bluuebunny/crossref_metadata_2025 huggingface dataset:
‘That's someone's grandma’: Teaching person‐centred care in a frailty context
Authors: Robinson Lucy , Andrew Inga , Kenny Lee , Garrad Sophie , Thomson Richard , Fisher James
Published: January 2024

Background

The ability to provide person‐centred care (PCC) is an essential skill for doctors and requires therapeutic empathy. We sought to evaluate a novel teaching approach to understand how medical students' personal reflections on an older person impact their views about PCC and frailty.

Approach

We designed a teaching session where students prepared an image and story about an older person they knew. Given the innovative nature of this, we set it in the context of a Plan Do Study Act cycle to ensure evaluation and continuous improvement at each stage. Students' contributions were discussed in a supportive environment, weaving together stories about individuals with the impacts of ageing they experienced. We evaluated the teaching with a pre‐ and post‐session ‘frailty’ word cloud and an online focus group.

Evaluation

Word cloud analysis showed a shift in the words students used when considering ‘frailty’, from words associated with illness and vulnerability to those associated with character and experience. Focus group themes supported these findings. Students expressed a change in their perception of frailty to consider ‘the person behind the patient’, which, unexpectedly, led to them also seeing ‘the person behind the medical student’. The session stimulated student reflection on challenges that may impact on delivery of truly person‐centred care.

Implications

This flexible teaching technique was an effective stimulus for medical students to consider the person behind the patient. Future work could consider how to promote retention of empathy as medical students make the transition to working as a doctor.
A normalization method that controls for total RNA abundance affects the identification of differentially expressed genes, revealing bias toward morning‐expressed responses
Authors: Laosuntisuk Kanjana , Vennapusa Amaranatha , Somayanda Impa M. , Leman Adam R. , Jagadish SV Krishna , Doherty Colleen J.
Published: January 2024

RNA‐Sequencing is widely used to investigate changes in gene expression at the transcription level in plants. Most plant RNA‐Seq analysis pipelines base the normalization approaches on the assumption that total transcript levels do not vary between samples. However, this assumption has not been demonstrated. In fact, many common experimental treatments and genetic alterations affect transcription efficiency or RNA stability, resulting in unequal transcript abundance. The addition of synthetic RNA controls is a simple correction that controls for variation in total mRNA levels. However, adding spike‐ins appropriately is challenging with complex plant tissue, and carefully considering how they are added is essential to their successful use. We demonstrate that adding external RNA spike‐ins as a normalization control produces differences in RNA‐Seq analysis compared to traditional normalization methods, even between two times of day in untreated plants. We illustrate the use of RNA spike‐ins with 3' RNA‐Seq and present a normalization pipeline that accounts for differences in total transcriptional levels. We evaluate the effect of normalization methods on identifying differentially expressed genes in the context of identifying the effect of the time of day on gene expression and response to chilling stress in sorghum.
Reading Culture of Teenagers in Social Media: A Study of Reading Habits and Perception of Online Literary and Educational Content by Teenagers
Authors: Kovalova Oleksandra , Shalman Tetiana
Published: January 2024

The article is devoted to the study of teenagers' reading culture on social media. The study aims to explore the reading culture of adolescents on social media platforms and assess the educational potential that these platforms (Instagram, TikTok, and YouTube) offer for teenage reading and education. As part of an effective study of teenagers' reading habits, the authors surveyed respondents. The survey results revealed the adolescents' perception of literary and educational content online. The study outlines the main trends in the reading culture of teenagers. It defines the preferences of adolescents in the literary aspect and describes the main factors influencing the reading culture. The paper describes the specifics of social media's influence on adolescent reading culture. In particular, it describes the role of book bloggers and book communities in shaping teenagers' tastes in reading. This study aims to investigate the reading culture of teenagers on social media and to assess the educational potential of these media platforms (Instagram, TikTok, and YouTube) for teenage reading and education. The object of the study is the reading culture of teenagers. The study applied such research methods as description, analysis and synthesis, comparison, generalization, modelling, and content analysis. The article examines the reading culture of adolescents on social networks. The authors describe the place of reading and social networks in teenagers' lives in the information society. The essence of blogging and digitalization in terms of book trends is described. The study of reading habits and perception of literary and educational content online by adolescents is analyzed. In addition, the authors summarize the main results of the study and assess the educational potential of social networks. The main age, gender, and social parameters of the respondents are determined.
One Small Bite for Man, One Giant Feast for Mankind
Authors: Sukel Kayt
Published: January 2024

The Deep Space Food Challenge is an open competition to drive the creation of food production technologies to provide “safe, nutritious, and tasty food” for long-duration flights. The winners relied on slever design and engineering to create palatable and shelf-stable meals.
Texas Can Go Big to Reach Net Zero
Authors: Webber Michael E.
Published: January 2024

While Texas political leaders openly dismiss and mock the risks of climate change and suspiciously eye policymakers in other states or countries who seek to reduce emissions, Texas industry, consumers, and cities are decarbonizing and doing so faster than those same countries. A recent study exploted multiple pathways for getting emissions down even farther.
Control of Resonant Disturbances on an Euler–Bernoulli Beam Using a Robust Partial Differential Equation Boundary Control Technique
Authors: Karagiannis Dimitri , Radisavljevic-Gajic Verica
Published: January 2024

