bluuebunny/crossref_metadata_2025 huggingface dataset:
Team-Led Empowerment
Authors: Hughes Maria V.
Published: September 2024

Background:

Individual states are becoming proactive in addressing the gaps in knowledge about newborns experiencing opioid withdrawal syndrome (ie, Neonatal Opioid Withdrawal Syndrome [NOWS]) through interdisciplinary efforts, perinatal learning collaboratives, and quality improvement initiatives.

Methods:

Descriptive statistics and a repeated measures analysis of variance were used to analyze the data. The 5-step project implemented a team-led, evidence-based, nursing intervention toolkit. This project was completed in a Midwest, nonprofit, level III neonatal intensive care hospital serving a high-minority, low-income demographic. The participants included 38 registered nurses.

Intervention:

A team-led initiative that developed a specialized toolkit aligned with the Indiana Perinatal Substance Use Practice Bundle. A pre-and posttraining assessment survey called “The Assessment of Nursing Knowledge and Self-Efficacy Related to NOWS” was developed to determine baseline knowledge and an increase in self-efficacy and knowledge. An educational curriculum intervention for onboarding new hires and completion of annual competencies was introduced.

Results:

Posttraining, knowledge increased, and self-efficacy scores improved by 0.85 points. The curriculum change integrated the toolkit into consistent onboarding and annual competencies.

Conclusion:

This comprehensive approach empowers nurses by equipping them with the skills and confidence necessary to provide quality care resulting in improved neonatal outcomes. Adopting a team-driven intervention for onboarding and annual competencies reinforce a dedication to continuous improvement and excellence in standards of care for newborns and their families.
Associations Between Hospital Nursing Resources and Breastfeeding Outcomes
Authors: Mason Aleigha , Lake Eileen T. , Clark Rebecca R. S.
Published: September 2024

Purpose:

To summarize how nursing resources and missed nursing care are associated with hospital breastfeeding outcomes, including human milk provision.

Background:

Nurses are the primary providers of breastfeeding support in the hospital. Nursing resources, eg, staffing and the work environment, enable nurses to carry out their work successfully. If resources are constrained, nurses may miss providing breastfeeding support. There is a gap in the literature about the relationships among nursing resources, missed nursing care, and breastfeeding outcomes.

Methods:

The Cumulative Index to Nursing and Allied Health Literature and PubMed were searched with keywords such as: “nurse staffing,” “nurse work environment,” “missed nursing care,” “breastfeeding,” “human milk,” and “lactation.” We included peer-reviewed studies of US samples in English published between 2014 and 2022.

Results:

Of 312 references, 8 met inclusion criteria: 5 quantitative and 3 qualitative. Better nurse staffing and breastfeeding support were associated with improved breastfeeding outcomes in the qualitative and quantitative literature. Missed care partially mediated the relationship between staffing and exclusive breast milk feeding rates. Better nurse work environments were associated with increased breastfeeding support and provision of human milk.

Conclusions:

Empirical evidence supports an association between the nurse work environment, nurse staffing, breastfeeding support, and outcomes. Implications for practice and research: Poor staffing may be associated with decreased breastfeeding support and outcomes. Hospital administrators and nurse managers may consider improving nurse staffing and the work environment to improve breastfeeding outcomes. Future research should simultaneously examine staffing and the work environment and address breastfeeding outcome disparities.
The Barriers and Perceived Benefits to Vulvar Self-Examination in the Management of Vulvar Lichen Sclerosus
Authors: Adamson Sarah R. , Willems Anneliese , Chew Christopher Y. , Saunders Helen , Keogh Louise , Veysey Emma
Published: September 2024

Objectives

It is common practice to advise people with vulvar lichen sclerosus to perform vulvar self-examination (VSE) to optimize topical therapy and detect changes that may represent active disease, scarring, and/or squamous cell carcinoma development. The aim of this study was to better understand people's willingness and potential barriers to performing VSE.

Materials and Methods

A cross-sectional survey was undertaken of all patients with vulvar LS presenting to a tertiary referral vulvar dermatology clinic in Australia, from June 2022 to January 2023. Patients who did not speak and read English were excluded. Ethics approval was obtained.

Results

Seventy-eight (66%) of 118 eligible patients completed the survey. Fifty-three (68%) of patients had examined their vulva at least once. Forty-one (49%) had been recommended VSE by a medical practitioner. All those recommended VSE had performed VSE at least once. In contrast, only 10 (27%) of the 37 patients not recommended VSE by a health professional had ever performed VSE. Seventy-nine percent of all patients reported that they were very likely or likely to perform VSE if it was recommended.

Patients with higher education level and tampon use were more likely to perform VSE. Self-reported back problems were associated with being less likely to perform VSE.

