bluuebunny/crossref_metadata_2025 huggingface dataset:
A call-to-action: integrate a learning health system framework into longitudinal population studies to improve health response in Africa
Authors: Kadengye Damazo T , Kiragga Agnes N
Published: January 2024

Longitudinal population studies (LPSs) in Africa have the potential to become powerful engines of change by adopting a learning health system (LHS) framework. This is a call-to-action opinion and highlights the importance of integrating an LHS approach into LPSs, emphasizing their transformative potential to improve population health response, drive evidence-based decision making, and enhance community well-being. Operators of LPS platforms, community members, government officials, and funding agencies have a role to contribute to this transformative journey of driving evidence-based interventions, promoting health equity, and fostering long-term public health solutions for African communities.
Effects of betaine on growth performance and intestinal health of rabbits fed different digestible energy diets
Authors: Li Zimei , Pu Junning , Zeng Tingxuan , Cai Jingyi , Jia Gang , Zhao Hua , Liu Guangmang , Zeng Qiufeng , Luo Yuheng , Tian Gang
Published: January 2024

An experiment was conducted to determine the effects of betaine on growth performance and intestinal health in rabbits fed diets with different levels of digestible energy. During a 36-d experiment, a total of 144 healthy 35-d-old weaned New Zealand white rabbits with a similar initial body weight (771.05 ± 41.79 g) were randomly distributed to a 2 × 3 factorial arrangement. Experimental treatments consisted of two levels of digestible energy (normal: 10.20 and low: 9.60 MJ/kg) and three levels of betaine (0, 500, and 1,000 mg/kg). Results indicated that rabbits fed the diet with low digestible energy (LDE) had reduced body gain/feed intake on days 1 to 14 and 1 to 36 (P < 0.05), increased the apparent total tract digestibility (ATTD) of neutral detergent fiber, acid detergent fiber (ADF), and n-free extract, and decreased the ATTD of gross energy (GE), crude fiber, and organic matter (OM; P < 0.05). The LDE diet upregulated the gene abundance levels of duodenum junctional adhesion molecule-3 (JAM-3) and downregulated the ileum toll-like receptor 4, myeloid differentiation factor 88, and interleukin-6 (IL-6; P < 0.05). Activities of amylase, lipase, trypsin, and the immunoglobulin M content in the jejunum were decreased in the LDE treatment group (P < 0.05). Dietary betaine supplementation increased the ATTD of GE, dry matter (DM), ADF, and n-free extract by LDE (P < 0.05). The villus height, crypt depth, and goblet cell numbers were decreased, and the villus–crypt ratio was increased in the duodenum (P < 0.05). The gene abundance levels of duodenum IL-2 were downregulated, and the duodenum JAM-2 and JAM-3 were upregulated (P < 0.05). Furthermore, the addition of betaine to the LDE diet increased the ATTD of GE, DM, and OM in rabbits (P < 0.05). Gene abundance levels of ileum IL-6 and duodenum JAM-3 were upregulated (P < 0.05). In summary, LDE diets can reduce the activity of intestinal digestive enzymes and decrease the ATTD of nutrients. However, the addition of betaine to LDE diets improved the intestinal barrier structure and nutrient ATTD in rabbits, with better results when betaine was added at an additive level of 500 mg/kg.
Impact of aging on copper isotopic composition in the murine brain
Authors: Lahoud Esther , Moynier Frédéric , Luu Tu-Han , Mahan Brandon , Borgne Marie Le
Published: January 2024

Aging is the main risk factor for Alzheimer's disease (AD). AD is linked to alterations in metal homeostasis and changes in stable metal isotopic composition can occur, possibly allowing the latter to serve as relevant biomarkers for potential AD diagnosis. Copper stable isotopes are used to investigate changes in Cu homeostasis associated with various diseases. Prior work has shown that in AD mouse models, the accumulation of 63Cu in the brain is associated with the disease's progression. However, our understanding of how the normal aging process influences the brain's isotopic composition of copper remains limited. In order to determine the utility and predictive power of Cu isotopes in AD diagnostics, we aim—in this study—to develop a baseline trajectory of Cu isotopic composition in the normally aging mouse brain. We determined the copper concentration and isotopic composition in brains of 30 healthy mice (WT) ranging in age from 6 to 12 mo, and further incorporate prior data obtained for 3-mo-old healthy mice; this range approximately equates to 20–50 yr in human equivalency. A significant 65Cu enrichment has been observed in the 12-mo-old mice compared to the youngest group, concomitant with an increase in Cu concentration with age. Meanwhile, literature data for brains of AD mice display an enrichment in 63Cu isotope compared to WT. It is acutely important that this baseline enrichment in 65Cu is fully constrained and normalized against if any coherent diagnostic observations regarding 63Cu enrichment as a biomarker for AD are to be developed.
Olive leaf extract effect on cardiometabolic risk factors: a systematic review and meta-analysis of randomized clinical trials
Authors: Álvares Andressa Anelo , Garcêz Anderson , Silva Lucas Tolio , Averbuch Natália , Garavaglia Juliano
Published: January 2024

Context

Olive leaf extract (OLE) is rich in phenolic compounds, which are known for their health benefits. Cardiovascular diseases, primarily coronary heart disease and stroke, are leading causes of mortality globally.

Objective

This systematic review aimed to assess the impact of OLE on cardiometabolic risk factors in adults. The selection of studies was based on intervention and outcomes, using relevant search descriptors.

