bluuebunny/crossref_metadata_2025 huggingface dataset:
Suicide by Ethyl Methacrylate Ingestion
Authors: Prahlow Samuel P. , Wilson Taylor , Gruszecki Amy C.
Published: August 2024

This case report characterizes a unique way in which suicide was accomplished through ingestion of chemicals typically used to create acrylic fingernails that resulted in death. Ethyl methacrylate and acrylic powder are commonly combined to form acrylic nails in nail salons. The process of applying acrylic nails utilizes each substance by mixing both before it typically solidifies within seconds of combining the two compounds. Ingestion of these compounds has not been previously described within the medical literature. The decedent was a nail technician at a local salon. He was found unresponsive in his yard which led to a 911 call. At the scene, a mostly empty 16-oz bottle of ethyl methacrylate, a chemical used at the salon where he worked, was found. At autopsy, the decedent's body had a strong chemical odor consistent with odors present at nail salons. Significant gastrointestinal tract damage was seen including discoloration within the esophagus, and the stomach contained a molded, hardened nail compound. The cause of death was ruled as complications of nail acrylic powder and liquid ethyl methacrylate ingestion. This case shows the unusual findings seen at autopsy from a decedent who committed suicide by ingestion of ethyl methacrylate with acrylic powder.
A False-Negative 123I-MIBG SPECT/CT With True-Positive 68Ga-DOTATATE PET/CT in a Patient With Neuroblastoma Following 177Lu-DOTATATE Therapy
Authors: Li Siqi , Xu Yanfeng , Lu Xia , Wang Wei , Yang Jigang
Published: August 2024

A 10-year-old girl with high-risk neuroblastoma underwent 123I-MIBG SPECT/CT and 68Ga-DOTATE PET/CT, which both showed multiple bone metastases. However, following 177Lu-DOTATATE therapy, only 68Ga-DOTATATE PET/CT identified residual lesions with negative 123I-MIBG SPECT/CT results. The case emphasized the complementary role of 68Ga-DOTATATE PET/CT and 123I-MIBG SPECT/CT after 177Lu-DOTATATE therapy.
Hamate Fracture
Authors: Russell Nancy G. , Kessler Michael W.
Published: August 2024

Hamate fractures are uncommon, but early and accurate diagnosis is critical to prevent negative outcomes. Hamate fractures may present initially to emergency departments, and diagnosis can be challenging. This case report of a common hamate fracture may aid in increasing emergency advanced practice nurse knowledge to identify these fractures in practice.
SANE Knowledge of HIV nPEP
Authors: Simms-Roberson Priscilla M. , Broda Piotr
Published: August 2024

Background:

Discussing the risk of exposure to human immunodeficiency virus (HIV) and assessing the need for HIV nonoccupational postexposure prophylaxis (nPEP) are essential components of providing care to victims of sexual assault. Current literature on the topic of HIV nPEP for victims of sexual assault surrounds risk of exposure, patient adherence, access and barriers, current practices, and standardized order sets. A significant gap in the literature concerning sexual assault nurse examiner (SANE) knowledge of HIV infection and HIV nPEP evidence-based practice guidelines was identified. The purpose of this research was to assess SANE knowledge surrounding HIV infection and evidence-based practice recommendations for HIV nPEP use in victims of sexual assault.

Methods:

A 20-item knowledge survey was created using QuestionPro. The aim of the survey was to measure SANE knowledge of HIV transmission, pathophysiology, nPEP medications, and evidence-based practice guidelines for victims of sexual assault. In addition to the 20 knowledge items, 15 demographic questions were included. The study design was cross-sectional, descriptive, and comparative. A total of 411 participants completed the survey.

Results:

Data analysis revealed knowledge deficits for topics such as risk of HIV transmission, nPEP indications, laboratory testing, drug regimens, nPEP timing, mechanism of action, medication contraindications, and adherence issues. The overall mean score for the knowledge survey among all participants was 13.36 out of 20 (66.8%).

Conclusion:

A knowledge deficit among SANEs surrounding HIV infection and HIV nPEP evidence-based practice guidelines for patients who experienced sexual assault was identified. The study highlights the need for additional education for specialized nurses who are providing care to victims of sexual assault.
Culturally Competent Care for Diverse Populations
Authors: Fabry Lindy , McDermott Sandi , Wilford Brandi
Published: August 2024

Transcultural nursing is a discipline that emphasizes culturally competent care for diverse populations, recognizing the influence of culture on health beliefs, values, practices, and outcomes. It requires nurses to respect cultural differences and similarities, but faces challenges in curriculum design, faculty development, and student assessment. This paper explores transcultural nursing education’s current state and future directions, addressing the American Association of Colleges of Nursing essentials for integrating cultural content into nursing curricula, reviewing Madeleine Leininger’s transcultural nursing theory, diversity, equity, and inclusion concepts, and discussing the main challenges of transcultural nursing education, including lack of student diversity, training, and resources. Strategies to overcome these challenges include interprofessional collaboration, cultural immersion, and evidence-based practice. The paper concludes with how emergency department nurses should incorporate this into practice.
Emergency Medicine Case Study on Local Anesthetic Systemic Toxicity
Authors: Hays Haley
Published: August 2024