Conclusions

More widespread VSE may result in earlier detection of the complications of vulvar lichen sclerosus. Most women would perform VSE if recommended by a health care provider; however, currently only half are receiving this advice. Further research should be performed to determine whether VSE affects clinical outcomes.
Multimodality Evaluation of Persistent Hyperparathyroidism in a Rare Case of Ectopic Submandibular Parathyroid Adenoma
Authors: Edamadaka Yeshwanth , Malhotra Gaurav , Daga Aaditya , Memon Saba S. , Lila Anurag R. , Bandgar Tushar
Published: September 2024

A 53-year-old woman of primary hyperparathyroidism with both ultrasound neck examination and planar 99mTc-MIBI scan being negative revealed a tracer-avid focus in the left submandibular region in early (15 minutes postinjection) 99mTc-MIBI SPECT/CT views, raising a suspicion of rare ectopic parathyroid adenoma. This finding was correlated on 4D-CT and confirmed on histopathology following surgical excision. Submandibular region is an unusual location for ectopic parathyroid adenoma. Nevertheless, high degree of suspicion with utilization of multimodality imaging including 99mTc MIBI-SPECT/CT and 4D-CT improves preoperative detection of parathyroid adenoma at rare ectopic sites as seen in this case of persistent hyperparathyroidism.
Novel therapies for pediatric low grade glioma
Authors: Demaliaj Dardan , Gardner Sharon L.
Published: September 2024

Purpose of review

Current biological findings provide new insights into the genetics driving growth of low-grade gliomas in pediatric patients. This has provided new targets for novel therapies. The purpose of this paper is to review novel therapies for pediatric low-grade gliomas that have been published in the past 24 months.

Recent findings

Low-grade gliomas are often driven by mitogen activated protein kinase (MAPK) alterations either with BRAF V600E point mutations or BRAF fusions. Current advances have also highlighted novel fusions of fibroblast growth factor receptor (FGFR), myeloblastosis family of transcription factors (MYB), meningioma 1 tumor suppressor (MN1), neurotrophic receptor kinase family of receptors (NTRK), Kristen RAS (Rat Sarcoma Virus) oncogene homolog in mammals (KRAS), Receptor tyrosine kinase ROS proto oncogene 1 (ROS1), protein kinase C alpha (PRKCA), and platelet derive growth factor receptor (PDGFR) amplification. Novel therapies have been employed and are showing encouraging results in pediatric low-grade gliomas. Current trials are underway with newer generation pan RAF inhibitors and mitogen activated protein kinase - kinase (MEK) inhibitors. Other early phase clinical trials have provided safety data in pediatric patients targeting FGFR fusion, NTRK fusion, PDGFR amplification and ROS1 mutations.

Historical treatment options in pediatric low-grade gliomas have utilized surgery, radiation therapy and conventional chemotherapy. Recently greater insight into their biology has found that alterations in MAPK driven pathways are often the hallmark of tumorigenesis. Targeting these novel pathways has led to tumor control and shrinkage without the use of conventional chemotherapy. Caution should be taken however, since these treatment options are still novel, and we do not fully appreciate the long-term effects. Nonetheless a new era of targeted medicine is here.
Reconstructing the diversity dynamics of paleo-grasslands using deep learning on superresolution images of fossil Poaceae pollen
Authors: Adaimé Marc-Élie , Kong Shu , Urban Michael A. , Street-Perrott F. Alayne , Verschuren Dirk , Punyasena Surangi W.
Published: September 2024

Despite its abundance in the fossil record, grass pollen is largely overlooked as a source of ecological and evolutionary data because most Poaceae species cannot be differentiated using traditional optical microscopy. However, deep learning techniques can quantify the small variations in grass pollen morphology visible under superresolution microscopy. We use the abstracted morphological features output by deep learning to estimate the taxonomic diversity and physiology of fossil grass pollen assemblages. Using a semi-supervised learning strategy, we trained convolutional neural networks (CNNs) on pollen images of 60 widely distributed grass species and unlabeled fossil Poaceae. Semi-supervised learning improved the CNN models’ capability to generalize feature recognition in fossil pollen specimens. Our models successfully captured both the taxonomic diversity of an assemblage and morphological differences between C3and C4species. We applied our trained models to fossil grass pollen assemblages from a 25,000-year lake-sediment record from eastern equatorial Africa and correlated past shifts in grass diversity with atmospheric CO2concentration and proxy records of local temperature, precipitation, and fire occurrence. We quantified grass diversity for each time window using morphological variability, calculating both Shannon entropy and morphotype counts from the specimens’ CNN features. Reconstructed C3:C4ratios suggest a gradual increase in C4grasses with rising temperature and fire activity across the late-glacial to Holocene transition. Our results demonstrate that quantitative machine-learned features of pollen morphology can significantly advance palynological analysis, enabling robust estimation of grass diversity and C3:C4ratio in ancient grassland ecosystems.

Significance

The pollen of most grass species are morphologically indistinguishable using traditional optical microscopy, but we show that they can be differentiated through deep learning analyses of superresolution images. Abstracted morphological features derived from convolutional neural networks can be used to quantify the biological and physiological diversity of grass pollen assemblages, withouta prioriknowledge of the species present, and used to reconstruct past changes in the taxonomic diversity and relative abundance of C4grasses in ancient grasslands. This approach unlocks ecological information that had been previously unattainable from the fossil pollen record and demonstrates that deep learning can solve some of the most intractable identification problems in the reconstruction of past vegetation dynamics.
Novel high-quality amoeba genomes reveal widespread codon usage mismatch between giant viruses and their hosts
Authors: Willemsen Anouk , Manzano-Marín Alejandro , Horn Matthias
Published: September 2024