Data Sources

The databases PubMed, EMBASE, and Web of Science were systematically searched for pertinent studies published up to August 2021.

Data Extraction

Only randomized clinical trials, either cross-over or parallel, involving adult individuals aged ≥18 years, were considered. Additionally, trials that had a comparative or placebo group and used pure OLEs for oral treatment were included.

Data Analysis

Twelve randomized clinical trials (RCTs) met the inclusion criteria. These trials had follow-up periods ranging from 2 days to 12 weeks and involved 703 patients aged 18 years–79 years. The outcomes demonstrated a positive correlation between the intervention group and glucose metabolism (4 RCTs), blood pressure (2 RCTs), lipid profile (2 RCTs), and inflammatory markers (2 RCTs). The RoB2 tool and the GRADE system were used to evaluate the risk of bias and the quality of evidence in the studies.

Conclusions

In the meta-analysis, fasting glycemia, as evaluated in studies using a low dose of OLE, showed a significant result favoring the control group. To obtain more consistent results, further clinical studies in humans, using similar methodologies, are required.

Systematic Review Registration

PROSPERO registration no. CRD42020200877.
A Study of the Criminal Victimization of Policewomen by Other Police Officers
Authors: Stinson Philip Matthew , Liederbach John , Wentzlof Chloe Ann , Parker Jordan M
Published: January 2024

Our research focuses on the criminal victimization of policewomen by other police officers. The data derive from a larger nationwide study on police crime, or cases in which police officers have been arrested for the perpetration of one or more criminal offenses. The current study identifies cases involving policewomen who are victims of police-perpetrated sexual harassment, official misconduct, stalking, indecent exposure, simple and aggravated assault, and rape. The specific goals of the research are three-fold: (1) explore the nature and character of police crimes perpetrated against policewomen, (2) describe cases of police crime perpetrated against policewomen that specifically involve some form of sexual violence, and (3) compare cases of police crime perpetrated against male and female police victims. Findings demonstrate the differential criminal victimization of policewoman, particularly in terms of cases involving police sexual violence (PSV) and officer-involved domestic violence (OIDV).
Unionization, licensure and workplace variation in pay inequality between immigrants and natives
Authors: Drange Ida , Helland Håvard , Hermansen Are Skeie
Published: January 2024

Organizational research has revealed considerable variation in immigrant–native pay inequalities across workplace contexts. However, less is known about how broader labor market institutions intersect in the local dynamics of wage setting between employees of immigrant and native backgrounds. We argue that union density and higher shares of employees in licensed occupations in workplaces constrain organizational opportunity structures for unequal pay according to immigrant backgrounds. Our analysis of longitudinal linked employer–employee administrative data for the Norwegian labor market shows that the wage gap between immigrants and natives decreases with increasing workplace unionization, but almost exclusively for immigrants who are union members. Next, licensure raises pay at the individual and workplace levels, although any reduction in immigrant–native pay gaps is contingent on immigrants’ access to licensed jobs. Our findings support the claim that institutional regulation in the workplace reduces the organizational scope of unequal pay based on immigrant status.
Adaptive changes in BMAL2 with increased locomotion associated with the evolution of unihemispheric slow-wave sleep in mammals
Authors: Yin Daiqing , Zhang Biao , Chong Yujie , Ren Wenhua , Xu Shixia , Yang Guang
Published: January 2024

Marine mammals, especially cetaceans, have evolved a very special form of sleep characterized by unihemispheric slow-wave sleep (USWS) and a negligible amount or complete absence of rapid-eye-movement sleep; however, the underlying genetic mechanisms remain unclear. Here, we detected unique, significant selection signatures in basic helix-loop-helix ARNT like 2 (BMAL2; also called ARNTL2), a key circadian regulator, in marine mammal lineages, and identified two nonsynonymous amino acid substitutions (K204E and K346Q) in the important PER-ARNT-SIM domain of cetacean BMAL2 via sequence comparison with other mammals. In vitro assays revealed that these cetacean-specific mutations specifically enhanced the response to E-box-like enhancer and consequently promoted the transcriptional activation of PER2, which is closely linked to sleep regulation. The increased PER2 expression, which was further confirmed both in vitro and in vivo, is beneficial for allowing cetaceans to maintain continuous movement and alertness during sleep. Concordantly, the locomotor activities of zebrafish overexpressing the cetacean-specific mutant bmal2 were significantly higher than the zebrafish overexpressing the wild-type gene. Subsequently, transcriptome analyses revealed that cetacean-specific mutations caused the upregulation of arousal-related genes and the downregulation of several sleep-promoting genes, which is consistent with the need to maintain hemispheric arousal during USWS. Our findings suggest a potential close relationship between adaptive changes in BMAL2 and the remarkable adaptation of USWS and may provide novel insights into the genetic basis of the evolution of animal sleep.
Estimated rates of progression to tuberculosis disease for persons infected with Mycobacterium tuberculosis in the United States
Authors: Ekramnia Mina , Li Yunfei , Haddad Maryam B. , Marks Suzanne M. , Kammerer J. Steve , Swartwood Nicole A. , Cohen Ted , Miller Jeffrey W. , Horsburgh C Robert , Salomon Joshua A. , Menzies Nicolas A.
Published: January 2024

Background:

In the United States, over 80% of tuberculosis (TB) disease cases are estimated to result from reactivation of latent TB infection (LTBI) acquired more than 2 years previously (“reactivation TB”). We estimated reactivation TB rates for the US population with LTBI, overall, by age, sex, race–ethnicity, and US-born status, and for selected comorbidities (diabetes, end-stage renal disease, and HIV).

