bluuebunny/crossref_metadata_2025 huggingface dataset:
A Computational Conformal Geometry Approach to Calculate the Large Deformation of Plates/Shells With Arbitrary Shapes
Authors: Liu Yipeng , Fan Wei , Ren Hui
Published: December 2023

High-accuracy numerical methods to solve the nonlinear Föppl–von Kármán (FvK) equations usually work well only in simple domains such as rectangular regions. Computational conformal geometry (CCG) provides a systematic method to transform complicated surfaces into simple domains, preserving the orthogonal frames such that the corresponding FvK equations can be solved by more effective numerical methods. Based on CCG, we proposed a general method for solving large deformation and nonlinear vibration of plate/shell structures with arbitrary shapes. The method can map any complex surface conformal to a rectangular region, and then FvK equations are solved in the rectangular region to study nonlinear vibration problems of any arbitrary shape plates/shells. The conform map is calculated by solving Laplace equations on a fine Delauney triangular mesh on the surface, which is numerically robust, and the map is harmonic and subsequently C∞ smooth, such that all the evaluations and spatial derivatives required by high accuracy methods at the regular nodes can be accurately and efficiently calculated. A variational function that is equivalent to the FvK equations is provided, such that the FvK equations can be solved by multiple numerical methods. The degree-of-freedom in solving the FvK equations is usually much less than that in the finite element methods described by displacements. The effectiveness of the proposed approach is verified by several benchmark examples, and the current method is suitable for calculating the large deflections and nonlinear dynamical responses of plates/shallow shells with arbitrary shapes.
Early Prediction of Human Intention for Human–Robot Collaboration Using Transformer Network
Authors: Zhang Xinyao , Tian Sibo , Liang Xiao , Zheng Minghui , Behdad Sara
Published: December 2023

Human intention prediction plays a critical role in human–robot collaboration, as it helps robots improve efficiency and safety by accurately anticipating human intentions and proactively assisting with tasks. While current applications often focus on predicting intent once human action is completed, recognizing human intent in advance has received less attention. This study aims to equip robots with the capability to forecast human intent before completing an action, i.e., early intent prediction. To achieve this objective, we first extract features from human motion trajectories by analyzing changes in human joint distances. These features are then utilized in a Hidden Markov Model (HMM) to determine the state transition times from uncertain intent to certain intent. Second, we propose two models including a Transformer and a Bi-LSTM for classifying motion intentions. Then, we design a human–robot collaboration experiment in which the operator reaches multiple targets while the robot moves continuously following a predetermined path. The data collected through the experiment were divided into two groups: full-length data and partial data before state transitions detected by the HMM. Finally, the effectiveness of the suggested framework for predicting intentions is assessed using two different datasets, particularly in a scenario when motion trajectories are similar but underlying intentions vary. The results indicate that using partial data prior to the motion completion yields better accuracy compared to using full-length data. Specifically, the transformer model exhibits a 2% improvement in accuracy, while the Bi-LSTM model demonstrates a 6% increase in accuracy.
A Dynamical Model for the Control of a Guyed Tensegrity Beam Under Large Displacements
Authors: Kurka Paulo R. G. , Paiva Victor A. S. M. , Silva-Teixeira Luis H. , Ramos Paola G. , Izuka Jaime H.
Published: December 2023

Most studies regarding models of tensegrity systems miss the possibility of large static deformations or provide elaborate and lengthy solutions to determine the system dynamics. Contrarily, this work presents a straightforward methodology to find the dynamic characteristics of a guyed tensegrity beam structure, allowing the application of vibration control strategies in conditions of large deformations. The methodology is based on a low-order, adaptive, nonlinear finite element model with pre-stressed components. The method is applied to numerical and experimental models of a class 2 tensegrity structure with a high length-to-width aspect ratio. Image processing and accelerometer data are combined to extract the experimental natural frequencies of the structure, which are compared to numerical results. Prony’s method is applied to estimate damping, and a numerical control strategy is employed using the dynamical model of the structure.
Thinking Beyond the Default User: The Impact of Gender, Stereotypes, and Modality on Interpretation of User Needs
Authors: Schauer Anastasia M. , Schaufel Hunter , Nunn Margaret , Kohls Noah D. , Fu Katherine
Published: December 2023

Throughout the mechanical design process, designers, the majority of whom are men, often fail to consider the needs of women, resulting in consequences ranging from inconvenience to increased risk of serious injury or death. Although these biases are well studied in other fields of research, the mechanical design field lacks formal investigation into this phenomenon. In this study, engineering students (n = 301) took a survey in which they read a Persona describing a student makerspace user and a Walkthrough describing the user’s interaction with the makerspace while completing a project. During the Walkthrough, the user encountered various obstacles or Pain Points. Participants were asked to recall and evaluate the Pain Points that the user encountered and then evaluated their perceptions of the makerspace and user. The independent variables under investigation were the gender of the user Persona (woman, gender-neutral, or man), the Walkthrough room case (crafting or woodworking makerspace), and the modality of the Persona and Walkthrough (text- or audio-based). Results showed that participants from the Text-based modality were better able to recall Pain Points compared to participants from the Audio-based modality. Pain Points were assessed as more severe when they impacted women users, potentially stemming from protective paternalism. In addition to finding that the gender of a user impacted the way a task environment was perceived, results confirmed the presence of androcentrism, or “default man” assumptions, in the way designers view end users of unknown gender. Promisingly, providing user Persona information in an audio modality significantly reduced this bias compared to text-based modalities, indicating that providing richer detail in user personas has the capability to reduce gender bias in designers.
Lean Flame Stabilization With Nanosecond Plasma Discharges in a Gas Turbine Model Combustor
Authors: Blanchard Victorien P. , Roqué Frédéric , Scouflaire Philippe , Laux Christophe O , Ducruix Sébastien
Published: December 2023

