bluuebunny/crossref_metadata_2025 huggingface dataset:
Economic income and survival in patients affected by glioblastoma: A systematic review and meta-analysis
Authors: Di Nunno Vincenzo , Gatto Lidia , Aprile Marta , Bartolini Stefania , Tosoni Alicia , Franceschi Enrico
Published: May 2024

Background

Within socioeconomic variables, economic income has been associated with the prognosis of patients with glioblastoma. However, studies investigating this issue provided conflicting results.

Methods

We carried out a systematic review and meta-analysis of studies investigating the correlation between economic income and survival in patients with glioblastoma. The inverse variance technique for hazard ratio (HR) assessment has been employed in reporting the random effect model.

Results

We included 12 studies for a total of 143 303 GBM patients (67 463 with high economic income, and 25 679 with low economic income). In the overall analysis, lower economic income resulted in poorer survival (pooled HR 1.09, 95% CI: 1.02–1.17, I2 = 64%). Variables like the type of Health Care System (public, private, or mixed) and the time in which patients have been treated (pre or post-EORTC-NCIC trial 22981/26981, CE.3 protocol advent) did not modify survival on pooled analysis.

Conclusions

Economic conditions and income influence the prognosis of patients with glioblastoma. A better understanding of the modifiable barriers leading to treatment disparities in more disadvantaged patients is warranted to make equal oncological care.
Perspective: Improving police recruitment outcomes for women through physical fitness support programs
Authors: Roman Ivonne , McGough Maureen Q
Published: May 2024

This perspective paper is anchored in the authors’ direct experiences with enhancing women’s recruitment in law enforcement through physical fitness programs and mentoring in Newark, NJ. The paper draws insights from a successful approach that boosted women’s performance in physical fitness tests (PFTs). The paper underscores the importance of gender inclusivity in police recruitment, detailing the implementation of the Women’s Leadership Academy (WLA) and its evolution into the nationwide 30x30 initiative. Key findings reveal that tailored physical training, effective mentoring, and support can significantly lower attrition and enhance gender diversity in policing. Recommendations for law enforcement agencies include adopting equitable PFT standards, establishing mentoring programs for women, and revising recruitment policies to align with current research and best practices. This paper also advocates for a paradigm shift towards comprehensive strategies that build an organizational culture of diversity and equality, specifically through initiatives aimed at enhancing women’s representation in policing with focussed physical fitness training and acclimatization.
Alzheimer’s disease: insights into pathology, molecular mechanisms, and therapy
Authors: Zheng Qiuyang , Wang Xin
Published: May 2024

Alzheimer’s disease (AD), the leading cause of dementia, is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. This condition casts a significant shadow on global health due to its complex and multifactorial nature. In addition to genetic predispositions, the development of AD is influenced by a myriad of risk factors, including aging, systemic inflammation, chronic health conditions, lifestyle, and environmental exposures. Recent advancements in understanding the complex pathophysiology of AD are paving the way for enhanced diagnostic techniques, improved risk assessment, and potentially effective prevention strategies. These discoveries are crucial in the quest to unravel the complexities of AD, offering a beacon of hope for improved management and treatment options for the millions affected by this debilitating disease.
Exercise as an anti-inflammatory Therapy in Axial Spondyloarthritis Therapeutic Intervention (EXTASI) study: a randomized controlled trial
Authors: Roberts Matthew J , Hamrouni Malik , Linsley Victoria , Moorthy Arumugam , Bishop Nicolette C
Published: May 2024

Objectives

Axial SpA (axSpA) is a chronic inflammatory disease, yet despite known anti-inflammatory effects of exercise, the effect of exercise on inflammatory immune cell populations and associated inflammatory profiles in axSpA is unknown. This randomized controlled trial investigated the effect of 12 weeks of walking on symptom severity, cardiometabolic health, inflammatory biomarkers and immune cell populations.

Methods

Twenty people (60% male) living with axSpA who were on a stable dose of NSAIDs participated. Participants were randomly assigned to control or exercise (30 min of walking five times per week). Participants were invited back every 4 weeks for assessment.

Results

There was a 0% dropout rate and no adverse events in the exercise group, showing walking exercise was well tolerated. Home-based walking for 12 weeks lowered the proportion of pro-inflammatory monocytes, whereas they increased in the control group. Changes were associated with lower IL-6 and CRP concentrations, lower spinal pain and lower systolic blood pressure in the exercise group, whereas these markers increased in the control group. Reductions in IL-6 and pro-inflammatory monocytes with exercise were independent of lower body fat percentage.

Conclusions

Supplementing NSAID therapy with walking exercise can improve inflammatory immune profiles in people with axSpA, coinciding with reductions in spinal pain. Importantly, the exercise was well tolerated, suggesting walking exercise can be used as an adjuvant anti-inflammatory therapy for NSAID treatments. This should now be explored in people living with axSpA who have had high enough disease activity to necessitate the prescription of biologic or synthetic DMARD treatments.

Trial registration

ClinicalTrials.gov (http://clinicaltrials.gov), NCT04368494.
Optimal exposure of mycophenolic acid for induction therapy of childhood lupus nephritis patients: an observational cohort study
Authors: Zhang Lu , Chen Lizhi , Liu Xiaohong , Huang Zhijun , Zheng Yifan , Tang Kejing , Jiang Xiaoyun , Chen Pan
Published: May 2024

Objectives

Mycophenolic acid (MPA) is recommended for lupus nephritis (LN) treatment, but with large inter-individual variability in pharmacokinetics (PK). The aim of this study is to reveal the relationship between MPA exposure and disease response and adverse drug reactions in pediatric LN patients.

