bluuebunny/crossref_metadata_2025 huggingface dataset:
The binding of RbgA to a critical 50S assembly intermediate facilitates YphC function in bacterial ribosomal assembly
Authors: Arpin Dominic , Palacios Armando , Basu Kaustuv , Ortega Joaquin
Published: December 2024

The intricate process of 50S ribosomal subunit assembly in Bacillus subtilis involves multiple parallel pathways converging into a crucial intermediate known as the 45S particle. RbgA and YphC, play pivotal roles in completing the maturation of the functional sites in the 45S particle. In this work, we found that RbgA and YphC can independently bind the 45S particle with high affinity, but when RbgA binds first to the particle, it significantly increases the binding affinity of YphC. Using cryo-electron microscopy, we determined that the changes exerted by RbgA and YphC when binding independently closely resemble those observed when the two factors bind to the 45S particle simultaneously. However, the structural analysis revealed that RbgA binding causes a conformational change that uncovers the binding site for YphC, thus increasing its binding affinity. We concluded that the functional interplay between RbgA and YphC primarily revolves around one factor promoting the binding of the other, rather than the binding of the two factors inducing entirely new conformational changes compared with those induced by the factors individually. These results highlight the synergic mechanism between two essential assembly factors, underscoring the intricate mechanism bacteria use to maximize the efficiency of the ribosome assembly process.
In silico and in vivo analyses of a novel variant in MYO6 identified in a family with postlingual non-syndromic hearing loss from Argentina
Authors: Buonfiglio Paula I , Bruque Carlos D , Salatino Lucía , Lotersztein Vanesa , Pace Mariela , Grinberg Sofia , Elgoyhen Ana B , Plazas Paola V , Dalamón Viviana
Published: December 2024

Hereditary hearing loss stands as the most prevalent sensory disorder, with over 124 non-syndromic genes and approximately 400 syndromic forms of deafness identified in humans. The clinical presentation of these conditions spans a spectrum, ranging from mild to profound hearing loss. The aim of this study was to identify the genetic cause of hearing loss in a family and functionally validate a novel variant identified in the MYO6 gene. After Whole Exome Sequencing analysis, the variant c.2775G>C p.Arg925Ser in MYO6 was detected in a family with postlingual non-syndromic hearing loss. By protein modeling a change in the electrostatic charge of the single alpha helix domain surface was revealed. Through a knockdown phenotype rescue assay in zebrafish, the detrimental effects of the identified variant on the auditory system was determined. These findings underscore the significance of a comprehensive approach, integrating both in silico and in vivo strategies, to ascertain the pathogenicity of this candidate variant. Such an approach has demonstrated its effectiveness in achieving an accurate genetic diagnosis and in promoting a more profound comprehension of the mechanisms that underlie the pathophysiology of hearing.
Presentation, management, and outcomes of central nervous system metastases in Africa: Systematic review and meta-analysis
Authors: O’Leary Sean , Yevudza W Elorm , Odiase Peace , Haider Muhammad Ammar , Newsome-Cuby Takara , Okikioluwa Odesanya , Darko Kwadwo , Weiss Hannah , Barrie Umaru , Banson Mabel , Totimeh Teddy
Published: December 2024

Background

Central nervous system (CNS) metastases are a significant health challenge, particularly in Africa. This study evaluates the preclinical characteristics, primary causes, management strategies, and outcomes of CNS metastases in Africa.

Methods

A systematic review of the literature was conducted using PubMed, Google Scholar, and Web of Science following PRISMA guidelines to identify studies on CNS metastases in Africa.

Results

Thirty-one articles were reviewed, including 28 retrospective studies and 3 case reports. The retrospective studies comprised 12 552 patients, with 681 (5.42%) diagnosed with CNS metastases. Nigeria reported the highest number of cases (323), followed by Tunisia (180). The mean patient age was 48.20 years (range: 44.48-51.93), with a higher proportion in women (69.97%, 95% confidence interval [CI]: 54.59-85.35). Common symptoms were headaches (44.87%, 95% CI: 20.76-68.97) and motor deficits (21.39%, 95% CI: 6.40-36.38). Diagnostic tools included MRI (38.27%, 95% CI: 18.08-58.47) and CT (51.28%, 95% CI: 29.13-73.42). The most common primary tumor sites were breast (41.33%, 95% CI: 24.87-57.79) and lung (14.85%, 95% CI: 4.90-24.79). Treatment strategies involved surgery (62.01%, 95% CI: 33.01-91.01), radiotherapy (68.97%, 95% CI: 41.31-96.63), and chemotherapy (60.72%, 95% CI: 32.95-88.50). Outcomes included improved disease status in 34.99% (95% CI: 13.92-56.07), mortality in 44.88% (95% CI: 20.88-68.89), and loss to follow-up in 1.83% (95% CI: 0-3.72).

