bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultrafast gelling bioadhesive based on blood plasma and gelatin for wound closure and healing
Authors: Gupta Ritvesh , Verma Devendra
Published: April 2024

Tissue adhesives offer a plethora of advantages in achieving efficient wound closure over conventional sutures and staples. Such materials are of great value, especially in cases where suturing could potentially damage tissues or compromise blood flow or in cases of hard-to-reach areas. Besides providing wound closure, the tissue adhesives must also facilitate wound healing. Previously, plasma-based tissue adhesives and similar bioinspired strategies have been utilized to aid in wound healing. Still, their application is constrained by factors such as high cost, diminished biocompatibility, prolonged gelation times, inadequate swelling, quick resorption, as well as short-term and inconsistent efficacy. To address these limitations, we report the development of a highly biocompatible and ultrafast-gelling tissue adhesive hydrogels. Freeze-dried platelet-rich plasma, heat-denatured freeze-dried platelet-poor plasma, and gelatin were utilized as the base matrix. Gelation was initiated by adding tetrakis hydroxymethyl phosphonium chloride. The fabricated gels displayed rapid gelation (3–4 s), low swelling, increased proliferation, and migration against L929 cells and had porcine skin tissue adhesion strength similar to that of plasma-based commercial glue (Tisseel®).
Global potential nitrogen recovery from anaerobic digestion of agricultural residues
Authors: Marconi Pietro , Rosa Lorenzo
Published: April 2024

Meeting the anticipated 50% increase in global food demand by 2050 requires a crucial reassessment of agricultural practices, particularly in terms of nitrogen fertilizers inputs. This study analyzes the technical potential of nitrogen recovery from livestock manure and crop residues, bringing attention to the often-overlooked resource of digestate derived from anaerobic digestion. Our analysis highlights the significant capacity of the anaerobic digestion process, yielding approximately 234 ± 5 million metric tons (Mt) of nitrogen annually, sourced 93% from livestock manure and 7% from crop residues. Additionally, we estimated that substituting synthetic nitrogen with nitrogen from anaerobic digestion has the potential to reduce greenhouse gas emissions by 70% (185 Mt CO2-eqyr−1). Lastly, 2.5 billion people could be sustained by crops grown using nitrogen from anaerobic digestion of manure and crop residues rather than synthetic nitrogen fertilizers. Although agricultural residues have double the technical potential of current synthetic nitrogen fertilizer production, 30% of croplands encounter difficulties in satisfying their nitrogen needs solely through crop residues and anaerobic digestion manure. This deficiency primarily results from inefficient reuse attributed to geographical mismatches between crop and livestock systems. This underscores the urgent need to reconnect livestock and cropping systems and facilitate the transport and reuse of manure in crop production. In conclusion, the mobilization of these large amounts of nitrogen from livestock manure and crop residues will require to overcome the nitrogen from anaerobic digestion green premium with incentives and subsidies.
Implementation of the SSH model in an optical ring resonator
Authors: Hotte-Kilburn Alexis , Bianucci Pablo
Published: April 2024

The implementation of physical models with topological features in optical systems has garnered much attention in recent times. In particular, on-chip integrated photonics platforms are promising platforms enabling us to take advantage of the promise of topologically robust modes against inevitable fabrication defects. Here, we propose to study the SSH model superimposed in an optical ring resonator in a quantitative way using electromagnetic simulations. We are interested in the localized states that appear when a topological phase transition is introduced into the ring. In particular, we examine the extent to which topologically protected modes maintain their properties in the presence of random deformations in the surrounding lattice. We find that the modes maintain their properties when small amounts of disorder are introduced into the system. We also study loss mechanisms in the localized states, distinguishing between losses to the adjacent waveguide and to radiation, finding that the topological protection only applies to the former.
An intelligent control method for a flexible-link manipulator with uncertain backlash and model uncertainty
Authors: Guo Shenghan , Cai Weiguo , Zhang Yaning , Zhang Hanyu , Liu Jun , Ye Xuying , Geng Qiankai
Published: April 2024

This study examines a new intelligent control method for a single-link flexible manipulator that addresses backlash and model uncertainty. First, a smooth backlash inverse model is constructed to mitigate backlash nonlinearity. Subsequently, a ‘disturbance-like’ term is formulated to recharacterize the coupled term composed of external disturbances and model uncertainty. A new adaptive controller is proposed to compensate for the unknown ‘disturbance-like’ term. Using the proposed control method, the stability of the system is evaluated using the direct Lyapunov theory, ensuring uniform ultimate boundedness. Finally, numerical simulations and experiments are conducted using the Quanser platform. The numerical simulation and experimental results show that the proposed control can ensure a faster convergence rate and effectively reduce actuator input chattering.
Separating path systems of almost linear size
Authors: Letzter Shoham
Published: April 2024

A separating path system for a graph

G
G

is a collection

P

\mathcal {P}

of paths in

G
G

such that for every two edges

e
e

and

f
f

, there is a path in

P

\mathcal {P}

that contains

e
e

but not

f
f

. We show that every

n
n

-vertex graph has a separating path system of size

O
(
n

log
∗

⁡
n
)

O(n \log ^* n)

. This improves upon the previous best upper bound of

O
(
n
log
⁡
n
)

O(n \log n)

, and makes progress towards a conjecture of Falgas-Ravry–Kittipassorn–Korándi–Letzter–Narayanan and Balogh–Csaba–Martin–Pluhár, according to which an

O
(
n
)