This paper presents an experimental study of lean flames stabilization with nanosecond repetitively pulsed discharges. The two-stage, swirled-stabilized, multipoint injector BIMER operates at atmospheric pressure with methane-air mixtures in the present study. It is representative in its design of a realistic lean premixed prevaporized injector of gas turbine engines operated at a lab-scale level. The lean blow-off extension with plasma is characterized. The combustion efficiency and the pollutant emissions are quantified near blow-off with and without plasma for 50-kW flames. We show that it is possible to stabilize lean flames down to an equivalence ratio of 0.3, with less than 5 ppm of NOX emitted, thanks to nanosecond repetitively pulsed (NRP) discharges with an electric power that represents less than 0.25% of the flame thermal power. This study also clearly shows that it is necessary to account for the plasma system integration at the early stage of the combustor design to fully benefit from the plasma stabilizing effects on the flame.
BIOSEGURIDAD Y LA CONSTITUCIÓN DE NUEVOS SUJETOS POLÍTICOS MÁS ALLÁ DE LO HUMANO. BIOSEGURIDAD Y LA CONSTITUCIÓN DE NUEVOS SUJETOS POLÍTICOS MÁS ALLÁ DE LO HUMANO
Authors: Dicenta Vilker Mara
Published: December 2023

"Durante el brote de Ébola en 2014, una enfermera madrileña contrajo el virus después de tratar a un misionero repatriado desde Sierra Leona. La enfermera tenía un perro, Excalibur, el cual fue “eliminado” tras clasificarse como riesgo para la salud pública.Basándome en un análisis de la historia en los medios, sugiero que el perro, Excalibur, fue actuado (enacted) como, al menos, tres perros : infectado, “ zoonoseando” o transmitiendo el virus, y vivo/muerto. Los tres perros-bioriesgo fueron entrelazados con diferentes prácticas de conocimiento, poder, gubernamentalidad y co-habitación.Minimizar riesgos durante emergencias conlleva acciones imaginativas. Éstas tuvieron lugar en el tratamiento del cura español repatriado, para el que se reabrió el hospital especializado en epidemias previamente desmantelado. También sucedió con otro perro en Estados Unidos, para el que se habilitó un centro militar abandonado. Sin embargo, con Excalibur, en lugar de tratar el (des)conocimiento del futuro como incierto (y así manejar los riesgos de Excalibur-con-Ebola), las autoridades españolas decidieron “eliminar” al perro, colapsando así la distinción entre los riesgos y el mismo Excalibur. Esta acción provocó que tanto personas como mascotas protestaran en la calle y en las redes de comunicación, materializando así una emergente ecología multi-especie. El evento, temporal y concentrado, hizo posible la visibilización de nuevos sujetos políticos (las mascotas) en otras formas de espacio y tiempo, así como el deseo de nuevas formas de organización de la vida (y la muerte) a la vez que renegociando los conceptos de lo público y lo privado. "
Stretchable photothermal membrane of NIR-II charge-transfer cocrystal for wearable solar thermoelectric power generation
Authors: Zhao Yu Dong , Jiang Wangkai , Zhuo Sheng , Wu Bin , Luo Peng , Chen Weifan , Zheng Min , Hu Jianchen , Zhang Ke-Qin , Wang Zuo-Shan , Liao Liang-Sheng , Zhuo Ming-Peng
Published: December 2023

Harvesting sunlight into cost-effective electricity presents an enticing prospect for self-powered wearable applications. The photothermal materials with an extensive absorption are fundamental to achieve optical and thermal concentration of the sunlight for efficiency output electricity of wearable solar thermoelectric generators (STEGs). Here, we synthesize an organic charge-transfer (CT) cocrystal with a flat absorption from ultraviolet to second near-infrared region (200 to 1950 nanometers) and a high photothermal conversion efficiency (PCE) of 80.5%, which is introduced into polyurethane toward large-area nanofiber membrane by electrospinning technology. These corresponding membranes demonstrate a high PCE of 73.7% under the strain more than 80%. Sandwiched with carbon nanotube–based thermoelectric fibers, the membranes as stretchable solar absorbers of STEGs could supply a notably increase temperature gradient, processing a maximum output voltage density of 23.4 volts per square meter at 1:00 p.m. under sunlight. This strategy presents an important insight in heat management for wearable STEGs with a desired electricity output.
Thermally generated spin current in the topological insulator Bi
2
Se
3
Authors: Jain Rakshit , Stanley Max , Bose Arnab , Richardella Anthony R. , Zhang Xiyue S. , Pillsbury Timothy , Muller David A. , Samarth Nitin , Ralph Daniel C.
Published: December 2023