Method

This was a population-based observational cohort study. A total of 86 pediatric LN patients treated with mycophenolate mofetil (MMF) for induction therapy were enrolled. The area-under the concentration-time curve (AUC) was calculated using MPA concentrations according to a limited sampling strategy. Receiver operating characteristic analysis was performed to assess the MPA-AUC threshold values. The cumulative incidence of renal remission and inactive systemic lupus erythematosus (SLE) over time was evaluated by Kaplan–Meier’s analysis.

Results

MPA-AUC was identified as an independent factor associated with renal remission and lupus activity at 6 and 12 months after MMF treatment, and the improved renal remission rates were correlated with higher MPA-AUC, with thresholds of 29.81 and 30.63 μg·h·mL−1 at 6 months and 12 months, respectively. Furthermore, the thresholds for maintaining the hypoactive state of LN were 30.96 and 31.19 μg·h·mL−1at 6 months and 12 months, respectively. Patients reaching target thresholds for MPA-AUC achieved renal response or stable disease earlier. In addition, the MPA-AUC threshold for decreasing MMF-related adverse reactions was 50.80 μg·h·mL−1.

Conclusion

The initial and long-term treatments of pediatric LN patients with MMF should be individualized according to the MPA-AUC, and the recommended MPA exposure is 31.19–50.80 μg·h·mL−1.
Endothelial progenitor cells for diabetic cardiac and kidney disease
Authors: Raleigh Matthew J , Pasricha Sachin V , Nauth Aaron , Ward Michael R , Connelly Kim A
Published: May 2024

The management of diabetes mellitus and its resultant end organ dysfunction represents a major challenge to global health-care systems. Diabetic cardiac and kidney disease commonly co-occur and are significant contributors to the morbidity and mortality of patients with diabetes, carrying a poor prognosis. The tight link of these parallel end organ manifestations suggests a deeper common underlying pathology. Here, we outline the mechanistic link between diabetic cardiac and kidney disease, providing evidence for the role of endothelial dysfunction in both processes and the potential for cellular therapy to correct these disorders. Specifically, we review the preclinical and clinical evidence for endothelial progenitor cell therapy in cardiac, kidney, and cardio-renal disease applications. Finally, we outline novel approaches to endothelial progenitor cell therapy through cell enhancement and the use of extracellular vesicles, discussing published and future work.
Comparative toxicological assessment of 2 bisphenols using a systems approach: evaluation of the behavioral and transcriptomic responses of Danio rerio to bisphenol A and tetrabromobisphenol A
Authors: Morash Michael G , Kirzinger Morgan W , Achenbach John C , Venkatachalam Ananda B , Nixon Jessica , Penny Susanne , Cooper Joëlle Pinsonnault , Ratzlaff Deborah E , Woodland Cindy L A , Ellis Lee D
Published: May 2024

The zebrafish (Danio rerio) is becoming a critical component of new approach methods (NAMs) in chemical risk assessment. As a whole organism in vitro NAM, the zebrafish model offers significant advantages over individual cell-line testing, including toxicokinetic and toxicodynamic competencies. A transcriptomic approach not only allows for insight into mechanism of action for both apical endpoints and unobservable adverse outcomes, but also changes in gene expression induced by lower, environmentally relevant concentrations. In this study, we used a larval zebrafish model to assess the behavioral and transcriptomic alterations caused by subphenotypic concentrations of 2 chemicals with the same structural backbone, the endocrine-disrupting chemicals bisphenol A and tetrabromobisphenol A. Following assessment of behavioral toxicity, we used a transcriptomic approach to identify molecular pathways associated with previously described phenotypes. We also determined the transcriptomic point of departure for each chemical by modeling gene expression changes as continuous systems which allows for the identification of a single concentration at which toxic effects can be predicted. This can then be investigated with confirmatory cell-based testing in an integrated approach to testing and assessment to determine risk to human health and the environment with greater confidence. This paper demonstrates the impact of using a multi-faceted approach for evaluating the physiological and neurotoxic effects of exposure to structurally related chemicals. By comparing phenotypic effects with transcriptomic outcomes, we were able to differentiate, characterize, and rank the toxicities of related bisphenols, which demonstrates methodological advantages unique to the larval zebrafish NAM.
Bringing a Structural Competency Framework to the (Simulated) Bedside: The Premature Discharge Objective Structured Clinical Exam
Authors: Ramsdell Amanda K. , Hupert Nathaniel , Abramson Erika , Safdieh Joseph E. , Katz Sydney
Published: May 2024

Problem

Structural competency is increasingly valued as a framework to address health equity within undergraduate medical education. As of academic year 2023–2024, the Liaison Committee on Medical Education (LCME) requires that medical schools have content regarding basic principles of structurally competent health care. Despite encouraging data about the effectiveness of structural competency curricula, most occur within the walls of a classroom and do not enter the authentic or simulated clinical space.

Approach

From 2022 to 2023, an objective structured clinical exam (OSCE) focused on premature discharge, previously known as discharge against medical advice, was integrated into the required fourth-year Health Policy course at Weill Cornell Medical College, which uses the framework of structural competency. After a simulated clinical encounter, students completed a reflection assignment and participated in group debriefing to reflect on how policy coursework affected their simulated clinical experience. Students completed an evaluation about their OSCE experience, and OSCE checklist performance was analyzed.