Conclusion

CNS metastases in Africa show a higher proportion in women, with breast and lung cancers as the primary sources. Improved diagnostic and treatment strategies are essential to better patient outcomes.
Diagnostic Accuracy of Lung and Abdominal Ultrasound for Tuberculosis in a German Multicenter Cohort of Patients With Presumed Tuberculosis Disease
Authors: Weber Stefan Fabian , Wolf Peter , Wetzstein Nils , Küpper-Tetzel Claus , Vehreschild Maria , Suárez Isabelle , Rybniker Jan , Klingmüller Angela , Weber Tim , Güttlein Maximilian , Tobian Frank , Koeppel Lisa , Beck Julia Selena , Wolf Rebecca , Manten Katharina , Zimmermann Stefan , Christopher Devasahayam Jesudas , Herth Felix , Bélard Sabine , Denkinger Claudia M ,   For the ALL POCUS TB Germany Study group, Ruby Lisa C , Gaeddert Mary , Weise Michael , Eichinger Monika , Blöck Benjamin , Sattaf Fabian , Prey Anna-Lia , Drummer Alena , Rauschning Dominic , Ludwig-Bettin Daniel , Pracht Elisa
Published: December 2024

Background

There is limited evidence on point-of-care ultrasound for tuberculosis (TB), but studies suggest high sensitivity, especially for lung ultrasound (LUS). However, insufficient data are available on specificity of the examination and its generalizability to a broader patient population.

Aims

Our study aimed to establish accuracy for lung, chest, and abdominal ultrasound, individually and in combination, for TB diagnosis.

Methods

We conducted a prospective diagnostic accuracy study among consecutive adult out- and inpatients with probable TB in three German referral hospitals. We applied a comprehensive standardized ultrasound protocol. TB diagnosis was established by a microbiological reference standard including polymerase chain reaction and culture.

Results

A total of 102 participants originating from 30 different countries were enrolled. HIV prevalence was 7/99 (7%) and 73/102 (72%) had confirmed TB. TB was limited to the lungs in 15/34 (44%) of refugees and 27/39 (69%) in nonrefugees. Focused assessment with sonography for HIV-associated tuberculosis had a sensitivity of 40% (95% confidence interval [CI], 30–52) and specificity of 55% (95% CI, 38–72). Additional findings, such as small subpleural consolidations on LUS had a high sensitivity (88%; 95% CI, 78–93), but a low specificity (17%; 95% CI, 8–35). Larger consolidations in the lung apices had a sensitivity of 19% (95% CI, 12–30) and a specificity of 97% (95% CI, 83–100).

Conclusions

Our study establishes the first data on LUS performance against a comprehensive reference standard. Overall, our data suggest that ultrasound does not meet the requirements for triage but previously described and novel ultrasound targets in combination could aid in the clinical decision making.

Registry: DRKS00026636
Efficient in situ epitope tagging of rice genes by nuclease-mediated prime editing
Authors: Li Xueqi , Zhang Sujie , Wang Chenyang , Ren Bin , Yan Fang , Li Shaofang , Spetz Carl , Huang Jinguang , Zhou Xueping , Zhou Huanbin
Published: December 2024

In situ epitope tagging is crucial for probing gene expression, protein localization, and the dynamics of protein interactions within their natural cellular context. However, the practical application of this technique in plants presents considerable hurdles. Here, we comprehensively explored the potential of the CRISPR/Cas nuclease-mediated prime editing and different DNA repair pathways in epitope tagging of endogenous rice (Oryza sativa) genes. We found that a SpCas9 nuclease/microhomology-mediated end joining (MMEJ)-based prime editing (PE) strategy (termed NM-PE) facilitates more straightforward and efficient gene tagging compared to the conventional and other derivative PE methods. Furthermore, the PAM-flexible SpRY and ScCas9 nucleases-based prime editors have been engineered and implemented for the tagging of endogenous genes with diverse epitopes, significantly broadening the applicability of NM-PE in rice. Moreover, NM-PE has been successfully adopted in simultaneous tagging of the MAP kinase (MPK) genes OsMPK1 and OsMPK13 in rice plants with c-Myc and HA tags, respectively. Taken together, our results indicate great potential of the NM-PE toolkit in the targeted gene tagging for Rice Protein Tagging Project, gene function study and genetic improvement.
Arabidopsis RNA–binding proteins interact with viral structural proteins and modify turnip yellows virus accumulation
Authors: Kiervel Déborah , Boissinot Sylvaine , Piccini Céline , Scheidecker Danile , Villeroy Claire , Gilmer David , Brault Véronique , Ziegler-Graff Véronique
Published: December 2024

As obligate intracellular parasites, viruses depend on host proteins and pathways for their multiplication. Among these host factors, specific nuclear proteins are involved in the life cycle of some cytoplasmic replicating RNA viruses, although their role in the viral cycle remains largely unknown. The polerovirus turnip yellows virus (TuYV) encodes a major coat protein (CP) and a 74 kDa protein known as the readthrough (RT) protein. The icosahedral viral capsid is composed of the CP and a minor component RT*, arising from a C-terminal cleavage of the full-length RT. In this study, we identified Arabidopsis (Arabidopsis thaliana) ALY family proteins as interacting partners of TuYV structural proteins using yeast 2-hybrid assays and co-immunoprecipitations in planta. ALY proteins are adaptor proteins of the THO-TREX-1 complex essential to the nuclear export of mature messenger RNAs (mRNAs). Although all 4 ALY proteins colocalized with the CP and the RT protein in the nucleus upon co-expression in agro-infiltrated Nicotiana benthamiana leaves, only the CP remained nuclear and colocalized with ALY proteins in TuYV-infected cells, suggesting that the CP is an essential partner of ALY proteins. Importantly, TuYV-infected A. thaliana 4xaly knock-out mutants showed a significant increase in viral accumulation, indicating that TuYV infection is affected by an unknown ALY-mediated antiviral defense mechanism or impairs the cellular mRNA export pathway to favor viral RNA translation. This finding underpins the crucial role played by nuclear factors in the life cycle of cytoplasmic RNA viruses.
Update on the structure and regulated biosynthesis of the apoplastic polymers cutin and suberin
Authors: Kosma Dylan K , Graça José , Molina Isabel
Published: December 2024

