bluuebunny/crossref_metadata_2025 huggingface dataset:
Barriers to Health Information Exchange Among Ambulatory Physicians: Results From a Nationally Representative Sample
Authors: Matthews Elizabeth B. , Stanhope Victoria , Hu Yuanyuan
Published: November 2023

Purpose:

Health information exchange (HIE) improves healthcare quality, but is underutilized by providers. This study used a nationally representative survey of ambulatory physicians to examine barriers to HIE, and identify which barriers have the greatest impact on providers' use of HIE.

Methods:

A pooled sample of 1,292 physicians from the 2018–2019 National Electronic Health Record Survey was used. Univariate statistics described rates and patterns of eight common barriers to HIE. Multivariate logistic regression examined the relationship between each barrier and the use of HIE.

Results:

Barriers to HIE were common and diverse. Negative attitudes toward HIE's ability to improve clinical quality significantly decreased HIE use (OR = .44, p < .01).

Conclusions:

To increase adoption of HIE, efforts should focus on addressing providers' negative attitudes toward HIE. These findings can guide targeted implementation strategies to improve HIE adoption.
Gender Disparities in the Clinical Trials and Real-World Utilization of Systemic Therapy in the Management of Urothelial Carcinoma
Authors: Miyagi Hiroko , Bozorgmehri Shahab , Batra Nikhil V. , Chatzkel Jonathan A. , Ramnaraign Brian Hemendra , Hitchcock Kathryn , Zlotecki Robert A. , Brisbane Wayne , Crispen Paul L. , O'Malley Padraic
Published: November 2023

Objectives:

The objectives of this study was (1) to examine the representation of women in clinical trials for systemic therapy in muscle-invasive (MIBC) or metastatic bladder cancer (BC) and (2) to determine the association between sex and systemic therapy in the treatment of MIBC or metastatic BC.

Methods:

A review of bladder cancer systemic therapy clinical trials cited by the National Comprehensive Cancer Network guidelines was performed. Proportions of women were compared with the corresponding proportions in the US population with bladder cancer between 1975 and 2018, based on the Surveillance, Epidemiology, and End Results database. We also used the National Cancer Database (NCDB) to identify 55,951 patients with American Joint Committee on Cancer clinical stage II, III, and IV bladder cancer between 2004 and 2015. We determined the predictors of systemic therapy for bladder cancer treatment using a multivariable logistic regression model.

Results:

26.9% of the US bladder cancer population were women; however, only 17.7% of participants in US clinical trials and 19.9% of participants in all clinical trials were female, indicating an absolute difference of 9.2% (95% confidence interval [CI]: 6.2%-12.1%; P < .001) and 7.0% (95% CI: 6.1%-7.9%; P < .001), respectively. Multivariable analysis of the NCDB showed that women had decreased odds of receiving systemic therapy compared with male patients with MIBC or metastatic BC (odds ratio: 0.93, 95% CI: 0.89-0.96; P < .001).

Conclusion:

Women are underrepresented in MIBC and/or metastatic BC systemic therapy clinical trials. In addition, women are less likely than men to receive systemic therapy for the treatment of MIBC or metastatic BC. Further research is needed to investigate the reasons for gender disparities in treatment of MIBC or metastatic BC as well as the participation in clinical trials.
Bone health: biology and nutrition
Authors: Rizzoli René , Chevalley Thierry
Published: November 2023

Purpose of review

Recent findings in the influence of dietary patterns, dairy products, beverages and microbiota composition and function on bone health are reviewed and discussed.

Recent findings

Evidence is accumulating on the increased risk of fracture in individuals following a vegan diet. Meta-analysis of randomized controlled trials indicates a favourable, though of low amplitude, effect of dairy products on bone mass accrual during childhood and adolescence. Though mostly based on results from observational studies, it seems that dairy product consumption, particularly fermented dairy products, is associated with a lower risk of hip fracture. Regular green tea drinkers may have a lower fracture risk than tea abstainers. Magnesium intake is beneficial for bone health. Prune supplements prevents bone loss in untreated postmenopausal women. This seems to be associated with modification of gut microbiota.

This information should help the medical practitioners facing questions from their patients on how to protect bone health through nutrition.
Nivolumab/Relatlimab-rmbw: A Novel Dual Combination Therapy to Treat Adult and Pediatric Patients With Unresectable or Metastatic Melanoma
Authors: Thomas Baily , Burns Madison , Pervanas Helen , Ciurescu Daniel , Dima Lorena
Published: November 2023

Background:

Immune checkpoint inhibitors control effector mechanisms and work to restore downregulated T-cells in patients with melanoma. Examples of such include programmed death-1 inhibitors and lymphocyte-activating gene 3 inhibitors. The combination of nivolumab, a programmed death-1 inhibitor, and relatlimab-rmbw, a lymphocyte-activating gene 3 inhibitor, has shown antitumor activity and improved progression-free survival in patients with unresectable or metastatic melanoma.

