bluuebunny/crossref_metadata_2025 huggingface dataset:
HPV16/18 antibodies 16-years after single dose of bivalent HPV vaccination: Costa Rica HPV vaccine trial
Authors: Porras Carolina , Romero Byron , Kemp Troy , Fantin Romain , Herrero Rolando , Hildesheim Allan , Ocampo Rebeca , Sierra Mónica S , Gail Mitchell H , Schussler John , Schiller John T , Lowy Douglas R , Pinto Ligia A , Liu Danping , Kreimer Aimée R ,   Costa Rica HPV Vaccine Trial Study Group, Cortés Bernal , González Paula , Herrero Rolando , Jiménez Silvia E , Porras Carolina , Rodríguez Ana Cecilia , Hildesheim Allan , Kreimer Aimée R , Lowy Douglas R , Schiffman Mark , Schiller John T , Sherman Mark , Wacholder Sholom , Pinto Ligia A , Kemp Troy J , Sidawy Mary K , Quint Wim , van Doorn Leen-Jan , Struijk Linda , Palefsky Joel M , Darragh Teresa M , Stoler Mark H
Published: November 2024

Background

The Costa Rica HPV Vaccine Trial provided initial evidence that 1 dose of the bivalent human papillomavirus (HPV) vaccine induces stabilizing antibody levels that may provide extended protection against HPV-16/18 infections. We report antibody seropositivity and stability 11 to 16 years after vaccination.

Methods

We invited a random subset of Costa Rica HPV Vaccine Trial participants (n = 398) who had received 3 doses and all women (n = 203) who had received 1 dose at 18 to 25 years of age to follow-up visits 11, 14, and 16 years after vaccination. We calculated HPV-16 and HPV-18 seropositivity and assessed change in enzyme-linked immunosorbent assay antibody levels 11 to 16 years after vaccination among 500 participants.

Results

By year 16, 99.4% (95% confidence interval [CI] = 96.8% to 100.0%) and 100.0% (95% CI = 98.9% to 100.0%) of 1-dose and 3-dose recipients, respectively, were HPV-16 seropositive and 98.8% (95% CI = 95.9% to 99.9%) and 100% (95% CI = 98.9% to 100.0%) of 1-dose and 3-dose recipients, respectively, were HPV-18 seropositive. Between years 11 and 16, women who had received 3 doses had a small but statistically significant decrease in the geometric mean concentration for HPV-16 of ‒12.4% (95% CI = ‒16.3% to ‒8.4%) and HPV-18 of ‒13.4% (95% CI = ‒17.2% to ‒9.4%). Among women who had received 1 dose, the decrease was statistically significant for HPV-16 at ‒8.9 (95% CI = ‒14.2% to ‒3.1%) but nonsignificant for HPV-18. Geometric mean concentration ratios of 3:1 dose (year 16) were 3.0 and 2.2 for HPV-16 and HPV-18, respectively.

Conclusions

HPV-16/18 seropositivity remained exceedingly high 16 years after vaccination. Over 5 years, small declines in antibodies were observed. Women should have protection for at least 20 years and likely much longer at the observed rate of decline.
Population-level impact of switching to 1-dose human papillomavirus vaccination in high-income countries: examining uncertainties using mathematical modeling
Authors: Brisson Marc , Laprise Jean-François , Drolet Mélanie , Chamberland Éléonore , Bénard Élodie , Burger Emily A , Jit Mark , Kim Jane J , Markowitz Lauri E , Sauvageau Chantal , Sy Stephen
Published: November 2024

Background

A concern in high-income countries is that switching to 1-dose human papillomavirus (HPV) vaccination could cause a rebound in HPV infection and cervical cancer if 1-dose efficacy or duration were inferior to 2 doses. Using mathematical modeling and up-to-date trial-based data, we projected the population-level effectiveness of switching from 2-dose to 1-dose vaccination under different vaccine efficacy and duration assumptions in high-income countries.

Methods

We used HPV-ADVISE (Agent-based Dynamic model for VaccInation and Screening Evaluation), a transmission-dynamic model of HPV infection and cervical cancer, varying key model assumptions to identify those with the greatest impact on projections of HPV-16 and cervical cancer incidence over time: 1) 1-dose vaccine efficacy and vaccine duration, 2) mechanisms of vaccine efficacy and duration over time, 3) midadult (>30 years of age) sexual behavior, 4) progression to cervical cancer among midadults, and 5) vaccination coverage and programs.

Results

In high-income countries, 1-dose vaccination would cause no appreciable rebound in HPV-16 infection, except for a limited rebound under the most pessimistic assumptions of vaccine duration (average, 25 years), because 1) the switch would occur when HPV prevalence is low because of high 2-dose vaccination coverage and 2) individuals would be protected during their peak ages of sexual activity (<35 to 40 years of age). Our model projects a more limited rebound in cervical cancer because of a shift to older age at infection, resulting in fewer life-years left to potentially develop cancer. Projections were robust when varying key model assumptions.

