bluuebunny/crossref_metadata_2025 huggingface dataset:
Virology and safety profile of Molnupiravir at three different doses for treatment of SARS‐CoV‐2: a systematic review and meta‐analysis
Authors: Sukaina Mahnoor , Shuja Syed Hasan , Rehan Syeda Tayyaba , Ochani Sidhant , Sheryar Muhammad
Published: January 2024

Molnupiravir is incorporated into the viral genome, thereby increasing errors, mismatching, and misdirecting the viral polymerase thereby, halting viral RNA replication of SARS‐CoV‐2. Following PRISMA guidelines, a thorough literature search was performed on electronic and medical databases from December 2022 till January 2023. Molnupiravir 800 mg showed significance in creating viral RNA error rate at Day 5 (WMD: 4.91; 95% CI; [1.19, 8.63] p = 0.01; I2 = 0%). Similarly, at 400 mg, Molnupiravir creates an RNA error rate (WMD: 2.27; 95% CI; 2.27 [0.50, 4.65] p = 0.02; I2 = 0%). Furthermore, exhibit a significant outcome for mean change in SARS‐CoV‐2 RNA viral load from baseline in nasopharyngeal sample at 800 mg Molnupiravir on Day 3 (WMD: −0.22; 95% CI; [−0.35, −0.08] p = 0.002; I2 = 0%), Day 5 (WMD: −0.32; 95% CI; [−0.53, −0.11] p = 0.003; I2 = 24%) and overall pooled analysis (WMD: −0.17; 95% CI; [−0.29, 0.33] p = 0.003; I2 = 32%). Moreover, Molnupiravir 400 mg significantly reduced the incidence of death compared to the placebo group (RR: 0.17; 95% CI; [0.07, 0.43] p = 0.0002; I2 = 0%). Molnupiravir effectively treats SARS‐CoV‐2 patients by eliminating the virus from the host.
ECB monetary policy communication events: Do they move euro area yields?
Authors: Jurkšas Linas , Kaminskas Rokas , Vasiliauskaitė Deimantė
Published: January 2024

This study aims to determine and compare the impact of four different types of European Central Bank (ECB) monetary policy communication events on euro area sovereign yields on an intraday basis since 2014. Our paper distinguishes it from similar studies in that we analyze a broad range of ECB communication types. The results reveal that ECB decisions and press conferences have the most substantial intraday impact on normalized sovereign yields while the impact of speeches and accounts appears to be much weaker. Countries with the highest debt levels (such as Italy, Spain, and France) experienced the most robust changes in fiscal costs, while the period encompassing the economic shock induced by the Covid‐19 pandemic shows weaker effects.
Genome‐wide loss‐of‐function genetic screen identifies INSIG2 as the vulnerability of hepatitis B virus‐integrated hepatoma cells
Authors: Fukuoka Makoto , Kodama Takahiro , Murai Kazuhiro , Hikita Hayato , Sometani Emi , Sung Jihyun , Shimoda Akiyoshi , Shigeno Satoshi , Motooka Daisuke , Nishio Akira , Furuta Kunimaro , Tatsumi Tomohide , Yusa Kosuke , Takehara Tetsuo
Published: January 2024

There are approximately 250 million people chronically infected with hepatitis B virus (HBV) worldwide. Although HBV is often integrated into the host genome and promotes hepatocarcinogenesis, vulnerability of HBV integration in liver cancer cells has not been clarified. The aim of our study is to identify vulnerability factors for HBV‐associated hepatocarcinoma. Loss‐of‐function screening was undertaken in HepG2 and HBV‐integrated HepG2.2.15 cells expressing SpCas9 using a pooled genome‐wide clustered regularly interspaced short palindromic repeats (CRISPR) library. Genes whose guide RNA (gRNA) abundance significantly decreased in HepG2.2.15 cells but not in HepG2 cells were extracted using the MAGeCK algorithm. We identified four genes (BCL2L1, VPS37A, INSIG2, and CFLAR) that showed significant reductions of gRNA abundance and thus potentially involved in the vulnerability of HBV‐integrated cancer cells. Among them, siRNA‐mediated mRNA inhibition or CRISPR‐mediated genetic deletion of INSIG2 significantly impaired cell proliferation in HepG2.2.15 cells but not in HepG2 cells. Its inhibitory effect was alleviated by cotransfection of siRNAs targeting HBV. INSIG2 inhibition suppressed the pathways related to cell cycle and DNA replication, downregulated cyclin‐dependent kinase 2 (CDK2) levels, and delayed the G1‐to‐S transition in HepG2.2.15 cells. CDK2 inhibitor suppressed cell cycle progression in HepG2.2.15 cells and INSIG2 inhibition did not suppress cell proliferation in the presence of CDK2 inhibitor. In conclusion, INSIG2 inhibition induced cell cycle arrest in HBV‐integrated hepatoma cells in a CDK2‐dependent manner, and thus INSIG2 might be a vulnerability factor for HBV‐associated liver cancer.
Regulator of G protein signaling 1 is a potential target in gastric cancer and impacts tumor‐associated macrophages
Authors: Wu Mengting , Xu Xuefei , Yang Chuqi , An Qingwen , Zhang Jingcheng , Zhao Zhengqi , Feng Yewen , Liang Weiyu , Fu Yufei , Zhang Guangji , Jiang Tao
Published: January 2024