Mechanism of Action & Pharmacokinetics/Pharmacodynamics:

The fixed-dose combination of nivolumab and relatlimab immunotherapy is approved for adults and pediatrics 12 years of age or older with metastatic or unresectable melanoma. Volume of distribution is 6.6 L for relatlimab and nivolumab, and half-life is 27 and 26 days, respectively. Clearance at steady state is 7.6 mL/h for nivolumab and 5.5 mL/h for relatlimab. Sex, age, race, and mild hepatic/renal impairment had no clinical effect on clearance. The exposure–response relationship and pharmacodynamic response for the safety and effectiveness of nivolumab/relatlimab-rmbw have not been fully characterized. Safety concerns include severe and fatal immune-mediated adverse reactions, infusion-related reactions, and complications of allogeneic hematopoietic stem cell transplantation, and fetal toxicity. Dosing is determined by patient's age and weight. Solution is infused over a 30-minute timeframe.

Clinical Trials:

In the RELATIVITY-047 trial, patients received nivolumab or nivolumab/relatlimab-rmbw. Results showed superiority of dual therapy over monotherapy with a progression-free survival of 10.1 months (95% CI, 6.4–15.7) compared with 4.6 months (95% CI, 3.4–5.6) and hazard ratio of 0.75 (95% CI, 0.62–0.92); P = 0.006, respectively. No safety concerns were observed compared with monotherapy with treatment-related adverse events occurring in 18.9% of patients on combination therapy compared with 9.7% on nivolumab alone.

Therapeutic Advance:

The novel mechanism and improvement in progression-free survival compared with standard of care highlight the therapeutic advancement of nivolumab/relatlimab-rmbw in the treatment of unresectable and metastatic melanoma.
Improving Clinician Communication through Action Research
Authors: Arndt Erica J. , Fleischer Anne , Spira Geela
Published: November 2023

There are many challenges to interdisciplinary communication in home care. Management often takes a top-down approach, instructing home care clinicians on methods to improve communication. In this pretest-posttest intervention study, a bottom-up approach was taken using a focus group to allow home care clinicians to identify, develop, and implement strategies to share critical clinical and social information. The participants in the intervention group were compared with a control group who did not participate in the focus group. We found that empowering home care clinicians to develop strategies to improve interdisciplinary communication was beneficial in improving interdisciplinary collaboration. Actively involving home care clinicians in identifying issues and developing solutions may lead to improved collaboration.
Mpox Knowledge, Attitudes, and Practices Among Persons Presenting for JYNNEOS Vaccination—District of Columbia, August to October 2022
Authors: Hassan Rashida , Wondmeneh Sarah , Gonzalez Jimenez Nathalie , Chapman Kelly , Mangla Anil , Ashley Patrick , Willut Christina , Lee Michelle , Rhodes Trevor , Gillani Sarah , Copen Casey , Jackson David A. , Waltenburg Michelle , Delaney Kevin P. , Miles Gillian , Agnew-Brune Christine , Oakley Lisa P. ,   DC PEP++ Project Team
Published: November 2023

Background

More than 30,000 mpox cases have been confirmed in the United States since May 2022. Mpox cases have disproportionally occurred among adult gay, bisexual, and other men who have sex with men; transgender persons; and Black and Hispanic/Latino persons. We examined knowledge, attitudes, and practices regarding mpox vaccination among adults presenting for vaccination to inform prevention efforts.

Methods

We collected mixed-methods data from a convenience sample of adults presenting for JYNNEOS vaccination at 3 DC Health mpox vaccine clinics during August–October 2022. Survey and interview topics included knowledge about mpox symptoms and vaccine protection, beliefs about vaccine access, and trusted sources of information.

Results

In total, 352 participants completed self-administered surveys and 62 participants completed an in-depth interview. Three main themes emerged from survey and interview data. First, most participants had a general understanding about mpox, but gaps remained in comprehensive understanding about mpox symptoms, modes of transmission, vaccine protection, personal risk, and vaccine dosing strategies. Second, participants had high trust in public health agencies. Third, participants wanted more equitable and less stigmatizing access to mpox vaccine services.

Conclusions

Nonstigmatizing, inclusive, and clear communication from trusted sources, including public health agencies, is needed to address mpox knowledge gaps and increase vaccine access and uptake in affected communities. Mpox outreach efforts should continue innovative approaches, including person-level risk assessment tools, to address community needs.
Taking Up the Challenge to Improve Name and Role Recognition in the Operating Room
Authors: Thota Bhavana , Rabinowitz Anna , Guttman Oren
Published: November 2023

The rise of the #TheatreCapChallenge in 2017, which saw participants donning surgical caps labeled with their names and roles, promises to be a seemingly simple intervention aimed at improving operating theater communication and patient safety. This narrative review strives to expand upon the perceived and studied benefits of this intervention and address potential concerns that have arisen with the use of these name and role-labeled surgical caps.
How Does Target Lesion Selection Affect RECIST? A Computer Simulation Study
Authors: Tareco Bucho Teresa M. , Tissier Renaud L.M. , Groot Lipman Kevin B.W. , Bodalal Zuhir , Delli Pizzi Andrea , Nguyen-Kim Thi Dan Linh , Beets-Tan Regina G.H. , Trebeschi Stefano
Published: November 2023

Objectives

Response Evaluation Criteria in Solid Tumors (RECIST) is grounded on the assumption that target lesion selection is objective and representative of the change in total tumor burden (TTB) during therapy. A computer simulation model was designed to challenge this assumption, focusing on a particular aspect of subjectivity: target lesion selection.