We present measurements of thermally generated transverse spin currents in the topological insulator Bi
2
Se
3
, thereby completing measurements of interconversions among the full triad of thermal gradients, charge currents, and spin currents. We accomplish this by comparing the spin Nernst magneto-thermopower to the spin Hall magnetoresistance for bilayers of Bi
2
Se
3
/CoFeB. We find that Bi
2
Se
3
does generate substantial thermally driven spin currents. A lower bound for the ratio of spin current density to thermal gradient is

J
s

∇

x

T

= (4.9 ± 0.9) × 10
6

(

ℏ

2
e

)

A

 

m

−
2

K

 
μ

m

−
1

, and a lower bound for the magnitude of the spin Nernst ratio is −0.61 ± 0.11. The spin Nernst ratio for Bi
2
Se
3
is the largest among all materials measured to date, two to three times larger compared to previous measurements for the heavy metals Pt and W. Strong thermally generated spin currents in Bi
2
Se
3
can be understood via Mott relations to be due to an overall large spin Hall conductivity and its dependence on electron energy.
An energy costly architecture of neuromodulators for human brain evolution and cognition
Authors: Castrillon Gabriel , Epp Samira , Bose Antonia , Fraticelli Laura , Hechler André , Belenya Roman , Ranft Andreas , Yakushev Igor , Utz Lukas , Sundar Lalith , Rauschecker Josef P , Preibisch Christine , Kurcyus Katarzyna , Riedl Valentin
Published: December 2023

In comparison to other species, the human brain exhibits one of the highest energy demands relative to body metabolism. It remains unclear whether this heightened energy demand uniformly supports an enlarged brain or if specific signaling mechanisms necessitate greater energy. We hypothesized that the regional distribution of energy demands will reveal signaling strategies that have contributed to human cognitive development. We measured the energy distribution within the brain functional connectome using multimodal brain imaging and found that signaling pathways in evolutionarily expanded regions have up to 67% higher energetic costs than those in sensory-motor regions. Additionally, histology, transcriptomic data, and molecular imaging independently reveal an up-regulation of signaling at G-protein-coupled receptors in energy-demanding regions. Our findings indicate that neuromodulator activity is predominantly involved in cognitive functions, such as reading or memory processing. This study suggests that an up-regulation of neuromodulator activity, alongside increased brain size, is a crucial aspect of human brain evolution.
Parkinson’s VPS35[D620N] mutation induces LRRK2-mediated lysosomal association of RILPL1 and TMEM55B
Authors: Pal Prosenjit , Taylor Matthew , Lam Pui Yiu , Tonelli Francesca , Hecht Chloe A. , Lis Pawel , Nirujogi Raja S. , Phung Toan K. , Yeshaw Wondwossen M. , Jaimon Ebsy , Fasimoye Rotimi , Dickie Emily A. , Wightman Melanie , Macartney Thomas , Pfeffer Suzanne R. , Alessi Dario R.
Published: December 2023

We demonstrate that the Parkinson’s VPS35[D620N] mutation alters the expression of ~220 lysosomal proteins and stimulates recruitment and phosphorylation of Rab proteins at the lysosome. This recruits the phospho-Rab effector protein RILPL1 to the lysosome where it binds to the lysosomal integral membrane protein TMEM55B. We identify highly conserved regions of RILPL1 and TMEM55B that interact and design mutations that block binding. In mouse fibroblasts, brain, and lung, we demonstrate that the VPS35[D620N] mutation reduces RILPL1 levels, in a manner reversed by LRRK2 inhibition and proteasome inhibitors. Knockout of RILPL1 enhances phosphorylation of Rab substrates, and knockout of TMEM55B increases RILPL1 levels. The lysosomotropic agent LLOMe also induced LRRK2 kinase–mediated association of RILPL1 to the lysosome, but to a lower extent than the D620N mutation. Our study uncovers a pathway through which dysfunctional lysosomes resulting from the VPS35[D620N] mutation recruit and activate LRRK2 on the lysosomal surface, driving assembly of the RILPL1-TMEM55B complex.
Simultaneous multitone microwave emission by dc-driven spintronic nano-element
Authors: Hamadeh Alexandre Abbass , Slobodianiuk Denys , Moukhader Rayan , Melkov Gennadiy , Borynskyi Vladyslav , Mohseni Morteza , Finocchio Giovanni , Lomakin Vitaly , Verba Roman , de Loubens Grégoire , Pirro Philipp , Klein Olivier
Published: December 2023

Current-induced self-sustained magnetization oscillations in spin-torque nano-oscillators (STNOs) are promising candidates for ultra-agile microwave sources or detectors. While usually STNOs behave as a monochromatic source, we report here clear bimodal simultaneous emission of incommensurate microwave oscillations in the frequency range of 6 to 10 gigahertz at femtowatt level power. These two tones correspond to two parametrically coupled eigenmodes with tunable splitting. The emission range is crucially sensitive to the change in hybridization of the eigenmodes of free and fixed layers, for instance, through a slight tilt of the applied magnetic field from the normal of the nanopillar. Our experimental findings are supported both analytically and by micromagnetic simulations, which ascribe the process to four-magnon scattering between a pair of radially symmetric magnon modes and a pair of magnon modes with opposite azimuthal index. Our findings pave the way for enhanced cognitive telecommunications and neuromorphic systems that use frequency multiplexing to improve communication performance.
Human motor augmentation with an extra robotic arm without functional interference
Authors: Dominijanni Giulia , Pinheiro Daniel Leal , Pollina Leonardo , Orset Bastien , Gini Martina , Anselmino Eugenio , Pierella Camilla , Olivier Jérémy , Shokur Solaiman , Micera Silvestro
Published: December 2023