The plant lipid polymers cutin and suberin play a critical role in many aspects of plant growth, development, and physiology. The mechanisms of cutin and suberin biosynthesis are relatively well understood thanks to just over 2 decades of work with primarily Arabidopsis (Arabidopsis thaliana) mutants. Recent advances in our understanding of cutin and suberin structure have arisen through the application of novel chemistries targeted at quantitative comprehension of intermolecular linkages, isolating intact suberins and cutins, and the application of advanced analytical techniques. The advent of high-throughput transcription factor binding assays and next-generation sequencing has facilitated the discovery of numerous cutin and suberin-regulating transcription factors and their gene promoter targets. Herein we provide an overview of aspects of cutin and suberin structure, biosynthesis, and transcriptional regulation of their synthesis highlighting recent developments in our understanding of these facets of cutin and suberin biology. We further identify outstanding questions in these respective areas and provide perspectives on how to advance the field to address these questions.
Chronic pain education: past, present, and future of psychedelics for the management of chronic pain
Authors: Robinson Christopher L , Solanki Pawan K , Snyder Sean , Amir Adam , Barreveld Antje , Mather Rory Vu , Cerda Ivo H , Motoc Michael , Chopra Harman , Yong Robert Jason , Castellanos Joel , Furnish Timothy , Kaye Alan D , Orhurhu Vwaire , Emerick Trent
Published: December 2024

Curricula involving psychedelic education are not a traditional part of most medical training programs. With an increase in awareness of psychedelics, research studies involving psychedelics, and prevalence of non-prescribed use, it is more important than ever for physicians and clinicians to understand the mechanisms, interactions, and potential side effects of this class of substances.
How do roses build failure-resistant anchoring tools?
Authors: Levavi Liat , Bar-On Benny
Published: December 2024

Rose prickles are small-scale, plant-based anchoring tools of multifunctional biomechanical roles, combining physical defense against herbivores and growth support on surrounding objects. By employing multiscale structural observations, nanomechanical characterizations, and finite-element simulations, we unveil that the dog rose (Rosa canina Linnaeus) prickle incorporates structural–mechanical modifications at different length scales, resulting in macroscopic stress-locking effects that provide the prickle extreme damage-resistant capabilities and secure its functional form against catastrophic failures. These functional design strategies, unique to plant-based biomechanical tools, may promote futuristic micro-engineered anchoring platforms for micro-robotics locomotion, biomedical microinjection, and micromechanical systems.
Half-Integer Random Resonance Compensation for Further Beam Power Ramp-up in the 3-GeV Rapid Cycling Synchrotron of the Japan Proton Accelerator Research Complex
Authors: Kojima Kunihiro , Harada Hiroyuki , Tamura Fumihiko , Okita Hidefumi , Chimura Motoki , Saha Pranab Kumar
Published: December 2024

A comprehensive study on random resonances was conducted to mitigate beam losses and ensure sufficient tunability of the operating point for further beam power ramp-up in the 3-GeV rapid cycling synchrotron of the Japan Proton Accelerator Research Complex. Low-intensity beam studies revealed considerable excitation of the half-integer random resonance. This half-integer random resonance was successfully compensated for using trim quadrupole magnets without exciting other higher-order resonances. By implementing a conventional theoretical procedure based on resonance driving terms, we identified the leakage field from extraction magnets as the primary source of the error field driving the random resonance. High-intensity beam studies confirmed that our resonance compensation approach substantially mitigated beam loss in higher-tune regions, making it highly effective in improving operating point tunability.
Costs of Financing U.S. Federal Debt Under a Gold Standard: 1791-1933
Authors: Payne Jonathan , Szőke Bálint , Hall George , Sargent Thomas J
Published: December 2024

From a new data set, we infer time series of term structures of yields on U.S. federal bonds during the gold standard era from 1791–1933 and use our estimates to reassess historical narratives about how the United States expanded its fiscal capacity. We show that U.S. debt carried a default risk premium until the end of the nineteenth century, when it started being priced as an alternative safe asset to U.K. debt. During the Civil War, investors expected the United States to return to a gold standard so the federal government was able to borrow without facing denomination risk. After the introduction of the National Banking System, the slope of the yield curve switched from down to up and the premium on U.S. debt with maturity less than one year disappeared.
Artificial intelligence software for detecting unsuspected lung cancer on chest radiographs in an asymptomatic population
Authors: Kim Taehee , Shin Heejun , Song Yong Sub , Lee Jong Hyuk , Kim Hyungjin , Shin Dongmyung
Published: December 2024

Background

Detecting clinically unsuspected lung cancer on chest radiographs is challenging. Artificial intelligence (AI) software that performs comparably to radiologists may serve as a useful tool.

Purpose

To evaluate the lung cancer detection performance of a commercially available AI software and to that of humans in a healthy population.

Materials and Methods

This retrospective study used chest radiographs from the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial in the United States between November 1993 and July 2001 with pathological cancer diagnosis follow-up to 2009 (median 11.3 years). The software's predictions were compared to the PLCO radiologists' reads. A reader study was performed with a subset comparing the software to 3 experienced radiologists.