The need for high-quality protist genomes has prevented in-depth computational and experimental studies of giant virus-host interactions. In addition, our current knowledge of host range is highly biased due to the few hosts used to isolate novel giant viruses. This study presents six high-quality amoeba genomes from known and potential giant virus hosts belonging to two distinct eukaryotic clades:AmoebozoaandDiscoba. We employ their genomic data to investigate the predictability of giant virus host range. Using a combination of long and short-read sequencing, we obtained highly contiguous and complete genomes ofAcanthamoeba castellanii, Acanthamoeba griffini,Acanthamoeba terricola,Naegleria clarki,Vermamoeba vermiformis, andWillaertia magna, contributing to the collection of sequences for the eukaryotic tree of life. We found that the six amoebae have distinct codon usage patterns and that, contrary to other virus groups, giant viruses often have different and even opposite codon usage with their known hosts. Conversely, giant viruses with matching codon usage are frequently not known to infect or replicate in these hosts. Interestingly, analyses of integrated viral sequences in the amoeba host genomes reveal potential novel virus-host associations. Matching of codon usage preferences is often used to predict virus-host pairs. However, with the broad-scale analyses performed in this study, we demonstrate that codon usage alone appears to be a poor predictor of giant virus host range. We discuss the potential strategies that giant viruses employ to ensure high viral fitness in non-matching hosts. Moreover, this study emphasises the need for more high-quality protist genomes. Finally, the amoeba genomes presented in this study set the stage for future experimental studies to better understand how giant viruses interact with different host species.
nSMase2-mediated exosome secretion shapes the tumor microenvironment to immunologically support pancreatic cancer
Authors: Hendley Audrey M. , Ashe Sudipta , Urano Atsushi , Ng Martin , Phu Tuan Anh , Peng Xianlu L. , Luan Changfei , Finger Anna-Marie , Jang Gun Ho , Kerper Natanya R. , Berrios David I. , Jin David , Lee Jonghyun , Riahi Irene R. , Gbenedio Oghenekevwe M. , Chung Christina , Roose Jeroen P. , Yeh Jen Jen , Gallinger Steven , Biankin Andrew V. , O’Kane Grainne M. , Ntranos Vasilis , Chang David K. , Dawson David W. , Kim Grace E. , Weaver Valerie M. , Raffai Robert L. , Hebrok Matthias
Published: September 2024

The pleiotropic roles of nSMase2-generated ceramide include regulation of intracellular ceramide signaling and exosome biogenesis. We investigated the effects of eliminating nSMase2 on early and advanced PDA, including its influence on the microenvironment. Employing the KPC mouse model of pancreatic cancer, we demonstrate that pancreatic epithelial nSMase2 ablation reduces neoplasia and promotes a PDA subtype switch from aggressive basal-like to classical. nSMase2 elimination prolongs survival of KPC mice, hinders vasculature development, and fosters a robust immune response. nSMase2 loss leads to recruitment of cytotoxic T cells, N1-like neutrophils, and abundant infiltration of anti-tumorigenic macrophages in the pancreatic preneoplastic microenvironment. Mechanistically, we demonstrate that nSMase2-expressing PDA cell small extracellular vesicles (sEVs) reduce survival of KPC mice; PDA cell sEVs generated independently of nSMase2 prolong survival of KPC mice and reprogram macrophages to a proinflammatory phenotype. Collectively, our study highlights previously unappreciated opposing roles for exosomes, based on biogenesis pathway, during PDA progression.

Graphical abstract
Invisible people: Exploring how well remote-sensed datasets reveal the distribution of forest-proximate populations
Authors: Rakotoarisoa Mirindra , Jones Julia P. G. , Rakotonarivo O. Sarobidy , Rajaonarivelo Manoa , Schüßler Dominik
Published: September 2024

Accurate information on the location and density of people living at the forest frontier is vital for effective and equitable forest conservation. We compare the location of settlements and estimated population density from three global-scale, remote-sensed datasets (World Settlement Footprint 2015, Open Buildings, WorldPop) with a fine-scale, manually-derived dataset of 3,136 human settlements, of which 95% had fewer than 150 households. The study region is located in north-eastern Madagascar, contains three protected areas and the largest unprotected block of humid forest of the island. The Open Buildings dataset detected a much higher proportion (94%) of settlements than did World Settlement Footprint (15%). Population density from WorldPop matches poorly with that estimated from our manually-derived dataset. The accuracy of all three datasets is worse in more remote, forested areas, further away from basic infrastructure. Open Buildings appears to best reveal the distribution of low density scattered populations in forested areas. However, further testing in other climatic regions is still needed. Making good use of appropriate remote-sensed data could revolutionize the inclusion of local communities in conservation policy and practice, improve the quality of inference in conservation research, particularly in times of a planned expansion of the global protected area network.
Dynamics of serum BDNF After Aerobic Exercise in Subacute Stroke Patients: A Sub-Analysis of the randomized controlled Phys-Stroke trial
Authors: Rackoll Torsten , Doppelbauer Lea , Neumann Konrad , Heinrich Nave Alexander ,   the Phys-Stroke study group
Published: September 2024

During the very early phase of stroke recovery, the brain is hypothesized to be in a neuroplastic state that is responsive to external stimuli. Here, brain-derived neurotrophic factor (BDNF) is thought to play an important role. BDNF, a member of the neurotrophin family, is implicated in processes such as synaptogenesis and long-term potentiation. Post-stroke, reduced BDNF levels are observed compared to the healthy population. An intervention that has been shown to elevate BDNF is Aerobic exercise. Yet, the impact of aerobic exercise in stroke patients remains unclear. This sub-analysis of the multicenter, randomized, controlled ’Physical Fitness Training in Patients with Subacute Stroke’ trial aimed to investigate serum BDNF dynamics and the effects of a four-week aerobic exercise intervention on long- term BDNF levels.