Materials and Methods

Disagreement among readers and the disagreement between individual reader measurements and TTB were analyzed as a function of the total number of lesions, affected organs, and lesion growth.

Results

Disagreement rises when the number of lesions increases, when lesions are concentrated on a few organs, and when lesion growth borders the thresholds of progressive disease and partial response. There is an intrinsic methodological error in the estimation of TTB via RECIST 1.1, which depends on the number of lesions and their distributions. For example, for a fixed number of lesions at 5 and 15, distributed over a maximum of 4 organs, the error rates are observed to be 7.8% and 17.3%, respectively.

Conclusions

Our results demonstrate that RECIST can deliver an accurate estimate of TTB in localized disease, but fails in cases of distal metastases and multiple organ involvement. This is worsened by the “selection of the largest lesions,” which introduces a bias that makes it hardly possible to perform an accurate estimate of the TTB. Including more (if not all) lesions in the quantitative analysis of tumor burden is desirable.
The ratio between SARS-CoV-2 RNA viral load and culturable viral titer differs depending on stage of infection
Authors: Porter Michael K , Viloria Winnett Alexander , Hao Linhui , Shelby Natasha , Reyes Jessica A , Schlenker Noah W , Romano Anne E , Tognazzini Colton , Feaster Matthew , Goh Ying-Ying , Gale, Jr Michael , Ismagilov Rustem F.
Published: November 2023

Analysis of incident, longitudinal RNA viral loads in saliva and nasal swabs and culturable viral titers in nasal swabs collected twice-daily by a tricenarian male infected with SARS-CoV-2 revealed the ratio between viral load and viral titer can be five orders of magnitude higher during early infection than late infection.
Effect of Chemotherapeutic Agents on Natural Transformation Frequency in Acinetobacter baylyi
Authors: Winter Macaulay Ralph , Vos Michiel , Buckling Angus , Johnsen Pål Jarle , Harms Klaus
Published: November 2023

Natural transformation is the ability of a bacterial cell to take up extracellular DNA which is subsequently available for recombination into the chromosome (or maintenance as an extrachromosomal element). Like other mechanisms of horizontal gene transfer, natural transformation is a significant driver for the dissemination of antimicrobial resistance. Recent studies have shown that many pharmaceutical compounds such as antidepressants and anti-inflammatory drugs can upregulate transformation frequency in the model species Acinetobacter baylyi. Chemotherapeutic compounds have been shown to increase abundance of antimicrobial resistance genes and increase colonisation rates of potentially pathogenic bacteria in patient gastrointestinal tracts, indicating an increased risk of infection and providing a pool of pathogenicity or resistance genes for transformable commensal bacteria. We here test for the effect of six cancer chemotherapeutic compounds on A. baylyi natural transformation frequency, finding two compounds, docetaxel and daunorubicin, to significantly decrease transformation frequency, and daunorubicin to also decrease growth rate significantly. Enhancing our understanding of the effect of chemotherapeutic compounds on the frequency of natural transformation could aid in preventing the horizontal spread of antimicrobial resistance genes.
Gardnerella pickettii sp. nov. (formerly Gardnerella genomic species 3) and Gardnerella greenwoodii sp. nov. (formerly Gardnerella genomic species 8) isolated from female urinary microbiome
Authors: Sousa Márcia , Ksiezarek Magdalena , Perovic Svetlana Ugarcina , Antunes-Lopes Tiago , Grosso Filipa , Ribeiro Teresa Gonçalves , Peixe Luísa
Published: November 2023

During an ongoing female urinary microbiome research study, strains c17Ua_112T and c31Ua_26T isolated from urine samples of a patient diagnosed with overactive bladder and a healthy postmenopausal woman, respectively, could not be allocated to any

Gardnerella

species with valid names. In this work, we aimed to characterize these strains. The 16S rRNA gene sequences confirmed that these strains are members of the genus

Gardnerella

. Phylogenetic analysis based on cpn60 strongly supported two clades, one encompassing c17Ua_112T and nine other strains from the public database, and the other including c31Ua_26T and three other strains, which were distinct from currently recognized species of the genus

Gardnerella

. Likewise, the phylogenomic tree also showed that strains c17Ua_112T and c31Ua_26T formed independent and robust clusters. Average nucleotide identity (ANI) and digital DNA–DNA hybridization (dDDH) values between c17Ua_112T and c31Ua_26T were 79.27 and 27.4 %, respectively. Strain c17Ua_112T showed the highest ANI (94.8 %) and dDDH values (59.8 %) with

Gardnerella piotii

UGent 18.01T, and strain c31Ua_26T revealed highest ANI (84.2 %) and dDDH (29.1 %) values with

Gardnerella swidsinskii

GS 9838-1T. Based on the data presented here, the two strains c17Ua_112T and c31Ua_26T represent two novel species of the genus

Gardnerella

, for which the names Gardnerella pickettii (c17Ua_112T=DSM 113414T=CCP 71T) and Gardnerella greenwoodii (c31Ua_26T=DSM 113415T=CCP 72T) are proposed.
Cortical network mechanisms in subcallosal cingulate deep brain stimulation for depression
Authors: Scherer M , Harmsen IE , Samuel N , Elias GJB , Germann J , Boutet A , MacLeod CE , Giacobbe P , Rowland NC , Lozano AM , Milosevic L
Published: November 2023

Identifying functional biomarkers of clinical success can contribute to therapy optimization, and provide insights into the pathophysiology of treatment-resistant depression and mechanisms underlying the potential restorative effects of subcallosal cingulate deep brain stimulation.