Outcomes

Of 82 students who participated in the curriculum, 68 completed a curricular evaluation, and 62 consented to have their OSCE performance evaluated for research. Mean overall OSCE checklist performance evaluating students’ patient-centered communication skills, harm reduction skills, and discharge planning and counseling was 14.3/16 (89.6%; standard deviation, 9.8%). Students reported it was valuable to focus on structural factors affecting care within the simulated clinical encounter by using the structural competency framework.

Next Steps

To the authors’ knowledge, this is the first OSCE for medical students designed to deepen their understanding of structural competency by embedding the experience into an existing course using the framework. Future work should explore how this curriculum affects students’ attitudes toward structurally vulnerable patients. With structural competency as an LCME requirement, the use of OSCEs may give educators a means to teach and assess fundamental concepts.
Building a Physician-Scientist Pathway for Underrepresented Medical Students Through a Summer Research Experience
Authors: Duncan Andrea F. , Sukra Liza , Portugues Alexandra , Fields British , Patton Kiara , Aredas Brenna , Ellison Angela M.
Published: May 2024

Problem

There is a need to increase the number of physician-scientists from underrepresented in medicine (URiM) groups. To engage URiM medical students, a committee of pediatric departmental leaders at the Children’s Hospital of Philadelphia created the Summer Underrepresented in Medicine Medical Student Research program. This 8-week, onsite research and clinical experience takes place during the summer between students’ first and second years of medical school.

Approach

Applications were solicited between 2019 and 2023 through nationwide outreach to medical school deans and members of URiM student organizations. Accepted students were assigned a mentor to lead their research and clinical exposure. A curriculum highlighting aspects of academic medicine was developed. Students received a $3,000–$5,500 stipend for in-person participation. In 2020 and 2021, adjustments were made (e.g., virtual programming) to avoid interruptions during the COVID-19 pandemic.

Outcomes

In the 2019–2023 application cycles, 298 students applied. Of 128 students who participated, 78 (61%) completed a postprogram survey. Students’ survey feedback was positive. They indicated the program met expectations (mean rating = 1.3; scale: 1 = strongly agree to 5 = strongly disagree). Students reported they learned valuable information/skills (mean = 1.3) and that participation was worth time spent away from other responsibilities (mean = 1.3). The 2019 cohort (n = 12) achieved a 100% residency match rate. In addition, 4 (33%) of these students reported they are obtaining additional degrees or are performing research. After the program, many mentors continued to include students in their research projects.

Next Steps

Next steps include incorporating a standardized, scored rubric for selecting applicants; adding 3 lead mentors, an executive committee, and a faculty advisory board; establishing earlier pathway programming (e.g., at elementary and middle school levels); continuing to track/support alumni throughout their careers; and pursuing federal funding to expand the program.
Magnetic sphincter augmentation in the management of gastro-esophageal reflux disease: a systematic review and meta-analysis
Authors: Fadel Michael G. , Tarazi Munir , Dave Madhav , Reddy Marcus , Khan Omar , Fakih-Gomez Naim , Ashrafian Hutan , Fehervari Matyas
Published: May 2024

Background:

Magnetic sphincter augmentation (MSA) through placement of the LINX device is an alternative to fundoplication in the management of gastro-esophageal reflux disease (GERD). This systematic review and meta-analysis aimed to assess efficacy, quality of life, and safety in patients that underwent MSA, with a comparison to fundoplication.

Methods:

A literature search of MEDLINE, Embase, Emcare, Scopus, Web of Science, and Cochrane library databases was performed for studies that reported data on outcomes of MSA, with or without a comparison group undergoing fundoplication, for GERD from January 2000 to January 2023. Meta-analysis was performed using random-effect models and between-study heterogeneity was assessed.

Results:

Thirty-nine studies with 8075 patients were included: 6983 patients underwent MSA and 1092 patients had laparoscopic fundoplication procedure. Ten of these studies (seven retrospective and three prospective) directly compared MSA with fundoplication. A higher proportion of individuals successfully discontinued proton-pump inhibitors (P<0.001; WMD 0.83; 95% CI: 0.72–0.93; I
2=96.8%) and had higher patient satisfaction (P<0.001; WMD 0.85; 95% CI: 0.78–0.93; I
2=85.2%) following MSA when compared to fundoplication. Functional outcomes were better after MSA than after fundoplication including ability to belch (P<0.001; WMD 0.96; 95% CI: 0.93–0.98; I
2=67.8) and emesis (P<0.001; WMD 0.92; 95% CI: 0.89–0.95; I
2=42.8%), and bloating (P=0.003; WMD 0.20; 95% CI: 0.07–0.33; I
2=97.0%). MSA had higher rates of dysphagia (P=0.001; WMD 0.41; 95% CI: 0.17–0.65; I
2=97.3%) when compared to fundoplication. The overall erosion and removal rate following MSA was 0.24% and 3.9%, respectively, with no difference in surgical reintervention rates between MSA and fundoplication (P=0.446; WMD 0.001; 95% CI: −0.001–0.002; I
2=78.5%).

Conclusions:

MSA is a safe and effective procedure at reducing symptom burden of GERD and can potentially improve patient satisfaction and functional outcomes. However, randomized controlled trials directly comparing MSA with fundoplication are necessary to determine where MSA precisely fits in the management pathway of GERD.
Does an aptitude for surgery exist and can we predict it? An experimental study
Authors: Ruchay Zino , Pape Julian , Cordt Julia-Sophie , Kerres Carolina , Siehl Sebastian , Jansone Karina , Ackermann Johannes , Guenther Veronika , Mettler Liselotte , Allahqoli Leila , Maass Nicolai , Nees Frauke , Alkatout Ibrahim
Published: May 2024

Background:

The selection and allocation of surgeons with a greater potential for high surgical performance are essential aspects of improving the quality, safety, and effectiveness of surgical procedures. Objective of this trial was to determine the existence of basic skills and traits that would predict better performance in surgery, and those predictive factors that constitute a driving force in different stages of training.