Data from 200 patients, with missing data imputed, revealed a modest increase in serum BDNF levels up to three months post-stroke (22.6 ng/ml, 95% CI 19.2 to 26) which plateaued until six months (24.3 ng/ml, 95% CI 20.6 to 27.9). Despite higher baseline BDNF levels in the exercise group, no treatment effect was observed until six months (training 24.6 ng/ml, 95% CI 20.2 to 29 vs relaxation: 24.3 ng/ml, 95% CI 19.8 to 28.8,p= 0.95). A sex-related interaction was identified in the relaxation group, with female patients exhibiting higher BDNF increases until end of follow up (20.9 ng/ml, 95% CI 15.7 to 26.2 (males) vs 31.0 ng/ml, 95% CI 22.9 to 39.0 (females),p= 0.039). Dose-response analyses and associations with recurrent events yielded no substantial differences.

While serum BDNF levels increased early after stroke in the first three months, aerobic exercise did not demonstrate a significant impact on BDNF levels within this dataset. Further investigations with more measurements during the early subacute phase are warranted to elucidate the interplay between exercise, BDNF, and recovery.
Acute myocardial infarction, 90 Cardiovascular proteins and Paroxysmal ventricular tachycardia: a Mendelian randomization study
Authors: Sun Ji , Wu Yang , Wu Hao-liang , Ji Ying-Ying , Chen Xumiao , Ji Cheng-cheng , Wu Su-Hua
Published: September 2024

Background: Previous studies have shown that acute myocardial infarction (AMI) may be associated with paroxysmal ventricular tachycardia (PVT). However, the causal effect between AMI and PVT, and whether cardiovascular proteins act as a mediator remain unclear. Methods: The genetic data of AMI, 90 Cardiovascular proteins (CVPs) and PVT were obtained from large-scale genome-wide association studies (GWAS). The Mendelian randomization analysis was applied to evaluate the casual association among the AMI, CVPs and PVT. The inverse variance weighting casual effect was regarded as main statistical method. We further investigated whether CVPs take a mediating role in the pathway from AMI to PVT. Results: There were three positive, including ESM-1 (OR 1.139, 95%CI 1.034-1.255, P-FDR=0.014), GAL (OR 1.105,95%CI 1.025-1.191, P-FDR=0.015) and PRL (OR 1.084, 95%CI 1.004-1.170, P-FDR=0.038), and four negative, including FAS (OR 0.928, 95%CI 0.885-0.974, P-FDR=0.009), LEP (OR 0.938, 95%CI 0.891-0.987, P-FDR=0.018), TNF-R1 (OR 0.930, 95%CI 0.883-0.979, P-FDR=0.014) and TNF-R2 (OR 0.928, 95%CI 0.883-0.974, P-FDR=0.009), casual effects between genetic liability of AMI on CVPs. We identified two positive,including IL-27 (OR 1.371, 95%CI 1.010-1.861, P-FDR=0.045) and MMP-12 (OR 1.330, 95%CI 1.035-1.709, P-FDR=0.045), and two negative, including LEP (OR 0.614, 95%CI 0.384-0.981, P-FDR=0.045) and TF (OR 0.714, 95%CI 0.514-0.992, P-FDR=0.045), casual effects between genetic liability of CVPs on PVT. In addition, the AMI played a positive casual effect on PVT (OR 1.736, 95%CI 1.300-2.318, P-FDR<0.001) mediating by LEP with 5.71%. Conclusions: The AMI was casually correlated to PVT, and LEP acted as a mediator in the pathway from AMI to PVT.
SNRK regulates TGFβ levels in atria to control cardiac fibrosis
Authors: Thirugnanam Karthikeyan , Rizvi Farhan , Jahangir Arshad , Homar Peter , Shabnam Fathima , Palecek Sean P. , Kumar Suresh N. , Pan Amy , Bai Xiaowen , Sekine Hidekazu , Ramchandran Ramani
Published: September 2024

Atrial fibrosis is central to the pathology of heart failure (HF) and atrial fibrillation (AF). Identifying precise mechanisms underlying atrial fibrosis will provide effective strategies for clinical intervention. This study investigates a metabolic serine threonine kinase gene,sucrose non-fermenting related kinase (SNRK),that we previously reported to control cardiac metabolism and function. Conditional knockout ofSnrkin mouse cardiomyocytes (SnrkcmcKO) leads to atrial fibrosis and subsequently HF. The precise mechanism underlying cardiomyocyte SNRK-driven repression of fibrosis is not known. Here, using mouse, rat, and human tissues, we demonstrate that SNRK expression is high in atria, especially in atrial cardiomyocytes. SNRK expression correlates with lower levels of pro-fibrotic protein transforming growth factor-beta 1 (TGFβ1) in the atrial cardiomyocytes. In HL-1 adult immortalized mouse atrial cells, using siRNA approaches, we show thatSnrkknockdown cells show more TGFβ1 secretion, which was also observed in heart lysates fromSnrkcardiac-specific knockout mice in vivo. These effects were exacerbated upon infusion of Angiotensin II. Results fromSnrkknockdown cardiomyocytes co-cultured with cardiac fibroblasts suggest that SNRK represses TGFβ1 signaling (Smad 2/3) in atrial CMs and prevents paracrine cardiac fibroblast activation (α-SMA marker). In conclusion, high SNRK expression in atria regulates cardiac homeostasis, by preventing the release of TGFβ1 secretion to block cardiac fibrosis. These studies will assist in developing heart chamber-specific fibrosis therapy for non-ischemic HF and AF.
Enabling Epitope Analysis of Glycoproteins via HDX-MS Using Antigens with Uniformed N-linked Glycans
Authors: Ota Takeshi , Takayama Masahiro , Ishihara Takeshi , Sato Masaaki , Ono Sawaka , Futamata Ryota , Fujitani Masaya , Rokushima Masatomo
Published: September 2024