O(n)

bound should hold.
Baseline unfolded protein response signaling adjusts the timing of the mammalian cell cycle
Authors: Chowdhury Soham P. , Solley Sabrina C. , Polishchuk Elena , Bacal Julien , Conrad Julia E. , Gardner Brooke M. , Acosta-Alvear Diego , Zappa Francesca
Published: April 2024

The endoplasmic reticulum (ER) is a single-copy organelle that cannot be generated de novo, suggesting coordination between the mechanisms overseeing ER integrity and those controlling the cell cycle to maintain organelle inheritance. The Unfolded Protein Response (UPR) is a conserved signaling network that regulates ER homeostasis. Here, we show that pharmacological and genetic inhibition of the UPR sensors IRE1, ATF6, and PERK in unstressed cells delays the cell cycle, with PERK inhibition showing the most penetrant effect, which was associated with a slowdown of the G1-to-S/G2 transition. Treatment with the small molecule ISRIB to bypass the effects of PERK-dependent phosphorylation of the translation initiation factor eIF2α had no such effect, suggesting that cell cycle timing depends on PERK’s kinase activity but is independent of eIF2α phosphorylation. Using complementary light and electron microscopy and flow cytometry-based analyses, we also demonstrate that the ER enlarges before mitosis. Together, our results suggest coordination between UPR signaling and the cell cycle to maintain ER physiology during cell division.
Solo regulates the localization and activity of PDZ-RhoGEF for actin cytoskeletal remodeling in response to substrate stiffness
Authors: Kunitomi Aoi , Chiba Shuhei , Higashitani Nahoko , Higashitani Atsushi , Sato Shinichi , Mizuno Kensaku , Ohashi Kazumasa
Published: April 2024

Recent findings indicate that Solo, a RhoGEF, is involved in cellular mechanical stress responses. However, the mechanism of actin cytoskeletal remodeling via Solo remains unclear. Therefore, this study aimed to identify Solo-interacting proteins using the BioID, a proximal-dependent labeling method, and elucidate the molecular mechanisms of function of Solo. We identified PDZ-RhoGEF (PRG) as a Solo-interacting protein. PRG colocalized with Solo in the basal area of cells, depending on Solo localization, and enhanced actin polymerization at the Solo accumulation sites. Additionally, Solo and PRG interaction was necessary for actin cytoskeletal remodeling. Furthermore, the purified Solo itself had little or negligible GEF activity, even its GEF-inactive mutant directly activated the GEF activity of PRG through interaction. Moreover, overexpression of the Solo and PRG binding domains, respectively, had a dominant-negative effect on actin polymerization and actin stress fiber formation in response to substrate stiffness. Therefore, Solo restricts the localization of PRG and regulates actin cytoskeletal remodeling in synergy with PRG in response to the surrounding mechanical environment.
Damage–repair events increase the instability of cortical microtubules in Arabidopsis
Authors: Yan Yu , Dai Liufeng , Wang Ting , Zhang Yi
Published: April 2024

Microtubules rely on dynamic assembly and disassembly for their functions. Increasing evidences support that the damage–repair of microtubule lattices can affect microtubule dynamics in vitro and in animal cells. Here we successfully established a way for visualizing damage–repair sites on microtubule lattices in plant cells, via labeling the tubulin proteins with the photoconvertible fluorescent protein mEOS3.2. We observed that the crossovers of the microtubule lattice were more prone to be damaged and repaired, with the frequency of damage–repair events positively correlated with the crossing angle between microtubules. The microtubules with damage–repair events displayed shorter lifespans and significantly increased severing frequency compared with the undamaged microtubules. These observations suggested that the damage–repair events promoted instability of cortical microtubules in plant cells.
Diagnostic interobserver agreement for thyroid fine-needle aspirates: Effects of reviewer experience and molecular diagnostics
Authors: Gokozan Hamza N , Mostyka Maria , Scognamiglio Theresa , Solomon James P , Beg Shaham , Stern Evan , Goyal Abha , Siddiqui Momin T , Heymann Jonas J
Published: April 2024

Objectives

Few cytologically indeterminate thyroid fine-needle aspirations (FNAs) harbor BRAF V600E. Here, we assess interobserver agreement for The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) category III (atypia of undetermined significance [AUS]) FNAs harboring BRAF V600E and contrast their features with those harboring non-BRAF V600E alterations, with attention to cytopathology experience.

Methods

Seven reviewers evaluated 5 AUS thyroid FNAs harboring BRAF V600E. To blind reviewers, cases were intermixed with 19 FNAs falling within other TBSRTC categories and in which genetic alterations other than BRAF V600E had been identified (24 FNAs total). Interobserver agreement against both “index” and most popular (“mode”) diagnoses was calculated. Four additional BRAF V600E cases were independently reviewed.

Results

Reviewers included 3 trainees and 3 American Board of Pathology (board)–certified cytopathologists. Board-certified cytopathologists, whose experience ranged from 2 to more than 15 subspecialty practice years, had known AUS rates. BRAF V600E was identified in 5 of 260 (2%) AUS FNAs. Interobserver agreement was higher among cytopathologists with more experience. Mode diagnosis differed from index diagnosis in 6 of 11 cases harboring RAS-like alterations; mode diagnosis was AUS in 4 of 5 BRAF V600E FNAs.