Conclusions

High protection during peak ages of sexual activity in high-income countries would likely mitigate any potential rebounds in HPV infection and cervical cancer under the most pessimistic assumptions of 1-dose efficacy and duration.
A cervical cancer control strategy for lower-resource settings: interventions to complement one-dose HPV vaccination
Authors: Campos Nicole G , Lowy Douglas R , de Sanjosé Silvia , Schiffman Mark
Published: November 2024

One-dose prophylactic HPV vaccination of pre-adolescents may reduce cervical cancer deaths dramatically in lower-resource settings, but the benefits of achieving immediate high coverage among pre-adolescents would not be realized for 20 to 40 years. Prophylactic vaccine efficacy is reduced after sexual debut, and current therapeutic intervention candidates designed to treat existing HPV infections or precancerous lesions have yielded insufficient evidence to warrant widespread use. However, we are developing a feasible, scalable, high-quality cervical screening approach that could prevent hundreds of thousands of deaths, while we work to achieve high coverage of one-dose vaccination for adolescent cohorts. A time-limited “one screen” campaign approach for lower-resource settings could complement parallel efforts to achieve high coverage with one-dose vaccination. This screen-triage-treat strategy would target the highest risk groups of screening age (ie, 25 to 49 years) for once-in-a-lifetime HPV testing of self-collected samples using a low-cost accurate HPV test; subsequent triage relying on extended genotyping and a validated deep-learning algorithm for automated visual evaluation (AVE) would stratify management based on risk to provide treatment for those most likely to develop cancer without overburdening health care systems. Early efficacy of this approach has been demonstrated in 9 countries within the HPV-AVE (PAVE) Study Consortium. We estimate that the cost per death averted of a screen-triage-treat campaign is of similar magnitude to prophylactic vaccination. We do not envision perpetual investment in ubiquitous brick-and-mortar screening programs if “one dose, one screen” is implemented with high coverage and targets the highest-risk populations. In collaboration with in-country stakeholders, efforts to ensure acceptability, risk communication, and cost-effectiveness are underway.
De-Med—a tool to identify and classify potentially inappropriate medication according to Beers criteria, STOPP, and FORTA: a cross-sectional study
Authors: Syed Jehath , Verma Auroshree , Chopra Vansh , Khemchandani Vineeta , Pereira Prathiba , Patil Vikram , Ramesh Madhan , Chalasani Sri Harsha
Published: November 2024

Objective

A significant number of older adults are affected by the use of potentially inappropriate medications (PIMs), leading to various adverse outcomes, such as increased physical and cognitive impairment, frailty, hospitalization, and mortality. The objective of this study was to develop and test the reliability and feasibility of the De-Med tool.

Methods

This tool was developed using ReactJS for data extraction and manipulation. Users can upload drug lists for analysis, and the software delineates PIMs adhering to the Beers 2019 version, Screening Tool of Older Persons’ Potentially Inappropriate Prescriptions (STOPP) Version 2, and Fit fOR The Aged (FORTA) 2021 criteria. Reliability was assessed by juxtaposing software-generated outputs with manual assessments conducted by independent research pharmacists using retrospective medication records. The System Usability Scale (SUS) and AttrakDiff Mini questionnaires were used to assess feasibility and usability, respectively.

Key findings

Manual and software-generated PIM identifications agreed completely, demonstrating high reliability (100% concordance). A total of 1496 PIMs were identified from 231 records, with an average of 0.63 encounters per patient. The overall usability score was 83.75, indicating “Excellent.” According to the AttrakDiff ratings, users attributed the software to both pragmatic (mean PQ:1.84) and hedonic (mean HQ:1.50) qualities, with moderate overall attractiveness (mean ATT:2.13).

Conclusions

This web-based tool successfully identified PIMs with perfect reliability, high usability, and a moderate level of attractiveness. This tool has the potential to improve medication management in older adults by reducing PIMs.
Angiostrongylus cantonensis Meningoencephalitis in Three Pediatric Patients in Florida, USA
Authors: Chance Melinda D , Noel Anniesha D , Thompson Amelia B , Marrero Natalie , Bula-Rudas Fernando , Horvat Christopher M , Green Jerril , Armstrong Jennifer E , Levent Fatma , Dudas Robert A , Shaffren Serena , Samide Aaron , Martinez Katie , Stockdale Kimberly , Chancey Rebecca J
Published: November 2024

Eosinophilic meningoencephalitis caused by Angiostrongylus cantonensis has been reported in several southern U.S. states and Hawai‘i. We present the first locally acquired human cases of A. cantonensis meningoencephalitis in three children in Florida, occurring between June 2021 and January 2022. Clinicians should be attuned to this possible diagnosis in this region.
Feasibility of creating a daily adaptive plan using automatic DIR-created target and OARs contours in patients with prostate cancer magnetic-resonance-guided adaptive radiotherapy
Authors: Saito Makoto , Abe Kota , Tsuneda Masato , Fujita Yukio , Abe Yukinao , Nishimura Tsumugi , Kodate Asuka , Kanazawa Aki , Harada Rintaro , Watanabe Miho , Uno Takashi
Published: November 2024

The purpose of this study was to evaluate the feasibility of treatment plans for prostate cancer with magnetic resonance (MR)-guided online adaptive radiotherapy, which are generated using deformable image registration (DIR)-created contours of the targets and organs. Totally, 150 fractions from 30 prostate cancer patients implanted with a hydrogel spacer and treated with the MR-Linac were studied. Reference treatment plans that satisfied all institutional dose constraints were initially created on planning MRI. The adaptive treatment plans were created on daily MRI based on the reference plan using the DIR-created contours, ensuring all dose constraints were met. Subsequently, a clinician manually created reference contours for each daily MRI. Finally, the dose volume histogram indices of the plan generated with DIR-created contours were re-evaluated with clinician created contours. The evaluated contours included the bladder wall, rectum wall, sigmoid, small bowel and planning target volume (PTV) for dose prescription. The PTV for dose prescription met the dose constraints in all fractions. The bladder and rectum walls met the dose constraint of maximum dose (D0.03 cc) in all fractions. Five patients failed to meet the sigmoid and small bowel dose constraints, with the largest deviation being 13.3% exceedance at D2 cc in the small bowel added 3 mm margin. This study suggests that most treatment plans created without modifying the DIR-created contours are clinically viable. However, dislodgements of the small bowel and sigmoid may exceed the extent of DIR propagation from the reference plan contours, and it is recommended that these contours be verified.
The Paradoxical Development of Liberal Governance: International Adoption Policy and Professional Social Work in Authoritarian South Korea, 1953–1976
Authors: Koo Youngeun
Published: November 2024