This article discusses and analyzes the capabilities and limitations of a series of related controllers for Euler–Bernoulli beam vibration, and the powerful capabilities of a robust second-order sliding mode backstepping control method are exhibited. Motivated by the open-loop unstable response to harmonic excitations at resonant frequencies, specific attention is given to disturbances at system resonant frequencies. It is shown that the second-order sliding mode backstepping controller provides arbitrary exponential stability of the beam position where other similar controllers cannot. Furthermore, it is shown that other controllers exhibit large (relative to the disturbance) steady-state harmonic vibrations, or otherwise do not return the system to the origin. This article is an extension of the Dynamic Systems and Control Division Vibrations Technical Committee “Best Vibrations Paper Award”-winning conference paper (Karagiannis and Radisavlejevic-Gajic, 2017, “Robust Boundary Control for an Euler Bernoulli Beam Subject to Unknown Harmonic Disturbances With a Focus on Resonance”). The previous work is significantly extended to include an exponentially stabilizing, second-order sliding mode controller and discusses several boundary conditions.
Smart Construction of Fe2O3 Nanowire Arrays on Carbon Cloth for Enhanced Supercapacitor and Lithium-Ion Battery
Authors: Yin Xiangyu , Liu Zhen , Li Xinyi , Qi Meili , Hu Ming , Mu Xin
Published: January 2024

Due to its excellent theoretical specific capacity, the transition metal oxide Fe2O3 has garnered significant attention due to its potential as a cathode material. Nevertheless, Fe2O3 remains a drawback due to low electrical conductivity and significant volume expansion in the charge and discharge process. In this experiment, we have reported a facile strategy for the Fe2O3 nanowire array grown on carbon cloth (Fe2O3@CC) by hydrothermal method. The prepared Fe2O3@CC composite served as an electrode for lithium-ion batteries (LIBs) and supercapacitors. Herein, we utilized the above-mentioned unique composite of Fe2O3@CC nanowire array supported on carbon cloth as a repetitive and directional composite of anode electrode composite with a high specific surface area. The supercapacitor exhibited a specific capacitance of 221.19 F g−1 after 500 cycles at a current density of 200 mA g−1. Fe2O3@CC nanowire composite was utilized in LIBs, demonstrating an exceptional rate capacity of 240.7 mAh g−1 at a high current density of 500 mA g−1, as well as a high reversible degree of 514.1 mAh g−1 after 100 cycles at 100 mA g−1.
Study on Cable Tension Characteristics of Shore-Based Constant Tension Mooring Systems Under the Coupling Effect of Wind, Wave, and Current
Authors: Wang Li , Liu Nan , Wang Shoujun , Chen Songgui
Published: January 2024

This paper proposes a shore-based constant tension mooring system, which improves the cable tension distribution by adjusting the length of the cable to maintain the constant tension of the cable between the ship and the mooring pile in order to solve the problem of poor safety and reliability of the traditional mooring system in the mooring process. First, based on the three-dimensional potential flow theory, this paper uses the hydrodynamic software AQWA to numerically simulate the dynamic response of the traditional mooring system under the coupling of wind, wave, and current in different sea states. Subsequently, a shore-based constant tension mooring system using the principle of volume-varying hydraulic control was studied. On the basis of a comprehensive analysis of the working principle of the constant tension hydraulic control mooring system, a mathematical model of the main working circuit is established. The system was numerically simulated by relying on matlab/Simulink simulation software. Finally, by comparing with traditional mooring systems, the results show that the maximum cable tension of the shore-based constant tension mooring system is significantly reduced so that the tension is controlled within a fixed range, and the safety factor of the mooring cable is significantly improved, thus reducing the risk of mooring system failure and improving the ship's survivability.
An Agent-Based Modeling Approach for the Diffusion Analysis of Electric Vehicles With Two-Stage Purchase Choice Modeling
Authors: Xu Jiawen , Bi Youyi
Published: January 2024

Diffusion research of innovative technologies is crucial for new product positioning and strategic planning in product design. As a versatile system simulation method, agent-based modeling (ABM) has been used in many previous studies on the diffusion analysis of electric vehicles (EVs). In these simulations, modeling consumers' purchase decisions is a significant step. Previous studies often adopt simple rule-based decision criteria in this step, while an accurate purchase decision model can contribute to a more reasonable diffusion analysis of EVs. To fill this gap, this brief presents an agent-based modeling approach for the diffusion analysis of electric vehicles with two-stage choice modeling. The core idea is to separate consumers' decision-making process for purchasing cars into two stages. Consumers first form a small choice set from the whole auto market. Then, they make the final choice from the choice set built in the first stage. In addition, the word-of-mouth (WOM) effect and consumers' social networks are also considered in the ABM, which can further improve the accuracy of the diffusion analysis. A case study using data collected from Shanghai, China, is presented to demonstrate the proposed approach. Our approach outperforms other ablation models as well as traditional statistical models in the prediction accuracy of EV's market share. The influence of factors such as government policy and technological improvement on the diffusion of EVs is also discussed. These insights can assist automakers in improving their product design and enhancing their market competitiveness.
Thermal analysis of implanter source head in radio-frequency inductively coupled plasma
Authors: Jeong Chang-Won , Ryu Choong-Mo , Lee Hee-Lak , Hwang Jong Jin , Moon Seung Jae
Published: January 2024

The inductively coupled plasma-ion implanter is a closed vacuum, and the temperature increase in the source head owing to plasma generation in the chamber was predicted by numerical simulation and verified via measurements. The heat generation of the source head inside the vacuum chamber was photographed using an infrared thermal-imaging camera and set as the main temperature boundary condition for analysis. The showerhead temperature was confirmed through thermocouple measurements to verify the simulation and ensure reliability. An error of less than 1% was obtained for the aperture and aperture cover. The simulation-analysis results and measured showerhead results obtained from the thermocouple equipment exhibited an error of less than 2%.
The Effects of Positive Versus Negative Self-Talk on Vertical Jump in Soccer Players: The Moderating Role of Need for Cognition
Authors: Horcajo Javier , Mateos Rafael
Published: January 2024