Regulator of G protein signaling 1 (RGS1) is closely associated with the tumor immune microenvironment and is highly expressed in various tumors and immune cells. The specific effects of RGS1 in the dynamic progression from chronic gastritis to gastric cancer have not been reported, and the role of tumor‐associated macrophages (TAMs) is also unclear. In the present study, RGS1 was identified as an upregulated gene in different pathological stages ranging from chronic gastritis to gastric cancer by using Gene Expression Omnibus (GEO) screening together with pancancer analysis of The Cancer Genome Atlas and clinical prognostic analysis. The results indicated that RGS1 is highly expressed in gastric cancer and has potential prognostic value. We confirmed through in vivo experiments that RGS1 inhibited the proliferation of gastric cancer cells and promoted apoptosis, which was further corroborated by in vitro experiments. Additionally, RGS1 influenced cell migration and invasion. In our subsequent investigation of RGS1, we discovered its role in the immune response. Through analyses of single‐cell and GEO database data, we confirmed its involvement in immune cell regulation, specifically TAM activation. Subsequently, we conducted in vivo and in vitro experiments to confirm the involvement of RGS1 in polarizing M1 macrophages while indirectly regulating M2 macrophages through tumor cells. In conclusion, RGS1 could be a potential target for the transformation of chronic gastritis into gastric cancer and has a measurable impact on TAMs, which warrants further in‐depth research.
Durvalumab after chemoradiotherapy in non‐small cell lung cancer with EGFR mutation: A real‐world study (HOT2101)
Authors: Tsuji Kosuke , Mizugaki Hidenori , Yokoo Keiki , Kobayashi Maki , Kawashima Yosuke , Kimura Nozomu , Yokouchi Hiroshi , Kikuchi Hajime , Sumi Toshiyuki , Kawai Yasutaka , Kobashi Kenta , Morita Ryo , Ito Kenichiro , Kitamura Yasuo , Minemura Hiroyuki , Nakamura Keiichi , Aso Mari , Honjo Osamu , Tanaka Hisashi , Takashina Taichi , Tsurumi Kyoji , Sugisaka Jun , Tsukita Yoko , Konno Satoshi , Oizumi Satoshi
Published: January 2024

Durvalumab has been administered to patients with unresectable stage III non‐small cell lung cancer (NSCLC). However, it remains unclear whether durvalumab benefits these patients with epidermal growth factor receptor (EGFR) mutation. We conducted a retrospective, multicenter study of patients with EGFR mutation who received chemoradiotherapy (CRT) between June 2018 and March 2021. We assessed patient characteristics, efficacy of durvalumab, and durvalumab safety before and after targeted therapy. We collected data on a total of 673 patients, of whom 401 (59.6%) underwent EGFR mutation testing. Fifty‐one patients were EGFR positive and 311 were EGFR negative. In the EGFR‐positive group, there were higher proportions of females, never‐smokers, and patients with adenocarcinoma histology. Of the 51 patients in the positive group and 311 in the negative group who received CRT, 45 (88.2%) and 247 (79.4%) received durvalumab, with median progression‐free survival of 23.0 and 24.2 months in the positive and negative groups, respectively (hazard ratio 1.03; 95% confidence interval: 0.64–1.67). The main adverse event was pneumonitis (positive group: 62.2%; 4.4% grade 3; negative group: 62.3%; 6.9% grade 3). No treatment‐related deaths were observed. Of the 45 patients in the positive group who received durvalumab, 14 (31.1%) received targeted therapy after durvalumab at the data cutoff. One patient discontinued targeted therapy after developing pneumonitis. In patients with unresectable stage III NSCLC with EGFR mutation, durvalumab after CRT is potentially safe and effective. This may be a suitable treatment sequence for these patients.
An engineered Accum‐E7 protein‐based vaccine with dual anti‐cervical cancer activity
Authors: Bikorimana Jean‐Pierre , Abusarah Jamilah , Gonçalves Marina , Farah Roudy , Saad Wael , Talbot Sebastien , Stanga Daniela , Beaudoin Simon , Plouffe Sebastien , Rafei Moutih
Published: January 2024

Worldwide prevalence of cervical cancer decreased significantly with the use of human papilloma virus (HPV)‐targeted prophylactic vaccines. However, these multivalent antiviral vaccines are inert against established tumors, which leave patients with surgical ablative options possibly resulting in long‐term reproductive complications and morbidity. In an attempt to bypass this unmet medical need, we designed a new E7 protein‐based vaccine formulation using Accum™, a technology platform designed to promote endosome‐to‐cytosol escape as a means to enhance protein accumulation in target cells. Prophylactic vaccination of immunocompetent mice using the Accum‐E7 vaccine (aE7) leads to complete protection from cervical cancer despite multiple challenges conducted with ascending C3.43 cellular doses (0.5‐, 1.0‐, and 2.0 × 106 cells). Moreover, the humoral response induced by aE7 was higher in magnitude compared with naked E7 protein vaccination and displayed potent inhibitory effects on C3.43 proliferation in vitro. When administered therapeutically to animals with pre‐established C3.43 or Tal3 tumors, the vaccine‐induced response synergized with multiple immune checkpoint blockers (anti‐PD‐1, anti‐CTLA4, and anti‐CD47) to effectively control tumor growth. Mechanistically, the observed therapeutic effect requires cross‐presenting dendritic cells as well as CD8 T cells predominantly, with a non‐negligible role played by both CD4+ and CD19+ lymphocytes. good laboratory practice (GLP) studies revealed that aE7 is immunogenic and well tolerated by immunocompetent mice with no observed adverse effects despite the use of a fourfold exceeding dose. In a nutshell, aE7 represents an ideal vaccine candidate for further clinical development as it uses a single engineered protein capable of exhibiting both prophylactic and therapeutic activity.
Synthesis, molecular docking, QSTR and in‐silico ADME studies of novel 1,3‐thiazolidine‐amide derivatives as hybrid bioactive heterocycles
Authors: Pund Amit A. , Pansare Dattatraya N. , Sarkate Aniket P. , Deshpande Prathmesh P. , Magare Baban K.
Published: January 2024