This article explores the development of international adoption policy in post-liberation South Korea, emphasizing the roles of American and Korean professional social workers. By analyzing the orphan registry and a pivotal international adoption law, it reveals how international adoption in South Korea presents a unique opportunity to observe the formation of modern social policy in a newly liberated nation during the Cold War. The study argues that adoption policy served as a crucial locus of transnational governance, where American and Korean social workers pursued their liberal ideals of professional social work within the context of the authoritarian policies of the South Korean state. However, their quest for scientific professionalism, standardized procedures, and public oversight led to a paradoxical evolution of adoption policy, diverging sharply from the trajectory seen in Western liberal democracies where social work significantly contributed to the consolidation and expansion of the welfare state. In South Korea, embedded transnationality and ideological mismatch resulted in the state’s further withdrawal and the creation of policy workarounds that undermined the core social work principle of the child’s best interests. This case highlights the complexities and blurred moral boundaries in the shaping of modern governance and the broader journey toward modernity under postcolonial, Cold War conditions.
Predictors of corporo-venocclusive dysfunction in men with bilateral nerve-sparing radical prostatectomy
Authors: Flores Jose M , Novaes Luis F , Vertosick Emily , Salter Carolyn , Liso Nicole , Vickers Andrew J , Mulhall John P , FECSM
Published: November 2024

Background

Erectile dysfunction (ED) is seen in some men who have undergone bilateral nerve-sparing surgery. Corporo-venocclusive dysfunction (CVOD) is the major pathway to permanent ED after radical prostatectomy (RP).

Aim

To identify comorbidity factors that are associated with the presence of CVOD in men who had undergone bilateral nerve-sparing RP.

Methods

We included patients who had no ED before RP, underwent bilateral nerve-sparing RP, were unresponsive to pharmacotherapy, and had a penile Duplex Doppler Ultrasound (PDDU) with a diagnosis of CVOD. PDDU was performed with a redosing vasoactive agent protocol. A logistic regression model was created to define predictors of CVOD, defined as end-diastolic velocity (EDV) ≥ 5 cm/s bilaterally.

Outcomes

CVOD diagnosis.

Results

135 patients with a median age of 60 (IQR 54, 64) years were included. 45% reported ≥2 comorbidities, 10% diabetes, 28% obstructive sleep apnea (OSA), and 44% were current or former smokers. At PDDU, 34% had less than penetration hardness erections, and 43% received 100 units of vasoactive agent. 44% were diagnosed with CVOD. Increased age at RP (OR 2.12 per 10 years, 95% CI 2.35, 3.73, P = .007) and OSA (OR 2.44, 95% CI 1.07, 5.73, P = .036) were associated with a diagnosis of CVOD.

Clinical implications

Comorbidities, especially OSA, have a role in erection recovery after surgery.

Strengths and limitations

The study used a well-established institutional RP nerve-sparing score, a strict PDDU vasoactive agent redosing protocol, validated cut-offs for CVOD diagnosis, and a validated erectile function questionnaire both pre- and post-operatively. The major limitation is that this is a cohort of men seeking treatment at a sexual medicine clinic for post-operative ED, which limits the generalizability of the results to patients without ED symptoms or who decided not to seek treatment. The dichotomous definition of comorbidities is also a limitation since patients can have differing degrees of comorbidities’ severity.

Conclusion

Older patients and the presence of OSA were associated with the presence of CVOD.
Mycorrhization and chemical seed priming boost tomato stress tolerance by changing primary and defence metabolic pathways
Authors: Giovannini Luca , Pagliarani Chiara , Cañizares Eva , Sillo Fabiano , Chitarra Walter , De Rose Silvia , Zampieri Elisa , Ioannou Andreas , Spanos Alexandros , Vita Federico , González-Guzmán Miguel , Fotopoulos Vasileios , Arbona Vicent , Balestrini Raffaella
Published: November 2024

Priming modulates plant stress responses before the stress appears, increasing the ability of the primed plant to endure adverse conditions and thrive. In this context, we investigated the effect of biological (i.e. arbuscular mycorrhizal fungi, AMF) agents and natural compounds (i.e. salicylic acid applied alone or combined with chitosan) against water deficit and salinity on a commercial tomato genotype (cv. Moneymaker). Effects of seed treatments on AMF colonization were evaluated, demonstrating the possibility of using them in combination. Responses to water and salt stresses were analysed on primed plants alone or in combination with the AMF inoculum in soil. Trials were conducted on potted plants by subjecting them to water deficit or salt stress. The effectiveness of chemical seed treatments, both alone and in combination with post-germination AMF inoculation, was investigated using a multidisciplinary approach that included ecophysiology, biochemistry, transcriptomics, and untargeted metabolomics. Results showed that chemical seed treatment and arbuscular mycorrhizal symbiosis modified the tomato response to water deficit and salinity triggering a remodelling of both transcriptome and metabolome, which ultimately elicited the plant antioxidant and osmoprotective machinery. The plant physiological adaptation to both stress conditions improved, confirming the success of the adopted approaches in enhancing stress tolerance.
A New Polyphonic Source from Sixteenth-Century Scotland
Authors: Newton-Jackson Paul , Coney David , Cook James
Published: November 2024