The purpose of this case study on local anesthetic systemic toxicity (LAST), a potentially life-threatening complication of local anesthetic, is to ensure that emergency nurse practitioners (ENPs) are knowledgeable on this disease process. Local anesthetics are used frequently, often daily, by ENPs, as well as multiple other health care providers for various procedures. They should be knowledgeable of the steps to resuscitate a patient who may have severe LAST. This case study reviews the emergency management of LAST, including pharmacologic treatment, deviations from routine advanced resuscitative guidelines, and disposition of the patient upon successful resuscitation. Additionally, risk assessment and clinical manifestations will be discussed. After reviewing this case study, ENPs should be able to recognize the presentation of LAST and provide emergent management to reduce complications, comorbidities, and death.
A Deep Learning Approach for Accurate Discrimination Between Optic Disc Drusen and Papilledema on Fundus Photographs
Authors: Sathianvichitr Kanchalika , Najjar Raymond P. , Zhiqun Tang , Fraser J. Alexander , Yau Christine W. L. , Girard Michael J. A. , Costello Fiona , Lin Mung Y. , Lagrèze Wolf A. , Vignal-Clermont Catherine , Fraser Clare L. , Hamann Steffen , Newman Nancy J. , Biousse Valérie , Milea Dan ,   for the BONSAI Group
Published: August 2024

Background:

Optic disc drusen (ODD) represent an important differential diagnosis of papilledema caused by intracranial hypertension, but their distinction may be difficult in clinical practice. The aim of this study was to train, validate, and test a dedicated deep learning system (DLS) for binary classification of ODD vs papilledema (including various subgroups within each category), on conventional mydriatic digital ocular fundus photographs collected in a large international multiethnic population.

Methods:

This retrospective study included 4,508 color fundus images in 2,180 patients from 30 neuro-ophthalmology centers (19 countries) participating in the Brain and Optic Nerve Study with Artificial Intelligence (BONSAI) Group. For training and internal validation, we used 857 ODD images and 3,230 papilledema images, in 1,959 patients. External testing was performed on an independent data set (221 patients), including 207 images with ODD (96 visible and 111 buried), provided by 3 centers of the Optic Disc Drusen Studies Consortium, and 214 images of papilledema (92 mild-to-moderate and 122 severe) from a previously validated study.

Results:

The DLS could accurately distinguish between all ODD and papilledema (all severities included): area under the receiver operating characteristic curve (AUC) 0.97 (95% confidence interval [CI], 0.96–0.98), accuracy 90.5% (95% CI, 88.0%–92.9%), sensitivity 86.0% (95% CI, 82.1%–90.1%), and specificity 94.9% (95% CI, 92.3%–97.6%). The performance of the DLS remained high for discrimination of buried ODD from mild-to-moderate papilledema: AUC 0.93 (95% CI, 0.90–0.96), accuracy 84.2% (95% CI, 80.2%–88.6%), sensitivity 78.4% (95% CI, 72.2%–84.7%), and specificity 91.3% (95% CI, 87.0%–96.4%).

Conclusions:

A dedicated DLS can accurately distinguish between ODD and papilledema caused by intracranial hypertension, even when considering buried ODD vs mild-to-moderate papilledema.
Genome description of a potentially new species of Streptomyces isolated from the Indian Sundarbans mangrove
Authors: Ghosh Anwesha , Bhambra Simran Kaur , Chandrasekaran Raghu , Bhadury Punyasloke
Published: August 2024

A potentially new species of Streptomyces was isolated from station 177 of the Sundarbans Seasonal Time Series in Indian Sundarbans mangrove. The isolate was cultured from sediment sample on TYS medium of salinity 15. Sequencing and annotation of the 16S rRNA showed 100% identity against S. laurentii NPS17 against GenBank/ENA/DDBJ. Annotation of the whole genome against GTDB database showed closest identity with S. terrae SKN60 and belong to the same clade as S. roseicoloratus TRM44457T and S. laurentii ATCC 31255. The genome is about 7.2 Mb and has a G+C % of 73%. The average amino acid identity (AAI) was 85.01% with S. roseicoloratus and 80.34% with S. roseolus. The genome of S. sp. SBR177 has all essential housekeeping genes and genes for secondary metabolite production.
SDoH-Aware Approach to Prostate Cancer Screening: Addressing Overdiagnosis of Prostate Cancer using PSA
Authors: Lewis Ashley , Khandwala Yash Samir , Hernandez-Boussard Tina , Brooks James D
Published: August 2024

This study investigates the potential of multimodal data for prostate cancer (PCa) risk prediction using the All of Us (AoU) research program dataset. By integrating polygenic risk scores (PRSs) with diverse clinical, survey, and genomic data, we developed a model that identifies established PCa risk factors, such as age and family history, and a novel factor: recent healthcare visits are linked to reduced risk. The model’s performance, notably the false positive rate, is improved compared to traditional methods, despite the lack of Prostate-Specific Antigen (PSA) data. The findings demonstrate that incorporating comprehensive multimodal data from AoU can enhance PCa risk prediction and provide a robust framework for future clinical applications.

Code Available

https://github.com/ashlew23/pc_multimodal
Genetic association and machine learning improves discovery and prediction of type 1 diabetes
Authors: McGrail Carolyn , Sears Timothy J. , Kudtarkar Parul , Carter Hannah , Gaulton Kyle
Published: August 2024