The current study analyzed the effects of positive versus negative self-talk on physical performance in soccer players from a multiprocess approach. We operationalized the process distinction using the need-for-cognition (NC) construct. Thus, NC was measured and self-talk (i.e., positive vs. negative) was manipulated between participants (i.e., 126 soccer players, age 18 years or older, who were competing in national, regional, or local competitions). Physical performance was assessed by a vertical-jump test. According to hypothesis, regression analyses indicated that positive versus negative self-talk influenced physical performance to a greater extent for high-NC individuals than for low-NC individuals. Specifically, among high-NC soccer players, relative to baseline, positive self-talk produced greater physical performance in the vertical-jump test than negative self-talk. In contrast, among low-NC soccer players, no difference was found between positive and negative self-talk on physical performance. These results supported the moderating role of NC.
Meropenem-ANT3310, a unique β-lactam-β-lactamase inhibitor combination with expanded antibacterial spectrum against Gram-negative pathogens including carbapenem-resistant
Acinetobacter baumannii
Authors: Zalacain Magdalena , Achard Pauline , Llanos Agustina , Morrissey Ian , Hawser Stephen , Holden Kirsty , Toomey Eleanor , Davies David , Leiris Simon , Sable Carole , Ledoux Adeline , Bousquet Justine , Castandet Jérôme , Lozano Clarisse , Everett Martin , Lemonnier Marc
Published: January 2024

ANT3310 is a novel broad-spectrum diazabicyclooctane serine β-lactamase inhibitor being developed in combination with meropenem (MEM) for the treatment of serious infections in hospitalized patients where carbapenem-resistant Gram-negative pathogens are expected. In this study, we evaluated the
in vitro
antibacterial activity of MEM in the presence of ANT3310 at 8 µg/mL against global clinical isolates that included
Acinetobacter baumannii
(
n
= 905), carbapenem-resistant Enterobacterales (CRE), carrying either oxacillinase (OXA) (
n
= 252) or
Klebsiella pneumoniae
carbapenemase (KPC) (
n
= 180) carbapenemases, and
Pseudomonas aeruginosa
(
n
= 502). MEM was poorly active against
A. baumannii,
as were MEM-vaborbactam, ceftazidime-avibactam, aztreonam-avibactam, cefepime-taniborbactam, cefepime-zidebactam, and imipenem-relebactam (MIC
90
values of ≥32 µg/mL). On the other hand, MEM-ANT3310 displayed an MIC
90
value of 4 µg/mL, similar to that observed with sulbactam-durlobactam, a drug developed to specifically treat
A. baumannii
infections. ANT3310 (8 µg/mL) additionally restored the activity of MEM against OXA- and KPC-producing CREs decreasing MEM MIC
90
values from >32 µg/mL to 0.25 and 0.5 µg/mL, respectively. The combination of 8 µg/mL of both MEM and ANT3310 prevented growth of 97.5% of
A. baumannii
and 100% of OXA- and KPC-positive CREs, with ~90% of
P. aeruginosa
isolates also displaying MEM MICs ≤8 µg/mL. Furthermore, MEM-ANT3310 was efficacious in both thigh and lung murine infection models with OXA-23
A. baumannii
. This study demonstrates the potent
in vitro
activity of the MEM-ANT3310 combination against both carbapenem-resistant
A. baumannii
and Enterobacterales clinical isolates, a key differentiator to other β-lactam/β-lactamase combinations.
Effectiveness and safety of nirmatrelvir-ritonavir in kidney transplant recipients with severe kidney dysfunction infected with COVID-19
Authors: Yang Hui , Yu Xin , Hou Wenjing , Liu Xiangduan , Chen Jiaojiao , Zhang Ying , Wang Ying , Zhu Ying , Qian Qing , Ma Kuifen , An Zhuoling
Published: January 2024

Transplant patients face an elevated risk of coronavirus disease 2019 (COVID-19) morbidity and mortality and commonly encounter renal dysfunction. Nirmatrelvir is primarily excreted through the kidneys. The dosage of nirmatrelvir/ritonavir (NR) needs to be adjusted according to the degree of renal function impairment. Nevertheless, NR is not recommended for patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min) due to a dearth of associated research. In this study, we focus on kidney transplant patients and document and analyze the experiences of using NR in individuals with severe kidney dysfunction. This was a retrospective multicenter study that included transplant recipients hospitalized for COVID-19 in five major tertiary hospitals in China from December 2022 to June 2023. The outcomes consisted of the disease progression rate by day 28, individual disease progression events, safety outcomes, information on adverse events (AEs), and the blood drug concentrations of immunosuppressants. Data were presented with descriptive statistics. All analyses were performed using SPSS version 22. In total, 40 patients were included in the analysis. Considering the potential interaction between drugs, all patients temporarily discontinued their immunosuppressants during the NR treatment. None of the 32 moderate patients experienced disease progression. However, among the eight patients with critical COVID-19, unfortunately, two of them died. During the medication period, four patients experienced a total of six AEs associated with NR. None of them experienced AEs with a maximum grade of ≥3. Blood drug concentrations of immunosuppressants were monitored in 22 of 40 patients, and the blood drug concentrations of immunosuppressants did not show a significant increase, but some patients experienced lower blood drug concentrations. Our findings supported the use of NR therapy for the treatment of COVID-19 in transplant patients with severe renal insufficiency. A modified dose of NR was well-tolerated.
Fluoride anodic films on stainless-steel fomites to reduce transmission infections
Authors: Conde Ana , Voces Daniel , Medel-Plaza Marina , Perales Celia , de Ávila Ana Isabel , Aguilera-Correa John Jairo , de Damborenea Juan Jose , Esteban Jaime , Domingo Esteban , Arenas Maria Angeles
Published: January 2024