Methods:

We collated nationally representative data for 2011–2012. Reactivation TB incidence was based on TB cases reported to the National TB Surveillance System that were attributed to LTBI reactivation. Person–years at risk of reactivation TB were calculated using interferon-gamma release assay (IGRA) positivity from the National Health and Nutrition Examination Survey, published values for interferon-gamma release assay sensitivity and specificity, and population estimates from the American Community Survey.

Results:

For persons aged ≥6 years with LTBI, the overall reactivation rate was estimated as 0.072 (95% uncertainty interval: 0.047, 0.12) per 100 person-years. Estimated reactivation rates declined with age. Compared to the overall population, estimated reactivation rates were higher for persons with diabetes (adjusted rate ratio [aRR] = 1.6 [1.5, 1.7]), end-stage renal disease (aRR = 9.8 [5.4, 19]), and HIV (aRR = 12 [10, 13]).

Conclusions:

In our study, individuals with LTBI faced small, non-negligible risks of reactivation TB. Risks were elevated for individuals with medical comorbidities that weaken immune function.
Tocilizumab Dose Tapering Based on a Model-Based Algorithm is Feasible in Clinical Practice: A Short Communication
Authors: Hooijberg Femke , Layegh Zohra , Leeuw Maureen , Boekel Laura , van den Berg Stefan P.H. , Ruwaard Jill , Bastida Carla , Huitema Alwin D.R. , Pel Sara , Elkayam Ori , de Vries Annick , Nurmohamed Mike , Rispens Theo , Dorlo Thomas P.C. , Wolbink Gertjan
Published: January 2024

Background:

Tocilizumab in the treatment of rheumatoid arthritis (RA) is a potential candidate for concentration-guided tapering because the standard dose of tocilizumab results in a wide range of serum concentrations, usually above the presumed therapeutic window, and an exposure–response relationship has been described. However, no clinical trials have been published to date on this subject. Therefore, the objective of this study was to assess the feasibility of the tapering of intravenous (iv) tocilizumab with the use of a pharmacokinetic model-based algorithm in RA patients.

Methods:

A randomized controlled trial with a double-blind design and follow-up of 24 weeks was conducted. RA patients who received the standard of tocilizumab for at least the past 24 weeks, which is 8 mg/kg every 4 weeks, were included. Patients with a tocilizumab serum concentration above 5 mg/L at trough were randomized between concentration-guided dose tapering, referred to as therapeutic drug monitoring (TDM), or the standard 8 mg/kg dose. In the TDM group, the tocilizumab dose was tapered with a recently published model-based algorithm to achieve a target concentration of 4–6 mg/L after 20 weeks of dose tapering.

Results:

Twelve RA patients were included and 10 were randomized between the TDM and standard dose group. The study was feasible regarding the predefined feasibility criteria and patients had a positive attitude toward therapeutic drug monitoring. In the TDM group, the tocilizumab trough concentration within patients decreased on average by 24.5 ± 18.3 mg/L compared with a decrease of 2.8 ± 12 mg/L in the standard dose group. None of the patients in the TDM group reached the drug range of 4–6 mg/L. Instead, tocilizumab concentrations of 1.6 and 1.5 mg/L were found for the 2 patients who completed follow-up on the tapered dose. No differences in RA disease activity were observed between the 2 study groups.

Conclusions:

This study was the first to show that it is feasible to apply a dose-reduction algorithm based on a pharmacokinetic model in clinical practice. However, the current algorithm needs to be optimized before it can be applied on a larger scale.
Development, Validation, and Clinical Application of an Ultra–High-Performance Liquid Chromatography Coupled With Tandem Mass Spectrometry Method for the Determination of 10 Antituberculosis Drugs in Human Serum
Authors: Fan Xudong , Guo Suhang , Zhang Ruoying , Cai Qingshan , Lang Yazhen , Huang Jinpeng , Chen Yuanyuan , Zhang Ying , Xu Yingying , Chen Meng , Yang Gaoyi , Cai Xinjun
Published: January 2024

Introduction:

Linezolid, moxifloxacin, rifapentine, rifabutin, cycloserine, clofazimine, bedaquiline, levofloxacin, prothionamide, and ethionamide are commonly used second-line antituberculosis (anti-TB) drugs. To support therapeutic drug monitoring in regular clinical practice, the authors sought to develop a method based on ultra–high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) that would allow for the simultaneous quantification of multiple second-line anti-TB drugs in human serum.

Methods:

Analytes were extracted from human serum by protein precipitation. UHPLC-MS/MS was performed using a gradient at a flow rate of 0.3 mL/min, and each sample was taken for 7.5 minutes. The mass spectrometry scanning mode used was electrospray ionization with multiple reaction monitoring in the positive mode.

Results:

Validation showed that endogenous substances in the sample did not interfere with the assay, and the relationship between X and Y was highly linear, with a coefficient of determination (R2) >0.9954 for each curve. The accuracy (85.0%–114.7%) and precision (intraday: 0.27%–9.32%; interday: 0.20%–7.66%) were less than 15.0%, and the internal standard-normalized matrix effects were consistent (coefficient of variation ≤4.40%). The analytes were stable in the final extract and human serum under various storage conditions (recovery: 87.0%–115.0%). The clinical applicability of the method was demonstrated by quantitative determination of analytes in serum samples obtained from patients with TB. Reproducibility of the drug concentrations measured in clinical samples was confirmed by incurred sample reanalysis.