In this article, we described synthesis of 1,3‐thiazolidine ‐ amide hybrid derivatives by two different methods from (S)‐2‐amino‐3‐(4‐(benzyloxy)phenyl)‐1‐(thiazolidin‐3‐yl)propan‐1‐one (4). In first method, catalytic amidation was carried out under microwave irradiation using Ceric Ammonium Nitrate (CAN) as a green catalyst where as in second conventional method; CDI was used as a significant coupling reagent to optimize reaction condition and yield of product. All new compounds were well characterized by 1H NMR, 13C NMR, IR and ESMS spectral techniques and evaluated in vitro antibacterial and antifungal activity. The molecular docking study revealed that the designed compounds snuggly fit in the active site of 4WMZ protein. In addition, the QSTR study of new compounds were carried out with the help of Toxicity Estimation Software Tool (T.E.S.T). The results showed slight toxic nature of new compounds. In‐silico ADME studies significant values of pharmacokinetic parameters and demonstrated good drug like characteristics based on Lipinski's rule of five.
Crocin enhances the sensitivity to paclitaxel in human breast cancer cells by reducing BIRC5 expression
Authors: Jia Yunhao , Yang Han , Yu Jinsong , Li Zhong , Jia Guangwei , Ding Bo
Published: January 2024

Paclitaxel (PTX) is one of the first‐line chemotherapeutic agents for treating breast cancer. However, PTX resistance remains a major hurdle in breast cancer therapy. Crocin, the main chemical constituent of saffron, shows anti‐cancer activity against various types of cancer. However, the effect of crocin on the resistance of PTX in breast cancer is still unknown. CCK‐8 and TUNEL assays were employed to detect cell viability and apoptosis, respectively. The targets of crocin were predicted using HERB database and the targets associated with breast cancer were acquired using GEPIA database. The Venn diagram was utilized to identify the common targets between crocin and breast cancer. Baculoviral inhibitor of apoptosis repeat containing 5 (BIRC5) expression was detected by qRT‐PCR and western blot analysis. The correlation between BIRC5 expression and survival was analyzed by Kaplan–Meier plotter and PrognoScan databases. Our data suggested that crocin aggravated PTX‐induced decrease of viability and increase of apoptosis in MCF‐7 and MCF‐7/PTX cells. BIRC5 was identified as the target of crocin against breast cancer. Crocin inhibited BIRC5 expression in MCF‐7 and MCF‐7/PTX cells. BIRC5 is overexpressed in breast cancer tissues, as well as PTX‐sensitive and PTX‐resistant breast cancer cells. BIRC5 expression is related to the poor survival of patients with breast cancer. Depletion of BIRC5 strengthened PTX‐induced viability reduction and promotion of apoptosis in MCF‐7 and MCF‐7/PTX cells. Moreover, BIRC5 overexpression reversed the inhibitory effect of crocin on PTX resistance in breast cancer cells. In conclusion, crocin enhanced the sensitivity of PTX in breast cancer cells partially through inhibiting BIRC5 expression.
Advancing the implementation of take‐home naloxone by community pharmacists: Testing the role of COM‐B
Authors: Moullin Joanna C. , Staniland Lexy , Uren Hannah , Nielsen Suzanne , Lenton Simon
Published: January 2024

Introduction

Opioid‐related overdose fatalities are rising despite the increased accessibility of take‐home naloxone (THN). Targeted implementation strategies are needed to improve the distribution of naloxone. This study investigates the effectiveness of a short video targeting pharmacists that addresses implementation barriers.

Methods

A pre‐post, mixed methods design was adopted to examine the effect of a brief behaviour change intervention (an educational video informed by the capability, opportunity, motivation affecting behaviour (COM‐B) model), on factors affecting pharmacists’ implementation of THN in Western Australia. Paired samples t‐tests for were used to investigate intentions, knowledge, skill, confidence, feasibility, appropriateness, acceptability, attitudes, anticipated patient reactions, social support and implementation climate. Structural equation modelling examined the associations between constructs and to test the proposed mediation of motivation on capability and opportunity affecting intentions to discuss and provide THN.

Results

We analysed data from 102 participants. At follow‐up and after all participants had viewed the video, participants had significantly improved intentions, skill, confidence, anticipated reactions, social support and perceptions that THN implementation was feasible, appropriate and acceptable. No significant differences were seen for attitudes, knowledge or implementation climate. The proposed mediation effect of motivation on the associations between opportunity and intentions and capability and intentions was not supported.