Type 1 diabetes (T1D) has a large genetic component, and expanded genetic studies of T1D can lead to novel biological and therapeutic discovery and improved risk prediction. In this study, we performed genetic association and fine-mapping analyses in 817,718 European ancestry samples genome-wide and 29,746 samples at the MHC locus, which identified 165 independent risk signals for T1D of which 19 were novel. We used risk variants to train a machine learning model (named T1GRS) to predict T1D, which highly differentiated T1D from non-disease and type 2 diabetes (T2D) in Europeans as well as African Americans at or beyond the level of current standards. We identified extensive non-linear interactions between risk loci in T1GRS, for example between HLA-DQB1*57 andINS,coding and non-coding HLA alleles, andDEXI, INSand other beta cell loci, that provided mechanistic insight and improved risk prediction. T1D individuals formed distinct clusters based on genetic features from T1GRS which had significant differences in age of onset, HbA1c, and renal disease severity. Finally, we provided T1GRS in formats to enhance accessibility of risk prediction to any user and computing environment. Overall, the improved genetic discovery and prediction of T1D will have wide clinical, therapeutic, and research applications.
Differences in bioprosthetic valve failure after aortic valve replacement in patients with immune mediated inflammatory diseases
Authors: Sefton Christopher , Leaphart Davis , Klein Benjamin , Santini Garrett , Patel Aditi , Husni M. Elaine , Vargo Patrick R. , Roselli Eric E. , Svensson Lars , Krishnaswamy Amar , Kapadia Samir , Menon Venu , Khot Umesh , Wassif Heba
Published: August 2024

Introduction

Immune-mediated inflammatory disease (IMID) is a subset of autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, and psoriasis that is emerging as a risk factor for many cardiovascular diseases including valvular disease.

Objectives

To determine whether IMID is associated with frequent and early development of bioprosthetic valve failure (BVF) after surgical aortic valve replacement (SAVR) and transcatheter valve replacement (TAVR).

Methods

Serial echocardiograms for patients who underwent SAVR and TAVR at Cleveland Clinic between 2000 and 2022 were assessed for time to development of BVF after procedure. ICD10 codes were used to stratify to those with and without IMID. Kaplan-Meier curve and cox proportional hazard regression analysis were used to assess for differences in development of BVF after TAVR and SAVR.

Results

351 TAVR patients (52 IMID and 299 controls) and 1961 SAVR patients (300 IMID and 1661 controls) were included. BVF after TAVR occurred in 12 (23.1%) IMID and 21 (7.0%) control patients, respectively, yielding an adjusted hazard ratio of 4.02 (1.81 - 8.92). Time to 50% of patients developing BVF was earlier among IMID, occurring at 6.6 years IMID and not reached in controls (p < 0.001). There were no significant differences in prevalence and time to development of BVF in IMID vs controls after SAVR.

Conclusion

After TAVR, BVF occurred earlier and more frequently in patients with IMID than controls. This risk should be included during shared decision making among IMID patients considered for TAVR, and may warrant more frequent monitoring post procedure. These differences in BVF were not seen after SAVR.
Synergistic combination therapy with ONC201 or ONC206, Enzalutamide and Darolutamide in preclinical studies of castration-resistant prostate cancer
Authors: Wu Laura , Pinho-Schwermann Maximilian , Zhou Lanlan , Zhang Leiqing , Huntington Kelsey E. , Malpass Ryan , Seyhan Attila A. , Carneiro Benedito A. , El-Deiry Wafik S.
Published: August 2024

Androgen receptor (AR) signaling plays a primary role in prostate cancer progression. Non-steroidal anti- androgens (NSAA) including enzalutamide, and apalutamide have been used to treat patients with advanced disease. However, patients with metastatic castration-resistant prostate cancer (mCPRC) develop resistance, resulting in limited overall survival benefit. Darolutamide is a novel next-generation androgen receptor- signaling inhibitor that is FDA approved for non-metastatic castration resistant prostate cancer (nmCRPC). Imipridone ONC201/TIC10 is first-in-class small molecule that activates the integrated stress response (ISR) and upregulates TNF-related apoptosis-inducing ligand (TRAIL). Our study investigates ISR and AR signaling in anti-tumor efficacy with ONC201 and enzalutamide or darolutamide against mCRPC cells. mCRPC cell lines 22RV1, LNCaP, DU145 and PC3 were treated with ONC201, darolutamide, and enzalutamide as single agents or in combinations. Combinations of ONC201 and darolutamide or enzalutamide demonstrated synergistic effects in mCRPC cells. Combinations of ONC201 and darolutamide or enzalutamide reduced PSA levels in LNCaP cells and induced of ATF4 in both LNCaP and 22RV1 cell lines. Darolutamide synergized with ONC201 regardless of AR status or castration sensitivityin vitro.Flow cytometric analysis showed increased intra-tumoral NK cells in mice treated with ONC201 and combination of ONC201 and darolutamide. Trends of increased TRAIL activation within NK cells were also observed in treatment groups. ONC201 and darolutamide demonstrated anti-tumor effectsin vivoin the 22RV1 CRPC model. Our results prompt further translational and clinical studies with imipridones ONC201 or ONC201 in combination with enzalutamide or darolutamide for treatment of castrate resistant advanced or metastatic prostate cancer.
Development of the novel amylin receptor activators with nanomolar potency by peptide mutagenesis
Authors: Lee Sangmin
Published: August 2024