Results

The analysis included 24 370 individuals (mean age 62.6±5.4; median age 62; cancer rate 2%), with 213 individuals (mean age 63.6±5.5; median age 63; cancer rate 46%) for the reader study. AI achieved higher specificity (0.910 for AI vs. 0.803 for radiologists, P < .001), positive predictive value (0.054 for AI vs. 0.032 for radiologists, P < .001), but lower sensitivity (0.326 for AI vs. 0.412 for radiologists, P = .001) than the PLCO radiologists. When we calibrated the sensitivity of AI to match it with the PLCO radiologists, AI had higher specificity (0.815 for AI vs. 0.803 for radiologists, P < .001). In the reader study, AI achieved higher sensitivity than readers 1 and 3 (0.608 for AI vs. 0.588 for reader 1, P = .789 vs. 0.588 for reader 3, P = .803) but lower specificity than reader 1 (0.888 for AI vs. 0.905 for reader 1, P = .814). Compared to reader 2, AI showed higher specificity (0.888 for AI vs. 0.819 for reader 2, P = .153) but lower sensitivity (0.888 for AI vs. 0.905 for reader 1, P = .814).

Conclusion

AI detects lung cancer on chest radiographs among asymptomatic individuals with comparable performance to experienced radiologists.
Cutaneous vasculitis in systemic lupus erythematosus: epidemiology and risk factors over a 20-year follow-up
Authors: Saleh Ahmed , Yee Chee-Seng , Acquah Aba , Gordon Caroline , Reynolds John A
Published: December 2024

Objectives

Cutaneous vasculitis (CV) is common in SLE, but the epidemiology and risk factors remain unclear. We aimed to identify the trends and risk factors for CV in patients with SLE over a period of 20 years.

Methods

The Birmingham Lupus Cohort is an observational longitudinal cohort of SLE patients. Patients were enrolled within 3 years of meeting their fourth ACR criterion. Disease activity, laboratory test results and treatment records were collected. A multivariable shared frailty Cox proportional hazard model was used to identify clinical, laboratory and treatment-related variables associated with the development of CV.

Results

We included 392 patients: 95.7% were female. The median (interquartile range) duration of follow-up was 9.2 (5.1–14.7) years. CV occurred in 27% of SLE patients, of whom 43.3% had two or more CV events. This study demonstrated a marked decline in the incidence rates of CV, decreasing from 34.4% (95% CI 29.7, 39.3) during the first 3 years after enrolment to 2.1% (95% CI 0.05, 11.5) after 18 years of follow-up. Development of CV was associated with RP, constitutional, mucocutaneous, musculoskeletal, haematological and cardiovascular involvement, anti-Sm antibodies, anti-dsDNA, and hypocomplementemia. However, the use of AZA and antimalarials was inversely associated with the development of CV. Patients with CV were more likely to develop at least one item of organ damage.

Conclusions

The incidence rates of CV in SLE decreased over the follow-up period and CV is associated with defined clinical, serological and treatment-related factors.
Willow oak (Quercus phellos) seedling roots continue respiration and growth during fall and winter in a soil temperature-dependent manner
Authors: Kressuk Jonathan M , Collins James T , Gardiner Emile S , Bataineh Mohammad M , Babst Benjamin A
Published: December 2024

Many greentree reservoirs (GTRs) and other bottomland hardwood forests have experienced a shift in tree species composition away from desired red oaks (Quercus section Lobatae), like willow oak (Quercus phellos L.), due to flood stress mortality. Trees experience flood stress primarily through their root system, so it is surmised that GTR flooding may be occurring before root systems have reduced their activity entering the winter. Because soils buffer seasonal temperature changes, we hypothesized that root activity would respond to the belowground environment rather than the aboveground environment. To investigate whether cold soil temperatures reduce root growth and respiration in willow oak during winter, soil temperatures for container seedlings were either held at 15 °C or transitioned to 10 or 5 °C in the late fall. Root elongation was measured in seedlings grown in rhizotron pots by analyzing repeated images of roots during the fall–winter transition period. Root respiration, measured at soil temperature levels, was used as an indicator of root energetic expenses. Also, root respiration was measured at 15 and 5 °C to determine Q10 values to test for acclimation to low soil temperature. Root elongation continued in winter, even after stem elongation stopped in soil temperatures ≥5 °C, a condition usually met throughout most of the native range of willow oak. Both root elongation and respiration rates decreased in cooler soil temperatures. However, Q10 values were unaffected by soil temperature treatment. These findings do not support root dormancy or cold acclimation of root respiratory activity but indicate that temperature directly and reversibly affected root respiration rate. Root elongation may have been dependent on photoassimilates produced by green leaves that were retained through much of winter. Overall, our results suggest that willow oak roots may continue a high rate of growth throughout winter, unlike most temperate species measured to date, and that soil temperature has a major influence over their growth and respiration rates.
Clonal differences in ecophysiological responses to imposed drought in selected Eucalyptus grandis × E. urophylla hybrids
Authors: Ferraz Tiago Massi , de Oliveira Maia Júnior Sebastião , de Souza Guilherme Augusto Rodrigues , Baroni Danilo Força , Rodrigues Weverton Pereira , de Sousa Elias Fernandes , Penchel Ricardo , Loos Rodolfo , de Assis Figueiredo Fábio Afonso Mazzei Moura , Rakocevic Miroslava , Campostrini Eliemar
Published: December 2024