Conclusions:

A simple and reliable analytical method was developed and validated for the simultaneous determination of 10 anti-TB drugs in human serum using UHPLC-MS/MS. Quantitation of anti-TB drugs in clinical samples confirmed that the assay is suitable for therapeutic drug monitoring in regular clinical practice.
Factors Influencing Plasma Concentrations of Valproic Acid in Pediatric Patients With Epilepsy and the Clinical Significance of CYP2C9 Genotypes in Personalized Valproic Acid Therapy
Authors: Ma Bingsuo , Yang Kun , Li Xinping , Su Ning , Yu Ting , Zou Yan , Xu Xingmeng , Wang Fei , Cheng Jingdong , Yan Zijun , Chen Tong , Zhang Liangming
Published: January 2024

Background:

The aim of this study was to investigate the factors affecting plasma valproic acid (VPA) concentration in pediatric patients with epilepsy and the clinical significance of CYP2C9 gene polymorphisms in personalized dosing using therapeutic drug monitoring and pharmacogenetic testing.

Methods:

The medical records of children with epilepsy who underwent therapeutic drug monitoring at our institution between July 2022 and July 2023 and met the inclusion criteria were reviewed. Statistical analysis was performed to determine whether age, sex, blood ammonia, liver function, kidney function, and other characteristics affected the concentration-to-dose ratio of VPA (CDRV) in these patients. To investigate the effect of CYP2C9 polymorphisms on CDRV, DNA samples were collected from patients and the CYP2C9 genotypes were identified using real-time quantitative PCR.

Results:

The mean age of 208 pediatric patients with epilepsy was 5.50 ± 3.50 years. Among these patients, 182 had the CYP2C9 *1/*1 genotype, with a mean CDRV (mcg.kg/mL.mg) of 2.64 ± 1.46, 24 had the CYP2C9 *1/*3 genotype, with a mean CDRV of 3.28 ± 1.74, and 2 had the CYP2C9 *3/*3 genotype, with a mean CDRV of 6.46 ± 3.33. There were statistical differences among these 3 genotypes (P < 0.05). The CDRV in these patients were significantly influenced by age, aspartate aminotransferase, total bilirubin, direct bilirubin, globulin, albumin/globulin ratio, prealbumin, creatinine, and CYP2C9 polymorphisms. In addition, multivariate linear regression analysis identified total bilirubin, direct bilirubin, and CYP2C9 polymorphisms as independent risk factors for high CDRV.

Conclusions:

Liver problems and mutations in the CYP2C9 gene increase VPA levels. This underscores the importance of considering these factors when prescribing VPA to children with epilepsy, thereby enhancing the safety and efficacy of the therapy.
Clinical efficacy of intratympanic steroid injection for treating idiopathic sudden sensorineural hearing loss
Authors: Kuo Liang-Kuan , Wu Jiunn-Liang , Li Yi-Lu , Hsu Heng-Jui
Published: January 2024

Background:

Idiopathic sudden sensorineural hearing loss (ISSNHL) is an emergency that causes permanent hearing loss if timely treatment is not provided. However, the evidence supporting the effect of intratympanic steroid injection (ITSI) starting time on hearing outcome is limited.

Methods:

We retrospectively enrolled 582 patients with ISSNHL who were treated with ITSIs and reviewed their clinical and audiological variables. The relationship between ITSI starting time and hearing recovery was analyzed.

Results:

The mean starting time of ITSI was 13.17 ± 16.53 days. The overall hearing recovery rate was 55.15% (recovery = mean hearing level gain of ≥10 dB). The recovery rates were 79.2%, 67.4%, 50%, 36.6%, and 17.8% for the ITSI starting times of 1 to 3, 4 to 7, 8 to 14, 15 to 28, and ≥29 days, respectively. A multivariate analysis revealed that ITST starting time (odds ratio [OR] = 0.94, 95% CI, 0.92-0.96, p < 0.001) and salvage therapy (OR = 0.55, 95% CI, 0.35-0.86, p = 0.009) were independent poor prognostic factors for patients with ISSNHL.

Conclusion:

Earlier ITSI treatment is associated with a higher hearing recovery rate. Comorbidities and post-ITSI complications were nonsignificant independent risk factors.
A retrospective cohort study of socioeconomic deprivation and post-liver transplant survival in adults
Authors: Hendele James B. , Nichols Jordan T. , Vutien Philip , Perkins James D. , Reyes Jorge , Dick André A.S.
Published: January 2024

The Area Deprivation Index is a granular measure of neighborhood socioeconomic deprivation. The relationship between neighborhood socioeconomic deprivation and recipient survival following liver transplantation (LT) is unclear. To investigate this, the authors performed a retrospective cohort study of adults who underwent LT at the University of Washington Medical Center from January 1, 2004, to December 31, 2020. The primary exposure was a degree of neighborhood socioeconomic deprivation as determined by the Area Deprivation Index score. The primary outcome was posttransplant recipient mortality. In a multivariable Cox proportional analysis, LT recipients from high-deprivation areas had a higher risk of mortality than those from low-deprivation areas (HR: 1.81; 95% CI: 1.03–3.18, p=0.04). Notably, the difference in mortality between area deprivation groups did not become statistically significant until 6 years after transplantation. In summary, LT recipients experiencing high socioeconomic deprivation tended to have worse posttransplant survival. Further research is needed to elucidate the extent to which neighborhood socioeconomic deprivation contributes to mortality risk and identify effective measures to improve survival in more socioeconomically disadvantaged LT recipients.
What Are the Predictors of Post-traumatic Stress Disorder Among Road Traffic Accident Survivors
Authors: Sabahi Zahra , Hasani Parham , Salehi-Pourmehr Hanieh , Beheshti Rasa , Sadeghi-Bazargani Homayoun
Published: January 2024

