bluuebunny/crossref_metadata_2025 huggingface dataset:
Sub-10-nm-sized Au@AuxIr1−x metal-core/alloy-shell nanoparticles as highly durable catalysts for acidic water splitting
Authors: Wang Huimin , Chen Zhe-ning , Wang Yuanyuan , Wu Dongshuang , Cao Minna , Sun Fanfei , Cao Rong
Published: February 2024

The absence of efficient and durable catalysts for oxygen evolution reaction (OER) is the main obstacle to hydrogen production through water splitting in an acidic electrolyte. Here, we report a controllable synthesis method of surface IrOx with changing Au/Ir compositions by constructing a range of sub-10-nm-sized core-shell nanocatalysts composed of an Au core and AuxIr1−x alloy shell. In particular, Au@Au0.43Ir0.57 exhibits 4.5 times higher intrinsic OER activity than that of the commercial Ir/C. Synchrotron X-ray-based spectroscopies, electron microscopy and density functional theory calculations revealed a balanced binding of reaction intermediates with enhanced activity. The water-splitting cell using a load of 0.02 mgIr/cm2 of Au@Au0.43Ir0.57 as both anode and cathode can reach 10 mA/cm2 at 1.52 V and maintain activity for at least 194 h, which is better than the cell using the commercial couple Ir/C‖Pt/C (1.63 V, 0.2 h).
Biofouling on titanium implants: a novel formulation of poloxamer and peroxide for in situ removal of pellicle and multi-species oral biofilm
Authors: Hussain Badra , Simm Roger , Bueno Jaime , Giannettou Savvas , Naemi Ali-Oddin , Lyngstadaas Ståle Petter , Haugen Håvard Jostein
Published: February 2024

Eradicating biofouling from implant surfaces is essential in treating peri-implant infections, as it directly addresses the microbial source for infection and inflammation around dental implants. This controlled laboratory study examines the effectiveness of the four commercially available debridement solutions ‘(EDTA (Prefgel®), NaOCl (Perisolv®), H2O2 (Sigma-Aldrich) and Chlorhexidine (GUM® Paroex®))’ in removing the acquired pellicle, preventing pellicle re-formation and removing of a multi-species oral biofilm growing on a titanium implant surface, and compare the results with the effect of a novel formulation of a peroxide-activated ‘Poloxamer gel (Nubone® Clean)’. Evaluation of pellicle removal and re-formation was conducted using scanning electron microscope (SEM), energy-dispersive X-ray spectroscopy and X-ray photoelectron spectroscopy to assess the surface morphology, elemental composition and chemical surface composition. Hydrophilicity was assessed through contact angle measurements. The multi-species biofilm model included Streptococcus oralis, Fusobacterium nucleatum and Aggregatibacter actinomycetemcomitans, reflecting the natural oral microbiome’s complexity. Biofilm biomass was quantified using safranin staining, biofilm viability was evaluated using confocal laser scanning microscopy, and SEM was used for morphological analyses of the biofilm. Results indicated that while no single agent completely eradicated the biofilm, the ‘Poloxamer gel’ activated with ‘H2O2’ exhibited promising results. It minimized re-contamination of the pellicle by significantly lowering the contact angle, indicating enhanced hydrophilicity. This combination also showed a notable reduction in carbon contaminants, suggesting the effective removal of organic residues from the titanium surface, in addition to effectively reducing viable bacterial counts. In conclusion, the ‘Poloxamer gel + H2O2’ combination emerged as a promising chemical decontamination strategy for peri-implant diseases. It underlines the importance of tailoring treatment methods to the unique microbial challenges in peri-implant diseases and the necessity of combining chemical decontaminating strategies with established mechanical cleaning procedures for optimal management of peri-implant diseases.
A multilevel intervention in pediatric primary care for youth tobacco control: Outcomes of implementing an Ask, Advise, and Connect model
Authors: Mays Darren , Macisco Joseph M , Hawkins Kirsten B , Sleiman Marcelo M , Yockel Mary Rose , Xie Shoulong , Phan Lilianna , Luta George , Lobo Tania , Abraham Anisha , Prokhorov Alexander V , Tercyak Kenneth P
Published: February 2024

Multilevel interventions in healthcare settings (e.g. Ask, Advise, and Connect; AAC) can reduce tobacco product use among adult patients: their effectiveness in pediatric practice is largely unknown. We implemented an AAC model in pediatric primary care to deter children’s tobacco use, and evaluated its effectiveness in a single-arm trial. At wellness visits, young patients (ages 12–17) completed a tablet-based assessment (Ask) of lifetime and current tobacco use. These data were made available within the electronic health record to pediatric primary care providers for preventive counseling (Advise). Providers then referred patients to an e-health evidence-based tobacco control intervention (Connect). Tobacco control outcomes were examined in the clinic population (N = 2219) and in a sample of patients (N = 388, 62% female, 39% non-White, M age = 15) over time, along with intervention engagement. Population use of tobacco products decreased following introduction of AAC (more than 2-fold). At the patient level, most children (80.9%) engaged with the intervention: those who were Black or African American, who never used tobacco products/were not susceptible to use, and who used fewer non-cigarette tobacco products were more likely to engage, but only after multiple prompts versus a single prompt. Engagement was positively associated with lowering children’s susceptibility to using tobacco at follow-up. A pediatric AAC model holds promise in deterring youth tobacco use, including among historically marginalized populations who may require additional support.
Spatial Variation of Oomycetes and Bacteria on Surfaces, Solutions, and Plants from a Commercial Hydroponic Greenhouse
Authors: McGehee Cora , Louyakis Artemis , Raudales Rosa E.
Published: February 2024