Materials and methods:

The randomized crossover training trial took place from January 2021 to December 2021 and was conducted at an educational training center for minimally invasive surgery. A total of n=87 physicians (residents and experts) from surgical disciplines and n=239 fifth-year medical students were studied. The participants underwent extensive neuropsychological testing and surgical training, which was performed with conventional as well as robot-assisted laparoscopy by way of identical brief tasks conducted six times in a randomized crossover setting. Main Outcome was the latent factor structure of ‘psychomotor skills’, ‘personality’, and ‘motivation’ based on structural equation modeling.

Results:

The training performance of both students and physicians was significantly explained by the interaction of the three factors (explained variance: 8.2% for students, 23.8% for physicians). In students, motivation (explained variance 8.4%) and personality (explained variance 4.5%) revealed the highest contribution to surgical training performance (explained variance through psychomotor skills 1.1%). In physicians, psychomotor skills (explained variance 27.4%) made the greatest contribution to surgical training performance (explained variance through motivation 2.3%; explained variance through personality 10.5%).

Conclusion:

The study showed that surgical performance is sensitive to, and fragile in regard of nonsurgery-related general individual traits. This aligns with the notion that early selection of surgeons with prospects of high surgical performance is possible, and perhaps even necessary in order to keep up with future demands on the medical system.
MRI-based deep learning and radiomics for prediction of occult cervical lymph node metastasis and prognosis in early-stage oral and oropharyngeal squamous cell carcinoma: a diagnostic study
Authors: Lan Tianjun , Kuang Shijia , Liang Peisheng , Ning Chenglin , Li Qunxing , Wang Liansheng , Wang Youyuan , Lin Zhaoyu , Hu Huijun , Yang Lingjie , Li Jintao , Liu Jingkang , Li Yanyan , Wu Fan , Chai Hua , Song Xinpeng , Huang Yiqian , Duan Xiaohui , Zeng Dong , Li Jinsong , Cao Haotian
Published: May 2024

Introduction:

The incidence of occult cervical lymph node metastases (OCLNM) is reported to be 20–30% in early-stage oral cancer and oropharyngeal cancer. There is a lack of an accurate diagnostic method to predict occult lymph node metastasis and to help surgeons make precise treatment decisions.

Aim:

To construct and evaluate a preoperative diagnostic method to predict OCLNM in early-stage oral and oropharyngeal squamous cell carcinoma (OC and OP SCC) based on deep learning features (DLFs) and radiomics features.

Methods:

A total of 319 patients diagnosed with early-stage OC or OP SCC were retrospectively enrolled and divided into training, test and external validation sets. Traditional radiomics features and DLFs were extracted from their MRI images. The least absolute shrinkage and selection operator (LASSO) analysis was employed to identify the most valuable features. Prediction models for OCLNM were developed using radiomics features and DLFs. The effectiveness of the models and their clinical applicability were evaluated using the area under the curve (AUC), decision curve analysis (DCA), and survival analysis.

Results:

Seventeen prediction models were constructed. The Resnet50 deep learning (DL) model based on the combination of radiomics and DL features achieves the optimal performance, with AUC values of 0.928 (95% CI: 0.881–0.975), 0.878 (95% CI: 0.766–0.990), 0.796 (95% CI: 0.666–0.927), and 0.834 (95% CI: 0.721–0.947) in the training, test, external validation set1, and external validation set2, respectively. Moreover, the Resnet50 model has great prediction value of prognosis in patients with early-stage OC and OP SCC.

Conclusion:

The proposed MRI-based Resnet50 DL model demonstrated high capability in diagnosis of OCLNM and prognosis prediction in the early-stage OC and OP SCC. The Resnet50 model could help refine the clinical diagnosis and treatment of the early-stage OC and OP SCC.
Changes in Donor Utilization and Outcomes for Patients Bridged With Durable Left Ventricular Assist Device
Authors: Akbar Armaan F. , Perdomo Dianela , Shou Benjamin L. , Zhou Alice L. , Ruck Jessica M. , Kilic Ahmet
Published: May 2024

We studied the impact of the 2018 heart allocation policy change on donor characteristics and posttransplant outcomes of left ventricular assist device (LVAD)-bridged heart transplant (HT) recipients. Left ventricular assist device-bridged adult HT recipients from October 2014 to October 2022 in the United Network for Organ Sharing database were categorized into old allocation policy (OAP) and new allocation policy (NAP) cohorts. Baseline characteristics, posttransplant outcomes, and subgroup analyses of unstable and stable LVAD-bridged recipients were assessed. The study included 7,384 HT recipients; 4,345 (58.8%) were transplanted in the OAP era and 3,039 (41.2%) in the NAP era. Old allocation policy recipients were most frequently status 1A at transplantation (71.1%), whereas NAP recipients were most frequently status 3 (40.0%), and status 4 (31.9%). Median donor sequence number (DSN) was higher in the NAP versus OAP era (9 vs. 3, p < 0.001). On multivariable analysis, NAP recipients had 20% higher 1 year mortality compared to OAP (adjusted hazard ratio [aHR] = 1.20 [95% confidence interval {CI}: 1.04–1.40], p = 0.01). Status 1 or 2 recipients had 28% higher 1 year mortality compared to status 1A (aHR = 1.28 [95% CI: 1.01–1.63], p = 0.04). Status 1 and 2 LVAD-supported recipients had higher mortality following the 2018 allocation change, indicating the need for closer surveillance of LVAD-bridged patients who may decompensate on the waitlist.
Estimating the Proportion of People Living With HIV Who May Benefit From the Reverse Algorithm for the Diagnosis of Incident Syphilis
Authors: Menza Timothy W. , Berry Stephen A. , Dombrowski Julia C. , Cachay Edward , Crane Heidi M. , Mayer Kenneth H.
Published: May 2024

