEGFA), respectively. We observed a maximum CpG methylation gain of 39% and 76% on the target allele when targeting the activating mutation and the common SNP, respectively. The epigenome editing translated into reduced TERT RNA expression in Hep-G2.

Conclusions

We applied an ASEE-mediated approach to silence TERT allele specifically. Our results show that the concept of dominant oncogene inactivation by allele-specific epigenome editing can be successfully translated into cancer models. This new strategy may have important advantages in comparison with existing therapeutic approaches, e.g., targeting telomerase, especially with regard to reducing adverse side effects.
Animal models of primary biliary cholangitis: status and challenges
Authors: Wang Xu , Wei Yi , Yang Yanlei , Yang Yunjiao , Li Haolong , Li Yongzhe , Zhang Fengchun , Wang Li
Published: November 2023

Background

Primary biliary cholangitis (PBC) is an autoimmune liver disease. The aetiology of PBC remains unclear, and its pathogenesis is complex. Animal models are essential to clarify the pathogenesis of PBC and explore the occurrence of early events.

Main body

Herein, we review recent research progress in PBC animal models, including genetically modified, chemically inducible, biologically inducible, and protein-immunised models. Although these animal models exhibit several immunological and pathological features of PBC, they all have limitations that constrain further research and weaken their connection with clinical practice.

Conclusion

The review will benefit efforts to understand and optimise animal models in order to further clarify PBC pathogenesis and molecular targets for therapeutic interventions.
Highly rarefied gas flows in rough channels of finite length
Authors: Shi Zheng , Zhao Yulong , Su Wei , Wu Lei
Published: November 2023

Highly rarefied gas flows through a rough channel of finite length with small bumps appended to its surfaces are investigated, by varying the accommodation coefficient $$\alpha$$
α
in Maxwell’s diffuse-specular boundary condition, the characteristic size and position of the bumps, and the channel length. First, we study the influence of the surface bumps and consider the rarefied gas flow in a unit channel with periodic boundary conditions to remove the end effect. It is found that the surface bumps have a significant impact on the flow permeability. When $$\alpha$$
α
is very small (i.e., nearly specular reflection of gas molecules at the channel surface), the apparent gas permeability is dramatically reduced, even in the presence of small bumps, to a value that is almost comparable to the one when fully diffuse gas-surface scattering is assumed. This impact can be taken into account through an effective accommodation coefficient, i.e., the permeability of the rough channel is taken equivalently as that of a smooth channel without bumps but having gas-surface scattering under the effective accommodation coefficient. Second, we study the end effect by connecting a smooth channel of length $$L_0$$

L
0

to two huge gas reservoirs. It is found that (i) the end correction length is large at small $$\alpha$$
α
. Consequently, the mass flow rate barely reduces with increasing $$L_0$$

L
0

rather than scales down by a factor of $$1/L_0$$

1
/

L
0

as predicted by the classical Knudsen diffusion theory; and (ii) the end correction is related to the channel’s aspect ratio. Finally, based on the effective accommodation coefficient and end correction, we explain the exotic flow enhancement in graphene angstrom-scale channels observed by Geim’s research group (Keerthi et al, Nature 558:420–424, 2018).
Ozone micron bubble pretreatment for antibiotic resistance genes reduction in hospital wastewater treatment
Authors: Hsiao Shui-Shu , Hsu Chia-Yu , Ananthakrishnan Balamurugan , Hsu Ming-Hao , Chien Yu-Ting , Wang Li-Pang , Tung Hsin-Hsin
Published: November 2023

Ozone micron bubble (OMB) treatment offers a promising approach to effectively eliminate Antibiotic Resistance Genes (ARGs) from infectious medical wastewater and mitigate the threat of drug resistance transmission. This study evaluated the effectiveness of OMB treatment for reducing ARGs from infectious medical wastewater in laboratory and on-site pilot treatment setups. In part, the presence of antibiotic residues in a hospital wastewater treatment plant (WWTP) and the impact of hospital wastewater on the distribution of ARGs in a wastewater collection system were also investigated. The results of wastewater collection system survey revealed a high prevalence of ARGs in the system, particularly mcr-1, largely originating from medical wastewater discharges. Furthermore, analysis of antibiotic residues in the hospital wastewater treatment system showed significant accumulation, particularly of quinolone antibiotics, in the biomass of the biological oxidation tank, suggesting a potential risk of ARG proliferation within the system. Comparison of wastewater samples from domestic and hospital WWTPs revealed a relatively higher abundance of ARGs in the latter, with differences ranging from 2.2 to sixfold between corresponding locations in the treatment plants. Notably, the biological oxidation unit of both WWTPs exhibited a greater proportion of ARGs among all sampled points, indicating the potential proliferation of ARGs within the biomass of the treatment units. ARG degradation experiments showed that OMB treatment resulted in a significantly lower CT value (9.3 mg O3 L−1 min) compared to ozone coarse bubble treatment (102 mg O3 L−1 min) under identical test conditions. Moreover, the use of OMB on site significantly reduced the accumulation of ARGs in hospital wastewater, underscoring its potential as an effective solution for mitigating ARG spread.
Smoking cessation interventions and implementations across multiple settings in Japan: a scoping review and supplemental survey
Authors: Nagasawa Tomomi , Saito Junko , Odawara Miyuki , Kaji Yuki , Yuwaki Keiichi , Imamura Haruhiko , Nogi Kazuya , Nakamura Masakazu , Shimazu Taichi
Published: November 2023

Background

Smoking is the leading risk factor for death worldwide. In Japan, although several evidence-based interventions (EBIs) for smoking cessation have been disseminated or adopted, there is a gap between scientific evidence and the actual implementation. This scoping review aimed to describe the knowledge gaps in local-level smoking cessation interventions in Japan, their implementation outcomes, implementation barriers and facilitators, and the use of implementation strategies.