The spatial distribution and diversity of plant pathogens and other microbial communities in commercial operations is the first step in identifying critical control points where crops may be at risk of disease. Our objective was to characterize the spatial variation of oomycete pathogens and bacteria across the production system of a greenhouse producing lettuce in hydroponics. We utilized DNA metabarcoding to identify oomycetes and 16S rRNA gene sequencing of bacteria from different production stages and sample types (surfaces, solutions, and roots) collected from a commercial greenhouse producing lettuce in deepwater culture. Pythium was the genus with the highest relative abundance (41 to 100%) across all production stages. P. dissotocum was detected in most samples, except for sowing and seedling surfaces and municipal water, where P. myriotylum was the most abundant species. Oomycete communities showed distinct clustering by production stages and sample types, where sowing and seedling surfaces and municipal water were separated from the rest. Proteobacteria had the highest relative abundance in the surfaces at the sowing (98%) and seedling (85%) stages. Municipal water was the only sample with less than 20% relative abundance of Proteobacteria and dominated by Cyanobacteria. Negative correlations between Pythium and 13 bacteria genera point to potential antagonists in hydroponics that should be further studied. Mapping the spatial variation of oomycetes and bacterial communities in a commercial greenhouse indicates that production stage and sample type influence microbial composition and potentially the risk to disease.
Effects of Obesity on Urogynecologic Prolapse Surgery Outcomes
Authors: Ringel Nancy E. , Lenger Stacy M. , High Rachel , Alas Alexandriah , Houlihan Sara , Chang Olivia H. , Pennycuff Jon , Singh Ruchira , White Amanda , Lipitskaia Lioudmila , Behbehani Sadikah , Sheyn David , Kudish Bela , Nihira Mikio , Sleemi Ambereen , Grimes Cara , Gupta Ankita , Balk Ethan M. , Antosh Danielle D.
Published: February 2024

OBJECTIVE:

To systematically review the literature on outcomes of pelvic organ prolapse (POP) surgery in patients from various body mass index (BMI) categories to determine the association between obesity and surgical outcomes.

DATA SOURCES:

PubMed, EMBASE, and Cochrane databases were searched from inception to April 12, 2022; ClinicalTrials.gov was searched in September 2022 (PROSPERO 2022 CRD42022326255). Randomized and nonrandomized studies of urogynecologic POP surgery outcomes were accepted in which categories of BMI or obesity were compared.

METHODS OF STUDY SELECTION:

In total, 9,037 abstracts were screened; 759 abstracts were identified for full-text screening, and 31 articles were accepted for inclusion and data were extracted.

TABULATION, INTEGRATION, AND RESULTS

Studies were extracted for participant information, intervention, comparator, and outcomes, including subjective outcomes, objective outcomes, and complications. Outcomes were compared among obesity categories (eg, BMI 30–34.9, 35–40, higher than 40), and meta-analysis was performed among different surgical approaches. Individual studies reported varying results as to whether obesity affects surgical outcomes. By meta-analysis, obesity (BMI 30 or higher) is associated with an increased odds of objective prolapse recurrence after vaginal prolapse repair (odds ratio [OR] 1.38, 95% CI, 1.14–1.67) and after prolapse repair from any surgical approach (OR 1.31, 95% CI, 1.12–1.53) and with complications such as mesh exposure after both vaginal and laparoscopic POP repair (OR 2.10, 95% CI, 1.01–4.39).

CONCLUSION:

Obesity is associated with increased likelihood of prolapse recurrence and mesh complications after POP repair.

SYSTEMATIC REVIEW REGISTRATION:

PROSPERO CRD42022326255.
Association of Sepsis With Neurologic Outcomes of Adult Patients Treated With Venoarterial Extracorporeal Membrane Oxygnenation
Authors: Tridon Chloé , Bachelet Delphine , El Baied Majda , Eloy Philippine , Ortuno Sofia , Para Marylou , Wicky Paul-Henri , Vellieux Geoffroy , de Montmollin Etienne , Bouadma Lila , Manceau Hana , Timsit Jean-François , Peoc’h Katell , Sonneville Romain
Published: February 2024

OBJECTIVES:

Neurologic outcomes of patients under venoarterial extracorporeal membrane oxygenation (VA-ECMO) may be worsened by secondary insults of systemic origin. We aimed to assess whether sepsis, commonly observed during ECMO support, is associated with brain injury and outcomes.

DESIGN:

Single-center cohort study of the “exposed-non-exposed” type on consecutive adult patients treated by VA-ECMO.

SETTING:

Medical ICU of a university hospital, France, 2013–2020.