Traffic accidents put tremendous burdens on the psychosocial aspects of communities. Post-traumatic stress disorder (PTSD), after an accident, is one of the most prevalent and incapacitating psychiatric conditions worldwide. In this systematic review, we aimed to investigate the predictors of PTSD in traffic accident victims. Primary search was conducted in November 2021 and updated in 2023. Studies were excluded if they used any analysis except regression for predictors. Cumulatively, primary and update searches retrieved 10,392 articles from databases, and of these, 87 studies were systematically reviewed. The predictors were categorized into sociodemographics, pretrauma, peritrauma, and post-trauma factors. The PTSD assessment time varied between 2 weeks and 3 years. Being a woman, having depression and having a history of road traffic accidents pretraumatically, peritraumatic dissociative experiences, acute stress disorder diagnosis, rumination, higher injury severity, and involvement in litigation or compensation after the trauma were significant predictors of PTSD.
Thyroglossal Duct Cyst Infection Caused by Neisseria gonorrhoeae: An Unusual Complication of Pharyngeal Gonorrhea
Authors: Roberts Abigail , Johnson Stephanie , Lee B. Craig
Published: January 2024

Neisseria gonorrhoeae is a human obligate pathogen whose clinical expression of disease ranges from localized genital infection to involvement of extragenital sites such as the conjunctiva and throat. We describe the second case of a thyroglossal duct abscess due to N. gonorrhoeae, an uncommon complication of pharyngeal gonococcal infection. The fortuitous occurrence in the same individual of these 2 conditions that both exhibit an occult clinical presentation likely accounts for rarity of this infection. We discuss the pertinent gonococcal and host factors that underlie the clinical manifestations of this infection. A particular focus is the fundamental role that the binding of the gonococcal opacity-associated protein to the ubiquitous human carcinoembryonic cell adhesion molecule plays in the pathogenesis of pharyngeal gonorrhea.
CXCR4 Expression and Cancer-associated Fibroblasts May Play an Important Role in the Invasion of Low-grade Endometrioid Carcinoma
Authors: Fukumitsu Chihiro , Sanada Sakiko , Ogasawara Sachiko , Tsuda Naotake , Murotani Kenta , Akao Mayuka , Ushijima Kimio , Akiba Jun , Yano Hirohisa
Published: January 2024

Well-differentiated endometrioid carcinoma (EC) is a low-grade cancer with relatively indolent behavior. However, even with well-differentiated histology, it sometimes tends to invade extensively and shows metastatic potential, suggesting that this is a group of cancers with heterogeneous behavior. In contrast, due to its tendency for younger onset, the treatment strategy for EC frequently considers fertility preservation, highlighting the need for a more accurate evaluation of myometrial invasion through biopsy and imaging diagnostics. We previously reported the involvement of the CXCR4–CXCL12 and CXCL14 axes in EC invasion. Accordingly, we investigated whether CXCR4 expression could reflect invasive potential and explored its interaction with cancer-associated fibroblasts that produce chemokines in the tumor microenvironment. Immunohistochemical expression of CXCR4 was assessed in 71 cases of EC (14 of EC confined to the endometrium and 57 of myoinvasive EC), 6 cases of endometrial intraepithelial neoplasia, and 42 cases of noncarcinomatous conditions. CXCR4 expression was significantly higher in myoinvasive EC than in noncancerous conditions, endometrial intraepithelial neoplasia, and endometrium-confined EC. By univariate and multivariate analysis, CXCR4 expression significantly reflected myometrial invasion. CXCR4 expression in the biopsied and resected specimens correlated weakly positively. Invasion and wound-healing assays were performed culturing an EC cell line in a cancer-associated fibroblast-conditioned medium. The invasion and wound-healing potentials were dependent on CXCR4 and cancer-associated fibroblast. Our study demonstrated that CXCR4 expression is an independent factor in myometrial invasion and can support diagnostic evaluation before treatment in the biopsy sample.
Adenoid Cystic Carcinoma of the Vulva and Vagina: A Clinicopathologic, Immunohistochemical, and Molecular Characterization of Five Cases
Authors: Doutel Delfim , Venda Diana , Silva Fernanda , Martins Carmo , Félix Ana , Ferreira Joana
Published: January 2024