Conclusions

Atypia of undetermined significance of thyroid FNAs harboring BRAF V600E is uncommon yet relatively reproducible, particularly among pathologists with experience. It is advisable to sequence BRAF across V600 in such cases.
Dupilumab in chronic actinic dermatitis: a retrospective case series
Authors: O’Reilly Marese , Paolino Alexandra , Pathmarajah Pirunthan , Ferguson John , Smith Catherine H , Sarkany Robert , Dawe Robert S , Salam Amr , Pink Andrew E , Fassihi Hiva , Ibbotson Sally
Published: April 2024

We report a retrospective case series from two UK photobiology units of 12 patients with concomitant atopic dermatitis (AD) and chronic actinic dermatitis (CAD) treated with dupilumab as a systemic monotherapy. While dupilumab is an effective therapy for moderate-to-severe AD, our results suggest that it may be less effective for the photosensitivity of CAD. In 11 of 12 patients with CAD, dupilumab was associated with improvement in dermatitis, but only half the patients noted improvement in photosensitivity.
Fostering Collaborative Teamwork—A Comprehensive Approach to Vascular Graft Infection Following Arterial Reconstructive Surgery
Authors: Tabaja Hussam , Chesdachai Supavit , Shah Aditya S , Stevens Ryan W , DeMartino Randall R , Erben Young M , Wilson Walter R , Baddour Larry M , DeSimone Daniel C
Published: April 2024

Vascular graft infection (VGI) is one of the most serious complications following arterial reconstructive surgery. VGI has received increasing attention over the past decade, but many questions remain regarding its diagnosis and management. In this review, we describe our approach to VGI through multidisciplinary collaboration and discuss decision making for challenging presentations. This review will concentrate on VGI that impacts both aneurysms and pseudoaneurysms excluding the ascending thoracic aorta.
Otitis in Patients With Community-Acquired Bacterial Meningitis: A Nationwide Prospective Cohort Study
Authors: Ranzenigo Martina , van Soest Thijs M , Hensen Erik F , Cinque Paola , Castagna Antonella , Brouwer Matthijs C , van de Beek Diederik
Published: April 2024

Background

Otitis is commonly associated with community-acquired bacterial meningitis, but the role of ear surgery as treatment is debated. In this study, we investigated the impact of otitis and ear surgery on outcome of adults with community-acquired bacterial meningitis.

Methods

We analyzed episodes of adults with community-acquired bacterial meningitis from a nationwide prospective cohort study in the Netherlands, between March 2006 and July 2021.

Results

A total of 2548 episodes of community-acquired bacterial meningitis were evaluated. Otitis was present in 696 episodes (27%). In these patients the primary causative pathogen was Streptococcus pneumoniae (615 of 696 [88%]), followed by Streptococcus pyogenes (5%) and Haemophilus influenzae (4%). In 519 of 632 otitis episodes (82%) an ear-nose-throat specialist was consulted, and surgery was performed in 287 of 519 (55%). The types of surgery performed were myringotomy with ventilation tube insertion in 110 of 287 episodes (38%), mastoidectomy in 103 of 287 (36%), and myringotomy alone in 74 of 287 (26%). Unfavorable outcome occurred in 210 of 696 episodes (30%) and in 65 of 696 episodes was fatal (9%). Otitis was associated with a favorable outcome in a multivariable analysis (odds ratio 0.74; 95% confidence interval [CI] .59–.92; P = .008). There was no association between outcome and ear surgery.

Conclusions

Otitis is a common focus of infection in community-acquired bacterial meningitis in adults, with S. pneumoniae being the most common causative pathogen. Presence of otitis is associated with a favorable outcome. Ear surgery's impact on the outcome of otogenic meningitis patients remains uncertain.
Lower Specificity of the European Society of Cardiology 2023 Diagnostic Criteria for Infective Endocarditis When Spondylodiscitis Is Regarded as a Vascular Phenomenon
Authors: Sunnerhagen Torgny , Rasmussen Magnus
Published: April 2024

The ESC diagnostic criteria for infective endocarditis (IE) added spondylodiscitis as a minor criterion. This resulted in that 11 of 1807 patients with Staphylococcus aureus, streptococcal, or Enterococcus faecalis bacteremia, were reclassified from possible to definite IE, of whom only two were treated as IE.
Evaluation of the aesthetics and clinical findings in patients with missing maxillary lateral incisors treated with a 10-year interval
Authors: Hedmo Cecilia , Lindsten Rune , Josefsson Eva
Published: April 2024

Introduction

The most common treatment approaches for patients missing maxillary lateral incisors are implant replacement (IT) and orthodontic space closure (SC). Treatment techniques change and improve over time, and it is of interest to know if improvements differ between the methods.

Aim

To compare the aesthetic outcome and other clinical findings in patients with one or two missing maxillary lateral incisors who were treated with a 10-year difference in time, with either orthodontic space closure or implant replacement.

Material and methods

A total of 88 patients were included in the study. Forty-four patients treated between 2011 and 2018 were included as the latter cohort (LC). The LC was compared to the early cohort (EC; n = 44), treated between 2001 and 2008. A total of 132 teeth was analysed: 62 teeth in the EC (28 teeth in IT cases and 34 teeth in SC cases) and 70 teeth in the LC (34 teeth in IT cases and 36 teeth in SC cases). Long-term clinical and aesthetic outcomes were evaluated.

Results

An improvement over time was found in crown length, BoP, papilla, the inclination of incisors, and overall appearance in IT cases and in crown colour and overbite in SC cases. A deterioration over time was found in crown length and BoP among the SC cases.