PATIENTS:

Patients with sepsis at the time of VA-ECMO cannulation (“sepsis” group) were compared with patients without sepsis (“no sepsis” group). The primary outcome measure was poor functional outcome at 90 days, defined by a score greater than or equal to 4 on the modified Rankin scale (mRS), indicating severe disability or death.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

A total of 196 patients were included (“sepsis,” n = 128; “no sepsis,” n = 68), of whom 87 (44.4%) had presented cardiac arrest before VA-ECMO cannulation. A poor functional outcome (mRS ≥ 4) was observed in 99 of 128 patients (77.3%) of the “sepsis” group and 46 of 68 patients (67.6%) of the “no sepsis” group (adjusted logistic regression odds ratio (OR) 1.21, 95% CI, 0.58–2.47; inverse probability of treatment weighting (IPTW) OR 1.24; 95% CI, 0.79–1.95). Subsequent analyses performed according to pre-ECMO cardiac arrest status suggested that sepsis was independently associated with poorer functional outcomes in the subgroup of patients who had experienced pre-ECMO cardiac arrest (adjusted logistic regression OR 3.44; 95% CI, 1.06–11.40; IPTW OR 3.52; 95% CI, 1.68–7.73), whereas no such association was observed in patients without pre-ECMO cardiac arrest (adjusted logistic regression OR 0.69; 95% CI, 0.27–1.69; IPTW OR 0.76; 95% CI, 0.42–1.35). Compared with the “no sepsis” group, “sepsis” patients presented a significant increase in S100 calcium-binding protein beta concentrations at day 1 (0.94 μg/L vs. 0.52 μg/L, p = 0.03), and more frequent EEG alterations (i.e., severe slowing, discontinuous background, and a lower prevalence of sleep patterns), suggesting brain injury.

CONCLUSION:

We observed a detrimental role of sepsis on neurologic outcomes in the subgroup of patients who had experienced pre-ECMO cardiac arrest, but not in other patients.
Regional lymph node mapping in patients with penile cancer undergoing radical inguinal lymph node dissection——retrospective cohort study
Authors: Tan Xingliang , Cai Taonong , Wang Yanjun , Wu Zhiming , Zhou Qianghua , Guo Shengjie , Li Jing , Yuan Gangjun , Liu Zhenhua , Li Zhiyong , Liu Zhicheng , Tang Yi , Zou Yuantao , Luo Sihao , Qin Zike , Zhou Fangjian , Lin Chunhua , Han Hui , Yao Kai
Published: February 2024

Background:

Radical inguinal lymph node dissection (rILND) is the most available treatment to cure penile cancer (PC) with limited inguinal-confined disease. However, guidelines regarding acceptable boundaries of rILND are controversial, and consensus is lacking. We aimed to standardize the surgical boundaries of rILND with definite pathological evidence and explore the distribution pattern of inguinal lymph nodes (ILNs) in PC.

Methods:

A total of 414 PC patients from two centers who underwent rILND were enrolled. The ILN distribution was divided into seven zones anatomically for pathological examination. Student’s t test and Kaplan‒Meier survival analysis were used.

Results:

ILNs displayed a funnel-shaped distribution with high density in superior regions. ILNs and metastatic nodes present anywhere within the radical boundaries. Positive ILNs were mainly concentrated in zone I (51.7%) and zone II (41.3%), but there were 8.7 and 12.3% in inferior zones V and VI, respectively, and 7.1% in the deep ILNs. More importantly, a single positive ILN and first-station positive zone was detected in all seven regions. Single positive ILNs were located in zones I through VI in 40.4%, 23.6%, 6.7%, 18.0%, 4.5% and 1.1%, respectively, and 5.6% presented deep ILN metastasis directly.

Conclusion:

We established a detailed ILN distribution map and displayed lymphatic drainage patterns with definite pathological evidence using a large cohort of PC patients. Single positive ILNs and first-station metastatic zones were observed in any region, even directly with deep ILN metastasis. Only rILND can ensure tumor-free resection without the omission of positive nodes.
Evaluation of cyclosporine 0.05% and artificial tears for the management of dry eye disease following cataract surgery: a randomized controlled trial
Authors: Ahmadi Hanieh , Tahmasbian Saeed , Janbazi Maryam , Amiri Arvin , Heidari Zahra
Published: February 2024

Purpose:

To compare the effects of cyclosporine 0.05% and artificial tears on dry eye disease following cataract surgery.

Methods:

This prospective, double-masked, randomized clinical trial enroled 60 eyes of 60 eligible cataract patients who completed the study. Patients were randomized to receive either cyclosporine 0.05% or artificial tear four times daily for 1 month following cataract surgery. Clinical assessments included refraction, corrected distance visual acuity, tear break-up time (TBUT), Schirmer’s test, and the visual analogue scale (VAS). An independent sample t-test was used to compare the means of the variables between the two groups.

Results:

Mean patient age was 64.15±9.17 (range, 45–90), of which 53% (n=32) were female. There was no significant difference in mean age (P=0.308) between the two groups. One month postoperatively, the cyclosporine 0.05% group had a significantly higher TBUT value (P=0.004). Schirmer’s result (P=0.095) and the VAS questionnaire scores (P=0.374) did not show a statistically significant difference between the two groups. There was no significant difference in the visual outcomes (P>0.05).