Amylin peptide hormone activates amylin receptors in brains and controls blood glucose and appetite. An amylin receptor activator pramlintide was developed for diabetes treatment. Currently, the amylin receptor activator with once-weekly injection has been tested for body weight reduction to treat obesity. Human amylin peptide was reported to form aggregates, while rat amylin has been shown soluble in aqueous solution. Here, multiple peptide activators for human amylin receptors were developed by introducing comprehensive mutagenesis to rat amylin peptide. The rat amylin peptide C-terminal fragment is known for interacting with human amylin receptor extracellular domain. The rat amylin peptide C-terminal fragment with eleven amino acids was used to screen for affinity-enhancing mutations. Up to twelve mutational combinations were found to significantly increase peptide affinity for amylin receptor extracellular domains by over 100-fold. Using these affinity-enhancing mutations, three representative rat amylin analogs with thirty-seven amino acids were made to test the potency increase for amylin receptor activation. All three mutated rat amylin analogs showed significant potency increases by 5- to 10-fold compared to endogenous rat amylin. These mutated peptide activators also showed higher potency for human amylin receptor activation than a clinical drug pramlintide. These amylin receptor activators developed in this study can be useful for the drug development targeting diabetes/obesity treatment.
Tissue and Peripheral T-cell Repertoire Predicts Immunotherapy Response and Progression-Free Survival in NSCLC Patients
Authors: Pino-González Manuel , Lázaro-Quintela Martín , Alonso-Álvarez Irene , Gallardo-Gómez María , Juaneda-Magdalena Laura , Francisco-Fernández Alejandro , Calabuig-Fariñas Silvia , Jantus-Lewintre Eloisa , Martínez-Fernández Mónica
Published: August 2024

Immunotherapy has opened new avenues of treatment for patients with advanced non-small cell lung cancer (NSCLC) without previous hope of survival. Unfortunately, only a small percentage of patients benefit from it, and it is still not well understood which tumor characteristics can be used to predict immunotherapy response. As the key cellular effectors of antitumor immunity, T cells are endowed with specialized T cell receptors (TCRs) to recognize and eliminate cancer cells. Here, we evaluated the potential of TCR repertoire as a predictive biomarker in patients treated with immunotherapy. With this aim, advanced NSCLC patients treated with immunotherapy at first-line were included. After obtaining peripheral blood and tissue samples at baseline, next-generation sequencing targeting TCRβ/γ was performed. Beyond TCR metrics, clonal space of the most frequent clones was determined. We found a positive association between uneven tumor-infiltrating TCRβ repertoire and the immunotherapy response. Moreover, the use of various tumor-infiltrating and circulating TRBV/J genes predicted the immunotherapy response. Our results indicate the importance of evaluating tissue and circulating TCRβ repertoire prior immunotherapy, showing it as a promising immunotherapy response biomarker in NSCLC patients.
Characterization and forecast of global influenza (sub)type dynamics
Authors: Bonacina Francesco , Boëlle Pierre-Yves , Colizza Vittoria , Lopez Olivier , Thomas Maud , Poletto Chiara
Published: August 2024

The (sub)type composition of seasonal influenza waves varies in space and time. (Sub)types tend to have different impacts on population groups, therefore understanding the drivers of their co-circulation and anticipating their composition is important for epidemic preparedness and response. FluNet provides data on influenza specimens by (sub)type for more than one hundred fifty countries. However, due to surveillance variations across countries, global analyses usually focus on (sub)type compositions, a kind of data which is difficult to treat with advanced statistical methods. We used Compositional Data Analysis to circumvent the problem and study trajectories of annual (sub)type compositions of countries. First, we examined global trends from 2000 to 2022. We identified a few seasons which stood out for the strong within-country (sub)type dominance due to either a new virus/clade taking over (2003/2004 season, A/H1N1pdm pandemic) or (sub)types’ spatial segregation (COVID-19 pandemic). Second, we showed that the composition trajectories of countries between 2010 and 2019 clustered in two macroregions characterized by (sub)type alternation vs. persistent mixing. Finally, we defined five algorithms for forecasting the next-year composition and we found that taking into account the global history of (sub)type composition in a Bayesian Hierarchical Vector AutoRegressive model improved predictions compared with naive methods. The joint analysis of spatiotemporal dynamics of influenza (sub)types worldwide revealed a hidden structure in (sub)type circulation that can be used to improve predictions of the (sub)type composition of next year’s epidemic according to place.
PREVALENCE OF ABNORMAL SEMINAL FLUID AND ASSOCIATED FACTORS AMONG PATIENTS ATTENDING FERTILITY CLINICS IN OSOGBO: A CROSS SECTIONAL STUDY
Authors: Awodele Kehinde , Adeyemo Sunday Charles , Olabode Eniola Dorcas , Fasanu Adeniyi Olaonipekun , Olaitan Lanre , Akindele Akintunde Rasaq , Olagunju Olufunso Abidemi , Aderinwale Adeola Dorcas
Published: August 2024

Background

Infertility is a global health issue that affects millions of couples worldwide, In Nigeria, the prevalence of infertility is particularly high underscoring the need for a better understanding of the factors contributing to male infertility at which Seminal Fluid Analysis (SFA) is the most important characteristics. This study aimed to assess the prevalence of abnormal seminal fluid and its associated factors among patients attending fertility clinics in Osogbo, Nigeria.

Methods and Findings

A descriptive cross-sectional study design was used among male patients attending fertility centers in Osogbo, Osun State. Fisher’s formula (n=z2pq/d2) was used to determine the sample size. 305 respondents were selected using multistage sampling technique. Pre-tested questionnaire was used to collect data from respondents. Patients who consented to the study were also made to undergo seminal fluid analysis. The results were analysed using IBM Statistical Product for Service Solution (SPSS) version 27. Descriptive statistics was used for all variables. Bivariate and multivariate analysis were done at p<0.05 as level of significance. Majority of the respondents, 257 (84.3%) had at least one abnormality of Seminal fluid. Multiple regression analysis revealed that respondents who were habitual drunkard were about five times more likely to have at least one abnormality in their seminal fluid (OR: 4.990, p: 0.004, C.I.: 1.688-14.749) and smokers were three times more likely to have at least one abnormality in their seminal fluid (p=0.005, OR=3.300 and C.I=1.396-4.273). Also, respondents with history of sexually transmitted infection were 3.5 times more likely to have at least one abnormality in their seminal fluid (p=0.039, OR=3.595 and C.I=1.072-14.146).