Discussion and Conclusions

A short video directly targeting identified implementation barriers has the ability to improve key influences in the provision of THN. Dissemination of information to community pharmacists is a challenge. Implementation strategies addressing knowledge and targeting other levels of influence on intentions and behaviour are required.
Safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of Exendin‐4‐IgG4‐Fc in healthy subjects: A phase 1, single‐centre, randomized, double‐blind, dose escalation study
Authors: Chen Gui‐Ling , Liu Yang , Gao Xue‐Feng , Wu Kai‐Qi , Yang Yun‐Kai , Chen Yong , Peng Cong‐Gao , Jin Ting‐Han , Huang Yu‐Bao , Zhang Yao‐Wen , Su Jing , Jiang Qi , Guo Tong , Zhao Jie , Peng Xiang‐Nan , Peng Jing‐Yu , Li Si‐Xiu , Sun Yong‐Li , Zhang Hong‐Mei , Fu Yan‐Li , Luo Dan , Ma Yaru , Shen Zhen‐Wei , Zhang Yun‐Tao , Shou Zhang‐Fei
Published: January 2024

Aim

Novel long‐acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin‐4‐IgG4‐Fc (E4F4) is a long‐acting glucagon‐like peptide‐1 receptor agonist. This first‐in‐human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects.

Methods

This single‐centre, randomized, double‐blind, placebo‐controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level.

Results

E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose‐dependent relationship between frequency, severity or causality of treatment‐emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45‐14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose‐dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose‐response relationship in the 1.8‐10.35 mg dose range, with an increased response at the higher doses.

Conclusion

E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5‐10.35 mg once every 2 weeks.
International comovements of public debt
Authors: Isomitdinov Hasan , Arčabić Vladimir , Lee Junsoo , Yun Youngjin , Payne James E.
Published: January 2024

This study presents evidence of global and regional comovements in public debt and examines their trends and features. We employ a Bayesian dynamic factor model with time‐varying parameters based on the debt‐to‐GDP ratio of 115 countries. We find the global factor accounts for 38 percent of the total variation in the debt ratio worldwide, but its share decreases over time. Countries with more financial openness and a greater share of external public debt are more exposed to global/regional comovements. The assertion that international financial integration encourages higher government borrowing applies primarily to high‐income countries and it does not hold globally.
Exam evaluation in prosthodontics across preclinical and clinical years from students' perspective: A cross‐sectional study
Authors: Alamoush Rasha A. , Sartawi Samiha , Salim Nesreen A. , Sawair Faleh , Haider Julfikar , Jamani Kifah
Published: January 2024

Introduction

The purpose of this study was to explore the students' perceptions and performance in prosthodontics theory exam.

Methods

A cross‐sectional descriptive study was conducted on 560 (80.82%) students of different levels (third, fourth and fifth years) to explore their opinions and performance with regard to a number of issues on a prosthodontics theory exam (exam evaluation, exam preparation, exam material, exam timing). Demographic data were also collected. Descriptive statistics were generated and Chi‐square test, independent samplet‐test, ANOVA test and Pearson's correlation coefficient were used to examine the associations between different variables. The significance level was set atp < .05.

Results

Students' responses regarding exam evaluation was influenced by their gender, study level, high‐school Grade Point Average (GPA) and undergraduate cumulative GPA. Perceived exam difficulty was significantly affected by gender (p = .03) and study level (p < .001), and negatively correlated to both high‐school GPA (p < .001) and university GPA (p = .03). The vast majority (88.2%) depended on lecture hand‐outs and lecture notes for study. Exam material and preparation were not significantly affected by any of the demographic variables with most respondents (76.8%) thinking that the lectures blended with prosthodontics laboratories/clinics would improve their understanding of the exam material. The suggested best time to conduct the exam was early afternoon (31.6%). Student performance was significantly affected by the study level (p < .001) and cumulative GPA (p < .001) with significant positive correlation between the high‐school GPA and the mark in the exam (r = .29,p < .001) and by the amount of time students spent for exam preparation (p < .001). Those students who reported using textbooks to prepare for the exam got significantly higher marks (66.1 ± 8.7) compared to the students who did not (62.8 ± 9.7) (p = .03).

Conclusions

Course level, GPA and gender were identified as the most influential factors in different aspects of exam evaluation and students' performance. Regular study and use of textbooks were demonstrated to improve academic performance. Additional orientation and guidance relating to the exam (especially for third year students) would be welcomed, as would alternate teaching methods such as small group discussions or study groups.
Expected Classification Accuracy for Categorical Growth Models
Authors: Murphy Daniel , Quesen Sarah , Brunetti Matthew , Love Quintin
Published: January 2024

Categorical growth models describe examinee growth in terms of performance‐level category transitions, which implies that some percentage of examinees will be misclassified. This paper introduces a new procedure for estimating the classification accuracy of categorical growth models, based on Rudner's classification accuracy index for item response theory–based assessments. Results of a simulation study are presented to provide evidence for the accuracy and validity of the approach. Also, an empirical example is presented to demonstrate the approach using data from the Indiana Student Performance Readiness and Observation of Understanding Tool growth model, which classifies examinees into growth categories used by the Office of Special Education Programs to monitor the progress of preschool children who receive special education services.
Large analysis of genetic manipulations reveals an inverse correlation between initial alcohol resistance and rapid tolerance phenotypes
Authors: Chvilicek Maggie M. , Seguin Alexandra , Lathen Daniel R. , Titos Iris , Cummins‐Beebee Pearl N. , Pabon Miguel A. , Miščević Maša , Nickel Emily , Merrill Collin B. , Rodan Aylin R. , Rothenfluh Adrian
Published: January 2024