Hydrogen deuterium exchange mass spectrometry (HDX-MS) is widely used for epitope analysis of the antibodies. However, epitope analysis of glycoproteins is challenging because of the heterogeneity of attached N-linked glycans. Recent studies have reported methods where N-linked glycans were removed at low pH following hydrogen deuterium exchange reactions, but the methods for glycoproteins remain controversial. Here, we demonstrate the utility of using antigens with uniformed N-linked glycans in glycoprotein epitope analysis by HDX-MS. By treating HEK293 cells with kifunensine, we were able to prepare antigens mainly with N-linked high-mannose-type glycans. Analysis of epitopes of a monoclonal antibody S309 using antigens prepared with this method allowed us to identify an epitope that included the previously reported N-linked glycan attachment sites for this anti-body. We propose that using antigens with uniformed glycans should be effective for epitope analysis of glycoproteins, such as virus spike proteins covered by glycan shields. Moreover, we believe that this approach accelerates research on vaccines and neutralizing antibodies against viruses that escape host immunity through glycan shields or mutations.
Neuropathological evidence of reduced amyloid beta and neurofibrillary tangles in multiple sclerosis cortex
Authors: Pansieri J. , Pisa M. , Yee S. , Gutnikova A. , Ridgeon E. , Hickman R. , Spencer J I , Esiri M. M. , DeLuca G. C.
Published: September 2024

Multiple sclerosis (MS) and Alzheimer’s disease (AD) are neurodegenerative diseases demonstrating age-related accumulation of disability. Inflammation lasting decades is a paradigmatic feature of MS pathology that variably relates to neurodegeneration, while the accumulation of Aβ plaques and neurofibrillary tangles (NFT) are cornerstones of AD pathology. However, few studies investigated the accumulation of amyloids in MS.

We investigated Aβ deposition and NFT density in temporal or frontal cortices derived from a large post-mortem cohort of MS (n=78) and age and sex-matched control (n=65) cases. We found reduced Aβ burden in MS cases compared with controls, particularly in cases below 65-years-of-age. NFT were similarly reduced in MS compared to controls, notably in cases above 65 years-of-age. Higher Aβ deposition predicted greater NFT density in MS. These findings suggest that MS-related factors may influence Aβ and NFT deposition and/or clearance. This work highlights new therapeutic perspectives relevant for both MS and AD.
Continual integration of single-cell multimodal data with MIRACLE
Authors: Zhou Jiahao , He Zhen , Wang Jing , Hu Shuofeng , Kan Tongtong , Dong Guohua , Shi Jinhui , Liu Runyan , Ou-Yang Le , Bo Xiaochen , Ying Xiaomin
Published: September 2024

Single-cell sequencing technologies have revolutionized our understanding of cellular heterogeneity and facilitated the construction of multi-omics cell atlases via data integration. However, updating these atlases with new data conventionally requires reintegration of all data and is computationally intensive, hindering timely updates and dynamic adjustments in biological and medical research. To address this challenge, we present Multimodal Integration with Continual Learning (MIRACLE), a novel online learning framework for the adaptive and efficient integration of single-cell multimodal data. MIRACLE employs dynamic architectures and data rehearsal strategies to support continual learning, allowing diverse data to be integrated while minimizing information loss over time. Our evaluations demonstrate that MIRACLE achieves accurate online integration with reduced computational requirements, effectively updating and expanding atlases with new cross-tissue and cross-modal data, and precisely identifying novel cell types and transferring labels across datasets. MIRACLE provides an efficient and flexible tool for single-cell community to integrate, share and explore biological knowledge from single-cell multimodal data.
Exercise-induced extracellular vesicles mediate apoptosis in human colon cancer cells in an exercise intensity-dependent manner
Authors: Ozerklig Berkay , Turkel Ibrahim , Yılmaz Merve , Vaizoglu Refika Dilara , Akan Handan Sevim , Dikmen Z. Gunnur , Saleem Ayesha , Kosar Sukran N.
Published: September 2024