Among 8455 people engaged in HIV care in 4 US cities, 4925 (58%) had treponemal testing at care entry. Of the 4925 tested, 3795 (77%) had a nonreactive result and might benefit from the reverse algorithm for a future incident syphilis diagnosis. Furthermore, low-barrier treponemal testing as a first step in the reverse algorithm may increase syphilis screening and decrease time to treatment.
Response to Antibiotic Treatment of Bacterial Vaginosis Predicts the Effectiveness of LACTIN-V (Lactobacillus crispatus CTV-05) in the Prevention of Recurrent Disease
Authors: Hemmerling Anke , Wierzbicki Michael R. , Armstrong Eric , Cohen Craig R.
Published: May 2024

Objectives

Live biotherapeutic products (LBPs) containing vaginal Lactobacillus crispatus are promising adjuvant treatments to prevent recurrent bacterial vaginosis (BV) but may depend on the success of initial antibiotic treatment.

Methods

A post hoc analysis of data collected during the phase 2b LACTIN-V randomized control trial (L. crispatus CTV-05) explored the impact of clinical BV cure defined as Amsel criteria 0 of 3 (excluding pH, per 2019 Food and Drug Administration guidance) 2 days after completion of treatment with vaginal metronidazole gel on the effectiveness of an 11-week LACTIN-V dosing regimen to prevent BV recurrence by 12 and 24 weeks.

Results

At enrollment, 88% of participants had achieved postantibiotic clinical BV cure. The effect of LACTIN-V on BV recurrence compared with placebo differed by initial clinical BV cure status. The LACTIN-V to placebo risk ratio of BV recurrence by 12 weeks was 0.56 (95% confidence interval, 0.35–0.77) among participants with initial clinical BV cure after metronidazole treatment and 1.34 (95% confidence interval, 0.47–2.23) among participants without postantibiotic clinical BV cure. Among women receiving LACTIN-V, those who had achieved postantibiotic clinical BV cure at enrollment reached higher levels of detectable L. crispatus CTV-05 compared with women failing to achieve postantibiotic clinical BV cure.

Conclusions

LACTIN-V seems to only decrease BV recurrence in women with clinical cure of BV after initial antibiotic treatment. Future trials of LBPs should consider limiting enrollment to these women.
Rescuing DNMT1 Fails to Fully Reverse the Molecular and Functional Repercussions of Its Loss in Mouse Embryonic Stem Cells
Authors: Elder Elizabeth , Lemieux Anthony , Legault Lisa-Marie , Caron Maxime , Bertrand-Lehouillier Virginie , Dupas Thomas , Raynal Noël J-M , Bourque Guillaume , Sinnett Daniel , Gévry Nicolas , McGraw Serge
Published: May 2024

Epigenetic mechanisms are crucial for developmental programming and can be disrupted by environmental stressors, increasing susceptibility to disease. This has sparked interest in therapies for restoring epigenetic balance, but it remains uncertain whether disordered epigenetic mechanisms can be fully corrected. Disruption of DNA methyltransferase 1 (DNMT1), responsible for DNA methylation maintenance, has particularly devastating biological consequences. Therefore, here we explored if rescuing DNMT1 activity is sufficient to reverse the effects of its loss utilizing mouse embryonic stem cells. However, only partial reversal could be achieved. Extensive changes in DNA methylation, histone modifications and gene expression were detected, along with transposable element de-repression and genomic instability. Reduction of cellular size, complexity and proliferation rate were observed, as well as lasting effects in germ layer lineages and embryoid bodies. Interestingly, by analyzing the impact on imprinted regions, we uncovered 20 regions exhibiting imprinted-like signatures. Notably, while many permanent effects persisted throughoutDnmt1inactivation and rescue, others arose from the rescue intervention. Lastly, rescuing DNMT1 after differentiation initiation worsened outcomes, reinforcing the need for early intervention. Our findings highlight the far-reaching functions of DNMT1 and provide valuable perspectives on the repercussions of epigenetic perturbations during early development and the challenges of rescue interventions.