Extra robotic arms (XRAs) are gaining interest in neuroscience and robotics, offering potential tools for daily activities. However, this compelling opportunity poses new challenges for sensorimotor control strategies and human-machine interfaces (HMIs). A key unsolved challenge is allowing users to proficiently control XRAs without hindering their existing functions. To address this, we propose a pipeline to identify suitable HMIs given a defined task to accomplish with the XRA. Following such a scheme, we assessed a multimodal motor HMI based on gaze detection and diaphragmatic respiration in a purposely designed modular neurorobotic platform integrating virtual reality and a bilateral upper limb exoskeleton. Our results show that the proposed HMI does not interfere with speaking or visual exploration and that it can be used to control an extra virtual arm independently from the biological ones or in coordination with them. Participants showed significant improvements in performance with daily training and retention of learning, with no further improvements when artificial haptic feedback was provided. As a final proof of concept, naïve and experienced participants used a simplified version of the HMI to control a wearable XRA. Our analysis indicates how the presented HMI can be effectively used to control XRAs. The observation that experienced users achieved a success rate 22.2% higher than that of naïve users, combined with the result that naïve users showed average success rates of 74% when they first engaged with the system, endorses the viability of both the virtual reality–based testing and training and the proposed pipeline.
DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc
1
Authors: Braillard Stéphanie , Keenan Martine , Breese Karen J. , Heppell Jacob , Abbott Michael , Islam Rafiqul , Shackleford David M. , Katneni Kasiram , Crighton Elly , Chen Gong , Patil Rahul , Lee Given , White Karen L. , Carvalho Sandra , Wall Richard J. , Chemi Giulia , Zuccotto Fabio , González Silvia , Marco Maria , Deakyne Julianna , Standing David , Brunori Gino , Lyon Jonathan J. , Castañeda-Casado Pablo , Camino Isabel , Martinez Martinez Maria S. , Zulfiqar Bilal , Avery Vicky M. , Feijens Pim-Bart , Van Pelt Natascha , Matheeussen An , Hendrickx Sarah , Maes Louis , Caljon Guy , Yardley Vanessa , Wyllie Susan , Charman Susan A. , Chatelain Eric
Published: December 2023

New drugs for visceral leishmaniasis that are safe, low cost, and adapted to the field are urgently required. Despite concerted efforts over the last several years, the number of new chemical entities that are suitable for clinical development for the treatment of
Leishmania
remains low. Here, we describe the discovery and preclinical development of DNDI-6174, an inhibitor of
Leishmania
cytochrome bc
1
complex activity that originated from a phenotypically identified pyrrolopyrimidine series. This compound fulfills all target candidate profile criteria required for progression into preclinical development. In addition to good metabolic stability and pharmacokinetic properties, DNDI-6174 demonstrates potent in vitro activity against a variety of
Leishmania
species and can reduce parasite burden in animal models of infection, with the potential to approach sterile cure. No major flags were identified in preliminary safety studies, including an exploratory 14-day toxicology study in the rat. DNDI-6174 is a cytochrome bc
1
complex inhibitor with acceptable development properties to enter preclinical development for visceral leishmaniasis.
The motility-matrix production switch in
Bacillus subtilis
—a modeling perspective
Authors: Dannenberg Simon , Penning Jonas , Simm Alexander , Klumpp Stefan
Published: December 2023

Phenotype switching can be triggered by external stimuli and by intrinsic stochasticity. Here, we focus on the motility-matrix production switch in
Bacillus subtilis
. We use modeling to describe the SinR-SlrR bistable switch and its regulation by SinI and to distinguish different sources of stochasticity. Our simulations indicate that intrinsic fluctuations in the synthesis of SinI are insufficient to drive spontaneous switching and suggest that switching is triggered by upstream noise from the Spo0A phosphorelay.

IMPORTANCE

The switch from motility to matrix production is the first step toward biofilm formation and, thus, to multicellular behavior in
Bacillus subtilis
. The transition is governed by a bistable switch based on the interplay of the regulators SinR and SlrR, while SinI transmits upstream signals to that switch. Quantitative modeling can be used to study the switching dynamics. Here, we build such a model step by step to describe the dynamics of the switch and its regulation and to study how spontaneous switching is triggered by upstream noise from the Spo0A phosphorelay.
Lactate-lactylation-HSPA6 axis promotes PRRSV replication by impairing IFN-β production
Authors: Pang Yu , Zhou Yanrong , Wang Yucheng , Fang Liurong , Xiao Shaobo
Published: December 2023