The growing concern arising from viruses with pandemic potential and multi-resistant bacteria responsible for hospital-acquired infections and outbreaks of food poisoning has led to an increased awareness of indirect contact transmission. This has resulted in a renewed interest to confer antimicrobial properties to commonly used metallic materials. The present work provides a full characterization of optimized fluoride anodic films grown in stainless steel 304L as well as their antimicrobial properties. Antibacterial tests show that the anodic film, composed mainly of chromium and iron fluorides, reduces the count and the percentage of the area covered by 50% and 87.7% for
Pseudomonas aeruginosa
and
Stenotrophomonas maltophilia
, respectively. Virologic tests show that the same treatment reduces the infectivity of the coronavirus HCoV-229E-GFP, in comparison with the non-anodized stainless steel 304L.

IMPORTANCE

The importance of environmental surfaces as a source of infection is a topic of particular interest today, as many microorganisms can survive on these surfaces and infect humans through direct contact. Modification of these surfaces by anodizing has been shown to be useful for some alloys of medical interest. This work evaluates the effect of anodizing on stainless steel, a metal widely used in a variety of applications. According to the study, the fluoride anodic layers reduce the colonization of the surfaces by both bacteria and viruses, thus reducing the risk of acquiring infections from these sources.
Regulation of tricarboxylate transport and metabolism in
Acinetobacter baylyi
ADP1
Authors: Baugh Alyssa C. , Defalco Justin B. , Duscent-Maitland Chantel V. , Tumen-Velasquez Melissa P. , Laniohan Nicole S. , Figatner Kayla , Hoover Timothy R. , Karls Anna C. , Elliott Kathryn T. , Neidle Ellen L.
Published: January 2024

Despite the significant presence of plant-derived tricarboxylic acids in some environments, few studies detail the bacterial metabolism of
trans
-aconitic acid (Taa) and tricarballylic acid (Tcb). In a soil bacterium,
Acinetobacter baylyi
ADP1, we discovered interrelated pathways for the consumption of Taa and Tcb. An intricate regulatory scheme tightly controls the transport and catabolism of both compounds and may reflect that they can be toxic inhibitors of the tricarboxylic acid cycle. The genes encoding two similar LysR-type transcriptional regulators, TcuR and TclR, were clustered on the chromosome with
tcuA
and
tcuB
, genes required for Tcb consumption. The genetic organization differed from that in
Salmonella enterica
serovar Typhimurium, in which
tcuA
and
tcuB
form an operon with a transporter gene,
tcuC
. In
A. baylyi
,
tcuC
was not cotranscribed with
tcuAB
. Rather,
tcuC
was cotranscribed with a gene, designated
pacI
, encoding an isomerase needed for Taa consumption. TcuC appears to transport Tcb and
cis
-aconitic acid (Caa), the presumed product of PacI-mediated periplasmic isomerization of Taa. Two operons,
tcuC-pacI
and
tcuAB
, were transcriptionally controlled by both TcuR and TclR, which have overlapping functions. We investigated the roles of the two regulators in activating transcription of both operons in response to multiple effector compounds, including Taa, Tcb, and Caa.

IMPORTANCE

Ingestion of Taa and Tcb by grazing livestock can cause a serious metabolic disorder called grass tetany. The disorder, which results from Tcb absorption by ruminants, focuses attention on the metabolism of tricarboxylic acids. Additional interest stems from efforts to produce tricarboxylic acids as commodity chemicals. Improved understanding of bacterial enzymes and pathways for tricarboxylic acid metabolism may contribute to new biomanufacturing strategies.
Borreliella burgdorferi
factor H-binding proteins are not required for serum resistance and infection in mammals
Authors: Cramer Nicholas A. , Socarras Kalya M. , Earl Joshua , Ehrlich Garth D. , Marconi Richard T.
Published: January 2024

The causative agent of Lyme disease (LD),
Borreliella burgdorferi
, binds factor H (FH) and other complement regulatory proteins to its surface.
B. burgdorferi
B31 (type strain) encodes five FH-binding proteins (FHBPs): CspZ, CspA, and the OspE paralogs OspE
BBN38
, OspE
BBL39
, and OspE
BBP38
. This study assessed potential correlations between the production of individual FHBPs, FH-binding ability, and serum resistance using a panel of infectious
B. burgdorferi
clonal populations recovered from dogs. FHBP production was assessed in cultivated spirochetes and by antibody responses in naturally infected humans, dogs, and eastern coyotes (wild canids). FH binding specificity and sensitivity to dog and human serum were also assessed and compared. No correlation was observed between the production of individual FHBPs and FH binding with serum resistance, and CspA was determined to not be produced in animals. Notably, one or more clones isolated from dogs lacked CspZ or the OspE proteins (a finding confirmed by genome sequence determination) and did not bind FH derived from canines. The data presented do not support a correlation between FH binding and the production of individual FHBPs with serum resistance and infectivity. In addition, the limited number and polymorphic nature of cp32s in
B. burgdorferi
clone DRI85A that were identified through genome sequencing suggest no strict requirement for a defined set of these replicons for infectivity. This study reveals that the immune evasion mechanisms employed by
B. burgdorferi
are diverse, complex, and yet to be fully defined.
Oral streptococci
S. anginosus
and
S. mitis
induce distinct morphological, inflammatory, and metabolic signatures in macrophages
Authors: Senthil Kumar Sangeetha , Gunda Venugopal , Reinartz Dakota M. , Pond Kelvin W. , Thorne Curtis A. , Santiago Raj Paul Victor , Johnson Michael D. L. , Wilson Justin E.
Published: January 2024