Conclusion:

Cyclosporine 0.05% was superior to artificial tears in improving tear stability after cataract surgery in the management of immediate postoperative dry eye. It may provide a more effective therapeutic option for the management of dry eye symptoms in the clinical setting.
Biomechanical effects of foot orthoses on jump landing performance: A systematic review
Authors: Jor Abu , Hu Mingyu , Koh Mark W.P. , Lau Noelle W.K. , Daryabor Aliyeh , Lam Wing-Kai , Kobayashi Toshiki
Published: February 2024

Jumping is involved in a wide range of sports and activities, and foot orthoses (FO) are suggested to enhance performance and prevent injury. The aim of this systematic review was to investigate whether using FO with different modifications affects jump landing biomechanics and improves performance in healthy individuals. The search strategy included 7 databases that identified 19 studies. The study quality was evaluated using a modified Downs and Black index. The primary outcome measures were joint kinematics, kinetics, muscle activity, vertical jump height, and horizontal jump distance. Our findings indicated that incorporating arch support with a rearfoot post and softer forefoot region into FO may improve several biomechanical variables during jump landing activities. Improvements in vertical ground reaction force loading rates, knee and ankle kinematics, and muscle cocontraction during jumping with FO could enhance jumping performance. In addition, improvements in hip, knee, ankle, and tibial kinematics and vertical ground reaction force loading rates during landing could reduce impact forces and related injuries. Although a limited number of studies have addressed the effects of FO on vertical jump height and horizontal jump distance, inserting such FO inside shoes with optimum bending stiffness could facilitate jumping performance. A rigorous exploration of the effect and mechanism of FO designs on jumping performance could benefit jumping-related activities and prevent ankle and knee injuries.
ATP Citrate Lyase Drives Vascular Remodeling Diseases Development Through Metabolic-Epigenetic Reprograming
Authors: Grobs Yann , Romanet Charlotte , Lemay Sarah-Eve , Bourgeois Alice , Voisine Pierre , Theberge Charlie , Sauvaget Melanie , Breuils-Bonnet Sandra , Martineau Sandra , Kabbout Reem El , Mougin Manon , Dumais Elizabeth , Perron Jean , Flamand Nicolas , Potus François , Provencher Steeve , Boucherat Olivier , Bonnet Sebastien
Published: February 2024

Our study explores the previously uncharted role of ATP-citrate lyase (ACLY) in vascular remodeling within the pulmonary and coronary arteries, providing novel insights into the pathogenesis of pulmonary hypertension and coronary artery diseases. ACLY, involved in de novo lipid synthesis and histone acetylation, has emerged as a key regulator in sustaining vascular smooth muscle cell (VSMC) proliferation and survival.

Utilizing human coronary and pulmonary artery tissues, our findings reveal an upregulation of ACLY expression during vascular remodeling processes. Inhibition of ACLY, achieved through pharmacological and molecular interventions in humans primary cultured VSMCs, leads to decreased proliferation, migration, and resistance to apoptosis. Mechanistically, these effects are associated with diminished glycolysis, lipid synthesis, GCN5-dependent histone acetylation, and FOXM1 activation.

In vivo experiments, combining pharmacological and VSMC-specific ACLY knockout mice, ACLY inhibition demonstrates its efficacy in mitigating coronary artery remodeling and reducing pulmonary hypertension. Notably, initiating ACLY inhibition post-disease onset reverses pathological conditions, positioning ACLY as a promising therapeutic target.

Human ex vivo tissue culture further supports our findings, showing reduced vascular remodeling in cultured human coronary artery rings and a reversal of pulmonary artery remodeling in precision-cut lung slices upon ACLY inhibition. This study introduces a groundbreaking concept, linking disparate abnormalities in vascular diseases to a common pathogenetic denominator, ACLY. The identified “multiple hit” therapeutic approach presents potential targets for addressing complex vascular diseases, offering avenues for future clinical interventions.

ONE SENTENCE SUMMARY

Our study delineates the pivotal role of ATP-citrate lyase in orchestrating vascular remodeling, establishing it as a compelling translational target for therapeutic interventions in pulmonary hypertension and coronary artery disease.
Conformational Space of the Translocation Domain of Botulinum Toxin: Atomistic Modeling and Mesoscopic Description of the Coiled-Coil Helix Bundle
Authors: Delort Alexandre , Cottone Grazia , Malliavin Thérèse E. , Müller Martin Michael
Published: February 2024

The toxicity of botulinum multi-domain neurotoxins (BoNTs) arises from a sequence of molecular events, in which the translocation of the catalytic domain through the membrane of a neurotransmitter vesicle plays a key role. A structural study (Lamet al., Nat. Comm., 2018) of the translocation domain of BoNT suggests that the interaction with the membrane is driven by the transition of anαhelical switch towards aβhairpin. Atomistic simulations in conjunction with the mesoscopicTwistermodel are used to investigate the consequences of this proposition for the toxin-membrane interaction. The conformational mobilities of the domain as well as the effect of the membrane, implicitly examined by comparing water and water-ethanol solvents, lead to the conclusion that the transition of the switch modifies the internal dynamics and the effect of membrane hydrophobicity on the whole protein. The central twoαhelices, helix 1 and helix 2, forming two coiled-coil motifs, are analyzed using theTwistermodel, in which the initial deformation of the membrane by the protein is caused by the presence of local torques arising from asymmetric positions of hydrophobic residues. Different torque distributions are observed depending on the switch conformations and permit to propose an origin for the mechanism opening the membrane.
Addressing the antibody germline bias and its effect on language models for improved antibody design
Authors: Olsen Tobias H. , Moal Iain H. , Deane Charlotte M.
Published: February 2024

