bluuebunny/crossref_metadata_2025 huggingface dataset:
Leveraging new opportunities and advances in high‐pressure homogenization to design non‐dairy foods
Authors: Sherman Irene Mary , Mounika Addanki , Srikanth Davanam , Shanmugam Akalya , Ashokkumar Muthupandian
Published: December 2023

High‐pressure homogenization (HPH) and ultrahigh‐pressure homogenization (UHPH) are emerging food processing techniques for stabilizing emulsions and food components under the pressure range from 60 to 400 MPa. Apart from this, they also support increasing nutritional profile, food preservation, and functionality enhancement. Even though the food undergoes the shortest processing operation, the treatment leads to modification of physical, chemical, and techno‐functional properties, in addition to the formation of micro‐sized particles. This study focuses on recent advances in using HPH/UHPH on plant‐based milk sources such as soybeans, almonds, hazelnuts, and peanuts. Overall, this systematic review provides an in‐depth analysis of the principles of HPH/UHPH, the mechanism of action, and their applications in other nondairy areas such as fruits and vegetables, meat, fish, and marine species. This work also deciphers the role of HPH/UHPH in modifying food components, their functional quality enhancement, and their provision of oxidative resistance to many foods. HPH is not only perceived as a technique for size reduction and homogenization; however, it does various functions like microbial inactivation, improvement of rheologies like texture and consistency, decreasing of lipid oxidation, and making positive modifications to proteins such as changes to the secondary structure and tertiary structure thereby enhancing the emulsifying properties, hydrophobicity of proteins, and other associated functional properties in many nondairy sources at pressures of 100–300 MPa. Thus, HPH is an emerging technique with a high throughput and commercialization value in food industries.
Vicarious defeat stress induces increased alcohol consumption in female mice: Role of neurokinin‐1 receptor and interleukin‐6
Authors: Decker Ramirez Ellie B. , Arnold Miranda E. , Schank Jesse R.
Published: December 2023

There is a high frequency of comorbidity of alcohol use disorder (AUD) and depression in human populations. We have studied this relationship in our lab using the social defeat stress (SDS) model, which results in both depression‐like behaviours and increased alcohol consumption in male mice. However, standard SDS procedures are difficult to use in female mice due to a lack of territorial aggression. In the experiments presented here, we used vicarious defeat stress (VDS) to assess social withdrawal and alcohol consumption in female C57BL6/J mice. We also assessed the expression of interleukin‐6 (IL6), which is a proinflammatory cytokine that is associated with depression in humans and sensitivity to SDS in mice. In these experiments, C57BL/6 female mice underwent 10 days of VDS where they witnessed the physical defeat of a male conspecific by an aggressive CD1 mouse. After the end of VDS, mice were either given access to alcohol or sacrificed for the measurement of IL6 expression. We found that VDS increased alcohol consumption and IL6 expression in the frontal cortex and hippocampus. Given that the neurokinin‐1 receptor (NK1R) can mediate both stress‐induced alcohol consumption and IL6 expression, we tested the ability of NK1R antagonism to reduce VDS‐induced alcohol consumption and found that this treatment reduced alcohol intake in both VDS‐exposed mice and in unstressed controls. The observed increase in alcohol consumption suggests that VDS is a model that can be utilized to study stress‐induced alcohol consumption in female mice, and that this is sensitive to NK1R antagonism.
Creativity: Challenges and Obstacles to Blossoming
Authors: Rykova Elena
Published: December 2023

This paper addresses the conditions for the development of creativity and the possible obstacles along the way. It explores conscious and unconscious mechanisms which either impede or support this process. Creativity is seen as a special case of relationships between internal and external objects, with some aspects being more consistent and others being more fluid throughout an individual's life. This paper is based on the clinical experience of psychodynamic work with clients whose psychological predicaments related to creativity impoverished different areas of their lives. The non‐exhaustive list of factors to be considered when working with those clients includes a blocked epistemophilic instinct, excessively repressed aggression, and strong negative projections. A harsh superego opposing a weak ‘internal supporter’ combined with an internalised negative parental attitude to their own creativity constitutes a powerful unconscious force which prevents it from blossoming. A high level of basic anxiety, a low degree of omnipotence, and the release of endorphins in response to suffering contribute to these difficulties. Insufficient capacity to sublimate emotions and an inability to free associate prevent clients from finding the links between ideas born in the mind and their expression that could be accessed by others.
El marco de razonamiento clínico de Bobath: Un modelo de ciencia de sistemas para abordar la complejidad de los trastornos del neurodesarrollo incluida la parálisis cerebral
Authors: Mayston Margaret J. , Saloojee Gillian M. , Foley Sarah E.
Published: December 2023