Conclusions

The study observed high prevalence of abnormal seminal fluid which was significantly associated with lifestyle habits such as smoking, alcohol as well as previous history of sexually transmitted infection. The study recommended that advocacy program for healthy lifestyle, early screening and public health education will further reduce the burden of abnormal seminal fluid and by implication, infertility among couples.
Protein degradation shapes developmental tempo in mouse and human neural progenitors
Authors: Nakanoh Shota , Stamataki Despina , Garcia-Perez Lorena , Azzi Chiara , Carr Hayley L , Pokhilko Alexandra , Yu Lu , Howell Steven , Skehel Mark , Oxley David , Andrews Simon , Briscoe James , Rayon Teresa
Published: August 2024

The speed of embryonic development varies considerably between mammalian species, yet the underlying molecular mechanisms remain poorly understood. To investigate the basis for species-specific developmental tempo, we performed a comprehensive comparative analysis of protein dynamics in mouse and human neural progenitors (NPs). Through a combination of targeted protein labelling, quantitative mass spectrometry, and protein depletion with self-labeling tags, we demonstrate that protein degradation is a key driver of tempo differences between mouse and human NPs. We observe a systematic 1.5-fold increase in protein half-lives in human NPs compared to mouse, independent of cellular compartment or protein function. This difference persists in post-mitotic neurons, indicating active degradation as the primary mechanism. Proteasomal activity is also ∼1.5-fold higher in mouse NPs, consistent with upregulation of proteasome-associated proteins. Importantly, increasing the rate of proteolytic degradation of a key transcriptional repressor in neural progenitors accelerates the expression of its target gene. Despite differences in degradation rates, protein synthesis rates are similar between species, resulting in higher protein content in human NPs. Our findings highlight the central role of protein degradation in controlling developmental tempo and provide insight into the molecular basis of evolutionary changes in developmental timing across species.
Cyclin A/B RxL Macrocyclic Inhibitors to Treat Cancers with High E2F Activity
Authors: Singh Shilpa , Gleason Catherine E. , Fang Min , Laimon Yasmin N. , Khivansara Vishal , Xie Shanhai , Durmaz Yavuz T. , Sarkar Aniruddha , Ngo Kenneth , Savla Varunika , Li Yixiang , Abu-Remaileh Muhannad , Li Xinyue , Tuladhar Bishma , Odeh Ranya , Hamkins-Indik Frances , He Daphne , Membreno Miles W. , Nosrati Meisam , Gushwa Nathan N. , Leung Siegfried S.F. , Fraga-Walton Breena , Hernandez Luis , Baldomero Miguel P , Lent Bryan M. , Spellmeyer David , Luna Joshua F. , Hoang Dalena , Gritsenko Yuliana , Chand Manesh , DeMart Megan K. , Metobo Sammy , Bhatt Chinmay , Shapiro Justin A. , Yang Kai , Dupper Nathan J. , Bockus Andrew T. , Doench John G. , Aggen James B. , Liu Li-Fen , Levin Bernard , Wang Evelyn W. , Vendrell Iolanda , Fischer Roman , Kessler Benedikt , Gokhale Prafulla C. , Signoretti Sabina , Spektor Alexander , Kreatsoulas Constantine , Singh Rajinder , Earp David J. , Garcia Pablo D. , Nijhawan Deepak , Oser Matthew G.
Published: August 2024

Cancer cell proliferation requires precise control of E2F1 activity; excess activity promotes apoptosis. Here, we developed cell-permeable and bioavailable macrocycles that selectively kill small cell lung cancer (SCLC) cells with inherent high E2F1 activity by blocking RxL-mediated interactions of cyclin A and cyclin B with select substrates. Genome-wide CRISPR/Cas9 knockout and random mutagenesis screens found that cyclin A/B RxL macrocyclic inhibitors (cyclin A/Bi) induced apoptosis paradoxically by cyclin B- and Cdk2-dependent spindle assembly checkpoint activation (SAC). Mechanistically, cyclin A/Bi hyperactivate E2F1 and cyclin B by blocking their RxL-interactions with cyclin A and Myt1, respectively, ultimately leading to SAC activation and mitotic cell death. Base editor screens identified cyclin B variants that confer cyclin A/Bi resistance including several variants that disrupted cyclin B:Cdk interactions. Unexpectedly but consistent with our base editor and knockout screens, cyclin A/Bi induced the formation of neo-morphic Cdk2-cyclin B complexes that promote SAC activation and apoptosis. Finally, orally-bioavailable cyclin A/Bi robustly inhibited tumor growth in chemotherapy-resistant patient-derived xenograft models of SCLC. This work uncovers gain-of-function mechanisms by which cyclin A/Bi induce apoptosis in cancers with high E2F activity, and suggests cyclin A/Bi as a therapeutic strategy for SCLC and other cancers driven by high E2F activity.
Chronic contractile activity induced skeletal muscle-derived extracellular vesicles increase mitochondrial biogenesis in recipient myocytes via transmembrane or peripheral membrane proteins
Authors: Obi Patience O. , Souza Tamiris F. G. , Seif Samira , Bydak Benjamin , Klassen Nicholas , West Adrian R. , Gordon Joseph W. , Saleem Ayesha
Published: August 2024