Conclusion

Among the IT cases, an improvement in outcomes was noted over time. When comparing SC cases the colour of the crown and overbite had improved, while crown length and BoP had deteriorated over time.
Efficacy of Dose Escalation of Oral 5-Aminosalicylic Acid for Ulcerative Colitis With a Mayo Endoscopic Subscore of 1: An Open Label Randomized Controlled Trial
Authors: Fukuda Tomohiro , Aoki Yasuhiro , Kiyohara Hiroki , Yokoyama Ayumi , Nakazawa Atsushi , Yoshimatsu Yusuke , Sugimoto Shinya , Nanki Kosaku , Mikami Yohei , Fukuhara Kayoko , Mizuno Shinta , Sujino Tomohisa , Mutaguchi Makoto , Takabayashi Kaoru , Morohoshi Yuichi , Hosoda Yasuo , Ogata Haruhiko , Iwao Yasushi , Naganuma Makoto , Kanai Takanori
Published: April 2024

Background

Endoscopic healing is generally defined as Mayo endoscopic subscore (MES) ≤1 in ulcerative colitis (UC). However, patients with an MES of 1 are at higher relapse risk than those with an MES of 0. This study evaluated the therapeutic efficacy of proactive dose escalation of oral 5-aminosalicylic acid (5-ASA) in UC patients with an MES of 1.

Methods

An open-label, randomized controlled trial was conducted in 5 hospitals between 2018 and 2022. Ulcerative colitis patients in clinical remission under oral 5-ASA therapy and diagnosed as having an MES of 1 were enrolled. Patients receiving maintenance therapy other than 5-ASA and immunomodulator were excluded. Patients were randomly assigned in a 1:1 ratio to receive either a dose-escalated (intervention) or constant dose (control) of 5-ASA. Concomitant immunomodulator was used as the stratification factor in the randomization. The primary end point was relapse within 1 year. The subgroup analysis was stratified for the use of immunomodulators.

Results

The full analysis set included 79 patients (39 intervention and 40 control). Immunomodulators were used in 20 (25.3%) patients. Relapse was less in the intervention group (15.4%) than the control group (37.5%; P = .026). In the subgroup with concomitant immunomodulators, relapse was also less in the intervention group (10.0%) than the control group (70.0%; P = .020). In patients without immunomodulators, the difference was not significant between 2 groups (intervention, 17.2%; control, 26.7%; P = .53).

Conclusions

Dose escalation of 5-ASA reduced relapse within 1 year in UC patients in clinical remission with an MES of 1.
Pneumocystis jirovecii Pneumonia Complicating Use of Upadacitinib in a Patient With Ulcerative Colitis and Primary Sclerosing Cholangitis: A Case Report
Authors: Chin Simone , Fox Lucy , Majumdar Avik , Oliver Mark , Choy Matthew C , De Cruz Peter
Published: April 2024

Lay Summary

Pneumocystis jirovecii is a ubiquitous, unicellular fungus that can cause pneumonia (PJP) in immunosuppressed individuals. We report the first case of PJP complicating upadacitinib use for ulcerative colitis. This report is of clinical relevance given the widespread uptake of JAK inhibition.
Massive genome reduction predates the divergence of Symbiodiniaceae dinoflagellates
Authors: Shah Sarah , Dougan Katherine E , Chen Yibi , Lo Rosalyn , Laird Gemma , Fortuin Michael D A , Rai Subash K , Murigneux Valentine , Bellantuono Anthony J , Rodriguez-Lanetty Mauricio , Bhattacharya Debashish , Chan Cheong Xin
Published: April 2024

Dinoflagellates in the family Symbiodiniaceae are taxonomically diverse, predominantly symbiotic lineages that are well-known for their association with corals. The ancestor of these taxa is believed to have been free-living. The establishment of symbiosis (i.e. symbiogenesis) is hypothesized to have occurred multiple times during Symbiodiniaceae evolution, but its impact on genome evolution of these taxa is largely unknown. Among Symbiodiniaceae, the genus Effrenium is a free-living lineage that is phylogenetically positioned between two robustly supported groups of genera within which symbiotic taxa have emerged. The apparent lack of symbiogenesis in Effrenium suggests that the ancestral features of Symbiodiniaceae may have been retained in this lineage. Here, we present de novo assembled genomes (1.2–1.9 Gbp in size) and transcriptome data from three isolates of Effrenium voratum and conduct a comparative analysis that includes 16 Symbiodiniaceae taxa and the other dinoflagellates. Surprisingly, we find that genome reduction, which is often associated with a symbiotic lifestyle, predates the origin of Symbiodiniaceae. The free-living lifestyle distinguishes Effrenium from symbiotic Symbiodiniaceae vis-à-vis their longer introns, more-extensive mRNA editing, fewer (~30%) lineage-specific gene sets, and lower (~10%) level of pseudogenization. These results demonstrate how genome reduction and the adaptation to distinct lifestyles intersect to drive diversification and genome evolution of Symbiodiniaceae.
Cardiometabolic health in people with HIV: expert consensus review
Authors: Batterham Rachel L , Bedimo Roger J , Diaz Ricardo S , Guaraldi Giovanni , Lo Janet , Martínez Esteban , McComsey Grace A , Milinkovic Ana , Naito Toshio , Noe Sebastian , O’Shea Donal , Paredes Roger , Schapiro Jonathan M , Sulkowski Mark S , Venter François , Waters Laura , Yoruk Ilksen Ungan , Young Benjamin
Published: April 2024

Objectives

To develop consensus data statements and clinical recommendations to provide guidance for improving cardiometabolic health outcomes in people with HIV based on the knowledge and experience of an international panel of experts.

Methods

A targeted literature review including 281 conference presentations, peer-reviewed articles, and background references on cardiometabolic health in adults with HIV published between January 2016 and April 2022 was conducted and used to develop draft consensus data statements. Using a modified Delphi method, an international panel of 16 experts convened in workshops and completed surveys to refine consensus data statements and generate clinical recommendations.