Measuring ecophysiological responses of Eucalyptus clones grown under reduced water availability could assist in clonal selection for climate resilience. We hypothesized that clonal variation in chlorophyll a fluorescence was more readily detected than variations in leaf-level gas exchanges when 2-year-old Eucalyptus grandis W.Hill ex Maiden × Eucalyptus urophylla S.T. Blake hybrid clones (C1, C2, C3 and C4) grown under rainfed (RF) and water-restricted (WR) conditions were evaluated during dry and rainy seasons, in the morning and midday diurnal periods. The C2 clone was the most drought tolerant as it had a similar net CO2 assimilation rate (A) considering the RF and WR conditions at midday during the dry season, while C1, C3 and C4 CO2 assimilation rates (A) decreased by 29.1%, 28.3% and 13%, respectively. This response was associated with a reduction to a lesser extent in leaf water potential, stomatal conductance (gs) and transpiration rates (E) (ca 10%, 30% and 13% under WR, respectively), when compared with the other clones during the dry season at midday. The lower leaf to air vapor pressure deficit of C2 contributed to its greater water-use efficiency (WUE), resulting in greater total dry mass gain. C1, C3 and C4 were less drought tolerant, decreasing gs, E and especially A under WR, resulting in lower WUE and total dry mass gain. Chlorophyll a fluorescence indexes were better indicators of drought tolerance compared with gas exchange parameters in definition of drought tolerance of clonal Eucalyptus. Three drought-sensitive clones showed low photochemical efficiency under WR, with the electron transport rate being impaired between photosystems II and I, indicated by the greater changes in photosynthetic performance index (PIabs). Under WR conditions, Fv/Fm, Ψ0, ΦE0 and PIabs decreased in all clones while ΦD0 and DI0/CS0 increased, with C2 showing the most stable responses suggesting that the photochemical apparatus was the less damaged by drought. Thus, C2 was the best clone for regions with water scarcity.

Statements
HIV-1 Vif global diversity and possible APOBEC-mediated response since 1980
Authors: Lewitus Eric , Li Yifan , Rolland Morgane
Published: December 2024

HIV-1 Vif’s principal function is to counter the antiretroviral activities of DNA-editing APOBEC3 cytidine deaminases. Unconstrained APOBEC3 activity introduces premature stop codons in HIV-1 genes and can lead to viral inactivation. To investigate the evolution and diversification of Vif over the HIV-1 pandemic and document evidence of APOBEC3-mediated pressure, we analyzed 4612 publicly available sequences derived from 10 dominant subtypes and circulating recombinant forms (CRFs) using the Hervé platform. We found widespread evidence of diversifying selection that was convergent across subtypes and CRFs, but remarkable stability in consensus sequences over time. Divergence and selection did not favor APOBEC3-interacting sites. We furthermore found that APOBEC3-induced substitutions in env and gag-pol genes increased over time and were positively associated with vif diversity. These results suggest that APOBEC3-driven adaptation in Vif is relatively rare and that permissiveness to human APOBEC3-induced substitution as a mechanism for generating diversity may be advantageous to HIV-1 evolution.
Competitive modulation of KV1.2 gating by LMAN2 and Slc7a5
Authors: Das Damayantee , Lamothe Shawn M. , Wong Anson A. , Baronas Victoria A. , Kurata Harley T.
Published: December 2024

KV1.2 is a prominent ion channel in the CNS, where it regulates neuronal excitability. KV1.2 structure and function are well understood, but there is less consensus on mechanisms of regulation of KV1.2 and other potassium channels by auxiliary proteins. We previously identified novel regulators of KV1.2 by a mass spectrometry approach. The neutral amino acid transporter Slc7a5 causes a dramatic hyperpolarizing shift of channel activation. In contrast, the transmembrane lectin LMAN2 is a recently identified candidate regulator that has the opposite effect on gating: large depolarizing voltages are required to activate KV1.2 channels co‐expressed with LMAN2. In this study, we characterized the functional interaction between LMAN2 and Slc7a5 on KV1.2 gating properties and identified key structural elements that underlie sensitivity to each regulator. When LMAN2 and Slc7a5 are expressed together, KV1.2 activation exhibits a bi‐modal voltage‐dependence, suggesting two distinct populations of channels regulated either by LMAN2 or Slc7a5, but not both. Using a KV1.2:1.5 chimeric approach, we identified specific regions between the S1 to S3 segments of the voltage sensing domain (VSD) that are distinct for either Slc7a5 or LMAN2 sensitivity. By replacing either segment with sequence from KV1.5, modulation by the corresponding regulator was selectively abolished. These results suggest that Slc7a5 and LMAN2 compete for interaction with the KV1.2 voltage sensor, leading to complex voltage‐dependence of channel activity when both regulators are present in the cell.
MiR‐21 suppression in macrophages promotes M2‐like polarization and attenuates kidney ischemia–reperfusion injury
Authors: Wang Xiaoyan , Ren Ting , Zhang Xinni , Pan Tianyi , Peng Fangyuan , Feng Jinghan , Sun Qian , Song NaNa , Ding Xiaoqiang , Jia Ping
Published: December 2024