Lactate, traditionally considered a metabolic by-product, has recently been identified as a substrate for the induction of lactylation, a newly identified epigenetic modification that plays an important role in the regulation of host gene expression. Our previous study showed that lactate levels were significantly elevated in cells infected with the porcine reproductive and respiratory syndrome virus (PRRSV), an
Arterivirus
that has devastated the swine industry worldwide for over 30 years. However, the role of elevated lactate in PRRSV infections remains unknown. In this study, we found that lactate was required for optimal PRRSV proliferation, and PRRSV infection increased cellular lactylation in a dose-dependent manner. Using the Cleavage Under Targets and Tagmentation (CUT&Tag) combined with RNA sequencing (RNA-seq) to screen the downstream genes regulated by lactylation in PRRSV-infected cells, we found that PRRSV-induced lactylation activated the expression of heat shock 70 kDa protein 6 (HSPA6). Follow-up experiments showed that HSPA6 is important for PRRSV proliferation by negatively modulating interferon (IFN)-β induction. Mechanistically, HSPA6 impeded the interaction between TNF-receptor-associated factor 3 (TRAF3) and inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε), thereby hindering the production of IFN-β. Taken together, these results indicate that the activated lactate-lactylation-HSPA6 axis promotes viral growth by impairing IFN-β induction, providing new therapeutic targets for the prevention and control of PRRSV infection. The results presented here also link lactylation to the virus life cycle, improving our understanding of epigenetic regulation in viral infection.

IMPORTANCE

As a newly identified epigenetic modification, lactate-induced lactylation has received attentions because it plays important roles in gene expression and contributes to tumorigenesis and the innate immune response. Previous studies showed that many viruses upregulate cellular lactate levels; however, whether virus-elevated lactate induces lactylation and the subsequent biological significance of the modification to viral infection have not been reported. In this study, we demonstrated that porcine reproductive and respiratory syndrome virus (PRRSV) infection induced cellular lactylation, which, in turn, upregulated the expression of HSPA6, an IFN-negative regulator. We also dissected the mechanism by which HSPA6 negatively regulates IFN-β production. To our knowledge, this is the first report to study virus-induced lactylation and establish the relationship between lactylation and virus infection.
Draft genome sequencing of a multidrug-resistant
Salmonella enterica
subspecies enterica serovar Typhimurium strain isolated from chicken in Bangladesh
Authors: Popy Najmun Nahar , Hoque M. Nazmul , Khan Mohammad Ferdousur Rahman , Biswas Limon , Rahman Mohammad Habibur , Saiduzzaman Md. , Rahman Marzia , Rahman Md. Bahanur
Published: December 2023

Herein this study, we sequenced the genome of a multidrug-resistant
Salmonella enterica
serovar Typhimurium strain MBR-MFRK-23 isolated from the liver tissue of a diseased layer chicken. The 4,964,854-bp draft genome comprises 50 contigs with 50.5× coverage and 52.1% GC content and is typed as
S. enterica
sequence type 19.
Stability of meropenem in portable elastomeric infusion devices: which protocol should be implemented in clinical practice?
Authors: Esteban-Cartelle Beatriz , Serrano Dolores R. , Pérez Menéndez-Conde Covadonga , Vicente-Oliveros Noelia , Álvarez-Díaz Ana , Fortún Abete Jesús , Martín-Dávila Pilar
Published: December 2023

Meropenem has an excellent activity against gram-positive and gram-negative bacteria, including multi-resistant microorganisms. Even though meropenem is a great candidate for outpatient parenteral antimicrobial therapy (OPAT), its physicochemical stability is a major challenge. This work aimed to demonstrate the suitability of including meropenem in OPAT by elucidating its physicochemical stability in a range of commonly prescribed concentrations within portable elastomeric infusion devices. Physical and chemical stability were evaluated at two concentrations commonly used in clinical practice (2 mg/mL and 25 mg/mL), and three temperatures (2–8°C, 25°C, and 32°C) using Accufuser portable elastomeric infusion devices. Drug adsorption onto portable elastomeric infusion devices was also determined at the end of the experiment. Meropenem stability significantly decreased at higher temperatures and when higher drug solution concentrations were used. Meropenem solutions at 2 mg/mL kept the drug content above 95% over 24 h at 2–8°C, but just for 8 h at 25°C. Nevertheless, solutions containing 25 mg/mL of meropenem showed a dramatic decrease in chemical stability after 8 h 2–8°C and just after 4 h at 25°C or 32°C. However, physical stability was kept favorable during this period. The drug adsorption on the material of the elastomeric infusion device was below 1%, indicating the suitability of the chosen device. We propose several administration protocols for meropenem in portable elastomeric infusion devices in clinical practice, according to the results obtained in our study. The results obtained in this study open up a possibility of administering meropenem in an OPAT setting despite its short stability.

IMPORTANCE

Although outpatient parenteral antibiotic therapy can be a good approach to treating infections, a lack of data regarding antibiotic stability in portable elastomeric infusion devices restricts its safe and effective use. Actually, meropenem is used for prolonged periods above 24 h, and it is not physicochemically stable, which can compromise efficacy and toxicity. This work is of high importance to show the clinicians the real shelf life of meropenem when administered in portable elastomeric infusion devices. We propose several administration protocols for meropenem in portable elastomeric infusion devices in clinical practice, according to the stability drug results obtained in our study.
The type III secretion system facilitates systemic infections of
Pseudomonas aeruginosa
in the clinic
Authors: Wu Tiantian , Zhang Zhenchuan , Li Tong , Dong Xu , Wu Dan , Zhu Lixia , Xu Kaijin , Zhang Ying
Published: December 2023