The effect of chronic contractile activity (CCA) on the biophysical properties and functional activity of skeletal muscle extracellular vesicles (Skm-EVs) is poorly understood due to challenges in distinguishing Skm-EVs originating from exercising musclein vivo. To address this, myoblasts were differentiated into myotubes, and electrically paced (3 h/day, 4 days @ 14 V). CCA evoked an increase in mitochondrial biogenesis in stimulatedvs. non-stimulated (CON) myotubes as expected. EVs were isolated from conditioned media from control and stimulated myotubes using differential ultracentrifugation and characterized biophysically using tunable resistive pulse sensing (TRPS, Exoid), TEM and western blotting. TEM images confirmed isolated round-shaped vesicles of about 30 - 150 nm with an intact lipid bilayer. The mean size of EVs ranged from 98 -138 nm, and was not altered by CCA. Zeta potential and total EV protein yield remained unchanged between groups, and total EV secretion increased after 4 days of CCA. Concomitant analysis of EVs after each day of CCA also demonstrated a progressive increase in CCA-EV concentration, while size and zeta potential remained unaltered, and EV protein yield increased in both CON-EVs and CCA groups. CCA-EVs were enriched with small-EVsvs. CON-EVs, concomitant with higher expression of small-EV markers CD81, Tsg101 and HSP70. In whole cell lysates, CD63 and ApoA1 were reduced with CCA in myotubes, whereas CD81, Tsg101, Flotillin-1 and HSP70 levels remained unchanged. To evaluate the functional effect of EVs secreted post-CCA, we treated C2C12 myoblasts with all EVs isolated from CON or CCA myotubes after each day of stimulation, and measured cell count, cell viability, protein yield and mitochondrial biogenesis in recipient cells. There was no effect on cell count, viability and protein yield. Myoblasts treated with CCA-EVs exhibited increased mitochondrial biogenesis as indicated by enhanced MitoTracker Red staining, cytochromecoxidase activity, and protein expression of electron transport chain subunit, CIV-MTCO1. Further, CCA-EV treatment enhanced maximal oxygen consumption rates (OCR), and ATP production in treated myoblasts. This increase in maximal OCR was abrogated when CCA-EVs pre-treated with proteinase K were co-cultured with myoblasts, indicating the pro-metabolic effect was likely mediated by transmembrane or peripheral membrane proteins in CCA-EVs. Our data highlight the novel effect of Skm-EVs isolated post-CCA in mediating pro-metabolic effects in recipient cells and thereby transmitting the effects associated with traditional exercise. Further investigation to interrogate the underlying mechanisms involved in downstream cellular metabolic adaptations is warranted.
Visualizing Liquid Distribution Across Hyphal Networks with Cellular Resolution
Authors: Clark Amelia J. , Masters-Clark Emily , Moratto Eleonora , Junier Pilar , Stanley Claire E.
Published: August 2024

Filamentous fungi and fungal-like organisms contribute to a wide range of important ecosystem functions. Evidence has shown the movement of liquid across mycelial networks in unsaturated environments, such as soil. However, tools to investigate liquid movement along hyphae at the level of the single cell are still lacking. Microfluidic devices permit the study of fungal and fungal-like organisms with cellular resolution as they can confine hyphae to a single optical plane, which is compatible with microscopy imaging over longer timescales and allows for precise control of the microchannel environment. The aim of this study was to develop a method that enables the visualization and quantification of liquid movement on hyphae of fungal and fungal-like microorganisms. For this, the Fungal-Fungal Interaction (FFI) microfluidic device was modified to allow for the maintenance of unsaturated microchannel conditions. Fluorescein-containing growth medium solidified with agar was used to track liquid transported by hyphae via fluorescence microscopy. Our key findings highlight the suitability of this novel methodology for the visualization of liquid movement by hyphae over varying time scales and the ability to quantify the movement of liquid along hyphae. Furthermore, we showed that at the cellular level, extracellular hyphal liquid movement can be bidirectional and highly dynamic, uncovering a possible link between liquid movement and hyphal growth characteristics. We envisage that this method can be applied to facilitate future research probing the parameters contributing to hyphal liquid movement and is an essential step for studying the phenomenon of fungal highways.
Assessing the Impact of Selective Attention on the Cortical Tracking of the Speech Envelope in the Delta and Theta Frequency Bands and How Musical Training Does (Not) Affect It
Authors: Schüller Alina , Mücke Annika , Riegel Jasmin , Reichenbach Tobias
Published: August 2024

Oral communication regularly takes place amidst background noise, requiring the ability to selectively attend to a target speech stream. Musical training has been shown to be beneficial for this task. Regarding the underlying neural mechanisms, recent studies showed that the speech envelope is tracked by neural activity in the auditory cortex, which plays a role in the neural processing of speech, including speech in noise. The neural tracking occurs predominantly in two frequency bands, the delta and the theta band. However, much regarding the specifics of these neural responses, as well as their modulation through musical training, still remain unclear. Here, we investigated the delta- and theta-band cortical tracking of the speech envelope of attended and ignored speech using magnetoencephalography (MEG) recordings. We thereby assessed both musicians and non-musicians to explore potential differences between these groups. The cortical speech tracking was quantified through source-reconstructing the MEG data and subsequently relating the speech envelope in a certain frequency band to the MEG data using linear models. We thereby found the theta-band tracking to be dominated by early responses with comparable magnitudes for attended and ignored speech, whereas the delta band tracking exhibited both earlier and later responses that were modulated by selective attention. Almost no significant differences emerged in the neural responses between musicians and non-musicians. Our findings show that only the speech tracking in the delta but not in the theta band contributes to selective attention, but that this mechanism is essentially unaffected by musical training.
Multiscale Responsive Kinetic Modeling: Quantifying Biomolecular Reaction Flux under Varying Electrochemical Conditions
Authors: Weckel-Dahman Hannah , Carlsen Ryan , Swanson Jessica M.J.
Published: August 2024