MicroRNA‐21 (miR‐21) is one of the most frequently upregulated miRNAs in response to kidney ischemia–reperfusion (IR) injury, exhibiting both protective and pathogenic effects depending on the cell type, disease state, and target signaling. In this study, we analyzed the function of miR‐21 in various cell types to elucidate its role in ischemia‐induced inflammation and acute kidney injury (AKI). Utilizing a mouse model of IR injury, we observed significant upregulation of miR‐21 in renal tubular epithelial cells and macrophages following IR. Deletion of miR‐21 in macrophages mitigated IR‐induced pro‐inflammatory cytokine production and AKI. However, conditional deletion of miR‐21 in proximal tubules or nonproximal tubules did not protect the kidneys against these effects. Mechanistically, miR‐21 inhibition promoted M2‐like polarization in macrophages and suppressed M1‐like polarization and proinflammatory cytokine production in kidneys. In vitro, miR‐21 knockdown in the mouse macrophage cell line Raw246.7 or genetic deletion of miR‐21 in bone marrow‐derived macrophages (BMDMs) increased the percentage of CD206+ cells (M2 phenotype) while decreasing the percentage of CD86+ cells (M1 phenotype) and the expressions of proinflammatory cytokines. Overexpression of miR‐21 in Raw264.7 cells reduced the percentage of CD206+ cells. Furthermore, we demonstrated that signal transducer and activator of transcription 3 (STAT3) was a target gene of miR‐21 in macrophages, and miR‐21 deletion promoted M2 macrophage polarization via STAT3 activation. In conclusion, miR‐21 plays a role in regulating macrophage polarization, and the blockade of miR‐21/STAT3 signaling may represent a novel therapeutic strategy for the prevention or treatment of AKI.
The Disproportionate Effects of the COVID-19 Pandemic on the Time Allocation of Recipients of NIH Career Development Awards Who Are Women or Caregivers of Dependents
Authors: Jacobson Clare E. , Griffith Kent A. , Krenz Chris , Jones Rochelle D. , Cutter Christina M. , Singer Kanakadurga , Paradis Kelly C. , Stewart Abigail J. , Feldman Eva L. , Settles Isis H. , Kerr Eve A. , Ubel Peter A. , Spector Nancy D. , Jagsi Reshma
Published: December 2024

Purpose

To understand time allocation of a national medical faculty cohort 1.5–2 years after the COVID-19 pandemic began compared with before.

Method

From August 2021–April 2022, the authors conducted a retrospective survey of 1,430 clinician-researchers who received National Institutes of Health career-development awards between 2006–2009 asking about domestic and professional time allocation prepandemic and at the time of surveys (TOS). Of 915 respondents (64%), the 830 who remained in academic positions constituted the analytic sample. Multivariable regression models identified demographic factors associated with each time outcome and change in time between prepandemic and TOS, and having experienced a ≥8-hour increase of total self-reported weekly professional work hours and domestic labor hours.

Results

Median self-reported weekly professional work hours were 55 hours/week prepandemic and 60 at TOS. On multivariable analysis, significant predictors of self-reported weekly professional work hours at TOS were having a non-child other dependent (+2.6 hours, P = .03), academic rank (associate −3.1 hours, assistant −9.0 hours; P < .001), and specialty (P < .001). Average self-reported TOS weekly domestic-labor hours were 23.1 among men and 30.2 among women (P < .001). Predictors of total self-reported TOS weekly domestic hours were being a woman (+5.6 hours; P < .001) and having children requiring supervision (+10.2 hours; P < .001). Overall, 9.3% of men (42/450) and 21.6% of women (88/407) experienced a ≥8-hour increase in domestic labor (P < .001). On multivariable analysis, women had higher odds of substantial domestic-labor increase (OR = 2.33, 95% CI: 1.47, 3.68), as did those with children requiring supervision (OR = 1.93, 95% CI: 1.25, 2.98) or other dependents (OR = 1.83, 95% CI: 1.13, 2.98).

Conclusions

This study illuminates demands on women and faculty with dependents during the COVID-19 pandemic and suggests increased flexibility and resources are of heightened importance.
“We’ve Changed, the World’s Changed”: Leveraging Knowledge From COVID-19 to Improve Self-Management for Cancer Survivors and Care Partners
Authors: Mansfield Kelly J. , Wawrzynski Sarah E. , Vega Marilisa , Kent-Marvick Jacqueline , Guo Jia-Wen , Cloyes Kristin G.
Published: December 2024

Background:

During the COVID-19 pandemic, cancer survivors and care partners navigated social interactions amidst the uncertainties of cancer-related vulnerability and risk. Vaccination offered a new tool for self-management yet created potential for conflict within survivors’ and care partners’ social networks.

Objective:

We examined cancer survivors’ and care partners’ perceptions of the impact of vaccine availability on social interactions.

Methods:

In May 2021, survivor and care partner participants in a prospective study of social support network interactions (N = 64) were invited to complete an online survey about COVID-19 vaccination and record an audio diary describing the impact of vaccine availability. Descriptive statistics summarized demographic data. Audio diaries were transcribed, inductively coded, themes developed, and narratively summarized.

Results:

Twenty-seven participants (42.9%) completed the survey and n = 21 (33.3%; n = 8 caregivers, 38.1%; and n = 13 survivors, 61.9%) recorded diaries. Eighty percent (n = 21) of the sample received the COVID-19 vaccine. Two themes illustrated the impact of COVID-19 vaccines within a cancer context: providing hope and reconnecting with life.

Conclusions:

Vaccination decisions allowed many cancer survivors and partners to reengage with their social networks. With limited guidance, many relied on their own knowledge, values, and experiences to determine how to preserve their health.

Implications for Practice:

Utilizing a shared decision-making model, nurses can help families develop strategies that enact their values to promote long-term health. Nursing education and support can be further strengthened to create patient self-efficacy when navigating social interactions in the post-COVID era.

What is Foundational:

This study addresses the need for improved self-management strategies for cancer survivors.
ASSESSING THE REPEATABILITY OF INNER CHOROID FLOW DEFICIT PERCENTAGE IN INTERMEDIATE AGE-RELATED MACULAR DEGENERATION AND CONTROLS
Authors: Romano Francesco , Ding Xinyi , Garcia Mauricio , Zhao Yan , Vingopoulos Filippos , Garg Itika , Stettler Isabella , Bennett Cade , Overbey Katherine , Finn Matthew J. , Ploumi Ioanna , Laìns Inês , Patel Nimesh A. , Wu David M. , Vavvas Demetrios G. , Husain Deeba , Miller Joan W. , Miller John B.
Published: December 2024

Purpose:

To assess repeatability of macular inner choroid flow deficit percentage in intermediate age-related macular degeneration and controls using various postprocessing approaches.