Pseudomonas aeruginosa
is a major opportunistic pathogen that can cause severe systemic infections. Here, we found that the type III secretion system effector ExoU was the main determinant of pathogenicity of a highly virulent clinical isolate strain, BSI_S5, of
P. aeruginosa
, which caused severe bloodstream infections and belongs to ST463/O4. Deletion of
exoU
showed significantly attenuated cytotoxicity and virulence
in vivo
, while deletion of two other unique genes from strain BSI_S5,
chr_1696
and
chr_4238
, which encodes type I secretion system permease/ATPase or polysaccharide biosynthesis protein, respectively, caused no apparent loss of toxicity compared to the parent strain, and complementation of the
ΔexoU
mutant restored its virulence. The presence of ExoU-induced lung lesions and the mucosal damage of gallbladder in mice, and the replication of the
ΔexoU
mutant was hindered
in vivo
compared with the parent strain. We show here for the first time that a clinical isolate with intact
exoU
harbored a mutation of T→G substitution in the adjacent specific Pseudomonas chaperone for ExoU (
spcU
), which caused phenylalanine to valine change at amino acid 94 of SpcU, resulting in significant loss of cytotoxicity. This finding suggests that intact
exoU
is not sufficient for cytotoxicity, but a functional downstream SpcU is required for ExoU secretion and cytotoxicity. Finally, we found that BSI_S5 harbored two types of insertion sequences adjacent to
exoU
, suggesting the potential of
exoU
to be transferred to other strains. Our study opens an avenue for further mechanistic study of
P. aeruginosa
systemic infections regarding its high pathogenicity and clinical spread.

IMPORTANCE

The identification of decisive virulence-associated genes in highly pathogenic
P. aeruginosa
isolates in the clinic is essential for diagnosis and the start of appropriate treatment. Over the past decades,
P. aeruginosa
ST463 has spread rapidly in East China and is highly resistant to β-lactams. Given the poor clinical outcome caused by this phenotype, detailed information regarding its decisive virulence genes and factors affecting virulence expression needs to be deciphered. Here, we demonstrate that the T3SS effector ExoU has toxic effects on mammalian cells and is required for virulence in the murine bloodstream infection model. Moreover, a functional downstream SpcU is required for ExoU secretion and cytotoxicity. This work highlights the potential role of ExoU in the pathogenesis of disease and provides a new perspective for further research on the development of new antimicrobials with antivirulence ability.
First trimester “clean catch” urine and vaginal swab sample distinct microbiological niches
Authors: Sung Juliana , Larsen Peter , Halverson Thomas M. , Waters Thaddeus P. , Goodman Jean R. , Wolfe Alan J.
Published: December 2023

Untreated asymptomatic bacteriuria (ASB) has been associated with adverse pregnancy outcomes. Thus, routine screening by standard urine culture (SUC) and treatment of ASB are currently recommended for all pregnant women. However, SUC often misses microbes detected by expanded quantitative urine culture methods (EQUC) and 16S rRNA gene (amplicon) sequencing. The existence of these microbes (urinary microbiome) challenges the current approach to ASB screening in pregnancy as it is limited by two assumptions: (i) the female bladder is naturally sterile and (ii) SUC identifies all clinically relevant uropathogens. To determine the uniqueness or similarity between urinary and vaginal microbiomes, we performed a prospective observational institutional review board (IRB)-approved cohort study of pregnant women with a singleton pregnancy <14 weeks undergoing routine ASB screening. Consented subjects provided paired midstream voided urine and vaginal swab samples, which were assessed by EQUC and amplicon sequencing. The similarity was determined by Spearman’s correlation; statistical significance was calculated using bootstrap analysis with 1,000 random samples and a significance threshold of
P
value < 0.001. We used the Bayes theorem to quantify how well the vaginal microbiome could be used as a proxy for a patient’s urinary microbiome and vice versa. Our findings provide evidence that EQUC and amplicon sequencing reveal similar views of urinary and vaginal microbiomes in first trimester pregnant women. However, while vaginal and urinary microbial compositions were significantly correlated for the same individual, they were by no means equivalent. The first trimester urinary and vaginal microbiomes are distinct enough to preclude their use as proxies of each other.

IMPORTANCE

Untreated asymptomatic bacteriuria (ASB) has been associated with adverse pregnancy outcomes, including pyelonephritis, preterm labor, and low birth weight infants. Thus, routine screening by standard urine culture (SUC) and treatment of ASB are currently recommended for all pregnant women. For this purpose, some researchers claim that vaginal swabs and urine samples can be used as proxies for each other. Because SUC often misses microbes, we used two more sensitive, recently validated detection methods to compare the composition of the urinary and vaginal microbiomes of pregnant females in their first trimester. Both methods yielded similar results. Vaginal and urinary microbial compositions for the same individual were significantly correlated; however, they were not equivalent. We argue that first trimester urinary and vaginal microbiomes are distinct enough to preclude their use as proxies for each other.
Uncovering the diversity and distribution of biosynthetic gene clusters of prochlorosins and other putative RiPPs in marine
Synechococcus
strains
Authors: Arias-Orozco Patricia , Zhou Lu , Yi Yunhai , Cebrián Rubén , Kuipers Oscar P.
Published: December 2023

Picocyanobacteria can synthesize a distinctive class of lanthipeptides referred to as prochlorosins. They are classified within the Nif11 family and are subject to post-translational modifications by a solitary promiscuous enzyme from the ProcM group. Their biological function is unknown but highly speculated upon. In this study, we conducted a comprehensive genome mining investigation of the
Synechococcus
and
Prochlorococcus
genomes to elucidate the genomic landscape associated with the biosynthetic gene clusters (BGCs) harboring prochlorosin genes. Our mining study led to a substantial expansion of the known prochlorosin repertoire identified in 15 picocyanobacterial genomes. We also identified a range of tailoring enzymes and gene families proximal to the
procA
/
syncA
genes. The recombination-related proteins we detected were of particular interest, as they may have a critical role in generating the diversity observed within this peptide family. Interestingly, we identified novel LAP/YcaO BGCs in
Synechococcus
that had not been previously described. These BGCs hold the potential to generate prochlorosins with secondary modifications and introduce new putative azol(in)e-containing ribosomally synthesized and post-translationally modified peptides precursors. Our investigation offers an in-depth analysis of the vast prochlorosin family.