Results

Overall, 10 data statements, five data gaps and 14 clinical recommendations achieved consensus. In the data statements, the panel describes increased risk of cardiometabolic health concerns in people with HIV compared with the general population, known risk factors, and the potential impact of antiretroviral therapy. The panel also identified data gaps to inform future research in people with HIV. Finally, in the clinical recommendations, the panel emphasizes the need for a holistic approach to comprehensive care that includes regular assessment of cardiometabolic health, access to cardiometabolic health services, counselling on potential changes in weight after initiating or switching antiretroviral therapy and encouraging a healthy lifestyle to lower cardiometabolic health risk.

Conclusions

On the basis of available data and expert consensus, an international panel developed clinical recommendations to address the increased risk of cardiometabolic disorders in people with HIV to ensure appropriate cardiometabolic health management for this population.
Correlation between antifungal clinical practices and a new clinical decision support system ANTIFON-CLIC® for the treatment of invasive candidiasis: a retrospective multicentre study
Authors: Bienvenu Anne-Lise , Cour Martin , Pavese Patricia , Guichon Céline , Leray Véronique , Chapuis Claire , Dureault Amélie , Mohkam Kayvan , Gallet Salomé , Bourget Stéphanie , Kahale Elham , Chaabane Wajih , Subtil Fabien , Maucort-Boulch Delphine , Talbot François , Dode Xavier , Richard Jean-Christophe , Leboucher Gilles
Published: April 2024

Background

Invasive candidiasis is still recognized as a major cause of morbidity and mortality. To support clinicians in the optimal use of antifungals for the treatment of invasive candidiasis, a computerized decision support system (CDSS) was developed based on institutional guidelines.

Objectives

To evaluate the correlation of this newly developed CDSS with clinical practices, we set-up a retrospective multicentre cohort study with the aim of providing the concordance rate between the CDSS recommendation and the medical prescription (NCT05656157).

Patients and methods

Adult patients who received caspofungin or fluconazole for the treatment of an invasive candidiasis were included. The analysis of factors associated with concordance was performed using mixed logistic regression models with department as a random effect.

Results

From March to November 2022, 190 patients were included from three centres and eight departments: 70 patients from centre A, 84 from centre B and 36 from centre C. Overall, 100 patients received caspofungin and 90 received fluconazole, mostly (59%; 112/190) for empirical/pre-emptive treatment. The overall percentage of concordance between the CDSS and medical prescriptions was 91% (173/190) (confidence interval 95%: 82%–96%). No significant difference in concordance was observed considering the centres (P > 0.99), the department of inclusion (P = 0.968), the antifungal treatment (P = 0.656) or the indication of treatment (P = 0.997). In most cases of discordance (n = 13/17, 76%), the CDSS recommended fluconazole whereas caspofungin was prescribed. The clinical usability evaluated by five clinicians was satisfactory.

Conclusions

Our results demonstrated the high correlation between current antifungal clinical practice and this user-friendly and institutional guidelines-based CDSS.
A comprehensive study on Geranium robertianum L. antibacterial potential
Authors: Stanković Marina M , Ristivojević Petar M , Ivković Đurđa D , Milutinović Milena G , Terzić Jelena N , Stefanović Olgica D
Published: April 2024

Aims

The research aimed to optimize the ultrasound-assisted extraction of secondary metabolites and the antibacterial activity of the plant species Geranium robertianum. The phytochemical profiles of the optimized extracts, as well as their antibacterial and synergistic activity with an antibiotic and their potential mechanisms of action and cytotoxicity, were examined.

Methods and results

Response Surface Methodology was used to optimize extraction conditions. Optimized ethanol and acetone extracts were tested via microdilution, checkerboard, time-kill kinetics, and cell membrane permeability methods. The extracts displayed broad antibacterial activity with minimum inhibitory concentrations ranging from 1.25 to 20 mg ml−1. In addition, the extract synergistically reacted with gentamicin against gentamicin-resistant strains of Escherichia coli and Staphylococcus aureus, enhancing the efficacy of the antibiotic up to 32-fold. The extracts demonstrated strain-dependent bactericidal activity in a 24-h time interval. They increase the permeability of the cell membrane, thus disrupting its normal functioning. The cytotoxic concentration (CC50) on human keratinocytes was 1771.24 ± 5.78 µg ml−1 for ethanol extract, and 958.01 ± 6.14 µg ml−1 for acetone extract. Kaempferol, ellagic acid, quercetin, and rutin were recognized as the main components in both extracts.

Conclusions

The findings of this study indicate that the extracts of G. robertianum can be considered as potential natural antibacterial agents in the control of microorganisms.
Large language models for biomedicine: foundations, opportunities, challenges, and best practices
Authors: Sahoo Satya S , Plasek Joseph M , Xu Hua , Uzuner Özlem , Cohen Trevor , Yetisgen Meliha , Liu Hongfang , Meystre Stéphane , Wang Yanshan
Published: April 2024

Objectives

Generative large language models (LLMs) are a subset of transformers-based neural network architecture models. LLMs have successfully leveraged a combination of an increased number of parameters, improvements in computational efficiency, and large pre-training datasets to perform a wide spectrum of natural language processing (NLP) tasks. Using a few examples (few-shot) or no examples (zero-shot) for prompt-tuning has enabled LLMs to achieve state-of-the-art performance in a broad range of NLP applications. This article by the American Medical Informatics Association (AMIA) NLP Working Group characterizes the opportunities, challenges, and best practices for our community to leverage and advance the integration of LLMs in downstream NLP applications effectively. This can be accomplished through a variety of approaches, including augmented prompting, instruction prompt tuning, and reinforcement learning from human feedback (RLHF).