Methods:

Cross-sectional, observational study. The authors included 1) 22 intermediate age-related macular degeneration and 24 control eyes, with 2) age >50 years, 3) visual acuity >20/32, and 4) no additional ocular and systemic confounders. Participants underwent four consecutive 6 × 6-mm optical coherence tomography angiography scans (2 acquired at 100-kHz and 2 at 200-kHz speed; PLEX Elite 9000) for intrasession analysis. Same protocol was repeated after 30 minutes for intersession analysis. Three slabs of different thicknesses were generated underneath Bruch membrane (4–14, 4–19, 4–24 µm). All slabs were processed with: 1) binarization-only using Phansalkar method (r = 4–15 pixels); 2) compensation + binarization; 3) averaging + binarization; 4) averaging + compensation + binarization. Inner choroid flow deficit percentage was measured within 3-mm and 5-mm circles, and measurements were repeated after excluding drusen areas. Repeatability was analyzed with generalized linear mixed-effects models, intraclass correlation coefficients, and Levene variance test.

Results:

Most postprocessing approaches demonstrated high repeatability (intraclass correlation coefficient >0.75) with no significant test–retest differences (P > 0.05). Compensation + binarization of 15-µm slabs at 200 kHz showed the highest repeatability (intraclass correlation coefficient: 0.96–0.98). Excluding drusen did not significantly affect inner choroid flow deficit percentage measurements (P > 0.05), showing increased intraclass correlation coefficients for 10-µm-thick and binarized-only slabs.

Conclusion:

Strong repeatability can be achieved with various postprocessing methods for assessing inner choroid flow deficit percentage, especially with compensation + binarization of 15-µm slabs acquired at 200 kHz. Drusen removal does not seem to affect repeatability in intermediate age-related macular degeneration when using a swept-source device, except for specific settings. These results contribute to refining choriocapillaris assessment, paving the way for future applications.
Visual Improvement With Wavefront-Guided Scleral Lenses for Irregular Corneal Astigmatism
Authors: Gelles John D. , Su Becky , Kelly David , Brown Nicolas , Wong Jenny , Yoon Geunyoung , Pfeifer Travis , Erdman Cameron , Hersh Peter S. , Greenstein Steven A.
Published: December 2024

Purpose:

To report interim results of a single center, randomized, double-blind, crossover-controlled clinical trial comparing wavefront-guided (wfg) scleral lenses (SLs) to traditional scleral lenses (tSLs) for patients with a history of irregular corneal astigmatism (ICA).

Methods:

Thirty-one ICA eyes of 18 participants were reviewed, 23 with keratoconus, six postcorneal refractive ectasia, and two postpenetrating keratoplasty. Patients with corneal or lens opacities were not excluded from participating. Participants underwent a diagnostic lens-based fitting with a tSL with standard spherocylindrical optics. Once the tSL was finalized, a comprehensive wavefront aberrometer-based system was used to capture the residual aberration of the tSL under scotopic conditions without pharmacologic dilation, and these data were used to create a wfgSL. Once the tSL and wgfSL were finalized, a double-blinded, randomized, crossover was conducted where the participants received lens A (tSL or wgfSL) or lens B (the alternative), each worn for a 4±1 week interval. Measurements of the visual acuity (VA) and total higher-order root mean squared (HORMS) were recorded at each interval under controlled lighting conditions. At the final visit, patient subjective preference for lens A or lens B was recorded.

Results:

The average HORMS for a fixed 5-mm pupil was 0.68±0.31 μm for tSL and 0.29±0.18 μm for wfgSL. Wavefront-guided SL provided an average HORMS improvement of 56% (P<0.001). All eyes showed a reduction in HORMS, ranging from 18% to 83%. Wavefront-guided SL provided an average VA improvement of 0.12±0.11 logMAR (P<0.01). Seventy-one percent of eyes showed one line or greater improvement, 26% showed no improvement, and 3% showed a reduction of VA with the wfgSL. The average VA with tSL was 0.14±0.16 logMAR and 0.03±0.11 logMAR for wfgSL. Seventeen of 18 patients subjectively preferred wfgSL.

Conclusion:

In eyes with ICA, wfgSL reduced HORMS and improved VA when compared with tSL. Patients subjectively preferred wfgSL to tSL. These interim results demonstrate the feasibility and generalizability of wfgSL in a typical clinical practice environment.
Factors Contributing to Follow-up Nonadherence After Infectious Keratitis Diagnosis
Authors: Dmitriev Pauline M. , Swaminathan Shreya , Zhang Qiang , Rapuano Christopher J. , Syed Zeba A.
Published: December 2024

Objectives:

To evaluate demographic, socioeconomic, and clinical factors associated with nonadherence with initial follow-up after a diagnosis of infectious keratitis.

Methods:

A retrospective chart review of patients aged 18 to 60 years who were diagnosed with infectious keratitis at the Wills Eye Hospital Emergency Room from March 2019 to September 2019 was conducted. The primary outcome was nonadherence with initial follow-up recommendation and included patients who did not follow-up in the time frame requested by the diagnosing physician and those who were lost to follow-up.