Tolerance occurs when, following an initial experience with a substance, more of the substance is required subsequently to induce identical behavioral effects. Tolerance is not well‐understood, and numerous researchers have turned to model organisms, particularly Drosophila melanogaster, to unravel its mechanisms. Flies have high translational relevance for human alcohol responses, and there is substantial overlap in disease‐causing genes between flies and humans, including those associated with Alcohol Use Disorder. Numerous Drosophila tolerance mutants have been described; however, approaches used to identify and characterize these mutants have varied across time and labs and have mostly disregarded any impact of initial resistance/sensitivity to ethanol on subsequent tolerance development. Here, we analyzed our own, as well as data published by other labs to uncover an inverse correlation between initial ethanol resistance and tolerance phenotypes. This inverse correlation suggests that initial resistance phenotypes can explain many ‘perceived’ tolerance phenotypes, thus classifying such mutants as ‘secondary’ tolerance mutants. Additionally, we show that tolerance should be measured as a relative increase in time to sedation between an initial and second exposure rather than an absolute change in time to sedation. Finally, based on our analysis, we provide a method for using a linear regression equation to assess the residuals of potential tolerance mutants. These residuals provide predictive insight into the likelihood of a mutant being a ‘primary’ tolerance mutant, where a tolerance phenotype is not solely a consequence of initial resistance, and we offer a framework for understanding the relationship between initial resistance and tolerance.
Regulation of headache response and transcriptomic network by the trigeminal ganglion clock
Authors: Han Chorong , Lim Ji Ye , Koike Nobuya , Kim Sun Young , Ono Kaori , Tran Celia K. , Mangutov Elizaveta , Kim Eunju , Zhang Yanping , Li Lingyong , Pradhan Amynah A. , Yagita Kazuhiro , Chen Zheng , Yoo Seung‐Hee , Burish Mark J.
Published: January 2024

Objective

To characterize the circadian features of the trigeminal ganglion in a mouse model of headache.

Background

Several headache disorders, such as migraine and cluster headache, are known to exhibit distinct circadian rhythms of attacks. The circadian basis for these rhythmic pain responses, however, remains poorly understood.

Methods

We examined trigeminal ganglion ex vivo and single‐cell cultures from Per2::LucSV reporter mice and performed immunohistochemistry. Circadian behavior and transcriptomics were investigated using a novel combination of trigeminovascular and circadian models: a nitroglycerin mouse headache model with mechanical thresholds measured every 6 h, and trigeminal ganglion RNA sequencing measured every 4 h for 24 h. Finally, we performed pharmacogenomic analysis of gene targets for migraine, cluster headache, and trigeminal neuralgia treatments as well as trigeminal ganglion neuropeptides; this information was cross‐referenced with our cycling genes from RNA sequencing data to identify potential targets for chronotherapy.

Results

The trigeminal ganglion demonstrates strong circadian rhythms in both ex vivo and single‐cell cultures, with core circadian proteins found in both neuronal and non‐neuronal cells. Using our novel behavioral model, we showed that nitroglycerin‐treated mice display circadian rhythms of pain sensitivity which were abolished in arrhythmic Per1/2 double knockout mice. Furthermore, RNA‐sequencing analysis of the trigeminal ganglion revealed 466 genes that displayed circadian oscillations in the control group, including core clock genes and clock‐regulated pain neurotransmitters. In the nitroglycerin group, we observed a profound circadian reprogramming of gene expression, as 331 of circadian genes in the control group lost rhythm and another 584 genes gained rhythm. Finally, pharmacogenetics analysis identified 10 genes in our trigeminal ganglion circadian transcriptome that encode target proteins of current medications used to treat migraine, cluster headache, or trigeminal neuralgia.

Conclusion

Our study unveiled robust circadian rhythms in the trigeminal ganglion at the behavioral, transcriptomic, and pharmacogenetic levels. These results support a fundamental role of the clock in pain pathophysiology.

Plain Language Summary

Several headache diseases, such as migraine and cluster headache, have headaches that occur at the same time each day. We learned that the trigeminal ganglion, an important pain structure in several headache diseases, has a 24‐hour cycle that might be related to this daily cycle of headaches. Our genetic analysis suggests that some medications may be more effective in treating migraine and cluster headache when taken at specific times of the day.
Deep‐learning model to improve histological grading and predict upstaging of atypical ductal hyperplasia / ductal carcinoma in situ on breast biopsy
Authors: Huang Chung‐Yen , Chang Ruey‐Feng , Lin Chih‐Yung , Hsieh Min‐Shu , Liao Po‐Chun , Wang Yu‐Jui , Kao Yu‐Chien , Porta Lorenzo , Lin Pin‐Yu , Lee Chien‐Chang , Lee Yi‐Hsuan
Published: January 2024

Aims

Risk stratification of atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS), diagnosed using breast biopsy, has great clinical significance. Clinical trials are currently exploring the possibility of active surveillance for low‐risk lesions, whereas axillary lymph node staging may be considered during surgical planning for high‐risk lesions. We aimed to develop a machine‐learning algorithm based on whole‐slide images of breast biopsy specimens and clinical information to predict the risk of upstaging to invasive breast cancer after wide excision.

Methods and Results

Patients diagnosed with ADH/DCIS on breast biopsy were included in this study, comprising 592 (740 slides) and 141 (198 slides) patients in the development and independent testing cohorts, respectively. Histological grading of the lesions was independently evaluated by two pathologists. Clinical information, including biopsy method, lesion size, and Breast Imaging Reporting and Data System (BI‐RADS) classification of ultrasound and mammograms, were collected. Deep DCIS consisted of three deep neural networks to evaluate nuclear grade, necrosis, and stromal reactivity. Deep DCIS output comprised five parameters: total patches, lesion extent, Deep Grade, Deep Necrosis, and Deep Stroma. Deep DCIS highly correlated with the pathologists' evaluations of both slide‐ and patient‐level labels. All five parameters of Deep DCIS were significantly associated with upstaging to invasive carcinoma in subsequent wide excisional specimens. Using multivariate logistic regression, Deep DCIS predicted upstaging to invasive carcinoma with an area under the curve (AUC) of 0.81, outperforming pathologists' evaluation (AUC, 0.71 and 0.69). After including clinical and hormone receptor status information, performance further improved (AUC, 0.87). This combined model retained its predictive power in two subgroup analyses: the first subgroup included unequivocal DCIS (excluding cases of ADH and DCIS suspicious for microinvasion) (AUC, 0.83), while the second excluded cases of high‐grade DCIS (AUC, 0.81). The model was validated in an independent testing cohort (AUC, 0.81).