This article discusses a new source of sacred polyphonic music from sixteenth-century Scotland, one which had remained hidden for more than five centuries as marginalia within a printed book. Despite containing only a small amount of music, this source can tell us a great deal about cultures of written and improvised liturgical music in pre-Reformation Scotland, a time and place from which very little notated music survives. The music in this source has no text, title, or attribution. However, we reveal the identity of the music as the tenor part of a faburden on the Office hymn Cultor Dei memento and we determine that it was most likely written down in Aberdeenshire, in the north-east of Scotland. Finally, by analysing the book’s non-musical annotations, we explore a series of likely owners of the book—and what it might have meant to own such an object—during the turbulent period in Scotland from the early sixteenth century to the late seventeenth.
Are all models wrong? Falsifying binary formation models in gravitational-wave astronomy using exceptional events
Authors: Passenger Lachlan , Thrane Eric , Lasky Paul , Payne Ethan , Stevenson Simon , Farr Ben
Published: November 2024

As the catalogue of gravitational-wave transients grows, several entries appear ‘exceptional’ within the population. Tipping the scales with a total mass of $\sim 150 \,{\rm M}_\odot$, GW190521 likely contained black holes in the pair-instability mass gap. The event GW190814, meanwhile, is unusual for its extreme mass ratio and the mass of its secondary component. A growing model-building industry has emerged to provide explanations for such exceptional events, and Bayesian model selection is frequently used to determine the most informative model. However, Bayesian methods can only take us so far. They provide no answer to the question: does our model provide an adequate explanation for exceptional events in the data? If none of the models we are testing provide an adequate explanation, then it is not enough to simply rank our existing models – we need new ones. In this paper, we introduce a method to answer this question with a frequentist p-value. We apply the method to different models that have been suggested to explain the unusually massive event GW190521: hierarchical mergers in active galactic nuclei and globular clusters. We show that some (but not all) of these models provide adequate explanations for exceptionally massive events like GW190521.
Deep drilling in the time domain with DECam – II: characterizing the light curves of candidates in the extragalactic fields
Authors: Graham Melissa L , Rollins Midori , Knop Robert A , Dhawan Suhail , Fonseca Alvarez Gloria , Phillips Christopher A , Nir Guy , Ramey Emily , Nugent Peter E
Published: November 2024

In this second paper on the DECam deep-drilling field (DDF) program, we release 2020 optical $gri$-band light curves for transients and variables in the extragalactic COSMOS and ELAIS fields based on time series observations with a 3-d cadence from semester 2021A through 2023A. In order to demonstrate the wide variety of time domain events detected by the program and encourage others to use the data set, we characterize the sample by presenting a brief analysis of the light-curve parameters such as time span, amplitude, and peak brightness. We also present preliminary light-curve categorizations, and identify potential stellar variables, active galactic nuclei, tidal disruption events, supernovae (SNe) (such as Type Ia, Type IIP, superluminous, and gravitationally lensed SNe), and fast transients. Where relevant, the number of identified transients is compared to the predictions of the original proposal. We also discuss the challenges of analyzing DDF data in the context of the upcoming Vera C. Rubin Observatory and its Legacy Survey of Space and Time, which will include DDFs. Images from the Dark Energy Camera DDF program are available without proprietary period and the light curves presented in this work are publicly available for analysis.
Late-time non-thermal emission from mildly relativistic tidal ejecta of compact objects merger
Authors: Sadeh Gilad
Published: November 2024

Mergers of compact objects [binary neutron stars or neutron star-black hole (NSBH)] with a substantial mass ratio ($q\gt 1.5$) are expected to produce a mildly relativistic ejecta within $\sim 20^\circ$ from the equatorial plane. We present a semi-analytic approach to calculate the expected synchrotron emission observed from various viewing angles, along with the corresponding radio maps, that are produced by a collisionless shock driven by such ejecta into the interstellar medium. This method reproduces well (up to $\sim 30~{{\ \rm per\ cent}}$ deviations) the observed emission produced by 2D numerical calculations of the full relativistic hydrodynamics. We consider a toroidal ejecta with an opening angle of $15^\circ \le \theta _ \text{open}\le 30^\circ$ and broken power-law mass distribution, $M(\gt \gamma \beta)\propto (\gamma \beta)^{-s}$ with $s=s_{\rm KN}$ at $\gamma \beta \lt \gamma _0\beta _0$ and $s=s_{\rm ft}$ at $\gamma \beta \gt \gamma _0\beta _0$ (where $\gamma$ is the Lorentz factor). The parameter values are chosen to characterize merger calculation results – a ‘shallow’ mass distribution, $1\lt s_{\rm KN}\lt 3$, for the bulk of the ejecta (at $\gamma \beta \approx 0.2$), and a steep, $s_{\rm ft}\gt 5$, ‘fast tail’ mass distribution. While the peak flux is dimmer by a factor of $\sim$2–3, and the peak time remains roughly the same (within 20 per cent), for various viewing angles compared to isotropic equivalent ejecta ($\theta _\text{open}=90^\circ$) considered in preceding papers, the radio maps are significantly different from the spherical case. The semi-analytic method can provide information on the ejecta geometry and viewing angle from future radio map observations and, consequently, constrain the ejection mechanism. For NSBH mergers with a significant mass ejection ($\sim 0.1\,{\rm M}_\odot$), this late non-thermal signal can be observed to distances of $\lesssim 200$ Mpc for typical parameter values.
Evolution of Sex-linked Genes and the Role of Pericentromeric Regions in Sex Chromosomes: Insights from Diploid Willows
Authors: Wang Yi , Zhang Ren-Gang , Hörandl Elvira , Zhang Zhi-Xiang , Charlesworth Deborah , He Li
Published: November 2024