Abstract

The versatile binding properties of antibodies have made them an extremely important class of biotherapeutics. However, therapeutic antibody development is a complex, expensive and time-consuming task, with the final antibody needing to not only have strong and specific binding, but also be minimally impacted by any developability issues. The success of transformer-based language models in protein sequence space and the availability of vast amounts of antibody sequences, has led to the development of many antibody-specific language models to help guide antibody discovery and design. Antibody diversity primarily arises from V(D)J recombination, mutations within the CDRs, and/or from a small number of mutations away from the germline outside the CDRs. Consequently, a significant portion of the variable domain of all natural antibody sequences remains germline. This affects the pre-training of antibody-specific language models, where this facet of the sequence data introduces a prevailing bias towards germline residues. This poses a challenge, as mutations away from the germline are often vital for generating specific and potent binding to a target, meaning that language models need be able to suggest key mutations away from germline.

In this study, we explore the implications of the germline bias, examining its impact on both general-protein and antibody-specific language models. We develop and train a series of new antibody-specific language models optimised for predicting non-germline residues. We then compare our final model, AbLang-2, with current models and show how it suggests a diverse set of valid mutations with high cumulative probability. AbLang-2 is trained on both unpaired and paired data, and is freely available (https://github.com/oxpig/AbLang2.git).
Fine-scale genetic structure and rare variant frequencies
Authors: Gagnon Laurence , Moreau Claudia , Laprise Catherine , Girard Simon L.
Published: February 2024

In response to the current challenge in genetic studies to make new associations, we advocate for a shift toward leveraging population fine-scale structure. Our exploration brings to light distinct fine-structure within populations having undergone a founder effect, challenging the prior perception of homogeneity. This underscores that smaller, but well-defined cohorts, demonstrate an important increase in rare variant frequencies, offering a promising avenue for new genetic variants’ discovery.
Science Education for the Youth (SEFTY): A Neuroscience Outreach Program for High School Students in Southern Nevada During the COVID-19 Pandemic
Authors: Ghani Nabih , Baker Hayley , Huntsinger Audrey , Chen Tiffany , Familara Tiffany D , Itorralba Jose Yani , Vanderford Fritz , Zhuang Xiaowei , Chang Ching-Lan , Vo Van , Oh Edwin C.
Published: February 2024

Laboratory outreach programs for K-12 students in the United States from 2020-2022 were suspended or delayed due to COVID-19 restrictions. While Southern Nevada also observed similar closures for onsite programs, we and others hypothesized that in-person laboratory activities could be prioritized after increasing vaccine doses were available to the public and masking was encouraged. Here, we describe how the Laboratory of Neurogenetics and Precision Medicine at the University of Nevada Las Vegas (UNLV) collaborated with administrators from a local school district to conduct training activities for high school students during the COVID-19 pandemic. The Science Education for the Youth (SEFTY) program’s curriculum was constructed to incorporate experiential learning, fostering collaboration and peer-to-peer knowledge exchange. Leveraging neuroscience tools from our UNLV laboratory, we engaged with 117 high school applicants from 2021-2022. Our recruitment efforts yielded a diverse cohort, with >41% Pacific Islander and Asian students, >9% African American students, and >12% multiracial students. We assessed the impact of the SEFTY program through pre- and post-assessment student evaluations, revealing a significant improvement of 20.3% in science proficiency (p<0.001) after participating in the program. Collectively, our laboratory curriculum offers valuable insights into the capacity of an outreach program to actively foster diversity and cultivate opportunities for academic excellence, even in the challenging context of a global pandemic.

Significance Statement

The Science Education for the Youth (SEFTY) program at UNLV successfully engaged 117 diverse high school students in neuroscience-based experiential learning, demonstrating the viability of in-person education during a pandemic. Significant improvements in science proficiency (20.3% increase) underscore the program’s effectiveness in fostering academic excellence and diversity. This initiative potentially serves as a model for maintaining high-quality, inclusive science education in challenging times.
Augmented Reality and Cross-Device Interaction for Seamless Integration of Physical and Digital Scientific Papers
Authors: Miah Md Ochiuddin , Kong Jun
Published: February 2024

Researchers face the challenge of efficiently navigating vast scientific literature while valuing printed papers in the digital age. Printed materials facilitate deeper engagement and comprehension, leading to superior exam performance and enhanced retention. However, existing digital tools often need to pay more attention to the needs of researchers who value the tactile benefits of printed documents. In response to this gap, we introduce AR-PaperSync, a transformative solution that leverages Augmented Reality (AR) and cross-device interaction technology. AR-PaperSync seamlessly integrates the physical experience of printed papers with the interactive capabilities of digital tools. Researchers can effortlessly navigate inline citations, manage saved references, and synchronize reading notes across mobile, desktop, and printed paper formats. Our user-centric approach, informed by in-depth interviews with six researchers, ensures that AR-PaperSync is tailored to its target users' needs. A comprehensive user study involving 28 participants evaluated AR-PaperSync's significantly improved efficiency, accuracy, and cognitive load in academic reading tasks compared to conventional methods. These findings suggest that AR-PaperSync enhances the reading experience of printed scientific papers and provides a seamless integration of physical and digital reading environments for researchers.
Hydrodynamic Radii of Intrinsically Disordered Proteins: Fast Prediction by Minimum Dissipation Approximation and Experimental Validation
Authors: Waszkiewicz Radost , Michaś Agnieszka , Białobrzewski Michał K. , Klepka Barbara P. , Cieplak-Rotowska Maja K. , Staszałek Zuzanna , Cichocki Bogdan , Lisicki Maciej , Szymczak Piotr , Niedzwiecka Anna
Published: February 2024