Conclusion

This study demonstrated that deep‐learning models can refine histological evaluation of ADH and DCIS on breast biopsies, which may help guide future treatment planning.
Species status and phylogenetic relationships of the enigmatic Negros Fruit Dove (Ptilinopus arcanus)
Authors: Nash John A. , Harrington Richard C. , Zyskowski Kristof , Near Thomas J. , Prum Richard O.
Published: January 2024

The Negros Fruit Dove Ptilinopus arcanus is an enigmatic bird known only from a single specimen collected on Negros Island, Philippines, in 1953. We extracted and sequenced ultra‐conserved elements from historical toe‐pad samples of the type specimen of P. arcanus and 27 other species of ptilinopine doves to investigate the species status and phylogenetic relationships of this taxon. We establish that P. arcanus represents a valid species, resolve its phylogenetic position at the base of the radiation of ‘core’ Ptilinopus fruit doves, and estimate that P. arcanus diverged from its most recent common ancestor several million years before Negros Island emerged from the seafloor. We also perform an ancestral range reconstruction to evaluate the effect of different altitudinal preferences on the putative historical range of this species, and we discuss how these findings can inform future efforts to relocate and potentially conserve this species.
Characterization of the MT‐2 Treg‐like cell line in the presence and absence of forkhead box P3 (FOXP3)
Authors: McCullough Morgan J , Tune Miriya K , Cabrera Johnny Castillo , Torres‐Castillo Jose , He Minghong , Feng Yongqiang , Doerschuk Claire M , Dang Hong , Beltran Adriana S , Hagan Robert S , Mock Jason R
Published: January 2024

CD4+ forkhead box P3 (FOXP3)+ regulatory T cells (Tregs) are essential in maintaining immune tolerance and suppressing excessive immune responses. Tregs also contribute to tissue repair processes distinct from their roles in immune suppression. For these reasons, Tregs are candidates for targeted therapies for inflammatory and autoimmune diseases, and in diseases where tissue damage occurs. MT‐2 cells, an immortalized Treg‐like cell line, offer a model to study Treg biology and their therapeutic potential. In the present study, we use clustered regularly interspaced palindromic repeats (CRISPR)‐mediated knockdown of FOXP3 in MT‐2 cells to understand the transcriptional and functional changes that occur when FOXP3 is lost and to compare MT‐2 cells with primary human Tregs. We demonstrate that loss of FOXP3 affects the transcriptome of MT‐2 cells and that FOXP3's potential downstream targets include a wide range of transcripts that participate in the cell cycle, promote growth and contribute to inflammatory processes, but do not wholly simulate previously reported human primary Treg transcriptional changes in the absence of FOXP3. We also demonstrate that FOXP3 regulates cell cycling and proliferation, expression of molecules crucial to Treg function and MT‐2 cell–suppressive activities. Thus, MT‐2 cells offer opportunities to address regulatory T‐cell functions in vitro.
Seasonal variation in risk and return trade‐off
Authors: Lee Deok‐Hyeon , Min Byoung‐Kyu
Published: January 2024

Existing studies show that firms with large macroeconomic risk do not earn higher returns, incompatible with the theoretical predictions of standard economic models. Using a broad set of macro‐related factors, we find the January seasonality of the macroeconomic risk–return relation. Firms with high macro risk deliver higher returns than firms with low risk in January, that is, the positive risk–return trade‐off holds. Conversely, the negative risk–return relation is observed in non‐January months. The seasonal variation in the macro risk–return relation cannot be explained by existing January effects, including the tax‐loss selling, window dressing, and pronounced gambling preference around New Year.
Tax avoidance and debt maturity in SMEs
Authors: Sánchez‐Ballesta Juan Pedro , Yagüe José
Published: January 2024

We investigate how tax avoidance affects the maturity structure of debt in firms where tax avoidance costs are presumably low, namely SMEs. Previous research has shown that creditors of listed tax‐avoiding companies impose shorter maturities to more frequently reassess the tax avoidance risks in debt contracts. Using a sample of 110,690 firm‐year observations of Spanish SMEs over the period 2007–2020, we examine the relationship between tax avoidance and debt maturity and the channels driving this relationship. We find that tax‐avoiding SMEs show a longer debt maturity. This effect is stronger for SMEs with higher profitability, lower earnings management incentives, and higher reliability of financial reporting. We also find that tax avoidance reduces leverage and short‐term debt, increases future cash flows, and decreases future cash flow volatility. Overall, these findings suggest that, unlike large firms, SMEs use cash tax savings to reduce leverage and short‐term debt in their financial structure and that tax avoidance is positively valued by their lenders.
Efficacy and safety of novel topical pigment‐correcting regimen with biweekly diamond tip microdermabrasion procedures on facial hyperpigmentation
Authors: Goberdhan Lisa , Schneider Katie , Makino Elizabeth T. , Bautista Arielle , Mehta Rahul C.
Published: January 2024

Background

Facial hyperpigmentation can negatively affect an individual's emotional and psychosocial well‐being.