The evolution of sex chromosomes can involve recombination suppression sometimes involving structural changes, such as inversions, allowing subsequent rearrangements, including inversions and gene transpositions. In the two major genus Salix clades, Salix and Vetrix, almost all species are dioecious, and sex-linked regions have evolved on chromosome 7 and 15, with either male or female heterogamety. We used chromosome conformation capture (Hi-C) and PacBio HiFi (high-fidelity) reads to assemble chromosome-level, gap-free X and Y chromosomes from both clades, S. triandra (15XY system), a basal species in the Vetrix clade, and the Salix clade species S. mesnyi (7XY system). Combining these with other available genome assemblies, we found inversions within the sex-linked regions, which are likely to be pericentromeric and probably recombined rarely in the ancestral species, before sex-linkage evolved. The Y-linked regions in all 15XY and 7XY species include partial duplicates containing exon 1 of an ARR17-like gene similar to male-determining factors in other Salicaceae species. We also found duplicates of a Y-specific gene, which we named MSF. The derived Salix clade 7XY chromosome systems appear to have evolved when these two genes transposed from the 15Y to the 7Y. Additionally, the 7Y chromosomes in S. dunnii and S. chaenomeloides probably evolved from the ancestral 7X of the Salix clade, involving a similar transposition, and loss of the ancestral 7Y. We suggest that pericentromeric regions that recombine infrequently may facilitate the evolution of sex linkage.
Convergent Degenerated Regulatory Elements Associated with Limb Loss in Limbless Amphibians and Reptiles
Authors: Zhu Chenglong , Li Shengyou , Zhang Daizhen , Zhang Jinjin , Wang Gang , Zhou Botong , Zheng Jiangmin , Xu Wenjie , Wang Zhengfei , Gao Xueli , Liu Qiuning , Xue Tingfeng , Zhang Huabin , Li Chunhui , Ge Baoming , Liu Yuxuan , Qiu Qiang , Zhang Huixian , Huang Jinghui , Tang Boping , Wang Kun
Published: November 2024

Limbs are a defining characteristic of tetrapods, yet numerous taxa, primarily among amphibians and reptiles, have independently lost limbs as an adaptation to new ecological niches. To elucidate the genetic factors contributing to this convergent limb loss, we present a 12 Gb chromosome-level assembly of the Banna caecilian (Ichthyophis bannanicus), a limbless amphibian. Our comparative analysis, which includes the reconstruction of amphibian karyotype evolution, reveals constrained gene length evolution in a subset of developmental genes across 3 large genomes. Investigation of limb development genes uncovered the loss of Grem1 in caecilians and Tulp3 in snakes. Interestingly, caecilians and snakes share a significantly larger number of convergent degenerated conserved noncoding elements than limbless lizards, which have a shorter evolutionary history of limb loss. These convergent degenerated conserved noncoding elements overlap significantly with active genomic regions during mouse limb development and are conserved in limbed species, suggesting their essential role in limb patterning in the tetrapod common ancestor. While most convergent degenerated conserved noncoding elements emerged in the jawed vertebrate ancestor, coinciding with the origin of paired appendage, more recent degenerated conserved noncoding elements also contribute to limb development, as demonstrated through functional experiments. Our study provides novel insights into the regulatory elements associated with limb development and loss, offering an evolutionary perspective on the genetic basis of morphological specialization.
Diversity of Transcriptional Regulatory Adaptation in E. coli
Authors: Dalldorf Christopher , Hefner Ying , Szubin Richard , Johnsen Josefin , Mohamed Elsayed , Li Gaoyuan , Krishnan Jayanth , Feist Adam M , Palsson Bernhard O , Zielinski Daniel C
Published: November 2024

The transcriptional regulatory network (TRN) in bacteria is thought to rapidly evolve in response to selection pressures, modulating transcription factor (TF) activities and interactions. In order to probe the limits and mechanisms surrounding the short-term adaptability of the TRN, we generated, evolved, and characterized knockout (KO) strains in Escherichia coli for 11 regulators selected based on measured growth impact on glucose minimal media. All but one knockout strain (Δlrp) were able to recover growth and did so requiring few convergent mutations. We found that the TF knockout adaptations could be divided into four categories: (i) Strains (ΔargR, ΔbasR, Δlon, ΔzntR, and Δzur) that recovered growth without any regulator-specific adaptations, likely due to minimal activity of the regulator on the growth condition, (ii) Strains (ΔcytR, ΔmlrA, and ΔybaO) that recovered growth without TF-specific mutations but with differential expression of regulators with overlapping regulons to the KO’ed TF, (iii) Strains (Δcrp and Δfur) that recovered growth using convergent mutations within their regulatory networks, including regulated promoters and connected regulators, and (iv) Strains (Δlrp) that were unable to fully recover growth, seemingly due to the broad connectivity of the TF within the TRN. Analyzing growth capabilities in evolved and unevolved strains indicated that growth adaptation can restore fitness to diverse substrates often despite a lack of TF-specific mutations. This work reveals the breadth of TRN adaptive mechanisms and suggests these mechanisms can be anticipated based on the network and functional context of the perturbed TFs.
WD-repeat containing protein-61 regulates endometrial epithelial cell adhesion indicating an important role in receptivity
Authors: Downing Poppy , Howe Madeleine , Sacco Michaela , Santos Leilani L , Menkhorst Ellen , Teh Wan Tinn , Lucky Tarana , Zhou Wei , Dimitriadis Evdokia
Published: November 2024