Oral streptococci, key players in oral biofilm formation, are implicated in oral dysbiosis and various clinical conditions, including dental caries, gingivitis, periodontal disease, and oral cancer. Specifically,
Streptococcus anginosus
is associated with esophageal, gastric, and pharyngeal cancers, while
Streptococcus mitis
is linked to oral cancer. However, no study has investigated the mechanistic links between these
Streptococcus
species and cancer-related inflammatory responses. As an initial step, we probed the innate immune response triggered by
S. anginosus
and
S. mitis
in RAW264.7 macrophages. These bacteria exerted time- and dose-dependent effects on macrophage morphology without affecting cell viability. Compared with untreated macrophages, macrophages infected with
S. anginosus
exhibited a robust proinflammatory response characterized by significantly increased levels of inflammatory cytokines and mediators, including TNF, IL-6, IL-1β, NOS2, and COX2, accompanied by enhanced NF-κB activation. In contrast,
S. mitis
-infected macrophages failed to elicit a robust inflammatory response. Seahorse Xfe96 analysis revealed an increased extracellular acidification rate in macrophages infected with
S. anginosus
compared with
S. mitis
. At the 24-h time point, the presence of
S. anginosus
led to reduced extracellular itaconate, while
S. mitis
triggered increased itaconate levels, highlighting distinct metabolic profiles in macrophages during infection in contrast to aconitate decarboxylase expression observed at the 6-h time point. This initial investigation highlights how
S. anginosus
and
S. mitis
, two Gram-positive bacteria from the same genus, can prompt distinct immune responses and metabolic shifts in macrophages during infection.

IMPORTANCE

The surge in head and neck cancer cases among individuals devoid of typical risk factors such as Human Papilloma Virus (HPV) infection and tobacco and alcohol use sparks an argumentative discussion around the emerging role of oral microbiota as a novel risk factor in oral squamous cell carcinoma (OSCC). While substantial research has dissected the gut microbiome’s influence on physiology, the oral microbiome, notably oral streptococci, has been underappreciated during mucosal immunopathogenesis.
Streptococcus anginosus
, a viridans streptococci group, has been linked to abscess formation and an elevated presence in esophageal cancer and OSCC. The current study aims to probe the innate immune response to
S. anginosus
compared with the early colonizer
Streptococcus mitis
as an important first step toward understanding the impact of distinct oral
Streptococcus
species on the host immune response, which is an understudied determinant of OSCC development and progression.
Where bacteria and eukaryotes meet
Authors: Chai Liraz , Shank Elizabeth A. , Zaburdaev Vasily
Published: January 2024

The international workshop “Interdisciplinary life of microbes: from single cells to multicellular aggregates,” following a virtual preassembly in November 2021, was held in person in Dresden, from 9 to 13 November 2022. It attracted not only prominent experts in biofilm research but also researchers from broadly neighboring disciplines, such as medicine, chemistry, and theoretical and experimental biophysics, both eukaryotic and prokaryotic. Focused brainstorming sessions were the special feature of the event and are at the heart of this commentary.
Exogenous butyrate inhibits butyrogenic metabolism and alters virulence phenotypes in
Clostridioides difficile
Authors: Pensinger Daniel A. , Dobrila Horia A. , Stevenson David M. , Hryckowian Nicole D. , Amador-Noguez Daniel , Hryckowian Andrew J.
Published: January 2024

The gut microbiome engenders colonization resistance against the diarrheal pathogen
Clostridioides difficile,
but the molecular basis of this colonization resistance is incompletely understood. A prominent class of gut microbiome-produced metabolites important for colonization resistance against
C. difficile
is short-chain fatty acids (SCFAs). In particular, one SCFA (butyrate) decreases the fitness of
C. difficile in vitro
and is correlated with
C. difficile
-inhospitable gut environments, both in mice and in humans. Here, we demonstrate that butyrate-dependent growth inhibition in
C. difficile
occurs under conditions where
C. difficile
also produces butyrate as a metabolic end product. Furthermore, we show that exogenous butyrate is internalized into
C. difficile
cells and is incorporated into intracellular CoA pools where it is metabolized in a reverse (energetically unfavorable) direction to crotonyl-CoA and (
S
)−3-hydroxybutyryl-CoA and/or 4-hydroxybutyryl-CoA. This internalization of butyrate and reverse metabolic flow of a butyrogenic pathway(s) in
C. difficile
coincides with alterations in toxin release and sporulation. Together, this work highlights butyrate as a marker of a
C. difficile
-inhospitable environment to which
C. difficile
responds by releasing its diarrheagenic toxins and producing environmentally resistant spores necessary for transmission between hosts. These findings provide foundational data for understanding the molecular and genetic basis of how
C. difficile
growth is inhibited by butyrate and how butyrate alters
C. difficile
virulence in the face of a highly competitive and dynamic gut environment.