Magnetoencephalography data were obtained from 15 individuals who underwent subcallosal cingulate deep brain stimulation for treatment-resistant depression and 25 healthy subjects. The first objective herein was to identify region-specific oscillatory modulations for the identification of discriminative network nodes expressing (i) pathological differences in TRD (responders and non-responders, stimulation-OFF) compared to healthy subjects, which (ii) were counteracted by stimulation in a responder-specific manner. The second objective of this work was to further explore the mechanistic effects of stimulation intensity and frequency.

Oscillatory power analyses led to the identification of discriminative regions that differentiated responders from non-responders based on modulations of increased alpha (8-12 Hz) and decreased gamma (32-116 Hz) power within nodes of the default mode, central executive, and somatomotor networks, Broca’s area, and lingual gyrus. Within these nodes, it was also found that low stimulation frequency had stronger effects on oscillatory modulation than increased stimulation intensity.

The identified discriminative network profile implies modulation of pathological activities in brain regions involved in emotional control/processing, motor control, and the interaction between speech, vision, and memory, which have all been implicated in depression. This modulated network profile may represent a functional substrate for therapy optimization. Stimulation parameter analyses revealed that oscillatory modulations can be strengthened by increasing stimulation intensity or, to an even greater extent, by reducing frequency.
From connectome to effectome: learning the causal interaction map of the fly brain
Authors: Pospisil Dean A. , Aragon Max J. , Dorkenwald Sven , Matsliah Arie , Sterling Amy R. , Schlegel Philipp , Yu Szi-chieh , McKellar Claire E. , Costa Marta , Eichler Katharina , Jefferis Gregory S.X.E. , Murthy Mala , Pillow Jonathan W.
Published: November 2023

A long-standing goal of neuroscience is to obtain a causal model of the nervous system. This would allow neuroscientists to explain animal behavior in terms of the dynamic interactions between neurons. The recently reported whole-brain fly connectome [1–7] specifies the synaptic paths by which neurons can affect each other but not whether, or how, they do affect each other in vivo. To overcome this limitation, we introduce a novel combined experimental and statistical strategy for efficiently learning a causal model of the fly brain, which we refer to as the “effectome”. Specifically, we propose an estimator for a dynamical systems model of the fly brain that uses stochastic optogenetic perturbation data to accurately estimate causal effects and the connectome as a prior to drastically improve estimation efficiency. We then analyze the connectome to propose circuits that have the greatest total effect on the dynamics of the fly nervous system. We discover that, fortunately, the dominant circuits significantly involve only relatively small populations of neurons—thus imaging, stimulation, and neuronal identification are feasible. Intriguingly, we find that this approach also re-discovers known circuits and generates testable hypotheses about their dynamics. Overall, our analyses of the connectome provide evidence that global dynamics of the fly brain are generated by a large collection of small and often anatomically localized circuits operating, largely, independently of each other. This in turn implies that a causal model of a brain, a principal goal of systems neuroscience, can be feasibly obtained in the fly.
CC-seq: Nucleotide-resolution mapping of Spo11 DNA double-strand breaks inS. cerevisiaecells
Authors: Brown George G. B. , Gittens William H. , Allison Rachal M. , Oliver Antony W. , Neale Matthew J
Published: November 2023

i.

During meiosis Spo11 generates DNA double-strand breaks to induce recombination, becoming covalently attached to the 5′ ends on both sides of the break during this process. Such Spo11 “covalent complexes” are transient in wild-type cells, but accumulate in nuclease mutants unable to initiate repair. The CC-seq method presented here details how to map the location of these Spo11 complexes genome-wide with strand-specific nucleotide-resolution accuracy in synchronisedSaccharomyces cerevisiaemeiotic cells.
Improving bacterial metagenomic research through long read sequencing
Authors: Greenman Noah , Hassouneh Sayf Al-Deen , Abdelli Latifa S. , Johnston Catherine , Azarian Taj
Published: November 2023

Metagenomic sequencing analysis is central to investigating microbial communities in clinical and environmental studies. Short read sequencing remains the primary data type for metagenomic research, however, long read sequencing promises advantages of improved metagenomic assembly and resolved taxonomic identification. To assess the comparative performance of short and long read sequencing data for metagenomic analysis, we simulated short and long read datasets using increasingly complex metagenomes comprised of 10, 20, and 50 microbial taxa. In addition, an empirical dataset of paired short and long read data from mouse fecal pellets was generated to assess feasibility. We compared metagenomic assembly quality, taxonomic classification capabilities, and metagenome-assembled genome recovery rates for both simulated and real metagenomic sequence data. We show that long read sequencing data significantly improves taxonomic classification capabilities and assembly quality. For simulated long read datasets, metagenomic assemblies were completer and more contiguous with higher rates of metagenome-assembled genome recovery. This resulted in more precise taxonomic classifications. Analysis of empirical data demonstrated that sequencing technology directly affects compositional results. Overall, we highlight strengths of long read sequencing for metagenomic studies of microbial communities over traditional short read approaches. Long read sequencing improved the accuracy of classification and abundance estimation. These results will aid researchers when considering which sequencing platforms to use for metagenomic projects.