Aims

Assess safety and tolerability of a combination of microdermabrasion (DG) procedures using a novel brightening pro‐infusion serum (EC‐DG) with a targeted at‐home treatment regimen in subjects with mild to severe facial hyperpigmentation, including melasma, post‐inflammatory hyperpigmentation, and dark spots.

Patients/Methods

This 12‐week, open‐label study enrolled 18 subjects (Fitzpatrick skin types I–IV) who underwent 6 in‐office DG procedures with EC‐DG (one procedure administered biweekly), along with daily topical application of a brightening treatment serum and dark spot cream. End points included change from baseline across multiple skin quality attributes and the Melasma Area and Severity Index (MASI), self‐assessment questionnaires, and tolerability assessments.

Results

The combination treatment was well tolerated and resulted in significant (p ≤ 0.05) improvements from baseline in radiance, tactile roughness, and moisturization/hydration immediately after the first treatment, in MASI score at day 3, and in overall hyperpigmentation at week 4. Most (94.1%) subjects were satisfied with treatment.

Conclusions

DG procedures using EC‐DG combined with a targeted at‐home skincare regimen are effective and tolerable for treating facial hyperpigmentation across a broad range of skin types.
Here, There and Everywhere: On the Responsible Use of Artificial Intelligence (AI) in Management Research and the Peer‐Review Process
Authors: Gatrell Caroline , Muzio Daniel , Post Corinne , Wickert Christopher
Published: January 2024

This editorial introduces and explains the Journal of Management Studies’ (JMS) new policy on artificial intelligence (AI). We reflect on the use of AI in conducting research and generating journal submissions and what this means for the wider JMS community, including our authors, reviewers, editors, and readers. Specifically, we consider how AI‐generated research and text could both assist and augment the publication process, as well as harm it. Consequentially, our policy acknowledges the need for careful oversight regarding the use of AI to assist in the authoring of texts and in data analyses, while also noting the importance of requiring authors to be transparent about how, when and where they have utilized AI in their submissions or underlying research. Additionally, we examine how and in what ways AI's use may be antithetical to the spirit of a quality journal like JMS that values both human voice and research transparency. Our editorial explains why we require author teams to oversee all aspects of AI use within their projects, and to take personal responsibility for accuracy in all aspects of their research. We also explain our prohibition of AI's use in peer‐reviewers’ evaluations of submissions, and regarding editors’ handling of manuscripts.
Contribution of soil seed banks to vegetation resilience in coastal freshwater wetlands of subtropical Australia
Authors: Grieger Rebekah , Capon Samantha J. , Hadwen Wade L. , Mackey Brendan
Published: January 2024

Questions

What role do soil seed banks play in the resilience of coastal freshwater wetland vegetation communities? How might soil seed bank composition and similarity to standing vegetation drive changes in vegetation expression, particularly given projected changes in climate?

Location

Sixty wooded coastal freshwater wetlands in southeast Queensland, Australia.

Methods

We surveyed standing vegetation and investigated soil seed bank composition through an 8‐month‐long emergence experiment.

Results

Soil seed bank assemblages were dominated by forb and sedge species (23% exotic), but composition varied throughout the study region. Spatial (north–south) and land‐use (urban–rural) gradients explained some variation in soil seed bank composition. Soil moisture and groundwater dependence also influenced species distributions, particularly for freshwater wetland species. The similarity of soil seed banks to standing vegetation was low. Species present in both extant and soil seed bank assemblages were commonly native wetland taxa, including one salt marsh species (Juncus kraussii).

Conclusions

Projected climatic changes will likely drive changes in coastal freshwater wetland vegetation communities through increases in the frequency and intensity of disturbances (e.g., storm surge). Our results suggest that regeneration from soil seed banks could promote four potential scenarios: (1) expansion of weed communities, (2) expansion of salt marsh communities, (3) maintenance and expansion of wetland/terrestrial species, and (4) transformation to an unvegetated open water zone because of reduced regeneration success under changing conditions. These diverse vegetation futures highlight the vulnerability of wooded coastal freshwater wetlands and the need for research and management interventions to maintain their biodiversity and ecosystem services.
Tongue flicking heralds flight behaviour following passive antipredator displays in dice snakes
Authors: Bjelica V. , Anđelković M. , Maričić M. , Tomović L. , Bonnet X. , Golubović A.
Published: January 2024

When captured, many prey respond by biting the predator or struggling to get free. However, one indirect escape option is death feigning (DF), in which complete immobility supposedly “tricks” the predator into abandoning its meal. But lying motionless and exposed to a predator is dangerous; therefore, individuals should optimize DF occurrence and duration. We captured colour polymorphic dice snakes (Natrix tessellata, Natricidae) (N = 271) in the field and measured two behavioural responses: (1) the occurrence and duration of immobility/DF; (2) the number of tongue‐flicking sequences (TF). Tongue flicking is an essential component of a key sensory mechanism to check the safety of the environment before attempting escape. We experimentally assessed the relationship between these two behaviours and the effects of phenotypic characteristic of snakes on the occurrence and duration of immobility and of TF. Snake phenotype had multiple effects. Gravid females avoided DF and displayed more TF sequences during the tests compared to non‐gravid females and males. Blotched snakes stayed immobile longer than green and melanistic snakes. Larger individuals remained in DF for longer and showed fewer TF sequences than smaller individuals. Snakes burdened with a recent meal postponed fleeing and displayed more TF sequences than snakes without food. Finally, snakes showing more TF sequences postponed fleeing, which suggests that dice snakes assessed predatory risks and adapted escape behaviour to their risk status. Future studies should examine how individuals estimate the appropriate timing to shift from immobility to escape.
Deep spatial‐temporal embedding for vehicle trajectory validation and refinement
Authors: Zhang Tianya Terry , Jin Peter J. , Piccoli Benedetto , Sartipi Mina
Published: January 2024