Endometrial receptivity is crucial for successful embryo implantation during early pregnancy. The human endometrium undergoes remodeling within each menstrual cycle to prepare or become receptive to an implanting blastocyst in the mid-secretory phase. However, the mechanisms behind these changes are not fully understood. Recently, using hormone-treated endometrial organoids to model receptivity, we identified that the transcriptional regulator WD-repeat-containing protein-61 (WDR61) was reduced in organoids derived from infertile women. In this study, we aimed to determine the role of WDR61 in endometrial receptivity. Here, we demonstrated that WDR61 immunolocalizes in the nuclei and cytosol of endometrial glandular epithelium, luminal epithelium, and stroma. The staining intensity of WDR61 was significantly higher during the receptive mid-secretory phase compared to the non-receptive proliferative phase in fertile women. In a functional experiment to model blastocyst adhesion to the endometrial epithelium, we found that adhesion of cytotrophoblast progenitor spheroids was blocked when siRNA was used to knockdown WDR61 in primary endometrial epithelial cells. Similarly, in Ishikawa cells (a receptive human endometrial epithelial cell line), siRNA knockdown of WDR61 significantly reduced the cell adhesive and proliferative capacities. qPCR revealed that WDR61 knockdown reduced expression of key genes involved in receptivity including HOXD10, MMP2, and CD44. Chromatin immunoprecipitation sequencing demonstrated that WDR61 directly targeted 2022 genes in Ishikawa cells, with functions including focal adhesion, intracellular signaling and epithelial-mesenchymal transition. Overall, these findings suggest that WDR61 promotes endometrial receptivity by modulating epithelial cell focal adhesions, proliferation, and epithelial–mesenchymal transition.
ASpdb: an integrative knowledgebase of human protein isoforms from experimental and AI-predicted structures
Authors: Yang Yuntao , Kumar Himansu , Xie Yuhan , Li Zhao , Li Rongbin , Chen Wenbo , Diala Chiamaka S , Ali Meer A , Xu Yi , Wu Albon , Hosseini Sayed-Rzgar , Bi Erfei , Zhao Hongyu , Kim Pora , Zheng W Jim
Published: November 2024

Alternative splicing is a crucial cellular process in eukaryotes, enabling the generation of multiple protein isoforms with diverse functions from a single gene. To better understand the impact of alternative splicing on protein structures, protein–protein interaction and human diseases, we developed ASpdb (https://biodataai.uth.edu/ASpdb/), a comprehensive database integrating experimentally determined structures and AlphaFold 2-predicted models for human protein isoforms. ASpdb includes over 3400 canonical isoforms, each represented by both experimentally resolved and predicted structures, and >7200 alternative isoforms with AlphaFold 2 predictions. In addition to detailed splicing events, 3D structures, sequence variations and functional annotations, ASpdb uniquely offers comparative analyses and visualization of structural alterations among isoforms. This resource is invaluable for advancing research in alternative splicing, structural biology and disease mechanisms.
MolluscDB 2.0: a comprehensive functional and evolutionary genomics database for over 1400 molluscan species
Authors: Liu Fuyun , Cai Bingcheng , Lian Shanshan , Chang Xinyao , Chen Dongsheng , Pu Zhongqi , Bao Lisui , Wang Jing , Lv Jia , Zheng Hongkun , Bao Zhenmin , Zhang Lingling , Wang Shi , Li Yuli
Published: November 2024

Mollusca represents the second-largest animal phylum but remains less explored genomically. The increase in high-quality genomes and diverse functional genomic data holds great promise for advancing our understanding of molluscan biology and evolution. To address the opportunities and challenges facing the molluscan research community in managing vast multi-omics resources, we developed MolluscDB 2.0 (http://mgbase.qnlm.ac), which integrates extensive functional genomic data and offers user-friendly tools for multilevel integrative and comparative analyses. MolluscDB 2.0 covers 1450 species across all eight molluscan classes and compiles ∼4200 datasets, making it the most comprehensive multi-omics resource for molluscs to date. MolluscDB 2.0 expands the layers of multi-omics data, including genomes, bulk transcriptomes, single-cell transcriptomes, proteomes, epigenomes and metagenomes. MolluscDB 2.0 also more than doubles the number of functional modules and analytical tools, updating 14 original modules and introducing 20 new, specialized modules. Overall, MolluscDB 2.0 provides highly valuable, open-access multi-omics platform for the molluscan research community, expediting scientific discoveries and deepening our understanding of molluscan biology and evolution.
CRISPRepi: a multi-omic atlas for CRISPR-based epigenome editing
Authors: Shi Leisheng , Li Shasha , Zhu Rongyi , Lu Chenyang , Xu Xintian , Li Changzhi , Huang Xinyue , Zhao Xiaolu , Mao Fengbiao , Li Kailong
Published: November 2024

CRISPR-based epigenome editing integrates the precision of CRISPR with the capability of epigenetic mark rewriting, offering a tunable and reversible gene regulation strategy without altering the DNA sequences. Various epigenome editing systems have been developed and applied in different organisms and cell types; however, the detailed information is discrete, making it challenging to evaluate the precision of different editing systems and design the optimal sgRNAs for further functional studies. Herein, we developed CRISPRepi (http://crisprepi.maolab.org/ or http://crisprepi.lilab-pkuhsc.org/), a pioneering platform that consolidates extensive sequencing data from 671 meticulously curated RNA-seq, ChIP-seq, Bisulfite-seq and ATAC-seq datasets in 87 cell types manipulated by 74 epigenome editing systems. In total, we have curated 5962 sgRNAs associated with 283 target genes from 2277 samples across six species. CRISPRepi incorporates tools for analyzing editing outcomes and assessing off-target effects by analyzing gene expression changes pre- and post-editing, along with the details of multi-omic epigenetic landscapes. Moreover, CRISPRepi supports the investigation of editing potentials for newly designed sgRNA sequences in a cell/tissue-specific context. By providing a user-friendly interface for searching and selecting optimal editing designs across multiple organisms, CRISPRepi serves as an integrated resource for researchers to evaluate editing efficiency and off-target effects among diverse CRISPR-based epigenome editing systems.
PolyASite v3.0: a multi-species atlas of polyadenylation sites inferred from single-cell RNA-sequencing data
Authors: Moon Youngbin , Herrmann Christina J , Mironov Aleksei , Zavolan Mihaela
Published: November 2024