The diffusion coefficients of globular and fully unfolded proteins can be predicted with high accuracy solely from their mass or chain length. However, this approach fails for intrinsically disordered proteins (IDPs) containing structural domains. We propose a rapid predictive methodology for estimating the diffusion coefficients of IDPs. The methodology uses accelerated conformational sampling based on self-avoiding random walks and includes hydrodynamic interactions between coarse-grained protein subunits, modeled using the generalized Rotne-Prager-Yamakawa approximation. To estimate the hydrodynamic radius, we rely on the minimum dissipation approximation recently introduced by Cichockiet al. Using a large set of experimentally measured hydrodynamic radii of IDPs over a wide range of chain lengths and domain contributions, we demonstrate that our predictions are more accurate than the Kirkwood approximation and phenomenological approaches. Our technique may prove valuable in predicting the hydrodynamic properties of both fully unstructured and multidomain disordered proteins.

TOC Graphic
REL2 overexpression in theAnopheles gambiaemidgut causes major transcriptional changes but fails to induce an immune response
Authors: Hoermann Astrid , Capriotti Paolo , Del Corsano Giuseppe , Inghilterra Maria Grazia , Habtewold Tibebu , Cai Julia A. , Saini Gauri Sachiko , Nguyen Huong , Windbichler Nikolai , Christophides George K.
Published: February 2024

The NF-κB-like transcription factor, REL2, is a key player in the mosquito Immunodeficiency (Imd) pathway and holds promise for controlling malaria parasite infections in genetically modifiedAnopheles gambiaemosquitoes. We engineered transgenic mosquitoes overexpressing REL2 from within the bloodmeal-inducible zinc carboxypeptidase A1 (CP) host gene in the adult posterior midgut. Our results confirmed elevated REL2 expression in the posterior midgut following a bloodmeal, with the corresponding protein localized within epithelial cell nuclei. While this induced overexpression triggered substantial transcriptional changes, accompanied by notable fitness costs, the resultant reduction inPlasmodium falciparuminfection was modest. An in-depth analysis of regulatory regions of differentially regulated genes allowed us to identify direct REL2 target genes and revealed signatures indicative of potential transcriptional repressors. To account for potential impacts of host gene modification, we also created a CP knockout line that caused marginal effects on mosquito fitness. These findings shed light on the observed absence of transcriptional activation and, in some cases, induced repression of antimicrobial peptides (AMPs) presumed to be under Imd pathway control. In conclusion, our study suggests that elevated REL2 expression in the posterior midgut may induce the upregulation of negative immune regulators, facilitating control over an otherwise unrestrained immune response, and that concurrent transcriptional derepression may be needed to effectively induce the mosquito immune response. This work contributes valuable insights into the intricate regulation of midgut immunity in malaria vector mosquitoes.
Intrinsic structural disorder on proteins is involved in the interactome evolution
Authors: Bustos Diego M
Published: February 2024

New mathematical tools help to understanding cell functions, adaptability and evolvability to discover hidden variables to predict phenotypes that could be tested in the future in wet labs. Different models have been successfully used to discover properties of the protein-protein interaction network or interactome. We found that in the hyperbolic Popularity-Similarity model cellular proteins with highest contents of structural intrinsic disorder cluster together in many different eukaryotic interactomes and not the prokaryoticE. coli, where proteins with high levels of intrinsic disorder are very low. We also found that the normalized theta variable from the Popularity-Similarity model for a protein family correlate to the seniority of the organisms in analysis.
Scaling laws of molecular residence time
Authors: Qin Shiyi , Yang Zhi , Huang Kai
Published: February 2024

Understanding the molecular residence autocorrelation function in liquid is of fundamental importance in physical and life science. Encoded in this function is not only the binding properties, but also the information of the liquid environment. Based on extensive in silico experiments and theoretical analysis, we reveal that power law residence scaling arises in both passive and active liquid, in contrast to the common sense of exponential decay. In simple homogeneous liquid, the scaling exponent depends solely on the system dimensionality. Such scaling law is robust against the superposition of diverse binding energies in single-phase liquid but can be breached if the system undergoes phase separation. Remarkably, in a dissipative system where phase separation is subject to non-equilibrium feedback controls, an anomalous power law emerges whose scaling exponent is in line with the puzzling residence scaling of transcription factors reported in recent experiments. Our results highlight the sensitivity of molecular residence to its surrounding liquid and suggest that active phase separation can serve as a scaling proofreading mechanism in gene regulation.
Multitask Knowledge-primed Neural Network for Predicting Missing Metadata and Host Phenotype based on Human Microbiome
Authors: Monshizadeh Mahsa , Hong Yuhui , Ye Yuzhen
Published: February 2024