IMPORTANCE

The gut microbiome engenders colonization resistance against the diarrheal pathogen
Clostridioides difficile,
but the molecular basis of this colonization resistance is incompletely understood, which hinders the development of novel therapeutic interventions for
C. difficile
infection (CDI). We investigated how
C. difficile
responds to butyrate, an end-product of gut microbiome community metabolism which inhibits
C. difficile
growth. We show that exogenously produced butyrate is internalized into
C. difficile
, which inhibits
C. difficile
growth by interfering with its own butyrate production. This growth inhibition coincides with increased toxin release from
C. difficile
cells and the production of environmentally resistant spores necessary for transmission between hosts. Future work to disentangle the molecular mechanisms underlying these growth and virulence phenotypes will likely lead to new strategies to restrict
C. difficile
growth in the gut and minimize its pathogenesis during CDI.
Pericytes modulate endothelial inflammatory response during bacterial infection
Authors: Carvalho Thaynara P. , Toledo Frank A. O. , Bautista Diego F. A. , Silva Monique F. , Oliveira Jefferson B. S. , Lima Pâmela A. , Costa Fabíola B. , Ribeiro Noelly Q. , Lee Jee-Yon , Birbrair Alexander , Paixão Tatiane A. , Tsolis Reneé M. , Santos Renato L.
Published: January 2024

Pericytes are located around blood vessels, in close contact with endothelial cells. We discovered that pericytes dampen pro-inflammatory endothelial cell responses. Endothelial cells co-cultured with pericytes had markedly reduced expression of adhesion molecules (PECAM-1 and ICAM-1) and proinflammatory cytokines (CCL-2 and IL-6) in response to bacterial stimuli (
Brucella ovis
,
Listeria monocytogenes
, or
Escherichia coli
lipopolysaccharide). Pericyte-depleted mice intraperitoneally inoculated with either
B. ovis
, a stealthy pathogen that does not trigger detectable inflammation, or
Listeria monocytogenes
, developed peritonitis. Further, during
Citrobacter rodentium
infection, pericyte-depleted mice developed severe intestinal inflammation, which was not evident in control mice. The anti-inflammatory effect of pericytes required connexin 43, as either chemical inhibition or silencing of connexin 43 abrogated pericyte-mediated suppression of endothelial inflammatory responses. Our results define a mechanism by which pericytes modulate inflammation during infection, which shifts our understanding of pericyte biology: from a structural cell to a pro-active player in modulating inflammation.

IMPORTANCE

A previously unknown mechanism by which pericytes modulate inflammation was discovered. The absence of pericytes or blocking interaction between pericytes and endothelium through connexin 43 results in stronger inflammation, which shifts our understanding of pericyte biology, from a structural cell to a player in controlling inflammation.
β-Hemolysin, not
agrA
mutation, inhibits the hemolysis of α-hemolysin in
Staphylococcus aureus
laboratory and clinical strains
Authors: Liu Lin , Zhuang Hemu , Wang Yanfei , Tu Yuexing , Yu Yunsong , Chen Yan , Wu Xueqing
Published: January 2024

Staphylococcus aureus
produces various hemolysins regulated by the Agr-QS system, except β-hemolysin encoded by the gene
hlb
. A classical laboratory
S. aureus
strain RN4220 displays only the β-hemolysin phenotype. It was suspected that the 8A mutation at the end of its
agrA
gene delayed the expressions of
hla
and
RNAIII
, then failed to express α- and δ-hemolysins. However,
hla
gene expression was detected at the later culture time without α-hemolysin phenotype, the reason for such a phenotype has not been clearly understood. We created
hlb
knockout and complementary mutants via homologous recombination in RN4220 and NRS049, two strains that normally produce β-hemolysin and carry
agrA
mutation. We found interestingly that the presence or absence of α-hemolysin phenotype in such strains depended on the expression of β-hemolysin instead of
agrA
mutations, which only inhibited δ-hemolysin expression. The hemolysis phenotype was verified by the Christie-Atkinson-Munch-Peterson (CAMP) test. Quantitative reverse transcription PCR was carried out to evaluate the relative gene expressions of
hlb
,
hla
, and
RNAIII
. The construction of mutants did not affect the
agrA
mutation status. We demonstrate that the absence of α-hemolysin in
S. aureus
RN4220 and NRS049 strains is attributed to their production of β-hemolysin instead of
agrA
mutation. Our findings broaden the understanding of the molecular mechanisms that control hemolysin expression in
S. aureus
that is crucial for the development of new therapeutic strategies to combat
S. aureus
infections.

IMPORTANCE

α-Hemolysin is a critical virulence factor in
Staphylococcus aureus
and its expression is largely controlled by the Agr-QS system. Nonetheless, the hemolysis phenotype and the regulation of the Agr-QS system in
S. aureus
still hold many mysteries. Our study finds that it is the expression of β- hemolysin rather than the
agrA
mutation that inhibits the function of the α-hemolysin in an important
S. aureus
strain RN4220 and a clinical strain presents a similar phenotype, which clarifies the misunderstood hemolytic phenotype and mechanism of
S. aureus
. Our findings highlight the interactions among different toxins and their biological roles, combined with QS system regulation, which is ultimately the true underlying cause of its virulence. This emphasizes the importance of considering the collaborative action of various factors in the infection process caused by this significant human pathogen.
Fault activity in the San Gabriel Mountains, southern California, USA: Insights from landscape morphometrics, erosion rates, and fault-slip rates
Authors: Mere Andre M. , McPhillips Devin
Published: January 2024