La actual práctica de desarrollo Bobath recomendada dentro del Marco de Razonamiento Clínico Bobath (BCRF) puede conceptualizarse utilizando la visión de la ciencia de los sistemas. Proporciona, así, una perspectiva holística de la interrelación e interconexión de las variables asociadas con la discapacidad aparecida durante la infancia. El BCRF se define como un marco exhaustivo de razonamiento clínico que puede aplicarse para ayudar a comprender las relaciones entre los dominios de la Clasificación Internacional del Funcionamiento, de la Discapacidad y de la Salud, cómo se puede influir en esos dominios y cómo influyen entre sí. El BCRF es un sistema de observación transdisciplinario y de razonamiento práctico que da lugar a un plan de intervención. Esto proporciona una comprensión holística de la complexidad de las situaciones asociadas a trastornos como la parálisis cerebral (PC) y la base para la gestión y habilitación a lo largo de la vida de personas que viven con trastornos neurológicos. El razonamiento clínico utilizado por el BCRF se basa en los importantes factores contextuales del individuo y su entorno social, principalmente la unidad familiar. Se basa en la comprensión de las interrelaciones entre el desarrollo típico y atípico, la fisiopatología (sensoriomotora, cognitiva, conductual) y la neurociencia, así como el impacto de funciones y estructuras corporales sobre la actividad y la participación. El modelo de ciencia de sistemas del BCRF es una forma útil de comprender y responder a la complejidad de la parálisis cerebral, con el objetivo global de optimizar la experiencia vivida de todo individuo en cualquier contexto.
Climatic effects on soil phosphorus pools and availability in sub‐Saharan Africa
Authors: Mutwale Nkumbu M. , Jorge Felicidade , Chabala Lydia Mumbi , Shepande Chizumba , Chishala Benson H. , Cambule Armindo , Nhantumbo Alfredo , Matangue Mario , Braun Melanie , Sandhage‐Hofmann Alexandra , Amelung Wulf
Published: December 2023

Phosphorus (P) is a key limiting nutrient in tropical and subtropical soils but with unknown responses to climate change. We hypothesized that storage and distribution of P pools differ between reference soil groups, but P availability increases with an increase in precipitation in native sub‐Saharan Africa, an underrepresented region in the global P database. To test these hypotheses, we sampled topsoils (0–10 cm; Arenosols, Lixisols, Acrisols) of uncultivated Savannah woodlands along climate gradients stretching from Mozambique to Zambia. Mean annual precipitation (MAP) ranged from 365 to 1227 mm. We extracted P fractions using Hedley's sequential fractionation, yielding resin‐exchangeable P, P in 0.5 M NaHCO3, 0.1 M NaOH, 1 M HCl and aqua regia. Extracts were analysed for total P using inductively coupled plasma–optical emission spectroscopy and inorganic P using the colorimetric molybdenum blue method. We found that total P contents were highest in Acrisols (235 ± 76 mg kg−1), followed by Lixisols (214 ± 45 mg kg−1) and Arenosols (133 ± 74 mg kg−1). Beside P storage, also P distribution differed between soils. Mean annual temperature (MAT) did not reveal significant correlations with P fractions. However, with increasing MAP, concentrations of almost all P pools increased; available Pi (Resin‐P) increased significantly in Arenosols while potentially bioavailable P (NaHCO3‐Po) increased in all soils, with MAP explaining 43% of data variability in Arenosols, 74% in Lixisols and 85% in Acrisols. Hence, P availability increased with an increase in MAP to different degrees, that is, climatic effects on P dynamics were soil‐group‐specific. Therefore, different regions in the native sub‐Saharan woodlands are likely prone to different soil fertility responses when climate changes.
Effects of pathogen reproduction system on the evolutionary and epidemiological control provided by deployment strategies for two major resistance genes in agricultural landscapes
Authors: Zaffaroni Marta , Rimbaud Loup , Rey Jean‐François , Papaïx Julien , Fabre Frédéric
Published: December 2023

Resistant cultivars are of value for protecting crops from disease, but can be rapidly overcome by pathogens. Several strategies have been proposed to delay pathogen adaptation (evolutionary control), while maintaining effective protection (epidemiological control). Resistance genes can be (i) combined in the same cultivar (pyramiding), (ii) deployed in different cultivars sown in the same field (mixtures) or in different fields (mosaics), or (iii) alternated over time (rotations). The outcomes of these strategies have been investigated principally in pathogens displaying pure clonal reproduction, but many pathogens have at least one sexual event in their annual life cycles. Sexual reproduction may promote the emergence of superpathogens adapted to all the resistance genes deployed. Here, we improved the spatially explicit stochastic model landsepi to include pathogen sexual reproduction, and we used the improved model to investigate the effect of sexual reproduction on evolutionary and epidemiological outcomes across deployment strategies for two major resistance genes. Sexual reproduction favours the establishment of a superpathogen when single mutant pathogens are present together at a sufficiently high frequency, as in mosaic and mixture strategies. However, sexual reproduction did not affect the strategy recommendations for a wide range of mutation probabilities, associated fitness costs, and landscape organisations.
A multi‐scale feature fusion convolutional neural network for facial expression recognition
Authors: Zhang Xiufeng , Fu Xingkui , Qi Guobin , Zhang Ning
Published: December 2023