Attaining a complete thermodynamic and kinetic characterization for processes involving multiple interconnected rare-event transitions remains a central challenge in molecular biophysics. This challenge is amplified when the process must be understood under a range of reaction conditions. Herein, we present a condition-responsive kinetic modeling framework that can combine the strengths of bottom-up rate quantification from multiscale simulations with top-down solution refinement using experimental data. Although this framework can be applied to any process, we demonstrate its use for electrochemically driven transport through channels and transporters. Using the Cl−/H+antiporter ClC-ec1 as a model system, we show how robust and predictive kinetic solutions can be obtained when the solution space is grounded by thermodynamic constraints, seeded through multiscale rate quantification, and further refined with experimental data, such as electrophysiology assays. Turning to the Shaker K+channel, we demonstrate that robust solutions and biophysical insights can also be obtained with sufficient experimental data. This multi-pathway method proves capable of identifying single-pathway dominant mechanisms but also highlights that competing and off-pathway flux is still essential to replicate experimental findings and to describe concentration-dependent channel rectification.
Flux balance analysis and peptide mapping elucidate the impact of bioreactor pH on Chinese Hamster Ovary (CHO) cell metabolism and N-linked glycosylation in the Fab and Fc regions of the produced IgG
Authors: Reddy Jayanth Venkatarama , Singh Sumit Kumar , Leibiger Thomas , Lee Kelvin H , Ierapetritou Marianthi , Papoutsakis Eleftherios Terry
Published: August 2024

Chinese Hamster Ovary (CHO) cells were grown at different bioreactor pH conditions to detail how bioreactor pH affects cell metabolism and site-specific N-linked glycosylation of the produced broadly neutralizing anti-HIV IgG monoclonal antibody VRC01. The data show that pH affects cell growth, glucose/lactate metabolism, IgG production rates, nonessential amino acid metabolism and ammonia accumulation. Parsimonious Flux Balance Analysis (pFBA) and Flux Variability Analysis (FVA) provide insight into the effect of pH on core intracellular reactions at the different pH conditions and culture durations. pFBA revealed the contribution of sources for the production of the toxic metabolite ammonia and provided insights into the switch from ammonia production to consumption. It also documented that culture duration and pH alter the complex bimodal patterns (production/uptake) of several essential and non-essential amino acids. The VRC01 IgG has N-linked glycosylation sites in both the Fc region and the Fab region. Site- specific N-linked glycan analysis using glycopeptide mapping demonstrated that pH significantly affects the glycosylation profiles of the two IgG sites. The Fc region glycans were completely fucosylated but did not contain any sialylation. The Fab region glycans were not completely fucosylated but contained sialylated glycans. Bioreactor pH affected both the fucosylation and sialylation indexes in the Fab region and the galactosylation index of the Fc region. However, fucosylation in the Fc region was unaffected thus demonstrating that the effect of pH on site- specific N-linked glycosylation is complex.
Spatial 3D genome organization controls the activity of bivalent chromatin during human neurogenesis
Authors: Ahanger Sajad Hamid , Zhang Chujing , Semenza Evan R. , Gil Eugene , Cole Mitchel A. , Wang Li , Kriegstein Arnold R. , Lim Daniel A.
Published: August 2024

The nuclear genome is spatially organized into a three-dimensional (3D) architecture by physical association of large chromosomal domains with subnuclear compartments including the nuclear lamina at the radial periphery and nuclear speckles within the nucleoplasm1–5. However, how spatial genome architecture regulates human brain development has been overlooked owing to technical limitations. Here, we generate high-resolution maps of genomic interactions with the lamina and speckles in cells of the neurogenic lineage isolated from midgestational human cortex, uncovering an intimate association between subnuclear genome compartmentalization, chromatin state and transcription. During cortical neurogenesis, spatial genome organization is extensively remodeled, relocating hundreds of neuronal genes from the lamina to speckles including key neurodevelopmental genes bivalent for H3K27me3 and H3K4me3. At the lamina, bivalent genes have exceptionally low expression, and relocation to speckles enhances resolution of bivalent chromatin to H3K4me3 and increases transcription >7-fold. We further demonstrate that proximity to the nuclear periphery – not the presence of H3K27me3 – is the dominant factor in maintaining the lowly expressed, poised state of bivalent genes embedded in the lamina. In addition to uncovering a critical role of subnuclear genome compartmentalization in neurogenic transcriptional regulation, our results establish a new paradigm in which knowing the spatial location of a gene is necessary to understanding its epigenomic regulation.
Neutrophils exposed to a cholesterol metabolite secrete extracellular vesicles that promote epithelial-mesenchymal transition and stemness in breast cancer cells
Authors: Krawczynska Natalia , Wang Yu , Lim Ki , Das Gupta Anasuya , Lenczowski Adam , Abughazaleh Marwan , Bendre Shruti V. , Kockaya Lara I. , Schane Claire P. , Fei Yifan , Hernandez Alvaro G , Drnevich Jenny , Chan Jefferson , Dobrucki Lawrence W. , Boppart Marni D. , Ostrander Julie , Nelson Erik R.
Published: August 2024