The broadly used 10X Genomics technology for single-cell RNA sequencing (scRNA-seq) captures RNA 3′ ends. Thus, some reads contain part of the non-templated polyadenosine tails, providing direct evidence for the sites of 3′ end cleavage and polyadenylation on the respective RNAs. Taking advantage of this property, we recently developed the SCINPAS workflow to infer polyadenylation sites (PASs) from scRNA-seq data. Here, we used this workflow to construct version 3.0 (v3.0, https://polyasite.unibas.ch/) of the PolyASite Atlas from a big compendium of publicly available human, mouse and worm scRNA-seq datasets obtained from healthy tissues. As the resolution of scRNA-seq was too low for robust detection of cell-level differences in PAS usage, we aggregated samples based on their tissue-of-origin to construct tissue-level catalogs of PASs. These provide qualitatively new information about PAS usage, in comparison to the previous PAS catalogs that were based on bulk 3′ end sequencing experiments primarily in cell lines. In the new version, we document stringency levels associated with each PAS so that users can balance sensitivity and specificity in their analysis. We also upgraded the integration with the UCSC Genome Browser and developed track hubs conveniently displaying pooled and tissue-specific expression of PASs.
TranscriptDB: a transcript-centric database to study eukaryotic transcript conservation and evolution
Authors: Ouedraogo Wend Yam D D , Ouangraoua Aida
Published: November 2024

Eukaryotic genes can encode multiple distinct transcripts through the alternative splicing (AS) of genes. Interest in the AS mechanism and its evolution across different species has stimulated numerous studies, leading to several databases that provide information on AS and transcriptome data across multiple eukaryotic species. However, existing resources do not offer information on transcript conservation and evolution between genes of multiple species. Similarly to genes, identifying conserved transcripts—those from homologous genes that have retained a similar exon composition—is useful for determining transcript homology relationships, studying transcript functions and reconstructing transcript phylogenies. To address this gap, we have developed TranscriptDB, a database dedicated to studying the conservation and evolution of transcripts within gene families. TranscriptDB offers an extensive catalog of conserved transcripts and phylogenies for 317 annotated eukaryotic species, sourced from Ensembl database version 111. It serves multiple purposes, including the exploration of gene and transcript evolution. Users can access TranscriptDB through various browsing and querying tools, including a user-friendly web interface. The incorporated web servers enable users to retrieve information on transcript evolution using their own data as input. Additionally, a REST application programming interface is available for programmatic data retrieval. A data directory is also available for bulk downloads. TranscriptDB and its resources are freely accessible at https://transcriptdb.cobius.usherbrooke.ca.
CRISPR knockout genome-wide screens identify the HELQ-RAD52 axis in regulating the repair of cisplatin-induced single-stranded DNA gaps
Authors: Pale Lindsey M , Khatib Jude B , Nusawardhana Alexandra , Straka Joshua , Nicolae Claudia M , Moldovan George-Lucian
Published: November 2024

Treatment with genotoxic agents, such as platinum compounds, is still the mainstay therapeutical approach for the majority of cancers. Our understanding of the mechanisms of action of these drugs is, however, imperfect and continuously evolving. Recent advances highlighted single-stranded DNA (ssDNA) gap accumulation as a potential determinant underlying cisplatin chemosensitivity, at least in some genetic backgrounds, such as BRCA mutations. Cisplatin-induced ssDNA gaps form upon restart of DNA synthesis downstream of cisplatin-induced lesions through repriming catalyzed by the PRIMPOL enzyme. Here, we show that PRIMPOL overexpression in otherwise wild-type cells results in accumulation of cisplatin-induced ssDNA gaps without sensitizing cells to cisplatin, suggesting that ssDNA gap accumulation does not confer cisplatin sensitivity in BRCA-proficient cells. To understand how ssDNA gaps may cause cellular sensitivity, we employed CRISPR-mediated genome-wide genetic screening to identify factors which enable the cytotoxicity of cisplatin-induced ssDNA gaps. We found that the helicase HELQ specifically suppresses cisplatin sensitivity in PRIMPOL-overexpressing cells, and this is associated with reduced ssDNA accumulation. We moreover identify RAD52 as a mediator of this pathway. RAD52 promotes ssDNA gap accumulation through a BRCA-mediated mechanism. Our work identified the HELQ-RAD52-BRCA axis as a regulator of ssDNA gap processing and cisplatin sensitization.
Monocyte/macrophage pyroptosis and C5b-9-induced cyst enlargement in Pkd1−/− mice
Authors: Yang Yang , Kong Deyang , Chen Meihan , Lv Jiayi , Zhou Jie , Xue Cheng , Song Shuwei , Song Minghui , Ma Lu , Mao Zhiguo , Mei Changlin
Published: November 2024

Background and hypothesis

The levels of C5b-9, terminal products of complement activation, were significantly elevated in autosomal dominant polycystic kidney disease (ADPKD). However, the precise mechanisms by which C5b-9 facilitates cyst growth remain incompletely elucidated.