Data description

The experimental metagenomic sequence data used for comparison of short and long read data from the same source are available from NCBI’s Sequence Read Archive (SRA) under Bioproject accession ID PRJNA1092431.
Z-Flipons conserved between human and mouse are associated with increased transcription initiation rates
Authors: Beknazarov Nazar , Konovalov Dmitry , Herbert Alan , Poptsova Maria
Published: November 2023

A long-standing question concerns the role of Z-DNA in transcription. Here we use a deep learning approach based on the published DeepZ algorithm that predicts Z-flipons based on DNA sequence, structural properties of nucleotides and omics data. We examined Z-flipons that are conserved between human and mouse genomes after generating whole-genome Z-flipons maps by training DeepZ on ChIP-seq Z-DNA data, then overlapping the results with a common set of omics data features. We revealed similar pattern of transcription factors and histone marks associated with conserved Z-flipons, showing enrichment for transcription regulation coupled with chromatin organization. 15% and 7% of conserved Z-flipons fell in alternative and bidirectional promoters. We found that conserved Z-flipons in CpG-promoters are associated with increased transcription initiation rates. Our findings empower further experimental explorations to examine how the flip to Z-DNA alters the readout of genetic information by facilitating the transition of one epigenetic state to another.
Antimicrobial peptides and proteins as alternative antibiotics for porcine semen preservation
Authors: Ros-Santaella Jose Luis , Nový Pavel , Scaringi Maria , Pintus Eliana
Published: November 2023

Background

Antimicrobial resistance (AMR) is nowadays a major emerging challenge for public health worldwide. The over- and misuse of antibiotics, including those for cell culture, are promoting AMR while also encouraging the research and employment of alternative drugs. The addition of antibiotics to the cell media is a must in sperm preservation, being gentamicin the most used for boar semen. Because of its continued use, several bacterial strains present in boar semen have developed resistance to this antibiotic. Antimicrobial peptides and proteins (AMPPs) are promising candidates as alternative antibiotics because their mechanism of action is less likely to promote AMR. In the present study, we tested two AMPPs (lysozyme and nisin; 50 and 500 µg/mL) as possible substitutes of gentamicin for boar semen preservation up to 48 h of storage.

Results

We found that both AMPPs improved sperm plasma membrane and acrosome integrity during semen storage. The highest concentration tested for lysozyme also kept the remaining sperm parameters unaltered, at 48 h of semen storage, and reduced the bacterial load at comparable levels of the samples supplemented with gentamicin (p>0.05). On the other hand, while nisin (500 µg/mL) reduced the total Enterobacteriaceae counts, it also decreased the rapid and progressive sperm population and the seminal oxidation-reduction potential (p<0.05).

Conclusions

The protective effect of lysozyme on sperm function together with its antimicrobial activity and inborn presence in body fluids, including semen and cervical mucus, makes this enzyme a promising antimicrobial agent for boar semen preservation.
Multi-omics analysis reveals discordant proteome and transcriptome responses in larval guts ofFrankliniellaoccidentalisinfected with an orthotospovirus.
Authors: Han Jinlong , Rotenberg Dorith
Published: November 2023

The western flower thrips,Frankliniellaoccidentalis, is the principal thrips vector ofOrthotospovirustomatomaculae(orderBunyavirales, familyTospoviridae), a devastating plant-pathogenic virus commonly referred to as tomato spotted wilt virus (TSWV). The larval gut is the gateway for virus transmission byF.occidentalisadults to plants. In a previous report, gut expression at the transcriptome-level was subtle but significant in response to TSWV in L1s. Since it has been well documented that the relationship between the expression of mRNA and associated protein products in eukaryotic cells is often discordant, we performed identical, replicated experiments to identify and quantify virus-responsive larval gut proteins to expand our understanding of insect host response to TSWV. While we documented statistically-significant, positive correlations between abundance of proteins (4,189 identified) and their cognate mRNAs expressed in first and second instar guts, there was virtually no alignment of individual genes identified to be differentially modulated by virus infection at the transcriptome and proteome levels. Predicted protein-protein interaction networks associated with clusters of co-expressed proteins revealed wide variation in correlation strength between protein and cognate transcript abundance, which appeared to be associated with the type of cellular processes, cellular compartments, and network connectivity represented by the proteins. In total, our findings indicate distinct and dynamic regulatory mechanisms of transcript and protein abundance (expression, modifications, and/or turnover) in virus-infected gut tissues. This study provides molecular candidates for future functional analysis of thrips vector competence and underscores the necessity of examining complex virus-vector interactions at a systems level.
Weakly alkaline conditions degrade aflatoxins through lactone ring opening
Authors: Sandlin Natalie , Lee Jiu , Zaccaria Marco , Domin Marek , Momeni Babak
Published: November 2023