Many studies use landscape form to determine spatial patterns of tectonic deformation, and these are particularly effective when paired with independent measures of rock uplift and erosion. Here, we use morphometric analyses and 10Be catchment-averaged erosion rates, together with reverse slip rates from the Sierra Madre–Cucamonga fault zone, to reveal patterns in uplift, erosion, and fault activity in the range front of the San Gabriel Mountains in southern California, USA. Our analysis tests two prevailing hypotheses: (1) the range front of the San Gabriel Mountains is at steady state, in which rock uplift balances erosion and topographic elevations are stable throughout time, and (2) that west-to-east increases in elevation, relief, erosion rate, and stream-channel steepness across the interior of the massif reflect a parallel reverse-slip rate gradient on the range-bounding Sierra Madre–Cucamonga fault zone. We show that although deviations from steady state occur, the range-front hillslopes and stream channels are typically both well-connected and adjusted to patterns in Quaternary uplift driven by motion on the range-front fault network. Accordingly, landscape morphometrics, 10Be erosion rates, and model erosion rates effectively image spatial and temporal patterns in uplift. Interpreted jointly, these data reveal comparable peak slip rates on the Sierra Madre–Cucamonga fault zone and show that they do not monotonically increase from west to east. Thus, the eastward-increasing gradients developed within the interior of the massif are not solely related to reverse slip on the range-front faults. Evaluated on shorter length scales (<10 km), morphometric data corroborate earlier descriptions of the Sierra Madre–Cucamonga fault zone as multiple individual faults or fault sections, with slip rates tapering toward fault tips. We infer that these patterns imply the predominance of independent fault or fault section ruptures throughout the Quaternary, though data cannot rule out the possibility of large, connected Sierra Madre–Cucamonga fault zone ruptures. Deeper in the hanging wall of the Sierra Madre–Cucamonga fault zone, secondary faults accommodate range-front uplift. Motion on these faults may contribute to active uplift of the highest topography within the massif, in addition to partly reconciling differences between geologic and geodetic Sierra Madre–Cucamonga fault zone reverse-slip rates. This study provides a new, unified perspective on tectonics and landscape evolution in the San Gabriel Mountains.
Ferroptosis in the Pathogenesis of Alzheimer’s Disease: The New Evidence for Validation of FAB Model
Authors: Aghajanov M. I. , Harutyunyan H. S. , Khamperyan A. Kh. , Karapetyan G. A. , Fereshetyan K. S. , Yenkoyan K. B.
Published: January 2024

Alzheimer’s disease is an age-associated progressive disorder, characterized by neurodegeneration and following cognitive decline. Several pathological alterations are implicated in its pathogenesis, hence etiology is still poorly understood. Ferroptosis is an alternative form of cell death, driven by intracellular accumulation of iron with subsequent reactive oxygen species formation, which damages membranes, proteins, and DNA, causing cell death. The imbalance in iron homeostasis is rapidly gaining weight as a neurodegeneration cause, increasing the need to develop in vivo and in vitro models to understand the role of ferroptosis in Alzheimer’s disease pathogenesis. This review focuses on the mechanisms of ferroptosis in the pathogenesis of AD, giving a detailed overview of the available in vivo and in vitro methods and their applications, as well as describing in detail the ferrous amyloid buthionine (FAB) model.
Heterogeneity in disease activity, frequency of treatments, and visual outcomes among patients with retinal vein occlusion: relationship between injection need and vision with as-needed ranibizumab
Authors: Bhisitkul Robert B , Campochiaro Peter A , Blotner Steven , Quezada-Ruiz Carlos , Liu Mimi , Haskova Zdenka
Published: January 2024

Background/aims

We characterised the relationships between monitoring frequency, ranibizumab injection need and vision in patients receiving as-needed (pro re nata; PRN) ranibizumab for macular oedema due to branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO) in this post-hoc analysis of SHORE and HORIZON.

Methods

Patients aged 18 years and older with macular oedema due to BRVO/CRVO were included in this analysis. Injection frequency and best-corrected visual acuity (BCVA) were evaluated by PRN injection frequency in the PRN dosing phase (months (M) 7–15) of SHORE and through 12 months of HORIZON. Prespecified PRN re-treatment criteria for each trial were based on protocol-prespecified BCVA and optical coherence tomography outcomes.

Results

After the initial 7 monthly ranibizumab injections, patients in SHORE gained a mean of 18.3 letters from baseline. Patients randomised to PRN, on average, maintained these gains. However, some patients experienced additional mean gains, whereas others suffered losses (range 4.0 (95% CI 0.7 to 7.3) to −4.6 (95% CI −11.8 to 2.6) letters in patients who received 0 and 6–7 PRN injections, respectively). In BRAVO and CRUISE (lead-in trials), patients experienced mean gains from baseline to M6 (monthly dosing) of 19.3 and 15.0 letters, respectively, with gains maintained with PRN from M6 to M12. However, mean BCVA changes from baseline to M12 varied in HORIZON (range −0.4 (95% CI −2.5 to 1.6) to −3.6 (95% CI −6.2 to −1.0) letters in patients who received zero and six injections, respectively, during the preceding PRN phase of BRAVO and CRUISE).