HIGHLIGHTS

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Extensive changes to epigenomic landscapes and gene expression following transient loss of DNMT1 activity

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Dysregulation of known imprinted regions and identification of 20 regions with imprinted-like signatures

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De-repression of MERVL and MT2 LTRs with evidence of chimeric gene transcript generation

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Shorter telomeres, DNA damage accumulation and reduction of cell size, internal complexity and proliferation rate

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Lasting effects upon differentiation toward germ layer lineages and embryoid bodies

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Worsened molecular and cellular outcomes when delayingDnmt1rescue until after differentiation initiation

GRAPHICAL ABSTRACT
Shadows over Caribbean reefs: Identification of a new invasive soft coral species,Xenia umbellata, in southwest Puerto Rico
Authors: Toledo-Rodriguez Daniel A. , Veglia Alex , Jimenez Marrero Nilda M. , Gomez-Samot Joyce M. , McFadden Catherine S. , Weil Ernesto , Schizas Nikolaos V.
Published: May 2024

In October 2023, several colonies of an alien soft coral species were reported on shallow reefs in southwest Puerto Rico. The soft coral was identified as a xeniid octocoral (species undetermined), resembling the octocoralUnomia stolonifera, which has invaded and overgrown reefs in Venezuela in recent years. To conclusively characterize the species of the invading xeniid, we employed multilocus barcoding targeting four genes (ND2, mtMutS, COI, and 28S) of three separate colonies across three locations in southwest Puerto Rico. Sequence comparisons with xeniid sequences from GenBank, including those from the generaXeniaandUnomia, indicated a 100% sequence identity (>3,000 bp combined) with the speciesXenia umbellata(Octocorallia : Malacalcyonacea : Xeniidae).Xenia umbellatais native to the Red Sea and to our knowledge, this represents the first confirmed case of this species as an invader on Caribbean reefs. Similar toU. stolonifera, X. umbellatais well known for its ability to rapidly overgrow substrate as well as tolerate environmental extremes. In addition,X. umbellatahas recently been proposed as a model system for tissue regeneration having the ability to regenerate completely from a single tentacle. These characteristics greatly amplifyX. umbellata’s potential to adversely affect any reef it invades. Our findings necessitate continued collaborative action between local management agencies and stakeholders in Puerto Rico, as well as neighboring islands, to monitor and control this invasion prior to significant ecological perturbation.
Embryo spatial 3D genomics
Authors: Ma Yuang , Gou Bo , Xu Yuetong , Shu Muya , Lu Falong , Li Xiang
Published: May 2024

The 3D architecture of the genome is crucial for controlling gene expression and organ development. Here, we introduce a spatial 3D genomics approach for assessing chromatin conformationin-situin tissue sections, by integrating microfluidic deterministic barcoding and SPRITE procedures. This method was applied to mouse embryo sections, revealing a hierarchical model of chromatin interactions within and between compartments in various organs. The intra-compartment interactions vary among organs to orchestrate gene expressions, while the inter-compartment interactions remain identical in the most organs. Beyond this, the liver exhibits overwhelmingly packed chromatin with enhanced adjacent-compartment interactions, possibly related to its physiology. These findings highlight the importance of tissue-spatial information in understanding embryonic chromatin organization. The approach presents a powerful tool for investigating these processes in tissues with high heterogeneity.

One Sentence Summary

A spatial 3D genomics approach was developed that accesses hierarchical chromatin conformationin-situin tissue sections.
Characterization of a Biochemical Mouse Model of Primary Aldosteronism for Thermal Therapies
Authors: Timmerman Sarah A. , Mullen Nathan , Taylor Angela E , Gilligan Lorna C , Pyle Marla , Shrestha Tej B. , Sebek Jan , Highland Margaret A. , Challapalli Ritihaas , Arlt Wiebke , Bossmann Stefan H. , Dennedy Michael Conall , Prakash Punit , Basel Matthew T.
Published: May 2024

Introduction

Aldosterone-producing adenoma (APA) is the most common cause of endocrine-related hypertension but surgery is not always feasible. Current medical interventions are associated with significant side effects and poor patient compliance. New APA animal models that replicate basic characteristics of APA and give physical and biochemical feedback are needed to test new non-surgical treatment methods, such as image-guided thermal ablation,

Methods

A model of APA was developed in nude mice using HAC15 cells, a human adrenal carcinoma cell line. Tumor growth, aldosterone production, and sensitivity to angiotensin II were characterized in the model. The utility of the model was validated via treatment with microwave ablation and characterization of the resulting physical and biochemical changes in the tumor.

Results

The APA model showed rapid and relatively homogeneous growth. The tumors produced aldosterone and steroid precursors in response to angiotensin II challenge, and plasma aldosterone levels were significantly higher in tumor bearing mice two hours after challenge verses non-tumor bearing mice. The model was useful for testing microwave ablation therapy, reducing aldosterone production by 80% in treated mice.

Conclusion

The HAC15 model is a useful tumor model to study and develop localized treatment methods for APA.
Improved differential expression analysis of miRNA-seq data by modeling competition to be counted
Authors: Jun Seong-Hwan , Halushka Marc K. , McCall Matthew N.
Published: May 2024

MicroRNAs play a central role in regulating gene expression and modulating diseases. Despite the importance of microRNAs, statistical methods for analyzing them have received far less attention compared to messenger RNAs. Commonly, messenger RNA-seq methods are applied to microRNA-seq data, which may produce erroneous results due to the highly competitive nature of microRNA sequencing. This study critically examines and challenges the assumptions of messenger RNA-seq methods when applied to microRNA-seq data. We propose a Negative Binomial Softmax Regression (NBSR) method to model the unique characteristics of microRNA-seq data. On both simulated and experimental datasets, NBSR outperforms existing methods and offers a new perspective for analyzing microRNA-seq data. NBSR is implemented in Python and freely available as open-source software.
PhoCoil: An Injectable and Photodegradable Single-component Recombinant Protein Hydrogel for Localized Therapeutic Cell Delivery
Authors: Gregorio Nicole E. , DeForest Cole A.
Published: May 2024