Regular exercise is known to reduce incidence rates and improve the prognosis of all cancers, but the underlying mechanisms remain elusive. Ample evidence suggests that exercise exerts therapeutic effects through extracellular vesicles (EVs), essential for cellular communication. Here, we hypothesized that exercise-induced EVs from serum of healthy young male participants will exert anti-tumorigenic effects on human colon cancer HT-29 cells, in an exercise intensity-dependent manner. 10 healthy young active males (25.4±6.2yrs, with maximal oxygen consumption (VO2max) = 45±3.7 ml.min-1.kg-1 participated in a randomized crossover trial. Participants underwent two different workload-matched, acute bouts of exercise: (1) moderate-intensity continuous exercise (MICE) at 50-55% V02max, and (2) high-intensity interval exercise (HIIE) at 90% V02max on a cycle ergometer. A control session of rest (PRE) was included. EVs were isolated from serum samples collected during PRE and immediately after each exercise session. EVs were co-incubated with colon cancer HT-29 cells (100 µg EVs/ml, 48-72h), and effect on cell viability, migration, and apoptosis measured. EV treatment reduced cell viability in all groups (PRE, MICE, HIIE) by 35%, 43% and 47% respectively, vs. PBS. EVs from HIIE group showed a significantly greater reduction in cell viability vs. PRE, therefore further analysis used these groups only. PRE-EVs reduced migration by 27%, and HIIE-EVs by 39%. EV from HIIE group increased expression of pro-apoptotic markers: Bax/Bcl-2 ratio by 56% and Caspase-3 by 30% vs. PBS, with no change observed in the PRE group. Further, 16% of cells in PRE, and 28% of cells in HIIE were TUNEL-positive, indicating DNA fragmentation, a hallmark feature of apoptosis. Our data show that exercise-induced EVs reduced cell viability, in an exercise intensity-dependent manner. HIIE-derived EVs exerted the most anti-tumorigenic effects: decreased cell viability, reduced cell migration, increase in pro-apoptotic protein expression, and elevated DNA fragmentation. It is likely these changes were mediated by altered EV Cargo induced by exercise, as the amount of EVs was the same in each treatment group. To our knowledge, this is the first human study that illustrates the therapeutic potential of exercise-induced EVs in cancer treatment.
Calculating and interpretingFSTin the genomics era
Authors: de Jong Menno J. , van Oosterhout Cock , Hoelzel A. Rus , Janke Axel
Published: September 2024

The relative genetic distance between populations is commonly measured using the fixation index (FST). Traditionally inferred from allele frequency differences, the question arises howFSTcan be estimated and interpreted when analysing genomic datasets with low sample sizes. Here, we advocate an elegant solution first put forward by Hudson et al. (1992):FST= (Dxy–πxy)/Dxy, whereDxyandπxydenote mean sequence dissimilaritybetweenandwithinpopulations, respectively. This multi-locusFST-metric can be derived from allele frequency data, but also from sequence alignment data alone, even when sample sizes are low and/or unequal. As with otherFST-metrices, the numerator denotes net divergence (Da), which is equivalent to thef2-statistic and Nei’sD(for realistic estimates ofDxyandπxy). In terms of demographic inference, net divergence measures the difference in increase ofDxyandπxysince the population split, owing to a reduction of coalescence times within populations as a result of genetic drift. Because different combinations ofΔDxyandΔπxycan produce identicalFST-estimates, no universal relationship exists betweenFSTand population split time. Still, in case of recent population splits, when novel mutations are negligible,FST-estimates can be accurately converted into coalescent units (τ. i.e., split time in multiples of 2Ne). This then allows to quantify gene tree discordance, without the need for multispecies coalescent based analyses, using the formula:Pdiscordance= ⅔·(1 –FST). To facilitate the use of the HudsonFST-metric, we implemented new utilities in the R package SambaR.
First record ofCulex pipiens(Diptera: Culicidae) in Alberta: Expanding distributions and ecotype patterns in a western Canadian province
Authors: Pan Ty , Seal Michaela , Shaw Hailey , Mohanaraj Shahaanaa , Morinaga Gen , Hogaboam Brittany , Jenkins Michael , Coker Alexandra , Soghigian John
Published: September 2024

Culex pipiensis an invasive mosquito found in temperate regions globally. It is considered among the most important disease vectors worldwide and is responsible for transmission of a range of pathogens, including West Nile virus, avian malaria, Saint Louis encephalitis, and filarial worms. Throughout its northern temperate range, this mosquito is found in two ecotypes: formpipiensand formmolestus. In Canada, this mosquito was previously thought restricted to the Pacific coast of British Columbia and the eastern provinces of Ontario, Quebec, and the Maritimes. Through routine mosquito surveillance and targeted trapping forCx. pipiens, we detected this mosquito in two Albertan municipalities earlier than suggested by species distribution modelling based on climate change data. We confirmed the identity of putativeCx. pipiensspecimens using DNA sequencing and found that formpipienswas the most common ecotype found in Alberta. Further, we compared the frequency of ecotypes in Alberta to elsewhere in North America and found a general trend of increased formpipiensin more northern latitudes, similar to previously reported results. We discuss our findings in context of vector-borne disease activity in Canada, particularly West Nile virus.
Degradation of PET plastic with engineered environmental bacteria
Authors: Banks Alice M. , Abdulmutalib Umar , Sonnendecker Christian , Kim Juhyun , Bosomworth Charlotte , Brown Stuart , Wei Ren , Álvarez-Ortega Carolina , Pomposiello Pablo , Avignone-Rossa Claudio , Larrouy-Maumus Gerald , Zimmermann Wolfgang , Jiménez José I.
Published: September 2024

Polyethylene terephthalate (PET) is one of the most widely used plastic materials in the food and textile industry. Consequently, post-consumer PET waste is a common environmental pollutant that leaks into the environment in the form of macro and microplastics with concerning health impacts. There is a pressing need to identify novel and sustainable solutions to process the abundance of PET waste contributing to this pollution. While there is extensive research into enzymes able to hydrolyse PETin vitro, a similar solution for discarded or difficult-to-collect PET based on whole-cell microbial catalysts is missing. In this work we report the engineering of environmental bacteria to use PET as a growth substrate. This was achieved by isolating a strain ofPseudomonas umsongensisable to use the PET monomer terephthalate as carbon source, engineering the strain to effectively secrete the high-activity PET hydrolase PHL7 through the addition of a recombinant TAT secretion leader sequence, and enhancing the bioavailability of PET by transforming it into an amorphous and macroporous structure by pre-treatment with an organic solvent. Our findings demonstrate the direct microbial consumption of PET, which could lead to improved and more sustainable upcycling strategies for this plastic.
Systemic extracellular acidification is a hallmark of aging
Authors: dos Santos Eliano , Xie Yining , Cao Enyuan , Foley Andrea , Taylor Max E. , Andrew Ivan , Young George , Trevaskis Natalie L. , Cochemé Helena M.
Published: September 2024