IMPORTANCE

Genome mining studies have revealed the remarkable combinatorial diversity of ribosomally synthesized and post-translationally modified peptides (RiPPs) in marine bacteria, including prochlorosins. However, mining strategies also prove valuable in investigating the genomic landscape of associated genes within biosynthetic gene cluster (BGC) specific to targeted RiPPs of interest. Our study contributes to the enrichment of knowledge regarding prochlorosin diversity. It offers insights into potential mechanisms involved in their biosynthesis and modification, such as hyper-modification, which may give rise to active lantibiotics. Additionally, our study uncovers putative novel promiscuous post-translational enzymes, thereby expanding the chemical space explored within the
Synechococcus
genus. Moreover, this research extends the applications of mining techniques beyond the discovery of new RiPP-like clusters, allowing for a deeper understanding of genomics and diversity. Furthermore, it holds the potential to reveal previously unknown functions within the intriguing RiPP families, particularly in the case of prochlorosins.
Non-Catalytic Domains of DNA Polymerase λ: Influence on Enzyme Activity and Its Regulation
Authors: Maltseva E. A. , Rechkunova N. I. , Lavrik O. I.
Published: December 2023

DNA polymerase λ (Polλ) belongs to the same structural X-family as DNA polymerase β, the main polymerase of base excision repair. The role of Polλ in this process remains not fully understood. A significant difference between the two DNA polymerases is the presence of an extended non-catalytic N-terminal region in the Polλ structure. The influence of this region on the interaction of Polλ with DNA and multifunctional proteins, poly(ADP-ribose)polymerase 1 (PARP1) and replication protein A (RPA), was studied in detail for the first time. The data obtained suggest that non-catalytic Polλ domains play a suppressor role both in relation to the polymerase activity of the enzyme and in interaction with DNA and PARP1.
Predicting the risk of glaucoma-related adverse events following secondary intraocular lens implantation in paediatric eyes: a 3-year study
Authors: Chen Hui , Xu Chaoqun , Jin Ling , Wang Zhenyu , Xu Jingmin , Zou Yingshi , Jin Guangming , Luo Lixia , Lin Haotian , Chen Weirong , Zheng Danying , Liu Yizhi , Liu Zhenzhen
Published: December 2023

Aims

To establish and evaluate predictive models for glaucoma-related adverse events (GRAEs) following secondary intraocular lens (IOL) implantation in paediatric eyes.

Methods

205 children (356 aphakic eyes) receiving secondary IOL implantation at Zhongshan Ophthalmic Center with a 3-year follow-up were enrolled. Cox proportional hazard model was used to identify predictors of GRAEs and developed nomograms. Model performance was evaluated with time-dependent receiver operating characteristic (ROC) curves, decision curve analysis, Kaplan-Meier curves and validated internally through C-statistics and calibration plot of the bootstrap samples.

Results

Older age at secondary IOL implantation (HR=1.5, 95% CI: 1.03 to 2.19), transient intraocular hypertension (HR=9.06, 95% CI: 2.97 to 27.67) and ciliary sulcus implantation (HR=14.55, 95% CI: 2.11 to 100.57) were identified as risk factors for GRAEs (all p<0.05). Two nomograms were established. At postoperatively 1, 2 and 3 years, model 1 achieved area under the ROC curves (AUCs) of 0.747 (95% CI: 0.776 to 0.935), 0.765 (95% CI: 0.804 to 0.936) and 0.748 (95% CI: 0.736 to 0.918), and the AUCs of model 2 were 0.881 (95% CI: 0.836 to 0.926), 0.895 (95% CI: 0.852 to 0.938) and 0.848 (95% CI: 0.752 to 0.945). Both models demonstrated fine clinical net benefit and performance in the interval validation. The Kaplan-Meier curves showing two distinct risk groups were well discriminated and robust in both models. An online risk calculator was constructed.

Conclusion

Two nomograms could sensitively and accurately identify children at high risk of GRAEs after secondary IOL implantation to help early identification and timely intervention.
Comorbid status in patients with osteomyelitis is associated with long-term incidence of extremity amputation
Authors: Schmidt Brian M , Keeney-Bonthrone Toby P , Hawes Armani M , Karmakar Monika , Frydrych Lynn M , Cinti Sandro K , Pop-Busui Rodica , Delano Matthew J
Published: December 2023

Introduction

Osteomyelitis is associated with significant morbidity, including amputation. There are limited data on long-term amputation rates following an osteomyelitis diagnosis. We sought to determine the incidence of amputation in patients with osteomyelitis over 2 years.