Adenoid cystic carcinoma (ACC) is a rare neoplasm most frequently observed in the salivary glands, that can occur in other organs, including the vulva and vagina. Oncogenic mechanisms involving MYB, NFIB, and MYB-NFIB rearrangements have been described, but evidence in the vulva and vagina remains scarce. Our aim is to report the clinicopathologic features, immunohistochemical, and molecular findings in a series of vulvar and vaginal ACCs. Five cases were included. Medical records and slides were reviewed. Formalin-fixed paraffin-embedded material was available in 4 cases, where additional immunohistochemical and molecular studies were carried out. Fluorescence in situ hybridization using MYB, MYBL1, and NFIB bacterial artificial chromosome–clones break-apart and MYB::NFIB BAC-clones fusion probes was performed. The patients’ mean age at diagnosis was 52 years. Tumor size ranged from 0.5 to 5 cm. Microscopic examination revealed tubular, cribriform, and solid patterns. Perineural invasion was seen in 4 cases. Patients were treated with surgery, some with adjuvant radiation therapy. During follow-up (mean: 11 yr), 4 patients developed local recurrences. Recently, one of these patients developed pulmonary disease. Cam 5.2, CK5/6, CD117, and DOG-1 were positive in all 4 cases and S100 and calponin were positive in 3 cases. MYB rearrangement was present in 3 cases, including one with concurrent MYB amplification. There were no MYBL1 or NFIB rearrangements and no MYB::NFIB fusions. Our findings corroborate that the histologic, immunohistochemical, and oncogenic background is similar between ACCs of the lower female genital tract and ACCs elsewhere, although the canonical MYB::NFIB fusion seems to be a less common finding in this location.
Clinical Significance of Tumor Immune Microenvironment in Endometrial Endometrioid Carcinoma, Grade 1 With DNA Mismatch Repair Protein Loss
Authors: Hachisuga Kazuhisa , Kawakami Minoru , Tomonobe Hiroshi , Maenohara Shoji , Kodama Keisuke , Yagi Hiroshi , Yasunaga Masafumi , Onoyama Ichiro , Asanoma Kazuo , Yahata Hideaki , Oda Yoshinao , Kato Kiyoko
Published: January 2024

The administration of immune checkpoint inhibitors (ICIs) is increasing in endometrial cancer, especially in the mismatch repair (MMR)-deficient group. To prevent unnecessary immune-related adverse events, ICIs need to be administered to more appropriate patients. The tumor immune microenvironment has been reported to be a predictive marker of the efficacy of ICI therapies. This study evaluated CD8, FoxP3, CD68, PD-L1, and β-catenin expression in endometrial endometrioid carcinoma, grade 1 (G1) with DNA mismatch repair protein loss (MMR loss), and their association with clinicopathological features. We retrospectively analyzed tumor samples from 107 patients with endometrial endometrioid carcinoma, G1 (MMR-deficient group: n=67; MMR-proficient group: n=40). Overall, 47 cases of MLH1/PMS2 loss and 20 cases of MSH2/MSH6 loss were observed. The patients with low intraepithelial CD8 expression significantly more frequently exhibited deep myometrial invasion, and the elderly group (≥60 y) significantly more frequently showed low stromal CD8 expression. In addition, FoxP3-positive cell count and FoxP3/CD8+ ratio were significantly correlated with the International Federation of Obstetrics and Gynecology 2023 stage and lymph node metastasis. In the Kaplan-Meier analysis, the patients with low intraepithelial or stromal CD8 expression had shorter progression-free survival (PFS) than those with high intraepithelial or stromal CD8 expression, albeit not significantly. We clarified that the tumor immune microenvironment had an impact on clinicopathological features within the group with MMR loss, which is the main target for ICIs, limited to endometrioid carcinoma, G1. Further studies are needed, including on patients administered ICIs.
Emendation of Appendix 9 of the International Code of Nomenclature of Prokaryotes to provide guidelines for naming genera after geographical locations
Authors: Oren Aharon
Published: January 2024

Following a proposal to emend Appendix 9 of the International Code of Nomenclature of Prokaryotes with guidelines for the naming of genera after geographical locations, I here report the outcome of the ballot on this proposal by the members of the International Committee on Systematics of Prokaryotes and present the guidelines to be incorporated in Appendix 9.
Reference-free Structural Variant Detection in Microbiomes via Long-read Coassembly Graphs
Authors: Curry Kristen D. , Yu Feiqiao Brian , Vance Summer E. , Segarra Santiago , Bhaya Devaki , Chikhi Rayan , Rocha Eduardo P.C. , Treangen Todd J.
Published: January 2024

Bacterial genome dynamics are vital for understanding the mechanisms underlying microbial adaptation, growth, and their broader impact on host phenotype. Structural variants (SVs), genomic alterations of 10 base pairs or more, play a pivotal role in driving evolutionary processes and maintaining genomic heterogeneity within bacterial populations. While SV detection in isolate genomes is relatively straightforward, metagenomes present broader challenges due to absence of clear reference genomes and presence of mixed strains. In response, our proposed method rhea, forgoes reference genomes and metagenome-assembled genomes (MAGs) by encompassing a single metagenome coassembly graph constructed from all samples in a series. The log fold change in graph coverage between subsequent samples is then calculated to call SVs that are thriving or declining throughout the series. We show rhea to outperform existing methods for SV and horizontal gene transfer (HGT) detection in two simulated mock metagenomes, which is particularly noticeable as the simulated reads diverge from reference genomes and an increase in strain diversity is incorporated. We additionally demonstrate use cases for rhea on series metagenomic data of environmental and fermented food microbiomes to detect specific sequence alterations between subsequent time and temperature samples, suggesting host advantage. Our innovative approach leverages raw read patterns rather than references or MAGs to include all sequencing reads in analysis, and thus provide versatility in studying SVs across diverse and poorly characterized microbial communities for more comprehensive insights into microbial genome dynamics.
NEAR: Neural Embeddings for Amino acid Relationships
Authors: Olson Daniel , Colligan Thomas , Demekas Daphne , Roddy Jack W. , Youens-Clark Ken , Wheeler Travis J.
Published: January 2024