Target Audience

Our focus is on making LLMs accessible to the broader biomedical informatics community, including clinicians and researchers who may be unfamiliar with NLP. Additionally, NLP practitioners may gain insight from the described best practices.

Scope

We focus on 3 broad categories of NLP tasks, namely natural language understanding, natural language inferencing, and natural language generation. We review the emerging trends in prompt tuning, instruction fine-tuning, and evaluation metrics used for LLMs while drawing attention to several issues that impact biomedical NLP applications, including falsehoods in generated text (confabulation/hallucinations), toxicity, and dataset contamination leading to overfitting. We also review potential approaches to address some of these current challenges in LLMs, such as chain of thought prompting, and the phenomena of emergent capabilities observed in LLMs that can be leveraged to address complex NLP challenge in biomedical applications.
The Impact of Mammographic, Radiologist, and Patient Factors on the Likelihood of Probably Benign (BI-RADS 3) Assessment at Diagnostic Mammography
Authors: Chesebro Allyson L , Abbasi Nooshin , Lacson Ronilda , Chikarmane Sona A , Licaros Andro R L , Giess Catherine S
Published: April 2024

Objective

To evaluate the association of mammographic, radiologist, and patient factors on BI-RADS 3 assessment at diagnostic mammography in patients recalled from screening mammography.

Methods

This Institutional Review Board–approved retrospective study of consecutive unique diagnostic mammography examinations in asymptomatic patients recalled from screening mammography March 5, 2014, to December 31, 2019, was conducted in a single large United States health care institution. Mammographic features (mass, calcification, distortion, asymmetry), breast density, prior examination, and BI-RADS assessment were extracted from reports by natural language processing. Patient age, race, and ethnicity were extracted from the electronic health record. Radiologist years in practice, recall rate, and number of interpreted diagnostic mammograms were calculated. A mixed effect logistic regression model evaluated factors associated with likelihood of BI-RADS 3 compared with other BI-RADS assessments.

Results

A total of 12 080 diagnostic mammography examinations were performed during the study period, yielding 2010 (16.6%) BI-RADS 3 and 10 070 (83.4%) other BI-RADS assessments. Asymmetry (odds ratio [OR] = 6.49, P <.001) and calcification (OR = 5.59, P <.001) were associated with increased likelihood of BI-RADS 3 assessment; distortion (OR = 0.20, P <.001), dense breast parenchyma (OR = 0.82, P <.001), prior examination (OR = 0.63, P = .01), and increasing patient age (OR = 0.99, P <.001) were associated with decreased likelihood. Mass, patient race or ethnicity, and radiologist factors were not significantly associated with BI-RADS 3 assessment. Malignancy rate for BI-RADS 3 lesions was 1.6%.

Conclusion

Asymmetry and calcifications had an increased likelihood of BI-RADS 3 assessment at diagnostic evaluation with low likelihood of malignancy, while radiologist features had no association.
N6-methyladenosine promotes TNF mRNA degradation in CD4+ T lymphocytes
Authors: van Vroonhoven Ellen C N , Picavet Lucas W , Scholman Rianne C , Sijbers Lyanne J P M , Kievit Corlinda R E , van den Dungen Noortje A M , Mokry Michal , Evers Anouk , Lebbink Robert J , Mocholi Enric , Coffer Paul J , Calis Jorg J A , Vastert Sebastiaan J , van Loosdregt Jorg
Published: April 2024

N6-methyladenosine (m6A) is a RNA modification that can regulate post-transcriptional processes including RNA stability, translation, splicing, and nuclear export. In CD4+ lymphocytes, m6A modifications have been demonstrated to play a role in early differentiation processes. The role of m6A in CD4+ T cell activation and effector function remains incompletely understood. To assess the role of m6A in CD4+ T lymphocyte activation and function, we assessed the transcriptome-wide m6A landscape of human primary CD4+ T cells by methylated RNA immunoprecipitation sequencing. Stimulation of the T cells impacted the m6A pattern of hundreds of transcripts including tumor necrosis factor (TNF). m6A methylation was increased on TNF messenger RNA (mRNA) after activation, predominantly in the 3′ untranslated region of the transcript. Manipulation of m6A levels in primary human T cells, the directly affected the expression of TNF. Furthermore, we identified that the m6A reader protein YTHDF2 binds m6A-methylated TNF mRNA, and promotes its degradation. Taken together, this study demonstrates that TNF expression in CD4+ T lymphocytes is regulated via m6A and YTHDF2, thereby providing novel insight into the regulation of T cell effector functions.
Antibacterial activity of Cymbopogon species essential oils against Xanthomonas citri and their use in post-harvest treatment for citrus canker management
Authors: Marin Vítor Rodrigues , Zamuner Caio Felipe Cavicchia , Hypolito Giovane Böerner , Ferrarezi Juliano Henrique , Alleoni Natália , Caccalano Mario Nicolas , Ferreira Henrique , Sass Daiane Cristina
Published: April 2024