High‐angle cameras are commonly used for trajectory data collection in transportation research. However, without refinement and validation, trajectory data obtained through video processing software may be unreliable, inaccurate, or incomplete. This paper focuses on a critical issue in the field of trajectory data acquisition and analysis—there is still no reliable and fully vetted trajectory dataset in the research community. The current practice for validating video‐based trajectory can be classified as indirect methods and direct methods. Indirect methods of trajectory validation use algorithms to efficiently correct data anomalies without human intervention but may overlook detailed driving behaviors, whereas direct methods involve meticulous manual verification to preserve data fidelity but are labor‐intensive and less scalable. The spatial‐temporal maps (STMaps) method offers an additional layer of verification to affirm the accuracy and reliability of trajectory data. To enhance the performance, the deep spatial‐temporal embedding model is proposed for trajectory instance segmentation on STMaps using the contrastive learning framework. The parity constraints at both pixel and instance levels guide the deep neural network to learn the embedding spaces that can be built on different backbone networks. The reconstructed Next Generation Simulation (NGSIM) highway dataset trajectory dataset is thoroughly validated against manually processed ground truth, and the error‐free NGSIM data are refined to be a reliable resource for transportation research based on car‐following behaviors, lane‐change frequency, consistency, and jerk value measurements.
Layers of Authority in Shāh Walī Allāh's Persian Interlinear Qur’ān Translation
Authors: Khan Nihal Ahmad
Published: January 2024

This article explores the genealogy of the Persian Qur’ān translation of the eighteenth‐century Indian scholar Shāh Walī Allāh (d. 1762/3). Firstly, I argue that this translation engendered a populist engagement with the Qur’ān, which allowed Walī Allāh to decentralize the interpretive agency of the Mughal scholarly class, all the while building his own authority. Including the Arabic text with the Persian translation allowed lay Muslims to recite the text, but with the new caveat of understanding it. Secondly, I argue that Walī Allāh's amalgamation between ‘under‐the‐line’ and ‘succinct summary’ models in his interlinear translation affirmed the inimitability doctrine. This is the belief that the Qur’ān is inherently defined as an Arabic text, in word and meaning. Thirdly, I argue that the inclusion of the Arabic text in this translation prevented the potential emergence of a hegemonic interpretation by a subversive political authority. The results of this hypothesis can be observed in relation to nineteenth‐century British efforts of translating Islamic law texts into English common law in India; and twentieth‐century attempts by secular nationalists in producing a Turkish‐only Qur’ān in modern Turkey. Walī Allāh's Qur’ān translation also carved a path for later Urdu and English Qur’ān translators to follow.
Comprehensive evaluation of patients with primary hyperoxaluria type 1: A nationwide study
Authors: Bakkaloğlu Sevcan A. , Büyükkaragöz Bahar , Pınarbaşı Ayşe Seda , Leventoğlu Emre , Saygılı Seha , Çomak Elif , Yıldırım Zeynep Y. , Akıncı Nurver , Dursun İsmail , Karabay Bayazıt Aysun , Kavaz Tufan Aslı , Akman Sema , Yılmaz Alev , Noyan Aytül , Ağbaş Ayşe , Serdaroğlu Erkin , Delibaş Ali , Elmacı Ahmet Midhat , Taşdemir Mehmet , Ezgü Fatih S. , Sever Lale
Published: January 2024

Background

Primary hyperoxaluria type 1 (PH1) is characterized by increased endogenous oxalate production and deposition as calcium oxalate crystals. The main manifestations are nephrocalcinosis/nephrolithiasis, causing impaired kidney function. We aimed to evaluate the clinical characteristics and overall outcomes of paediatric PH1 patients in Turkey.

Methods

This is a nationwide, multicentre, retrospective study evaluating all available paediatric PH1 patients from 15 different paediatric nephrology centres in Turkey. Detailed patient data was collected which included demographic, clinical and laboratory features. Patients were classified according to their age and characteristics at presentation: patients presenting in the first year of life with nephrocalcinosis/nephrolithiasis (infantile oxalosis, Group 1), cases with recurrent nephrolithiasis diagnosed during childhood (childhood‐onset PH1, Group 2), and asymptomatic children diagnosed with family screening (Group 3).

Results

Forty‐eight patients had a mutation consistent with PH1. The most common mutation was c.971_972delTG (25%). Infantile oxalosis patients had more advanced chronic kidney disease (CKD) or kidney failure necessitating dialysis (76.9% vs. 45.5%). These patients had much worse clinical course and mortality rates seemed to be higher (23.1% vs. 13.6%). Patients with fatal outcomes were the ones with significant comorbidities, especially with cardiovascular involvement. Patients in Group 3 were followed with better outcomes, with no kidney failure or mortality.

Conclusion

PH1 is not an isolated kidney disease but a systemic disease. Family screening helps to preserve kidney function and prevent systemic complications. Despite all efforts made with traditional treatment methods including transplantation, our results show devastating outcomes or mortality.

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