Conclusion

The BRVO/CRVO population is heterogenous with a varied response to ranibizumab treatment.
Two-year outcomes of different subretinal fluid drainage techniques during vitrectomy for fovea-off rhegmatogenous retinal detachments: ELLIPSOID-2 study
Authors: McKay Bryon R , Bansal Aditya , Kryshtalskyj Michael , Wong David T , Berger Alan R , Muni Rajeev H
Published: January 2024

Background

The purpose of the study is to compare visual acuity, complications and outer retinal integrity following subretinal fluid (SRF) drainage from the peripheral retinal breaks (PRBs) versus posterior retinotomy (PR) versus perfluorocarbon liquid (PFCL) for macula-off rhegmatogenous retinal detachments (RRDs) at 2 years post-surgery.

Methods

Retrospective analysis of 300 consecutive patients with primary RRD undergoing 23-gauge pars plana vitrectomy with SRF drainage through (1) PRB (n=100), (2) PR (n=100) or (3) with PFCL (n=100). Primary outcomes were visual acuity (best-corrected visual acuity (BCVA)) and complications (cystoid macular oedema (CMO) and epiretinal membrane (ERM)). Secondary outcomes were discontinuity of the external limiting membrane (ELM), ellipsoid zone (EZ) and interdigitation zone (IDZ) at 2 years post-surgery.

Results

Mean (±SD) logMAR BCVA at 24 months was better in the PRB compared with PR and PFCL, with PFCL having the worst BCVA (PRB 0.5±0.6; PR 0.7±0.5; PFCL 0.9±0.7, p=0.001). CMO was higher with PFCL (PRB 29.7%; PR 30.2%; PFCL 45.9%, p=0.0015) and ERM formation was higher in PR (PRB 62.6%; PR 93.0%; PFCL 68.9%, p=0.002). There were no differences in ELM or EZ discontinuity. However, IDZ discontinuity was higher in PFCL (PRB 34%; PR 27%; PFCL 46%, p=0.002) at 2 years.

Conclusions

Visual acuity was worse and discontinuity of the IDZ and CMO was greater in eyes with PFCL-assisted drainage compared with PRB or PR. Drainage technique may impact long-term visual acuity and photoreceptor integrity.
Low-dose atropine 0.01% for the treatment of childhood myopia: a pan-India multicentric retrospective study
Authors: Saxena Rohit , Gupta Vinay , Dhiman Rebika , Joseph Elizabeth , Agarkar Sumita , Neena R , Magdalene Damaris , Jethani Jitendra , Ganesh Sandra C , Patil Minal , Gogri Pooja , Gadaginamath Shailesh , Sen Pradhnya , Sukhija Jaspreet , Mishra Deepak , Matalia Jyoti H , Sahu Anupam , Kapoor Smita , Nishanth Shruti , Chaurasia Shweta , Pawar Neelam , Deori Nilutparna , Sivaraman Viswanathan , Bordoloi Anamika , Tibrewal Shailja , Singh Davinder , Prasad Priyanka , Phuljhele Swati , Sharma Namrata
Published: January 2024

Objective

The objective of this study was to assess the efficacy of low-dose atropine 0.01% in controlling myopia progression among Indian children over a 2-year period.

Methods

This retrospective study, conducted across 20 centres in India, monitored the progression of myopia over 2 years after initiating treatment with 0.01% atropine eye drops. This included children between 6 and 14 years with baseline myopia ranging from −0.5 D to −6 D, astigmatism≤−1.5 D, anisometropia ≤ −1 D and documented myopia progression of ≥0.5 D in the year prior to starting atropine. Subjects with any other ocular pathologies were excluded.

Results

A total of 732 children were included in the data analysis. The mean age of the subjects was 9.3±2.7 years. The mean myopia progression at baseline (1 year before starting atropine) was −0.75±0.31 D. The rate of myopia progression was higher in younger subjects and those with higher baseline myopic error. After initiating atropine, myopia progression significantly decreased to −0.27±0.14 D at the end of the first year and −0.24±0.15 D at the end of the second year (p<0.001). Younger children (p<0.001) and higher baseline myopia (p<0.001) was associated with greater myopia progression and poor treatment response (p<0.001 for both).

Conclusion

Low-dose atropine (0.01%) effectively reduces myopia progression over 2 years in Indian children.
European priority review vouchers for neglected disease product development
Authors: Ridley David B , Lasanta Agustín Martín , Storer Jones Ffion , Ridley Sarah K
Published: January 2024

Introduction

Neglected diseases are a significant global health challenge. Encouraging the development of therapeutics and vaccines for these diseases would address an important unmet medical need. We propose a priority review voucher programme for the European Union (EU). The developer of a drug or vaccine for a neglected disease would receive a voucher for accelerated assessment of a different product at the European Medicines Agency (EMA).

Methods

This study uses retrospective observational data to estimate the potential commercial value of the proposed voucher programme using a five-step approach: (1) estimating the time saved in the EMA accelerated regulatory review; (2) gauging time reductions in accelerated pricing and reimbursement decisions by EU member states; (3) selecting 10 high-revenue products launched between 2015 and 2020 representing typical voucher users; (4) analysing IQVIA MIDAS sales data for the selected products and (5) calculating the net present value (NPV) of the voucher based on the 10 products.

Results

The accelerated EMA review would reduce regulatory time by an average of 182 days. Additionally, products could save more than a year in many member states through an expedited 120-day pricing and reimbursement review. The estimated NPV of regulatory acceleration by two quarters would be €100 million. In addition, if France, Italy and Spain reviewed pricing and reimbursement in only 120 days, then the value would double.

Conclusion

An EU voucher estimated at more than €100 million, coupled with a US$100 million counterpart, offers a meaningful incentive for novel product development. However, the voucher programme should be part of a comprehensive strategy for tackling neglected diseases, rather than a standalone solution.