Protein language models (PLMs) have recently demonstrated potential to supplant classical protein database search methods based on sequence alignment, but are slower than common alignment-based tools and appear to be prone to a high rate of false labeling. Here, we present NEAR, a method based on neural representation learning that is designed to improve both speed and accuracy of search for likely homologs in a large protein sequence database. NEAR’s ResNet embedding model is trained using contrastive learning guided by trusted sequence alignments. It computes per-residue embeddings for target and query protein sequences, and identifies alignment candidates with a pipeline consisting of residue-level k-NN search and a simple neighbor aggregation scheme. Tests on a benchmark consisting of trusted remote homologs and randomly shuffled decoy sequences reveal that NEAR substantially improves accuracy relative to state-of-the-art PLMs, with lower memory requirements and faster embedding and search speed. While these results suggest that the NEAR model may be useful for standalone homology detection with increased sensitivity over standard alignment-based methods, in this manuscript we focus on a more straightforward analysis of the model’s value as a high-speed pre-filter for sensitive annotation. In that context, NEAR is at least 5x faster than the pre-filter currently used in the widely-used profile hidden Markov model (pHMM) search tool HMMER3, and also outperforms the pre-filter used in our fast pHMM tool, nail.
Acute toxicity effects of pesticides on beneficial organisms – Dispelling myths for a more sustainable use of chemicals in agricultural environments
Authors: Mata Luis , Knapp Rosemary A. , McDougall Robert , Overton Kathy , Hoffmann Ary A. , Umina Paul A.
Published: January 2024

Agricultural practitioners, researchers and policymakers are increasingly advocating for integrated pest management (IPM) to reduce pesticide use while preserving crop productivity and profitability. Selective pesticides, putatively designed to act on pests while minimising impacts on off-target organisms, have emerged as one such option – yet evidence of whether these compounds control pests without adversely affecting natural enemies and other beneficial species (henceforth beneficials) remains scarce. At present, the selection of pesticides compatible with IPM often considers a single (or a limited number of) widely distributed beneficial species, without considering undesired effects on co-occurring beneficials. In this study, we conducted standardised laboratory bioassays to assess the acute toxicity effects of 20 chemicals on 15 beneficial species at multiple exposure timepoints, with the specific aims to: (1) identify common and diverging patterns in acute toxicity responses of tested beneficials; (2) determine if the effect of pesticides on beetles, wasps and mites is consistent across species within these groups; and (3) assess the impact of mortality assessment timepoints on International Organisation for Biological Control (IOBC) toxicity classifications. Our work demonstrates that in most cases, chemical toxicities cannot be generalised across a range of beneficial insects and mites providing biological control, a finding that was found even when comparing impacts among closely related species of beetles, wasps and mites. Additionally, we show that toxicity impacts increase with exposure length, pointing to limitations of IOBC protocols. This work challenges the notion that chemical toxicities can be adequately tested on a limited number of ‘representative’ species; instead it highlights the need for careful consideration and testing on a range of regionally and seasonally relevant beneficial species.
MEDIATOR SUBUNIT 25 modulates ERFVII-controlled hypoxia responses in Arabidopsis
Authors: Schippers Jos H.M. , von Bongartz Kira , Laritzki Lisa , Frohn Stephanie , Frings Stephanie , Renziehausen Tilo , Augstein Frauke , Winkels Katharina , Sprangers Katrien , Sasidharan Rashmi , Vertommen Didier , Breusegem Frank Van , Hartman Sjon , Beemster Gerrit T. S. , Mhamdi Amna , van Dongen Joost T. , Schmidt-Schippers Romy R.
Published: January 2024

Flooding impairs plant growth through oxygen deprivation, which activates plant survival and acclimation responses. Low-oxygen responses are generally associated with activation of group VII ETHYLENE-RESPONSE FACTOR (ERFVII) transcription factors. However, mechanism and molecular components by which ERFVII factors initiate gene expression are not fully elucidated. Here, we show that the Mediator complex subunitAtMED25 is recruited by RELATED TO APETALA 2.2 (RAP2.2) and RAP2.12 to coordinate gene expression during hypoxia inArabidopsis thaliana.. Themed25mutants display reduced low-oxygen stress tolerance.AtMED25 associates with several ERFVII-controlled hypoxia core genes and its loss impairs transcription under hypoxia due to decreasing RNA polymerase II recruitment. Protein complex pulldown assays demonstrate that the Mediator complex built aroundAtMED25 is adjusted under low-oxygen conditions. Moreover, during hypoxia, no functional cooperation betweenAtMED25 and the two subunitsAtMED8 andAtMED16 occurs, contrasting previous observations made for other conditions. In addition,AtMED25 function under hypoxia is independent from ethylene signalling. Finally, a functional conservation at the molecular level was found for the MED25-ERFVII module betweenArabidopsis thalianaand the monocotOryza sativa, pointing to a potentially universal role of MED25 in enabling ERFVII-dependent transcript responses to hypoxia in plants.
Combining machine learning algorithms and single-cell data to study the pathogenesis of Alzheimer’s disease
Authors: Cui Wei , Zhang Liang , Zheng Fang-Rui , Li Xi Huang , Xie Gui-Lin
Published: January 2024