Hydrogel biomaterials offer great promise for 3D cell culture and therapeutic delivery. Despite many successes, challenges persist in that gels formed from natural proteins are only marginally tunable while those derived from synthetic polymers lack intrinsic bioinstructivity. Towards the creation of biomaterials with both excellent biocompatibility and customizability, recombinant protein-based hydrogels have emerged as molecularly defined and user-programmable platforms that mimic the proteinaceous nature of the extracellular matrix. Here, we introduce PhoCoil, a dynamically tunable recombinant hydrogel formed from a single protein component with unique multi-stimuli responsiveness. Physical crosslinking through coiled-coil interactions promotes rapid shear-thinning and self-healing behavior, rendering the gel injectable, while an included photodegradable motif affords on-demand network dissolution via visible light. PhoCoil gel photodegradation can be spatiotemporally and lithographically controlled in a dose-dependent manner, through complex tissue, and without harm to encapsulated cells. We anticipate that PhoCoil will enable new applications in tissue engineering and regenerative medicine.
KF4 anti-CELA1 Antibody and Purified α1-Antitrypsin Have Similar but Not Additive Efficacy in Preventing Emphysema in Murine α1-Antitrypsin Deficiency
Authors: Devine Andrew J. , Smith Noah J. , Joshi Rashika , Brooks-Patton Brandon , Dunham Jenna , Varisco Ansley N. , Goodman Emily M. , Fan Qiang , Zingarelli Basilia , Varisco Brian M.
Published: May 2024

Alpha-1 antitrypsin (AAT) deficiency is the most common genetic cause of emphysema. Chymotrypsin-like Elastase 1 (CELA1) is a serine protease neutralized by AAT and is important in emphysema progression.Cela1-deficiency is protective in a murine models of AAT-deficient emphysema. KF4 anti-CELA1 antibody prevented emphysema in PPE and cigarette smoke models in wild type mice. We evaluated potential toxicities of KF4 and its ability to prevent emphysema in AAT deficiency. We found Cela1 protein expression in mouse lung, pancreas, small intestine, and spleen. In toxicity studies, mice treated with KF4 25 mg/kg weekly for four weeks showed an elevation in blood urea nitrogen and slower weight gain compared to lower doses or equivalent dose IgG. In histologic grading of tissue injury of the lung, kidney, liver, and heart, there was some evidence of liver injury with KF4 25 mg/kg, but in all tissues, injury was less than in control mice subjected to cecal ligation and puncture. In efficacy studies, KF4 doses as low as 0.5 mg/kg reduced the lung elastase activity ofAAT-/-mice treated with 0.2 units of PPE. In this injury model,AAT-/-mice treated with KF4 1 mg/kg weekly, human purified AAT 60 mg/kg weekly, and combined KF4 and AAT treatment had less emphysema than mice treated with IgG 1 mg/kg weekly. However, the efficacy of KF4, AAT, or KF4 & AAT was similar. While KF4 might be an alternative to AAT replacement, combined KF4 and AAT replacement does not confer additional benefit.
Population genomics of a naturalCannabis sativaL. collection from Iran identifies novel genetic loci for flowering time, morphology, sex and chemotyping
Authors: Dehnavi Mahboubeh Mostafaei , Damerum Annabelle , Taheri Sadegh , Ebadi Ali , Panahi Shadab , Hodgin George , Brandley Brian , Salami Seyed Alireza , Taylor Gail
Published: May 2024

Future breeding and selection ofCannabis sativaL. for drug production and industrial purposes require a source of germplasm with wide genetic variation, such as that found in wild relatives and progenitors of highly cultivated plants. Limited directional selection and breeding have occurred in this crop, especially informed by molecular markers. Here, we investigated the population genomics of a natural cannabis collection of male and female individuals from differing climatic zones in Iran. Using Genotyping-By-Sequencing (GBS), we sequenced 228 genotypes from 35 populations. The results obtained from GBS were used to perform association analysis identifying links between genotype and important phenotypes, including inflorescence characteristics, flowering time, plant morphology, tetrahydrocannabinol (THC) content, cannabidiol (CBD) content and sex. Approximately 23,266 significant SNPs of high quality were detected to establish associations between markers and traits, and population structure showed that Iranian cannabis plants fall into five groups. A comparison of Iranian samples from this study to global data suggests that the Iranian population is distinctive and, in general, is closer to marijuana than to hemp, although some populations in this collection are closer to hemp. The GWAS results showed that novel genetic loci, not previously identified, contribute to sex, yield and chemotype traits in cannabis and are worthy of further study.
Single cell profiling of bone metastasis ecosystems from multiple cancer types reveals convergent and divergent mechanisms of bone colonization
Authors: Liu Fengshuo , Ding Yunfeng , Xu Zhan , Hao Xiaoxin , Pan Tianhong , Miles George , Wu Yi-Hsuan , Liu Jun , Bado Igor L. , Zhang Weijie , Wu Ling , Gao Yang , Yu Liqun , Edwards David G. , Chan Hilda L. , Aguirre Sergio , Dieffenbach Michael Warren , Chen Elina , Shen Yichao , Hoffman Dane , Dominguez Luis Becerra , Rivas Charlotte Helena , Chen Xiang , Wang Hai , Gugala Zbigniew , Satcher Robert L. , Zhang Xiang H.-F.
Published: May 2024

Bone represents congenial soil for metastatic seeds and is frequently affected by metastasis of multiple cancer types. The histological and molecular characteristics of bone metastases (BMs) are diverse but poorly understood. Herein, we performed single-cell RNA-seq on 34 BMs from 6 cancer types and identified 3 ecosystem archetypes characterized by enrichment of macrophages/osteoclasts (Mφ-OC), regulatory/exhausted T cells (Treg-Tex), and monocytes (Mono), respectively. Breast cancer BMs are mostly the Mφ-OC archetype driven by the osteolytic vicious cycle, whereas kidney cancers BMs mainly belong to the Treg-Tex archetype that lacks osteoclasts. Lung cancers BMs evenly distributed across all archetypes. Further analyses revealed parallel mechanisms of immunosuppression and bone remodeling. Elevated estrogen signaling distinguishes macrophages in the Mφ-OC subtype, which was investigated in a companion study. Together, we elucidated that divergent mechanisms toward bone colonization and that BMs of different origins can adopt the same mechanism through convergent evolution or adaptation.