Methods

Three groups of chronic-onset Pkd1−/− mice were established: one group received intravenous injections of 0.5 mg/kg C5b-9, another was administered 1.0 mg/kg monoclonal anti-C9 antibodies, and a control group received 1 mg/kg IgG isotype control. All treatments were administered biweekly for two months (postnatal day 180–240). Renal macrophages from distinct subsets were sorted using fluorescence-activated cell sorting. To deplete macrophages, liposome clodronate was injected intraperitoneally. Sublethal irradiation followed by bone marrow reconstruction was performed in Pkd1−/− mice to evaluate the role of bone marrow-derived macrophages (BMDMs) in ADPKD progression.

Results

(i) In vitro, sublytic C5b-9 did not affect the viability of renal tubular epithelial cells, but significantly induced M1-like polarization and pyroptosis of BMDMs. (ii) In vivo, C5b-9 notably triggered pyroptosis of Ly6C+ monocytes and a reduction in circulating monocyte numbers as cysts enlarged. (iii) Residual Ly6C+ monocytes infiltrated renal tissues and differentiated into Ly6C+ macrophages, which exhibited a greater susceptibility to pyroptosis compared to Ly6C− macrophages. (iv) Although limited evidence has recently suggested that Ly6C− monocytes may also be affected by C5b-9, upregulation of CCR2 in Ly6C− macrophages was observed in C5b-9-treated Pkd1−/− mice, implying that Ly6C− monocytes could represent a significant source of M2 macrophages.

Conclusions

C5b-9 infusion promoted renal tubular epithelial cell proliferation by inducing pyroptosis of Ly6C+ monocytes/macrophages, contributing to progressive cyst enlargement in chronic-onset PKD mice.
The prognostic impact of CDKN2A/B hemizygous deletions in IDH-mutant glioma
Authors: Ippen Franziska M , Hielscher Thomas , Friedel Dennis , Göbel Kirsten , Reuss David , Herold-Mende Christel , Krieg Sandro , Deimling Andreas v , Wick Wolfgang , Sahm Felix , Suwala Abigail K
Published: November 2024

Background

Homozygous deletions of CDKN2A/B are known to predict poor prognosis in gliomas, but the impact of hemizygous deletions is less clear. This study aimed to evaluate the prognostic significance of hemizygous CDKN2A/B deletions in IDH-mutant low-grade astrocytomas and oligodendrogliomas.

Methods

Tissue samples diagnosed as astrocytoma, IDH-mutant and oligodendroglioma, IDH-mutant, 1p/19q co-deleted CNS WHO grade 2 and 3 were collected from the archives of the Institute of Neuropathology in Heidelberg. DNA methylation analysis was performed on formalin-fixed paraffin-embedded samples. Evaluation of the CDKN2A/B locus was performed by visual inspection of copy-number plots derived from methylation-array data for each case. Hemizygous and homozygous losses were assessed in relation to whole chromosomal or larger segmental losses and gains in the chromosomal profile. Survival probabilities were assessed using the Kaplan–Meier method.

Results

A total of 334 low-grade glioma cases were identified, including 173 astrocytomas and 161 oligodendrogliomas. Hemizygous deletions in CDKN2A/B (37/173 in astrocytomas, 15/161 in oligodendrogliomas) did not confer significantly worse survival outcomes compared to CDKN2A/B wild-type cases in neither low-grade astrocytoma (log-rank P = .2556; HR 2.29, 95% CI [0.76; 6.40], P = .135) nor oligodendroglioma (log-rank P = .2760; HR 0.17; 95% CI [0.01; 5.05]; P = .305), regardless of CNS WHO grade, which was further demonstrated on a subgroup of astrocytoma, IDH mutant CNS WHO 4 cases (log-rank P = .1680; HR 4.55, 95% CI [0.88; 24.51], P = .0689).

Conclusions

Hemizygous CDKN2A/B deletions do not significantly worsen OS or progression-free survival in IDH-mutant astrocytomas and oligodendrogliomas, CNS WHO grades 2 and 3.
Health Benefits of Olive Leaf: The Focus on Efficacy of Antiglycation Mechanisms
Authors: Demirer Büşra , Samur Gülhan
Published: November 2024

Olive leaves have been a therapeutic herbal agent for diseases for centuries. Olive leaves contain many health-beneficial nutrients and bioactive components. There is much evidence for the positive effects of the phenolic compounds they contain on health. The main active phenolic component in olive leaves is oleuropein, which can constitute 6%–9% of the leaf's dry matter and has been intensively studied for its promising results/effects on human health. In addition, olive leaf provides health benefits through bioactive components, such as secoiridoids, flavonoids, triterpenes, and lignans. The anti-inflammatory, antioxidant, anticancer, antidiabetic, and antihypertensive properties of bioactive components, especially oleuropein, are well known. In addition, various health benefits, such as neuroprotective effects and microbiota modulation, are also mentioned. In recent years, in vitro studies have shown that olive leaves and bioactive components from olive leaves may have antiglycation effects. Currently, it is thought that the components found in olive leaves have a direct or indirect antiglycation effect. It is thought that, their direct effects include reducing the interaction between sugars and amino acids, nucleic acids, and lipids and sequestering reactive dicarbonyl species, and their indirect effects include preventing the formation of advanced glycation end-products (AGEs) by reducing inflammation and oxidative stress. However, in vivo and clinical studies are needed to prove these mechanisms and understand how their metabolism works in the human body. This review examines the beneficial health effects of olive leaves and their potential antiglycation role.