Microbial signatures in the human microbiome have been linked to various human diseases, and Machine Learning (ML) models have been developed for microbiome-based disease prediction, although improvements remain to be made in accuracy, reproducibility and interpretability. On the other hand, confounding factors, including host’s gender, age and BMI can have a significant impact on human’s microbiome, complicating microbiome-based human phenotype predictions. We recently developed MicroKPNN, an interpretable ML model that achieved promising performance for human disease prediction based on microbiome data. MicroKPNN explicitly incorporates prior knowledge of microbial species into the neural network. Here we developed MicroKPNN-MT a unified model for predicting human phenotype based on microbiome data, as well as additional metadata including age, body mass index (BMI), gender and body site. In MicroKPNNMT, the metadata information, when available, will be used as additional input features for prediction, or otherwise will be predicted from microbiome data using additional decoders in the model. We applied MicroKPNN-MT to microbiome data collected in mBodyMap, covering healthy individuals and 25 different diseases, and demonstrated its potential as a predictive tool for multiple diseases, which at the same time provided predictions for much of the missing metadata (e.g., the BMI information was missing for 94% of the samples). Our results showed that incorporating real or predicted metadata helped improve the accuracy of disease predictions, and more importantly, helped improve the generalizability of the predictive models. Finally, our model enables the interpretation of predictive models and the identification of potential microbial markers affecting host phenotypes.
Resistance genes are distinct in protein-protein interaction networks according to drug class and gene mobility
Authors: Moumi Nazifa Ahmed , Brown Connor L. , Ahmed Shafayat , Vikesland Peter J. , Pruden Amy , Zhang Liqing
Published: February 2024

With growing calls for increased surveillance of antibiotic resistance as an escalating global health threat, improved bioinformatic tools are needed for tracking antibiotic resistance genes (ARGs) across One Health domains. Most studies to date profile ARGs using sequence homology, but such approaches provide limited information about the broader context or function of the ARG in bacterial genomes. Here we introduce a new pipeline for identifying ARGs in genomic data that employs machine learning analysis of Protein-Protein Interaction Networks (PPINs) as a means to improve predictions of ARGs while also providing vital information about the context, such as gene mobility. A random forest model was trained to effectively differentiate between ARGs and nonARGs and was validated using the PPINs of ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, andEnterobacter cloacae), which represent urgent threats to human health because they tend to be multi-antibiotic resistant. The pipeline exhibited robustness in discriminating ARGs from nonARGs, achieving an average area under the precision-recall curve of 88%. We further identified that the neighbors of ARGs, i.e., genes connected to ARGs by only one edge, were disproportionately associated with mobile genetic elements, which is consistent with the understanding that ARGs tend to be mobile compared to randomly sampled genes in the PPINs. This pipeline showcases the utility of PPINs in discerning distinctive characteristics of ARGs within a broader genomic context and in differentiating ARGs from nonARGs through network-based attributes and interaction patterns. The code for running the pipeline is publicly available athttps://github.com/NazifaMoumi/PPI-ARG-ESKAPE
Impact of Butyrate on Small and Large Airways: Effects on Cell Viability, Inflammatory Changes and Permeability
Authors: Yildiz Abdullah Burak , Aksoy Gizem Tuse , Konyalilar Nur , Kayalar Ozgecan , Korkunc Seval Kubra , Bayram Hasan
Published: February 2024

Chronic airway diseases, such as Chronic Obstructive Pulmonary Disease (COPD) and asthma pose a significant global health burden. The pathophysiology involves chronic inflammation, with oxidative stress playing a crucial role in disease severity. Current treatments, especially for COPD, have limitations, necessitating exploration of alternative therapeutic approaches. In this study, we investigated the potential effects of butyrate, a short-chain fatty acid, on airway epithelial cells. Human bronchial epithelial cells (BEAS-2B) and bronchiolar epithelial carcinoma cells (A549) were cultured and exposed to hydrogen peroxide (H2O2) to induce oxidative stress. Butyrate was then applied at various concentrations, and the impact on cell viability, epithelial permeability, inflammatory cytokines, and gene expression was assessed. Our cell viability experiments revealed a dose-dependent reduction in viability with H2O2, while butyrate was found to be safe as it did not affect cell viability. Additionally, butyrate showed decrease in small airway permeability. Butyrate demonstrated anti- inflammatory properties, suppressing H2O2-induced release of interleukin (IL)-6, IL-8, and granulocyte macrophage colony-stimulating factor (GM-CSF) in large airways. Gene expression analysis further highlighted complex regulatory effects of butyrate on inflammatory pathways. Our study suggests that butyrate may have potential therapeutic benefits in chronic airway diseases by modulating inflammation, permeability, and gene expression. However, further research, including in vivo studies and exploration of endogenous butyrate utilization, is needed to fully understand its pharmacodynamics and clinical relevance. Our findings contribute to the understanding of short-chain fatty acids as potential candidates for respiratory disease treatment.
Ultra-low coverage fragmentomic model of cell-free DNA for cancer detection based on whole-exome regions
Authors: Sangphukieo Apiwat , Noisagul Pitiporn , Thongkumkoon Patcharawadee , Chaiyawat Parunya
Published: February 2024