Small extracellular vesicles (sEVs) are emerging as critical mediators of intercellular communication in the tumor microenvironment (TME). Here, we investigate the mechanisms by which sEVs derived from neutrophils treated with the cholesterol metabolite, 27-hydroxycholesterol (27HC), influence breast cancer progression. sEVs released from 27HC treated neutrophils enhance epithelial-mesenchymal transition (EMT) and stem-like properties in breast cancer cells, resulting in loss of adherence, increased migratory capacity and resistance to cytotoxic chemotherapy. Decreased microRNAs (miRs) within the sEVs resulted in activation of the WNT/β-catenin signaling pathway in recipient cells and suggest that this may be a predominant pathway for stem-like phenotype and EMT. Our findings underscore a novel mechanism by which 27HC-modulated neutrophils contribute to breast cancer pathophysiology through EV-mediated intercellular communication, suggesting potential therapeutic targets in cancer treatment.
Event generator for jet tomography in electron-ion collisions
Authors: Ke Weiyao , Zhang Yuan-Yuan , Xing Hongxi , Wang Xin-Nian
Published: August 2024

We develop the first event generator, the electron-heavy-ion-jet-interaction-generator (eHIJING), for the jet tomography study of electron-ion collisions. In this generator, energetic jet partons produced from the initial hard scattering undergo multiple collisions with the nuclear target. The collision rate is proportional to the transverse-momentum-dependent (TMD) gluon density in the nucleus, which is given by a simple model inspired by the physics of gluon saturation. Medium-modified QCD splitting functions within the higher-twist (HT) and generalized higher-twist (GHT) frameworks are utilized to simulate parton showering in the nuclear medium that takes into account the non-Abelian Landau-Pomeranchuck-Midgal interference effect. Employing eHIJING, we revisit hadron production in semi-inclusive deep inelastic scattering (SIDIS) as measured by EMC, HERMES, and recent CLAS experiments. eHIJING with both GT and GHT frameworks gives reasonably good descriptions of these experimental data. Predictions for experiments at the future electron-ion colliders are also provided. It is demonstrated that future measurements of the transverse momentum broadening of single hadron spectra can be used to map out the two-dimensional kinematic (Q2, xB) dependence of the jet transport coefficient q^ in cold nuclear matter.

Published by the American Physical Society
2024
Nuclear mass radius and pressure in the Skyrme model
Authors: Martín-Caro Alberto García , Huidobro Miguel , Hatta Yoshitaka
Published: August 2024

We compute the mass radius, scalar radius, tensor radius, baryon number radius, and mechanical radius of nuclei with baryon number B=1,2,3,4,5,6,7,8, 32, 108 in the Skyrme model. The relations between these radii and the nuclear gravitational form factors are investigated. We also compute the ‘pressure’ distribution and find that it is negative in the core region for all the nuclei with B>1. This suggests that the way mechanical stability is achieved in nuclei is qualitatively different than in the nucleon.

Published by the American Physical Society
2024
Multiple Mellin-Barnes integrals and triangulations of point configurations
Authors: Banik Sumit , Friot Samuel
Published: August 2024

Mellin-Barnes (MB) integrals are a well-known type of integrals appearing in diverse areas of mathematics and physics, such as in the theory of hypergeometric functions, asymptotics, quantum field theory, solid-state physics, etc. Although MB integrals have been studied for more than a century, it is only recently that, due to a remarkable connection found with conic hulls, N-fold MB integrals can be computed analytically for N>2 in a systematic way. In this article, we present an alternative novel technique by unveiling a new connection between triangulations of point configurations and MB integrals, to compute the latter. To make it ready to use, we have implemented our new method in the package oniculls.wl, an already existing software dedicated to the analytic evaluation of MB integrals using conic hulls. The triangulation method is remarkably faster than the conic hull approach and can thus be used for the calculation of higher-fold MB integrals, as we show here by testing our code on the case of the off-shell massless scalar one-loop N-point Feynman integral up to N=15, for which the MB representation has 104 folds. Among other examples of applications, we present new simpler solutions for the off-shell one-loop massless conformal hexagon and two-loop double-box Feynman integrals, as well as for some complicated 8-fold MB integrals contributing to the hard diagram of the two-loop hexagon Wilson loop in general kinematics.

Published by the American Physical Society
2024
Enhanced muonization by active-sterile neutrino mixing in protoneutron stars
Authors: Ray Anupam , Qian Yong-Zhong
Published: August 2024

We study νμ−νs and ν¯μ−ν¯s mixing in the protoneutron star (PNS) created in a core-collapse supernova (CCSN). We point out the importance of the feedback on the general composition of the PNS in addition to the obvious feedback on the νμ lepton number. We show that for our adopted mixing parameters δm2∼102  keV2 and sin22θ consistent with the current constraints, sterile neutrino production is dominated by the Mikheyev–Smirnov–Wolfenstein conversion of ν¯μ into ν¯s and that the subsequent escape of ν¯s increases the νμ lepton number, which in turn enhances muonization of the PNS primarily through νμ+n→p+μ−. While these results are qualitatively robust, their quantitative effects on the dynamics and active neutrino emission of core-collapse supernovae should be evaluated by including νμ−νs and ν¯μ−ν¯s mixing in the simulations.

Published by the American Physical Society
2024
Graph theoretical approach to conformal correlators
Authors: Irges Nikos , Kastrinakis Stylianos
Published: August 2024

We introduce a discrete, graph theoretical approach to conformal field theory correlators. In a certain basis, called the squid basis, the correlator of N scalar operators can be expressed as the determinant of a natural, conformally covariant metric on a weighted graph, called the squid graph. We present the construction of this metric and discuss its possible role in constraining conformal data.

Published by the American Physical Society
2024