Extracting valuable insights from high-throughput biological data of Alzheimer’s disease to enhance understanding of its pathogenesis is becoming increasingly important. We engaged in a comprehensive collection and assessment of Alzheimer’s microarray datasets GSE5281 and GSE122063 and single-cell data from GSE157827 from the NCBI GEO database. The datasets were selected based on stringent screening criteria: a P-value of less than 0.05 and an absolute log fold change (|logFC|) greater than 1. Our methodology involved utilizing machine learning algorithms, efficiently identified characteristic genes. This was followed by an in-depth immune cell infiltration analysis of these genes, gene set enrichment analysis (GSEA) to elucidate differential pathways, and exploration of regulatory networks. Subsequently, we applied the Connectivity Map (cMap) approach for drug prediction and undertook single-cell expression analysis. The outcomes revealed that the top four characteristic genes, selected based on their accuracy, exhibited a profound correlation with the Alzheimer’s disease (AD) group in terms of immune infiltration levels and pathways. These genes also showed significant associations with multiple AD-related genes, enhancing the potential pathogenic mechanisms through regulatory network analysis and single-cell expression profiling. Identified three subpopulations of astrocytes in late-stage of AD Prefrontal cortex dataset. Discovering dysregulation of the expression of the AD disease-related pathway maf/nrf2 in these cell subpopulations Ultimately, we identified a potential therapeutic drug score, offering promising avenues for future Alzheimer’s disease treatment strategies.
Efficient parameter estimation for ODE models of cellular processes using semi-quantitative data
Authors: Dorešić Domagoj , Grein Stephan , Hasenauer Jan
Published: January 2024

Quantitative dynamical models facilitate the understanding of biological processes and the prediction of their dynamics. The parameters of these models are commonly estimated from experimental data. Yet, experimental data generated from different techniques do not provide direct information about the state of the system but a non-linear (monotonic) transformation of it. For such semi-quantitative data, when this transformation is unknown, it is not apparent how the model simulations and the experimental data can be compared. Here, we propose a versatile spline-based approach for the integration of a broad spectrum of semi-quantitative data into parameter estimation. We derive analytical formulas for the gradients of the hierarchical objective function and show that this substantially increases the estimation efficiency. Subsequently, we demonstrate that the method allows for the reliable discovery of unknown measurement transformations. Furthermore, we show that this approach can significantly improve the parameter inference based on semi-quantitative data in comparison to available methods. Modelers can easily apply our method by using our implementation in the open-source Python Parameter EStimation TOolbox (pyPESTO).
Induction of common beanOVATE Family Protein 7(PvOFP7) promotes resistance to common bacterial blight
Authors: Gaudin Charlotte , Preveaux Anne , Aubineau Nathan , Le Goff Damien , Jacques Marie-Agnès , Chen Nicolas W.G.
Published: January 2024

Common bacterial blight of bean (CBB) is a devastating seed-transmitted disease caused byXanthomonas phaseolipv.phaseoliandXanthomonas citripv.fuscanson common bean (Phaseolus vulgarisL.). The genes responsible for CBB resistance are largely unknown. moreover, the lack of reproducible and universal transformation protocol limits the study and improvement of genetic traits in common bean. We producedX. phaseolipv.phaseolistrains expressing artificially-designed Transcription-Activator Like Effectors (dTALEs) to target 14 candidate genes and performedin plantaassays in a susceptible common bean genotype to analyse if the transcriptional induction of these genes could confer resistance to CBB. Induction ofPvOFP7,PvAP2-ERF71andPvExpansinA17resulted in CBB symptom reduction. In particular,PvOFP7induction led to strong symptom reduction, linked to reduced bacterial growthin plantaat early colonisation stages. RNA-Seq analysis revealed up-regulation of cell wall formation and primary metabolism, and major down-regulation of Heat Shock Proteins. Our results demonstrate that PvOFP7 is contributes to CBB resistance, and underline the usefulness of dTALEs for highlighting genes of quantitative activity.
Frequently Together, Among Model Systems Molecular Alterations: Cancer Maintenance Markers with Translational Study Design
Authors: Ylagan Maya , Xu Qi , Kowalski Jeanne
Published: January 2024

In contrast to cancer driver gene alterations, genes with alterations occurring frequently together are unlikely to play a direct role in tumor development, and more likely to contribute to normal cellular functions necessary for the ongoing maintenance and survival of the tumor, with the most robust of these genes preserved across model systems. We introduce two molecular signature-centric methods, RECO (recurring and co-occurring) and Crosstalk, to identify gene sets characterized by molecular alterations that occur frequently together across sample model systems. Our overall approach builds a cancer information exchange among samples systems based on an analysis of gene and sample-level signature pairs using RECO and Crosstalk methods. The results may be used to design translational studies from gene signature discovery in patients to its application in cell lines and patient-derived xenograft models, alongside the discovery of potential cancer maintenance markers. We demonstrate the capabilities of our approach by exploring the discovery of frequently together molecular alterations between patient tumors and cell lines, and between histologically similar tumors with different sites of origin, and their associations with outcomes in several cancers. As understudied, expanded markers, genes with frequently occurring molecular alterations between systems offer potentially new insights into similar cancer etiology and treatment targets outside the norm, in addition to informing on translational study design.

Availability and implementation:The method is implemented at:https://github.com/kmlabdms/CIERCE