Cell-free DNA (cfDNA) has shown promise as a non-invasive biomarker for cancer screening and monitoring. The current advanced machine learning (ML) model, known as DNA evaluation of fragments for early interception (DELFI), utilizes the short and long fragmentation pattern of cfDNA and has demonstrated exceptional performance. However, the application of cfDNA-based model can be limited by the high cost of whole-genome sequencing (WGS). In this study, we present a novel ML model for cancer detection that utilizes cfDNA profiles generated from all protein-coding genes in the genome (exome) with only 0.08X of WGS coverage. Our model was trained on a dataset of 721 cfDNA profiles, comprising 426 cancer patients and 295 healthy individuals. Performance evaluation using a ten-fold cross-validation approach demonstrated that the new ML model using whole-exome regions, called xDELFI, can achieve high accuracy in cancer detection (Area under the ROC curve; AUC=0.896, 95%CI = 0.878 - 0.916), comparable to the model using WGS (AUC=0.920, 95%CI = 0.901 – 0.936). Notably, we observed distinct fragmentation patterns between exonic regions and the whole-genome, suggesting unique genomic features within exonic regions. Furthermore, we demonstrate the potential benefits of combining mutation detection in cfDNA with xDELFI, which enhance the model sensitivity. Our proof-of-principle study indicates that the fragmentomic ML model based solely on whole-exome regions retains its predictive capability. With the ultra-low sequencing coverage of the new model, it could potentially improve the accessibility of cfDNA-based cancer diagnosis and aid in early detection and treatment of cancer.
Resilience, mental health, sleep, and smoking mediate pathways between lifetime stressors and Multiple Sclerosis severity
Authors: Polick Carri S. , Darwish Hala , de Olivera Leo Pestillo , Watson Ali , Nickenig Vissoci Joao Ricardo , Calhoun Patrick S. , Ploutz-Snyder Robert , Connell Cathleen M. , Braley Tiffany J. , Stoddard Sarah A.
Published: February 2024

Intro

Lifetime stressors (e.g., poverty, violence, discrimination) have been linked to Multiple Sclerosis (MS) features; yet mechanistic pathways and relationships with cumulative disease severity remain nebulous. Further, protective factors like resilience, that may attenuate the effects of stressors on outcomes, are seldom evaluated.

Aim

To deconstruct pathways between lifetime stressors and cumulative severity on MS outcomes, accounting for resilience.

Methods

Adults with MS (N=924) participated in an online survey through the National MS Society listserv. Structural Equation Modeling was used to examine the direct and indirect effect of lifetime stressors (count/severity) on MS severity (self-reported disability, relapse burden, fatigue, pain intensity and interference), via resilience, mental health (anxiety and depression), sleep disturbance, and smoking.

Results

The final analytic model had excellent fit (GFI=0.998). Lifetime stressors had a direct relationship with MS severity (β=0.27, p<.001). Resilience, mental health, sleep disturbance, and smoking significantly mediated the relationship between lifetime stressors and MS severity. The total effect of mediation was significant (β=0.45).

Conclusions

This work provides foundational evidence to inform conceptualization of pathways by which stress could influence MS disease burden. Resilience may attenuate effects of stressors, while poor mental health, smoking, and sleep disturbances may exacerbate their impact. Parallel with usual care, these mediators could be targets for early multimodal therapies to improve disease course.

Highlights

Lifetime stressors directly and indirectly relate to MS severity.

Resilience, mental health, sleep, and smoking were mediators.

Resilience attenuated the effects of stressors on mental health, sleep, and smoking.

Multi-modal interventions are needed to help improve MS symptom severity.
Associations of a multidimensional polygenic sleep health score and a sleep lifestyle index on health outcomes and their interaction in a clinical biobank
Authors: Paz Valentina , Wilcox Hannah , Goodman Matthew , Wang Heming , Garfield Victoria , Saxena Richa , Dashti Hassan S.
Published: February 2024

Sleep is a complex behavior regulated by genetic and environmental factors, and is known to influence health outcomes. However, the effect of multidimensional sleep encompassing several sleep dimensions on diseases has yet to be fully elucidated. Using the Mass General Brigham Biobank, we aimed to examine the association of multidimensional sleep with health outcomes and investigate whether sleep behaviors modulate genetic predisposition to unfavorable sleep on mental health outcomes. First, we generated a Polygenic Sleep Health Score using previously identified single nucleotide polymorphisms for sleep health and constructed a Sleep Lifestyle Index using data from self-reported sleep questions and electronic health records; second, we performed phenome-wide association analyses between these indexes and clinical phenotypes; and third, we analyzed the interaction between the indexes on prevalent mental health outcomes. Fifteen thousand eight hundred and eighty-four participants were included in the analysis (mean age 54.4; 58.6% female). The Polygenic Sleep Health Score was associated with the Sleep Lifestyle Index (β=0.050, 95%CI=0.032, 0.068) and with 114 disease outcomes spanning 12 disease groups, including obesity, sleep, and substance use disease outcomes (p<3.3×10−5). The Sleep Lifestyle Index was associated with 458 disease outcomes spanning 17 groups, including sleep, mood, and anxiety disease outcomes (p<5.1×10−5). No interactions were found between the indexes on prevalent mental health outcomes. These findings suggest that favorable sleep behaviors and genetic predisposition to healthy sleep may independently be protective of disease outcomes. This work provides novel insights into the role of multidimensional sleep on population health and highlights the need to develop prevention strategies focused on healthy sleep habits.