Methods

This study comprised two approaches: (1) a comprehensive scoping review of primary and grey literature, and (2) a supplemental survey of organizations in the grey literature. For the scoping review, we included original studies or reports on smoking cessation interventions targeting adults aged 18 years and older, or providers of cessation support at various settings (community, workplace, school, and clinical settings) in Japan. The extracted data included basic characteristics, intervention categories, implementation outcomes, factors influencing implementation, and implementation strategies for each intervention. Responses to the supplemental survey were extracted same used for the scoping review. To gain a deeper understanding, semi-structured interviews were conducted with some of the organizations in the survey.

Results

A total of 600 interventions with 691 intervention components, based on EBIs in the 2020 US Surgeon General Report, from 498 articles were included in the data extraction; 32 of the 88 organizations responded to the survey. Regarding the overall knowledge about smoking cessation intervention components, behavioral counseling, and cessation medication in clinical settings were mostly reported (34.7%). Implementation outcomes were measured in 18 articles (3.0%) and penetration was mostly reported. Regarding influential factors, “available resources,” and “knowledge and beliefs about the intervention” for barriers, and “relative priority” for facilitators were mostly reported. Implementation strategies were measured in 29 articles (4.8%), and “Train and educate stakeholders” was mostly reported.

Conclusions

Most EBIs reported in the Japanese literature included smoking cessation treatments in clinical settings. While a few articles focused on the implementation indicators in Japan, significant knowledge and experience were extracted from the grey literature, especially in the workplace and community settings. Future research should focus more on implementation to reduce the knowledge gap regarding smoking cessation interventions.
Could We Have Improved on ADAURA? Refining Global Research Practices to Reduce Cancer Care Disparities
Authors: West Howard (Jack) , Akhade Amol , Gyawali Bishal
Published: November 2023

ADAURA was a positive trial, but could changes have improved it and reduced global care disparities?
Elaheh Kheirandish. Baghdad and Isfahan: A Dialogue of Two Cities in an Age of Science ca
Authors: Aydın Sena
Published: November 2023

Elaheh Kheirandish. Baghdad and Isfahan: A Dialogue of Two Cities in an Age of Science ca kitabının değerlendirmesi.
Dag Nikolaus Hasse & Amos Bertolacci (eds.). The Arabic, Hebrew and Latin Reception of Avicenna’s Metaphysics
Authors: Arslan M. Fatih
Published: November 2023

Dag Nikolaus Hasse & Amos Bertolacci (eds.). The Arabic, Hebrew and Latin Reception
of Avicenna’s Metaphysics. Scientia Graeco-Arabica, Bd 7. Berlin; Boston: De Gruyter,
2012. viii + 398 sayfa. ISBN 9783110215755
Çağmînî’nin Gezegen ve Yıldız Cisimlerinin Hacimleri Üzerine Yazdığı Kısa Risale: Editio princeps ve Çeviri
Authors: Ragep Sally P.
Published: November 2023

Bu makale, Mahmûd el-Çağmînî’ye (etkin olduğu dönem 600/1200 civarı) atfedilen, gök cisimlerinin hacim- lerini ele alan ve kendisinin Batlamyusçu teorik astronomiye giriş niteliğindeki el-Mulahhas’ına bir ek olmasını amaçlamış olabileceği kısa risalesini incelemekte ve Arapça tahkikli metniyle tercümesini sunmaktadır. Risale, me- safeler bahsine değinmeksizin gökcisimlerinin büyüklüklerine odaklanmaktadır. Eser, Güneş’in üstünde ve altında yer alan gök cisimleri, Dünya’ya kıyasla bu cisimlerin yaklaşık hacimleri, bu cisimlerin hacimlerine göre azalan sı- rayla büyüklükleri ve her birinin kübik fersah (cubic fersah) –bu, Dünya’nın hacmi ve her cisim için belirtilen göreli hacim için türetilmiş fersah değerine dayalı matematiksel bir hesap birimidir– cinsinden ölçülen cisim büyüklükleri gibi muhtelif bilgileri içerir. Bu çalışma için başvurulan nüshalarda herhangi bir kaynak belirtilmemektedir. Fakat Çağmînî’nin -on üçüncü yüzyılda hem Almagest hem de Gezegen Hipotezleri’inin ulaşılabilir olmasına rağmen- tadil edilmiş Batlamyusçu değerleri tercih ettiği aşikardır. Çağmînî’nin aracı kaynaklardaki verileri orijinal Batlamyus değerleri olarak kabul edip etmediği ise belirsizdir. Tahkik için kullanılan dört nüshadan üçü, ölçümle ilgili olan ve Sinan Paşa’nın Kadızâde’nin el-Mulahhas şerhine yazdığı haşiyeden iktibas edilmiş kısa bir ek bölümü içermektedir.