Research design and methods

Observational cohort study of 1186 inpatients with osteomyelitis between 2004 and 2015 and stratified by osteomyelitis location status to evaluate the impact on amputation, mortality rates, readmission data, and inpatient days.

Results

Persons with diabetes had 3.65 times greater probability of lower extremity amputation (p<0.001), readmission (p<0.001), and longer inpatient stay (p<0.001) and had higher 2-year mortality (relative risk (RR) 1.23, p=0.0027), adjusting for risk factors. Male gender (RR 1.57, p<0.001), black race (RR 1.41, p<0.05), former smoking status (RR 1.38, p<0.01), myocardial infarction (RR 1.72, p<0.001), congestive heart failure (RR 1.56, p<0.001), peripheral vascular disease (RR 2.25, p<0.001) and renal disease (RR 1.756, p<0.001) were independently associated with amputation. Male gender (RR 1.39, p<0.01), black race (RR 1.27, p<0.05), diabetes (RR 2.77, p<0.001) and peripheral vascular disease (RR 1.59, p<0.001) had increased risk of lower, not upper, extremity amputation.

Conclusions

Patients with osteomyelitis have higher rates of amputation and hospitalization. Clinicians must incorporate demographic and comorbid risk factors to protect against amputation.
Is the awarding gap at UK medical schools influenced by ethnicity and medical school attended? A retrospective cohort study
Authors: Brown Celia , Goss Charlotte , Sam Amir H
Published: December 2023

Objectives

To better characterise the Awarding Gap (AG) between black, Asian and other minority ethnic (BAME) and white students in UK undergraduate medical education by examining how it affects eight minority ethnicity subgroups (Bangladeshi, black, Chinese, Indian, Pakistani, mixed, other Asian background and other ethnic background) and whether the AG varies by medical school attended.

Design

Retrospective cohort study.

Setting

Data extracted from the UK Medical Education Database on students enrolled at 33 UK medical schools in the academic years starting 2012, 2013 and 2014.

Participants

16 020 ‘Home’ tuition fee status students who sat the University Clinical Aptitude Test on entry to university and obtained a UK Foundation Programme (UKFP) application score on exit.

Primary outcome measure

UKFP Z-scores on exit from medical school.

Results

There were significant differences in UKFP Z-scores between ethnicity subgroups. After white students, mixed ethnicity students performed best (coefficient −0.15 standard deviations [SD]) compared with white students, (95% confidence interval [CI] −0.23 to −0.08, p<0.001) and Pakistani students scored lowest (coefficient −0.53 SD, 95% CI −0.60 to −0.46, p<0.001). In pairwise comparisons of scores between all nine individual ethnicity subgroups, 15/36 were statistically significant. The AG varied considerably across medical schools. The largest gap showed the coefficient for BAME was −0.83 SD compared with white students (95% CI −1.18 to −0.49, p<0.001), while the smallest demonstrated no statistically significant difference in performance between BAME and white students (+0.05 SD, 95% CI −0.32 to 0.42, p=0.792).

Conclusions

BAME students are significantly disadvantaged by the current UK medical education system. There are clear differences in medical school outcomes between students from different ethnicity subgroups, and the size of the AG also varies by medical school attended. Urgent and effective action must be taken to address the AG and achieve an equal learning environment for our future doctors.
Regional and racial disparities in major amputation rates among medicare beneficiaries with diabetes: a retrospective study in the southeastern USA
Authors: Lobo Jennifer Mason , Kang Hyojung , Brennan Meghan B , Kim Soyoun , McMurry Timothy L , Balkrishnan Rajesh , Anderson Roger , McCall Anthony , Sohn Min-Woong
Published: December 2023

Objective

While rates for non-traumatic lower extremity amputations (LEA) have been declining, concerns exist over disparities. Our objectives are to track major LEA (MLEA) rates over time among Medicare beneficiaries residing in a high diabetes prevalence region in the southeastern USA (the diabetes belt) and surrounding areas.

Methods

We used Medicare claims files for ~900 000 fee-for-service beneficiaries aged ≥65 years in 2006–2015 to track MLEA rates per 1000 patients with diabetes. We additionally conducted a cross-sectional analysis of data for 2015 to compare regional and racial disparities in major amputation risks after adjusting for demographic, socioeconomic, access-to-care and foot complications and other health factors. The Centers for Disease Control and Prevention defined the diabetes belt as 644 counties across Appalachian and southeastern US counties with high prevalence.

Results

MLEA rates were 3.9 per 1000 in the Belt compared with 2.8 in the surrounding counties in 2006 and decreased to 2.3 and 1.6 in 2015. Non-Hispanic black patients had 8.5 and 6.9 MLEAs per 1000 in 2006 and 4.8 and 3.5 in 2015 in the Belt and surrounding counties, respectively, while the rates were similar for non-Hispanic white patients in the two areas. Although amputation rates declined rapidly in both areas, non-Hispanic black patients in the Belt consistently had >3 times higher rates than non-Hispanic whites in the Belt. After adjusting for patient demographics, foot complications and healthcare access, non-Hispanic blacks in the Belt had about twice higher odds of MLEAs compared with non-Hispanic whites in the surrounding areas.

Discussion

Our data show persistent disparities in major amputation rates between the diabetes belt and surrounding counties. Racial disparities were much larger in the Belt. Targeted policies to prevent MLEAs among non-Hispanic black patients are needed to reduce persistent disparities in the Belt.