Understanding the critical pathophysiological processes that promote age-related disease is needed to uncover effective targets for preventive medicine. Here, we investigate how extracellular pH changes with age and its impact on longevity, using fly and mouse models. We find that extracellular acidification occurs in flies during aging and correlates to mortality rate. With age, flies also become more susceptible to die from acidotic stress, which can be prevented by alkalotic treatment. Acidification is caused by insufficient acid elimination, linked to downregulation of genes in the fly excretory tract that control pH and ATP production, essential for active secretion initiation. In mice, we show that lymph-drained interstitial fluids acidify with age. Expression of genes, whose pathogenic loss-of-function variants cause tubular acidosis in humans, is decreased in the kidneys of aging mice. Overall, this study sheds light on dysregulated systemic acid-base balance as a conserved pathophysiological mechanism of aging.
Interplay of YEATS2 and GCDH mediates histone crotonylation and drives EMT in head and neck cancer
Authors: Pant Deepak , Kakani Parik , Joshi Rushikesh , Agrawal Shruti , Samaiya Atul , Shukla Sanjeev
Published: September 2024

The regulation of gene expression is an integral cellular process orchestrated by epigenetic marks like histone modifications. Perturbations in the activity or abundance of epigenetic factors can lead to tumorigenesis. Remarkably, several metabolites influence the epigenetic landscape in cells. Here, we investigated the interplay between a highly expressed epigenetic factor, YEATS2, and a metabolic enzyme, GCDH, in regulating epithelial-to-mesenchymal transition in head and neck cancer. We report that the histone reader YEATS2 is responsible for increased invasive potential in head and neck cancer in an SP1-dependent manner. YEATS2 functions by maintaining histone crotonylation, and its abrogation leads to a global decrease in the H3K27Cr mark. Mechanistically, we report that YEATS2 maintains high H3K27Cr levels at the promoter of the EMT-promoting geneSPARC. Further, we found that the addition of the H3K27Cr mark is also dependent on the crotonyl-CoA-producing enzyme GCDH. Overall, we describe a novel mechanism of interplay between epigenetics and metabolism in head and neck tumorigenesis, which results in the enhanced expression of EMT-related genes in a histone crotonylation-dependent manner.
Integrating spatial profiles and cancer genomics to identify immune-infiltrated mismatch repair proficient colorectal cancers
Authors: Wala Jeremiah , de Bruijn Ino , Coy Shannon , Gagné Andréanne , Chan Sabrina , Chen Yu-An , Hoffer John , Muhlich Jeremy , Schultz Nikolaus , Santagata Sandro , Sorger Peter K
Published: September 2024

Predicting the progression of solid cancers based solely on genetics is challenging due to the influence of the tumor microenvironment (TME). For colorectal cancer (CRC), tumors deficient in mismatch repair (dMMR) are more immune infiltrated than mismatch repair proficient (pMMR) tumors and have better prognosis following resection. Here we quantify features of the CRC TME by combining spatial profiling with genetic analysis and release our findings via a spatially enhanced version of cBioPortal that facilitates multi-modal data exploration and analysis. We find that ∼20% of pMMR tumors exhibit similar levels of T cell infiltration as dMMR tumors and that this is associated with better survival but not any specific somatic mutation. These T cell-infiltrated pMMR (tipMMR) tumors contain abundant cells expressing PD1 and PDL1 as well as T regulatory cells, consistent with a suppressed immune response. Thus, like dMMR CRC, tipMMR CRC may benefit from immune checkpoint inhibitor therapy.

SIGNIFICANCE

pMMR tumors with high T cell infiltration and active immunosuppression are identifiable with a mid-plex imaging assay whose clinical deployment might double the number of treatment-naïve CRCs eligible for ICIs. Moreover, the low tumor mutational burden in tipMMR CRC shows that MMR status is not the only factor promoting immune infiltration.
Analytical Assessment of Metagenomic Workflows for Pathogen Detection with NIST RM 8376 and Two Sample Matrices
Authors: Kralj Jason G. , Servetas Stephanie L. , Forry Samuel P. , Hunter Monique E. , Dootz Jennifer N. , Jackson Scott A.
Published: September 2024

We assessed the analytical performance of metagenomic workflows using NIST Reference Material 8376 DNA from bacterial pathogens spiked into two simulated clinical samples: cerebral spinal fluid (CSF) and stool. Sequencing and taxonomic classification were used to generate signals for each sample and taxa of interest, and to estimate the limit of detection (LOD), the response function, and linear dynamic range. We found that the LODs for taxa spiked into CSF ranged from approximately (0.1 to 0.3) copy/μL, with a linearity of 0.96 to 0.99. For stool, the LODs ranged from (10 to 221) copy/μL, with a linearity of 0.99 to 1.01. Further, discriminating differentE. colistrains proved to be workflow-dependent, as only one classifier:database combination of the three tested showed the ability to differentiate the two pathogenic and commensal strains. Surprisingly, when we compared the response functions of the same taxa in the two different sample types, we found those functions to be the same, despite large differences in LODs. This suggests that the “agnostic diagnostic” theory for metagenomics may apply to different target organismsanddifferent sample types. Using RMs, we were able to generate quantitative analytical performance metrics for each workflow and sample set, enabling relatively rapid workflow screening before employing clinical samples. This makes these RMs a useful tool that will generate data needed to support translation of metagenomics into regulated use.