Results:

Two hundred and seventeen patients were included with a mean age of 39.0±11.6 years, and 38.2% of patients were nonadherent. Patients who identified as non-Hispanic White were more likely to be nonadherent compared with Hispanic White patients (odds ratio [OR]=5.00, 95% confidence interval [CI]: 1.27–20.00, P=0.021). Additional variables associated with nonadherence included lower income (OR=0.92, 95% CI: 0.85–0.99, P=0.020) and government versus private insurance (OR=2.13, 95% CI: 1.09–4.15, P=0.027). Among clinical variables, patients not cultured at the initial evaluation were more likely to be nonadherent (OR=2.54, 95% CI: 1.36–4.77, P=0.004).

Conclusions:

Race, income, insurance, and corneal culturing had associations with follow-up nonadherence. Identifying barriers to follow-up for infectious keratitis may have important implications in preventing vision loss and other complications.
Exploring the Functional Mechanism of Action of Sanxiankaixin Powder in Preventing and Treating Reproductive Aging Based on Network Pharmacology and Molecular Docking
Authors: Liu Zhiming , Li Zhong , Sun Yuan , Zhao Feng , Chen Shaofeng , Zhao Yu , Zhang Zhe , Liao Zhihui , Geng Qiang
Published: December 2024

Background:

To explore the functional mechanism of Sanxiankaixin powder (SXKXP) in preventing and treating reproductive aging (RA) through network pharmacology and molecular docking technology.

Methods:

The traditional Chinese medicine systems pharmacology database and analysis platform was utilized to identify the major active components of SXKXP. The SwissTargetPrediction algorithm was used to identify potential SXKXP targets for RA prevention and treatment. GeneCards and OMIM were used to identify RA disease targets, whereas Venny 2.1.0 was utilized to find common targets. Protein-protein interaction analysis was conducted with STRING, and network diagrams were created with Cytoscape. We performed a gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis using the DAVID database. The compound-drug–component-core target-KEGG pathway networks were created with Cytoscape software. Finally, we used PubChem, UniProt, PDB, PyMoL, and AutoDock software for molecular docking.

Results:

It was found that 93 effective components in SXKXP directly acted on 56 core disease targets to prevent and treat RA through multiple pathways, among which kaempferol, luteolin, 8-Prenylkaempferol, quercetin, and Schisandrol B were the core components, and AKT1, estrogen receptor 1 (ESR1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), tumor necrosis factor (TNF), and interleukin 6 (IL-6) were important targets. The results of the GO enrichment analysis showed that apoptosis, cell proliferation, plasma membrane, and ATP binding may be closely related to RA. The KEGG pathway enrichment analysis results suggested that the AGE-RAGE signaling pathway in diabetic complications and the PI3K-Akt signaling pathway play important roles. Molecular docking results suggested that the core components were well bound to important targets.

Conclusion:

SXKXP interferes with biological processes such as oxidation and inflammatory reactions through multiple targets and pathways to prevent and treat RA. This study provides the research direction and theoretical basis for the experimental research of SXKXP on RA prevention and treatment.
Phase 2 study of the safety and efficacy of QTORIN rapamycin in the treatment of microcystic lymphatic malformations
Authors: Treat James , Martini Jeffrey , Connor Jason T. , Small Alison , Funk Tracy , Waner Milton , Teng Joyce
Published: December 2024

Objectives:

The objective of this Phase 2 study was to determine the safety and efficacy of QTORIN rapamycin 3.9% anhydrous gel for the treatment of cutaneous microcystic lymphatic malformations (LM).

Design:

The study was a multicenter, baseline-controlled Phase 2 clinical trial.

Setting:

The study was performed at 5 clinical sites in the United States.

Participants:

Participants were ≥6 years old with a clinical diagnosis of cutaneous microcystic LM.

Intervention:

Participants self-administered topical QTORIN rapamycin once daily for 12 weeks.

Main Outcome Measurements:

Outcomes were measured via standardized clinician- and patient-reported outcomes, including clinician global impression of change, clinician global impression of severity (CGI-S), patient global impression of severity, patient global impression of change (PGI-C), as well as lesion leaking or bleeding, thickness/height/size of lesion, LM symptom severity scale, dermatology life quality index, and overall patient satisfaction.

Results:

Safety, clinical examinations, laboratory evaluations, and quantification of sirolimus blood levels, suggested that QTORIN rapamycin was generally safe and well-tolerated. Efficacy indicated statistically significant improvements in endpoints with treatment. Clinician and patient reports were supported by visual photographs showing significant improvement in lesions over the course of treatment.

Conclusions:

This Phase 2 study provides compelling evidence of the safety and efficacy of QTORIN rapamycin, a novel 3.9% topical sirolimus formulation, for the treatment of microcystic LM and supports further development including a larger trial in this patient population.
The evolution of a quality improvement curriculum in a family nurse practitioner residency program
Authors: Yamada Kiera , Price Paula Susanne , Gorgone Bronwyn , Robertson Bethany
Published: December 2024

There is a wide variation in the curricular emphasis and implementation nationally across programs for teaching quality improvement (QI) in family nurse practitioner (FNP) programs. This variation among curriculum plans often leaves NP graduates unsure as to how to identify and effect change within their organizations. This manuscript describes the development of an initial QI curriculum and subsequent enhancements over a 3-year time frame and outlines the curriculum development process, implementation, and program outcomes within an FNP residency program. This report also focuses on the importance of reinforcing the role of QI within the personal identity of the FNP, ensuring quality care to patients.