Aflatoxins (AFs) are fungal metabolites that ubiquitously contaminate many common food crops and contribute to major foodborne diseases in humans and animals. The ability to remove AFs from common food and feed commodities will improve health standards and limit the economic impact inflicted by AF food contamination. Known chemical strategies have used strong acids and bases to remove contaminating AF, but these methods often lead to ecological waste issues downstream. In this study, we explore the application of weaker acidic and alkaline conditions to removes two types of AFs, AFB1and AFG2. We find that a pH 9 buffered environment reduces AFB1and AFG2by more than 50% and 95%, respectively, within 24 hours. We show that AF degradation is through lactone ring opening, which is a known cause of AF toxicity, and provide a potential structure of the AFG2degradation byproduct. Further, we confirm that incubation in the pH 9 environment reduces the genotoxicity of AFB1. Our findings indicate that a weakly alkaline environment may adequately detoxify AF-contaminated food or feed without the need to apply stronger or harsher basic conditions.
Cost-utility analysis of low-dose pioglitazone in a population with prediabetes and a history of stroke and TIA
Authors: Yuan Fei , Spence J. David , Tarride Jean-Eric
Published: November 2023

BACKGROUND

Among patients with type 2 diabetes and a history of strokes or transient ischemic attacks, pioglitazone significantly reduces the risk of recurrent stroke. The Insulin Resistance Intervention in Stroke (IRIS) trial found that pioglitazone also reduced the risks of stroke or transient ischemic attacks and new-onset diabetes among patients with insulin resistance. As reported by our previous work, the low-dose pioglitazone was found to provide most of the clinical benefit of high-dose pioglitazone, with fewer adverse effects. We report a model-based economic evaluation to determine the cost-effectiveness of the low-dose pioglitazone versus placebo.

METHODS

A lifetime Markov model, with an annual cycle length and five health states (event-free, myocardial infarction, stroke, new-onset diabetes, death), was developed. Transition probabilities were extracted from a subgroup of IRIS patients with insulin resistance, defined by a glycosylated hemoglobin level of 5.7% to 6.4% (mean follow-up of 5 years). Health state costs and utilities were based on public sources and literature data, respectively. Utilities were weighted by time spent in health states to calculate quality-adjusted life years (QALYs). The incremental cost per QALY gained was estimated for the population. Annual discount rates of 0%, 1.5%, and 3% were applied. In addition to deterministic analyses, probabilistic sensitivity analyses were conducted to deal with parameter uncertainty. The analyses were conducted from a Canadian public payer perspective in 2023 Canadian dollars.

RESULTS

The base case results indicated that over a lifetime, the expected costs were CAN$31,534 for low-dose pioglitazone and CAN$55,076 for placebo, resulting in a cost saving of CAN$23,542 in favor of the low-dose pioglitazone. Expected QALYs were 25.10 for the low-dose pioglitazone daily and 19.32 for placebo, resulting in a difference of 5.78 QALYs in favor of low-dose pioglitazone. Probability sensitivity analyses with varying discount rates confirmed these results.

CONCLUSIONS

Compared with placebo, low-dose pioglitazone is the dominant strategy.

Key Points

Question

Compared with a placebo, is low-dose pioglitazone cost-effective in treating stroke/ transient ischemic attack (TIA) and new-onset diabetes in a simulated population with prediabetics?

Findings

Over a lifetime, the expected costs were CAN$31,534 for low-dose pioglitazone and CAN$55,076 for placebo, resulting in a cost saving of CAN$23,542 in favor of low-dose pioglitazone. Expected QALYs were 25.10 for low-dose pioglitazone daily and 19.32 for placebo, resulting in a difference of 5.78 QALYs in favor of low-dose pioglitazone. Sensitivity and scenario analyses confirmed the results.

Meaning

The model-based economic evaluation indicates that low-dose pioglitazone, compared with placebo, is the dominant strategy.
MolecularWebXR: Multiuser discussions about chemistry and biology in immersive and inclusive VR
Authors: Cortés Rodríguez Fabio J. , Frattini Gianfranco , Phloi-Montri Sittha , Pinto Meireles Fernando Teixeira , Terrien Danaé A. , Cruz-León Sergio , Dal Peraro Matteo , Schier Eva , Lindorff-Larsen Kresten , Limpanuparb Taweetham , Moreno Diego M. , Abriata Luciano A.
Published: November 2023

MolecularWebXR is a new website for education, science communication and scientific peer discussion in chemistry and biology, based on modern web-based Virtual Reality (VR) and Augmented Reality (AR). With no installs as it is all web-served, MolecularWebXR enables multiple users to simultaneously explore, communicate and discuss concepts about chemistry and biology in immersive 3D environments, by manipulating and passing around objects with their bare hands and pointing at different elements with natural hand gestures. User may either be present in the same real space or distributed around the world, in the latter case talking naturally with each other thanks to built-in audio features. Although MolecularWebXR is most immersive when running in the web browsers of high-end AR/VR headsets, its WebXR core also allows participation by users with consumer devices such as smartphones, possibly inserted into cardboard goggles for deeper immersivity, or even in computers and tablets. MolecularWebXR comes with preset VR rooms that cover topics from general, inorganic and organic chemistry, biophysics and structural biology, and general biology; besides, new content can be added at will through moleculARweb’s PDB2AR tool or by contacting the lead authors. We verified MolecularWebXR’s ease of use and versatility by people aged 12-80 years old in entirely virtual sessions or in mixed real-virtual sessions at various science outreach events, in courses at the bachelor, masters and early doctoral levels, in scientific collaborations, and in conference lectures. MolecularWebXR is available for free use without registration athttps://molecularwebxr.org, and a blog post version of this preprint with embedded videos is available athttps://go.epfl.ch/molecularwebxr-blog-post.
Climate-Change Driven Decline of an Insect Pathogen Increases the Risk of Defoliation by a Forest Pest Insect
Authors: Liu Jiawei , Kyle Colin , Wang Jiali , Kotamarthi Rao , Koval William , Dwyer Greg
Published: November 2023