Citrus canker is a disease caused by the gram-negative bacterium Xanthomonas citri subp. citri (X. citri), which affects all commercially important varieties of citrus and can lead to significant losses. Fruit sanitization with products such as chlorine-based ones can reduce the spread of the disease. While effective, their use raises concerns about safety of the workers. This work proposes essential oils (EOs) as viable alternatives for fruit sanitization. EOs from Cymbopogon species were evaluated as to their antibacterial activity, their effect on the bacterial membrane, and their ability to sanitize citrus fruit. The in vitro assays revealed that the EOs from C. schoenanthus and C. citratus had a lower bactericidal concentration at 312 mg L−1, followed by 625 mg L−1 for C. martini and C. winterianus. Microscopy assay revealed that the bacterial cell membranes were disrupted after 15 min of contact with all EOs tested. Regarding the sanitizing potential, the EOs with higher proportions of geraniol were more effective in sanitizing acid limes. Fruit treated with C. shoenanthus and C. martini showed a reduction of ∼68% in the recovery of viable bacterial cells. Therefore, these EOs can be used as viable natural alternatives in citrus fruit disinfection.
Biobank donation in search of public benefits and the potential impact of intellectual property rights over access to health-technologies developed: A focus on the bioethical implications
Authors: McMahon Aisling M , Kolawole Opeyemi I
Published: April 2024

The availability of biomaterials is a key component of health research and the development of new health-technologies (including, diagnostics, medicines, and vaccines). People are often encouraged by biobanks to donate samples altruistically to such biobanks. While empirical evidence suggests many donors are motivated by the desire to contribute towards developing new health-technologies for society. However, a tension can arise as health-technologies whose development is contributed to by donors’ biomaterials will often be protected by intellectual property rights (IPRs), including patents. Patents give rightsholders control over how patented technologies are used and can be used in a way that impedes public access to technologies developed. Yet, there are no binding European legal obligations mandating disclosure to donors of how IPRs can operate over downstream health-technologies and how they could impact access to health-technologies developed, nor are there legally binding obligations to ensure public accessibility of technologies developed. Focusing on the bioethical implications posed, this article argues that the current situation can impact donors’ autonomy and dignity interests. A more holistic approach is needed for biobank donation, which embeds a consideration of donors’ expectations/interests from the point of donation through to how such samples are used and how health-technologies developed are accessed. We put forward avenues that seek to address such issues.
Comparing transit spectroscopy pipelines at the catalogue level: evidence for systematic differences
Authors: Mugnai Lorenzo V , Swain Mark R , Estrela Raissa , Roudier Gael M
Published: April 2024

The challenge of inconsistent results from different data pipelines, even when starting from identical data, is a recognized concern in exoplanetary science. As we transition into the JWST era and prepare for the ARIEL space mission, addressing this issue becomes paramount because of its implications on our understanding of exoplanets. Although comparing pipeline results for individual exoplanets has become more common, this study is the first to compare pipeline results at the catalogue level. We present a comprehensive framework to statistically compare the outcomes of data analysis reduction on a population of exoplanets and we leverage the large number of observations conducted using the same instrument configured with HST-WFC3. We employ three independent pipelines: Iraclis, excalibur, and CASCADe. Our combined findings reveal that these pipelines, despite starting from the same data and planet system parameters, yield substantially different spectra in some cases. However, the most significant manifestations of pipeline differences are observed in the compositional trends of the resulting exoplanet catalogues. We conclude that pipeline-induced differences lead to biases in the retrieved information, which are not reflected in the retrieved uncertainties. Our findings underscore the critical need to confront these pipeline differences to ensure the reproducibility, accuracy, and reliability of results in exoplanetary research. Our results demonstrate the need to understand the potential for population-level bias that pipelines may inject, which could compromise our understanding of exoplanets as a class of objects.
Multiscale accretion in dense cloud cores and the delayed formation of massive stars
Authors: Vázquez-Semadeni Enrique , Gómez Gilberto C , González-Samaniego Alejandro
Published: April 2024

The formation mechanism of massive stars remains one of the main open problems in astrophysics, in particular the relationship between the mass of the most massive stars and that of the cores in which they form. Numerical simulations of the formation and evolution of molecular clouds, within which dense cores and stars form self-consistently, show that the core mass increases in time, and also that the most massive stars tend to appear later than lower mass stars. We present an idealized model that incorporates accretion onto the cores as well as onto the stars, in which the core mass growth is regulated by a ‘gravitational choking’ mechanism that does not involve any form of support. This process is of purely gravitational origin, and causes some of the mass accreted onto cores to stagnate there, rather than being transferred to the stars. In addition, we estimate the mass of the most massive allowed star before its photoionizing radiation is capable of overcoming the accretion flow. This model constitutes a proof of concept for the simultaneous growth of the gas reservoir and the stellar mass, the delay in the formation of massive stars observed in numerical simulations, the need for massive, dense cores in order to form massive stars, and the observed correlation between the mass of the most massive star and the mass of the cluster it resides in. Also, our model implies that by the time massive stars begin to form in a core, a number of low-mass stars are expected to have already formed.
A JWST investigation into the bar fraction at redshifts 1 ≤ z ≤ 3
Authors: Le Conte Zoe A , Gadotti Dimitri A , Ferreira Leonardo , Conselice Christopher J , de Sá-Freitas Camila , Kim Taehyun , Neumann Justus , Fragkoudi Francesca , Athanassoula E , Adams Nathan J
Published: April 2024