HIGHLIGHTS

Analyses of bone metastases from 6 cancer types revealed three immune archetypes.

Archetypes diverge on immune trajectories, and features of tumor and stromal cells.

Dominant cell type in each archetype undergoes convergent evolution.

Regulatory networks converge on osteoclasts and Tregs to drive archetype formation.

Graphic Abstract
Crosslinker Architectures Impact Viscoelasticity in Dynamic Covalent Hydrogels
Authors: Lin Yung-Hao , Lou Junzhe , Xia Yan , Chaudhuri Ovijit
Published: May 2024

Dynamic covalent crosslinked (DCC) hydrogels represent a significant advance in biomaterials for regenerative medicine and mechanobiology. These gels typically offer viscoelasticity and self-healing properties that more closely mimicin vivotissue mechanics than traditional, predominantly elastic, covalent crosslinked hydrogels. Despite their promise, the effects of varying crosslinker architecture – side chain versus telechelic crosslinks – on the viscoelastic properties of DCC hydrogels have not been thoroughly investigated. This study introduces hydrazone-based alginate hydrogels and examines how side-chain and telechelic crosslinker architectures impact hydrogel viscoelasticity and stiffness. In hydrogels with side-chain crosslinking (SCX), higher polymer concentrations enhance stiffness and decelerates stress relaxation, while an off-stoichiometric hydrazine-to-aldehyde ratio leads to reduced stiffness and shorter relaxation time. In hydrogels with telechelic crosslinking, maximal stiffness and slowest stress relaxation occurs at intermediate crosslinker concentrations for both linear and star crosslinkers, with higher crosslinker valency further increasing stiffness and relaxation time. Our result suggested different ranges of stiffness and stress relaxation are accessible with the different crosslinker architectures, with SCX hydrogels leading to slower stress relaxation relative to the other architectures, and hydrogels with star crosslinking (SX) providing increased stiffness and slower stress relaxation relative to hydrogels with linear crosslinking (LX). The mechanical properties of SX hydrogels are more robust to changes induced by competing chemical reactions compared to LX hydrogels. Our research underscores the pivotal role of crosslinker architecture in defining hydrogel stiffness and viscoelasticity, providing crucial insights for the design of DCC hydrogels with tailored mechanical properties for specific biomedical applications.
A method for filtering abnormal modified base calling in Oxford Nanopore Technologies sequencing
Authors: Jia Ruikai , Wang Yusha , Ye Hua , Ma Xiaoshu
Published: May 2024

Background

gene synthesis sequencing using the long-read Oxford Nanopore Technologies (ONT) provides a cost-effective option for gene synthesis quality control. Despite the advantage of using long reads, however, accurate base calling is influenced by modified bases.

Results

We introduce a method for filtering abnormal modified base calling in Oxford Nanopore Technologies sequencing. This method is based on the mapping results and perform an exact binomial test on the proportion of single base forward and reverse chain depth to determine the presence of abnormal modified base calling. Based on Sanger sequencing results, this method detected 96.79% of effective abnormal modified base calling, and the accuracy of gene synthesis sequencing increased from 99.40% before calibration to 99.98% after calibration, significantly reducing the proportion of requiring secondary gene synthesis sequencing.

Conclusion

This method can accurately filter abnormally modified base calling sites, reduce the proportion of using Sanger for secondary sequencing, thereby saving costs, and improving efficiency.
A pressure-jump EPR system to monitor millisecond conformational exchange rates of spin-labeled proteins
Authors: Grosskopf Julian D. , Sidabras Jason W. , Altenbach Christian , Anderson Jim R. , Mett Richard R. , Strangeway Robert A. , Hyde James S. , Hubbell Wayne L. , Lerch Michael T.
Published: May 2024

Site-directed spin labeling electron paramagnetic resonance (SDSL-EPR) using nitroxide spin labels is a well-established technology for mapping site-specific secondary and tertiary structure and for monitoring conformational changes in proteins of any degree of complexity, including membrane proteins, with high sensitivity. SDSL-EPR also provides information on protein dynamics in the time scale of ps-μs using continuous wave lineshape analysis and spin lattice relaxation time methods. However, the functionally important time domain of μs-ms, corresponding to large-scale protein motions, is inaccessible to those methods. To extend SDSL-EPR to the longer time domain, the perturbation method of pressure-jump relaxation is implemented. Here, we describe a complete high-pressure EPR system at Q-band for both static pressure and millisecond-timescale pressure-jump measurements on spin-labeled proteins. The instrument enables pressure jumps both up and down from any holding pressure, ranging from atmospheric pressure to the maximum pressure capacity of the system components (∼3500 bar). To demonstrate the utility of the system, we characterize a local folding-unfolding equilibrium of T4 lysozyme. The results illustrate the ability of the system to measure thermodynamic and kinetic parameters of protein conformational exchange on the millisecond timescale.