Importance

Assessing the analytical performance of metagenomic workflows, especially when developing clinical diagnostics, is foundational for ensuring that the measurements underlying a diagnosis are supported by rigorous characterization. To facilitate the translation of metagenomics into clinical practice, workflows must be tested using control samples designed to probe the analytical limitations (e.g. limit of detection). Spike-ins allow developers to generate fit-for-purpose control samples for initial workflow assessments and inform decisions about further development. However, clinical sample types include a wide range of compositions and concentrations, each presenting different detection challenges. In this work, we demonstrate how spike-ins elucidate workflow performance in two highly dissimilar sample types (stool and CSF); and we provide evidence that detection of individual organisms is unaffected by background sample composition, making detection sample agnostic within a workflow. These demonstrations and performance insights will facilitate translation of the technology to the clinic.
Nucleoprotein phase-separation affinities revealed via atomistic simulations of short peptide and RNA fragments
Authors: Ramachandran Vysakh , Brown William , Potoyan Davit A
Published: September 2024

Liquid-liquid phase separation of proteins and nucleic acids into condensate phases is a versatile mechanism for ensuring compartmentalization of cellular biochemistry. RNA molecules play critical roles in these condensates, particularly in transcriptional regulation and stress responses, exhibiting a wide range of thermodynamic and dynamic behaviors. However, deciphering the molecular grammar that governs the stability and dynamics of protein-RNA condensates remains challenging due to the multicomponent and heterogeneous nature of these biomolecular mixtures. In this study, we employ atomistic simulations of twenty distinct mixtures containing minimal RNA and peptide fragments to dissect the phase-separating affinities of all twenty amino acids in the presence of RNA. Our findings elucidate chemically specific interactions, hydration profiles, and ionic effects that synergistically promote or suppress protein-RNA phase separation. We map a ternary phase diagram of interactions, identifying four distinct groups of residues that promote, maintain, suppress, or disrupt protein-RNA clusters.
Germinated brown rice research: bibliometric analysis of progress, hotspots and trends
Authors: Zhang Wenyang , Niu Hao , Zhao Yewang , Zhang Qiang , Yang Fuxue , Zhang Hong
Published: September 2024

To gain a deeper understanding of global research trends and focal points in germinated brown rice, this article takes the relevant literature on germinated brown rice in the core database of Web of Science as the research object. By using bibliometric analysis, the literature on germinated brown rice published from 2003 to 2023 is deeply analyzed, and the global research progress, hotspots and future development trend of germinated brown rice are summarized. Since 2018, research on germinated brown rice has been rapidly developing, with a significant surge in interest since 2020. China leads in the number of publications, institutions, and core authors in this research area. The primary research topics include the nutritional value, physiological active components, and industrial applications of germinated brown rice. Current research frontiers involve identifying, evaluating, and enhancing bioactive substances in germinated brown rice for food applications. Research in this field remains active, and application scenarios are becoming increasingly diverse. Future studies may explore new directions in related equipment and ingredients.
Differential participation of the corticospinal and corticorubral neurons during motor execution in the rat
Authors: Rodriguez-Moreno Paola , Loza-Vaqueiro Juliana , Olivares-Moreno Rafael , Rojas-Piloni Gerardo
Published: September 2024

The sensorimotor cortex is crucial for learning and executing new movements with precision (Nudo & Frost, 2007). It selectively modulates sensory information flow and represents motor information in a spatially organized manner (Canedo, 1997; Chen et al., 2017). The pyramidal system is made up layer 5 pyramidal tract neurons (PTNs), which are organized into populations with distinct morphological, genetic and functional properties. These subpopulations project to different subcortical structures in a segregated manner (Nudo & Frost, 2007).

To understand whether PTNs projecting to different structures play distinct functional roles in motor control, we characterized two types of layer 5 neurons in the motor cortex: corticorubral (CR) neurons, which project to the red nucleus, and corticospinal (CS) neurons, which project to the spinal cord.

To analyze movement performance in rats, we compared the selective optogenetic inhibition of motor cortex CS or CR neurons during lever movement execution in response to a light stimulus. As the animals progressed through the training sessions, the variability of lever trajectories decreased, and the movements became more stereotyped. Photoinhibition of CS or CR neurons increased the performance variability of learned movements but differentially affected kinematic parameters. CR neuron inhibition affected amplitude, duration, reaction times, speed, and acceleration of the movement. In contrast, inhibition of CS neurons mainly altered the duration, speed, and acceleration of the movement. We conclude that CS and CR are complementary pathways for transmitting information rather than copies of the same motor command.
Development of Machine Learning-Based Mpox Surveillance Models in a Learning Health System
Authors: Reyes Nieva Harry , Zucker Jason , Tucker Emma , McLean Jacob , DeLaurentis Clare , Gunaratne Shauna , Elhadad Noémie
Published: September 2024

We developed machine learning and deep learning models to identify mpox cases from clinical notes as part of a learning health system initiative. Lasso regression outperformed deep learning models, excelled in minimizing false positives, and may prove helpful for flagging missed or delayed diagnoses as part of continuous quality improvement.