The effects of climate change on forest-defoliating insects are poorly understood, a problem that is especially urgent in the case of the spongy moth (formerly “the gypsy moth”,Lymantria dispar). For decades following its introduction in 1869, the spongy moth severely defoliated North American forests, but the introduction of the pathogenEntomophaga maimaigain 1989 drastically lowered defoliation levels.E. maimaiga, however, needs cool, moist conditions, whereas climate change is bringing hot, dry conditions to the range of the spongy moth. Here we use an empirically validated mathematical model to project that climate change will sharply reduceE. maimaigainfection rates, greatly increasing spongy moth defoliation. Recent data show that defoliation has strongly rebounded, supporting our projections. Our work shows that the effects of climate change on insect pathogens can have dire consequences for forests, and demonstrates the importance of understanding how climate change can alter species interactions.
Design of efficient artificial enzymes using crystallographically-enhanced conformational sampling
Authors: Rakotoharisoa Rojo V. , Seifinoferest Behnoush , Zarifi Niayesh , Miller Jack D.M. , Rodriguez Joshua M. , Thompson Michael C. , Chica Roberto A.
Published: November 2023

The ability to create efficient artificial enzymes for any chemical reaction is of great interest. Here, we describe a computational design method for increasing catalytic efficiency ofde novoenzymes to a level comparable to their natural counterparts without relying on directed evolution. Using structural ensembles generated from dynamics-based refinement against X-ray diffraction data collected from crystals of Kemp eliminases HG3 (kcat/KM125 M−1s−1) and KE70 (kcat/KM57 M−1s−1), we design from each enzyme ≤10 sequences predicted to catalyze this reaction more efficiently. The most active designs displaykcat/KMvalues improved by 100–250-fold, comparable to mutants obtained after screening thousands of variants in multiple rounds of directed evolution. Crystal structures show excellent agreement with computational models. Our work shows how computational design can generate efficient artificial enzymes by exploiting the true conformational ensemble to more effectively stabilize the transition state.
An adaptable plasmid scaffold for CRISPR-based endogenous tagging
Authors: Philip Reuben , Sharma Amit , Matellan Laura , Erpf Anna C. , Hsu Wen-Hsin , Tkach Johnny M. , Wyatt Haley D. M. , Pelletier Laurence
Published: November 2023

Endogenous tagging makes it possible to study a protein’s localization, dynamics, and function within its native regulatory context. This is typically accomplished via CRISPR, which involves inserting a sequence encoding a functional tag into the reading frame of a gene. However, this process is often inefficient. Here, we introduce the “quickTAG,” or qTAG system, a versatile collection of optimized repair cassettes designed to make CRISPR-mediated tagging more accessible. By including a desired tag sequence linked to a selectable marker in the cassette, integrations can be quickly isolated post-editing. The core sequence scaffold within these constructs incorporates several key features that enhance flexibility and ease of use, such as: specific cassette designs for N- and C-terminus tagging; standardized cloning sequences to simplify the incorporation of homology arms for HDR or MMEJ-based repairs; restriction sites next to each genetic element within the cassette for easy modification of tags and selectable markers; and the inclusion of lox sites flanking the selectable marker to allow for marker gene removal following integration. We showcase the versatility of these cassettes with a diverse range of tags, demonstrating their applications in fluorescence imaging, proximity-dependent biotinylation, epitope tagging, and targeted protein degradation. The adaptability of this scaffold is also exhibited by incorporating novel tags such as mStayGold, which offer enhanced brightness and photostability, reconciling prolonged live-cell imaging of proteins at their endogenous levels. Finally, by leveraging the restriction sites, entirely distinct cassette structures and editing schemes were developed. These enabled scenarios that included conditional expression tagging, selectable knockout tagging, and safe-harbor expression. Our existing and forthcoming collection of plasmids will be accessible through Addgene. It includes ready-to-use constructs targeting common subcellular marker genes, as well as an assortment of tagging cassettes for the tagging of genes of interest. The qTAG system offers an accessible framework to streamline endogenous tagging and will serve as an open resource for researchers to adapt and tailor for their own experiments.
Parameter estimation in a whole-brain network model of epilepsy: comparison of parallel global optimization solvers
Authors: Penas David R. , Hashemi Meysam , Jirsa Viktor K. , Banga Julio R.
Published: November 2023