The presence of a stellar bar in a disc galaxy indicates that the galaxy hosts in its main part a dynamically settled disc and that bar-driven processes are taking place in shaping its evolution. Studying the cosmic evolution of the bar fraction in disc galaxies is therefore essential to understand galaxy evolution in general. Previous studies have found, using the Hubble Space Telescope (HST), that the bar fraction significantly declines from the local Universe to redshifts near one. Using the first four pointings from the JWST Cosmic Evolution Early Release Science Survey and the initial public observations for the Public Release Imaging for Extragalactic Research, we extend the studies of the bar fraction in disc galaxies to redshifts 1 ≤ $z$ ≤ 3, that is, for the first time beyond redshift two. We only use galaxies that are also present in the Cosmic Assembly Near-IR Deep Extragalactic Legacy Survey on the Extended Groth Strip and Ultra Deep Survey HST observations. An optimized sample of 368 close-to-face-on galaxies is visually classified to find the fraction of bars in disc galaxies in two redshift bins: 1 ≤ $z$ ≤ 2 and 2 < $z$ ≤ 3. The bar fraction decreases from $\approx 17.8^{+ 5.1}_{- 4.8}$ per cent to $\approx 13.8^{+ 6.5}_{- 5.8}$ per cent (from the lower to the higher redshift bin), but is about twice the bar fraction found using bluer HST filters. Our results show that bar-driven evolution might commence at early cosmic times and that dynamically settled discs are already present at a lookback time of ∼11 Gyr.
Immune-tumor interaction dictates spatially directed evolution of esophageal squamous cell carcinoma
Authors: Zhou Yong , Mo Shanlan , Cui Heyang , Sun Ruifang , Zhang Weimin , Zhuang Xiaofei , Xu Enwei , Li Hongyi , Cheng Yikun , Meng Yongsheng , Liu Meilin , Yan Ting , Liu Huijuan , Zhang Ling , Yang Bin , Xi Yanfeng , Wang Shubin , Cheng Xiaolong , Li ShuaiCheng , Liu Zhihua , Zhan Qimin , Hu Zheng , Cui Yongping
Published: April 2024

Esophageal squamous cell carcinoma (ESCC) is a poor-prognostic cancer type with extensive intra- and inter-patient heterogeneity in both genomic variations and tumor microenvironment (TME). However, the patterns and drivers of spatial genomic and microenvironmental heterogeneity of ESCC remain largely unknown. Here, we generated a spatial multi-omic atlas by whole-exome, transcriptome, and methylome sequencing of 507 tumor samples from 103 patients. We identified a novel tumor suppressor PREX2, accounting for 22% of ESCCs with frequent somatic mutations or hyper-methylation, which promoted migration and invasion of ESCC cells in vitro. Analysis of the TME and quantification of subclonal expansion indicated that ESCCs undergo spatially directed evolution, where subclones mostly originated from the tumor center but had a biased clonal expansion to the upper direction of the esophagus. Interestingly, we found upper regions of ESCCs often underwent stronger immunoediting with increased selective fitness, suggesting more stringent immune selection. In addition, distinct TMEs were associated with variable genomic and clinical outcomes. Among them, hot TME was associated with high immune evasion and subclonal heterogeneity. We also found that immunoediting, instead of CD8+ T cell abundance, acts as an independent prognostic factor of ESCCs. Importantly, we found significant heterogeneity in previously considered potential therapeutic targets, as well as BRCAness characteristics in a subset of patients, emphasizing the importance of focusing on heterogeneity in ESCC targeted therapy. Collectively, these findings provide novel insights into the mechanisms of the spatial evolution of ESCC and inform precision therapeutic strategies.
Nicotinic Receptor Alpha-5 Subunit Gene Polymorphism is Associated With Heavy Smoking Under a Range of Nicotine Dosing Conditions
Authors: Zuo Yantao , Rose Jed E , Davis James M , Behrens Kelsey A , Golaub Aisha A , Chandra Upasana U , Aarons Emily K , Morgan-Glover Janiece D , Mukhin Alexey G
Published: April 2024

Introduction

This study aimed to assess the role of the rs16969968 variant of nicotinic receptor alpha-5 subunit in regulating smoking behavior and nicotine intake in response to nicotine manipulations among dependent smokers in a naturalistic environment.

Aims and Methods

Sixty-nine adults (19 females) smoking 10 or more cigarettes per day (CPD) were asked to complete four 2-week study phases during which they smoked exclusively one of two types of Spectrum nicotine research cigarettes (FTC nicotine yield 0.8 and 1.6 mg, respectively), their usual brand of cigarettes, or their usual brand of cigarettes while wearing a 21-mg nicotine patch. Measurements included rs16969968 genotype, number of CPD, smoking topography, and plasma cotinine.

Results

Compared to controls (G/G carriers), A allele carriers reported smoking 4 to 5 more CPD across all conditions (all ps < .05). Mean total smoke volume per day and cotinine were greater in A allele carriers than in controls (ps = .05, .046, respectively). No significant genotype differences were found in smoking compensation indices for the switch from medium to high-nicotine-yield cigarettes. Nicotine patch-induced reductions in cigarettes smoked per day and total smoke volume per day showed significant interactions between genotype and pre-patch levels, with heavier smokers showing greater effects of genotype (p = .052 and p = .006, respectively).

Conclusions

Results suggest that the rs16969968 variants regulate the heaviness of smoking primarily by their impact on daily numbers of cigarettes smoked, but no genotype differences were found in smoking compensation after switching from medium to high-nicotine cigarettes.

Implications

The differences in daily cigarette consumption between rs16969968 risk-allele carriers and controls are shown to be consistent regardless of manipulations of cigarette nicotine content and transdermal nicotine supplementation and markedly greater among dependent smokers than those observed in the general smoker populations. G/G allele carriers, relative to A allele carriers, appeared to be more sensitive to the nicotine patch manipulation, reducing their smoking to a greater extent. These findings support continued efforts in the development of personalized intervention strategies to reduce the rs16969968-conveyed genetic propensity for heavy smoking.