The Virtual Epileptic Patient (VEP) refers to a computer-based representation of a patient with epilepsy that combines personalized anatomical data with dynamical models of abnormal brain activities. It is capable of generating spatio-temporal seizure patterns that resemble those recorded with invasive methods such as stereoelectro EEG data, allowing for the evaluation of clinical hypotheses before planning surgery. This study highlights the effectiveness of calibrating VEP models using a global optimization approach. The approach utilizes SaCeSS, a cooperative metaheuristic capable of parallel computation, to yield high-quality solutions without requiring excessive computational time. Through extensive benchmarking, our proposal successfully solved a set of different configurations of VEP models, demonstrating better scalability and superior performance against other parallel solvers. These results were further enhanced using a Bayesian optimization framework for hyperparameter tuning, with significant gains in terms of both accuracy and computational cost. Additionally, we added an scalable uncertainty quantification phase after model calibration, and used it to assess the variability in estimated parameters across different problems. Overall, this study has the potential to improve the estimation of pathological brain areas in drug-resistant epilepsy, thereby to inform the clinical decision-making process.

Author summary

Motivated by the problem of parameter estimation in a set of whole-brain network models of epilepsy (of increasing complexity), this study addresses the question of choosing a robust global optimization solver that can be accelerated by exploiting parallelism in different infrastructures, from desktop workstations to supercomputers. By leveraging data-driven techniques with robust cooperative global optimization methods, we aim to achieve accurate parameter estimation with reduced reliance on prior information. This is due to the dependency of Bayesian inference on the level of information in the prior, while this approach allows us to quantify uncertainty in the absence of any prior knowledge effectively. In this work, we construct an efficient and accurate method to perform parameter estimation and uncertainty quantification for the VEP model, and we use it to infer the brain regional epileptogenicity from source and sensor level whole-brain data. Of specific interest is the ability of our method to produce inference for high-dimensional state-space models governed by deterministic, stochastic, well-behaved, and stiff differential equations, using only partial observations and sparse encoding from system states to the observation.
Human lncRNAs harbor conserved modules embedded in different sequence contexts
Authors: Ballesio Francesco , Pepe Gerardo , Ausiello Gabriele , Novelletto Andrea , Helmer-Citterich Manuela , Gherardini Pier Federico
Published: November 2023

We analyzed the structure of human long non-coding RNA (lncRNAs) genes to investigate whether the non-coding transcriptome is organized in modular domains, as is the case for protein-coding genes. To this aim, we compared all known human lncRNA exons and identified 340 pairs of exons with high sequence and/or secondary structure similarity but embedded in a dissimilar sequence context. We grouped these pairs in 106 clusters based on their reciprocal similarities. These shared modules are highly conserved between humans and the four great ape species, display evidence of purifying selection and likely arose as a result of recent segmental duplications. Our analysis contributes to the understanding of the mechanisms driving the evolution of the non-coding genome and suggests additional strategies towards deciphering the functional complexity of this class of molecules.

Author summary

The Human genome includes more than 18,000 genes coding for RNAs that are not translated into proteins, called long non-coding RNAs (lncRNA). Mounting evolutionary and experimental evidence shows that a large amount of these RNAs have a specific function, mainly as regulators of a diverse set of biological processes. Here we set out to investigate whether these genes have a modular organization similar to that of protein-coding genes. Accordingly, we compared the sequence of all the exonic regions of human lncRNAs and identified 106 clusters of non-repetitive exonic modules shared between this class of genes. These modules display evidence of purifying selection, are highly conserved between humans and the four great ape species, and may represent distinct functional units that have been shuffled among multiple lncRNA genes, in a manner similar to the exon-shuffling process that is observed in the coding genome.
ARalstonia solanacearumtype III effector alters the actin and microtubule cytoskeleton to promote bacterial virulence in plants
Authors: Hiles Rachel , Rogers Abigail , Jaiswal Namrata , Zhang Weiwei , Butchacas Jules , Merfa Marcus V. , Klass Taylor , Kaser Erica , Jacobs Jonathan M. , Staiger Christopher J. , Helm Matthew , Iyer-Pascuzzi Anjali S.
Published: November 2023

Cellular responses to biotic stress frequently involve signaling pathways that are conserved across eukaryotes. These pathways include the cytoskeleton, a proteinaceous network that senses external cues at the cell surface and signals to interior cellular components. During biotic stress, dynamic cytoskeletal rearrangements serve as a platform from which early immune-associated processes are organized and activated. Bacterial pathogens of plants and animals use proteins called type III effectors (T3Es) to interfere with host immune signaling, thereby promoting virulence. We previously found that RipU, a T3E from the soilborne phytobacterial pathogenRalstonia solanacearumK60 (RsK60), co-localizes with the plant cytoskeleton. Here, we show that RipU fromRsK60 (RipUK60) physically associates with both actin and tubulin and disrupts actin and microtubule cytoskeleton organization. We find that pharmacological disruption of the tomato (Solanum lycopersicum) cytoskeleton promotesRsK60 colonization. RipUK60suppresses cell surface-triggered immune responses including flg22-mediated reactive oxygen species (ROS) production and callose deposition. Importantly, tomato plants inoculated withRsK60 lacking RipUK60(ΔripUK60) had reduced wilting symptoms and significantly reduced root colonization when compared to plants inoculated with wild-typeRsK60. Collectively, our data suggest thatRsK60 uses the type III effector RipUK60to remodel cytoskeletal organization, thereby promoting pathogen virulence.