This paper designs a new facial Expression recognition network called a multi‐scale feature Fusion Convolutional neural Network (EFCN). This network is proposed to solve two problems in the facial expression recognition task. First, there are many commonalities between faces of different expression categories, and the recognition task cannot be precisely performed when the commonality is greater than the individuality. Secondly, facial detail features have a significant impact on the final results of expression recognition, while the image detail features extracted by traditional convolutional neural networks are not sufficient. In order to address the above issues, the feature enhancement network (FEN) and the detail information enhancement module (DEM) are designed. The FEN fuses deep and shallow features. Accordingly, the feature map contains richer information, making it easy to identify the samples. The DEM extracts and fuses the features passed by the backbone network with multi‐scale features to enhance the network's ability to extract features from small regions of the face. We validated the proposed method on three datasets, RAF‐DB, CK+, and JAFFE, and achieved 84.50%, 97.86%, and 91.05% accuracy, respectively, and the experimental results showed the effectiveness of the proposed method in this paper. For example, on the JAFFE dataset, the recognition accuracy of this method surpasses the MLT method by 1.87%.
Protists regulate microbially mediated organic carbon turnover in soil aggregates
Authors: Liao Hao , Hao Xiuli , Li Yiting , Ma Silin , Gao Shenghan , Cai Peng , Chen Wenli , Huang Qiaoyun
Published: December 2023

Soil protists, the major predator of bacteria and fungi, shape the taxonomic and functional structure of soil microbiome via trophic regulation. However, how trophic interactions between protists and their prey influence microbially mediated soil organic carbon turnover remains largely unknown. Here, we investigated the protistan communities and microbial trophic interactions across different aggregates‐size fractions in agricultural soil with long‐term fertilization regimes. Our results showed that aggregate sizes significantly influenced the protistan community and microbial hierarchical interactions. Bacterivores were the predominant protistan functional group and were more abundant in macroaggregates and silt + clay than in microaggregates, while omnivores showed an opposite distribution pattern. Furthermore, partial least square path modeling revealed positive impacts of omnivores on the C‐decomposition genes and soil organic matter (SOM) contents, while bacterivores displayed negative impacts. Microbial trophic interactions were intensive in macroaggregates and silt + clay but were restricted in microaggregates, as indicated by the intensity of protistan‐bacterial associations and network complexity and connectivity. Cercozoan taxa were consistently identified as the keystone species in SOM degradation‐related ecological clusters in macroaggregates and silt + clay, indicating the critical roles of protists in SOM degradation by regulating bacterial and fungal taxa. Chemical fertilization had a positive effect on soil C sequestration through suppressing SOM degradation‐related ecological clusters in macroaggregate and silt + clay. Conversely, the associations between the trophic interactions and SOM contents were decoupled in microaggregates, suggesting limited microbial contributions to SOM turnovers. Our study demonstrates the importance of protists‐driven trophic interactions on soil C cycling in agricultural ecosystems.
The impact of long‐distance commuting on salaries and employment in host regions in Chile
Authors: Carriel Viviana , Pérez‐Trujillo Manuel , Lufin Marcelo , Atienza Miguel
Published: December 2023

Long‐distance commuting (LDC) is an increasingly relevant strategy of labor mobility worldwide and is therefore key to understanding the structure and dynamics of labor markets. However, little is known about the effect that LDC has on the labor market equilibrium of host territories. This paper addresses this gap for the case of Chile. While LDC is a useful strategy for improving salary and employment on a national scale, our results show a negative effect for residents in host territories (on a local scale), particularly when LDC results in commuters with similar characteristics to residents competing for the same jobs.
Preparedness for the transition to medical registrar from senior house officer—What's the problem?
Authors: Shannon Eileen , Cantillon Peter
Published: December 2023

Introduction

Transitions in clinical training are a hallmark in medical trainee's careers. The transition from senior house officer (SHO) to the role of medical registrar is often viewed as one of the most challenging, but to date, there is little research exploring why the transition is proving problematic for so many learners. The aim of this study was to explore the experiences of trainees preparing to make this transition.

Methods

Using an interpretative phenomenological analysis (IPA) approach, this qualitative study employed semi‐structured interviews to explore the lived experiences of transition in a purposive sample of trainees on the cusp of transition from SHO to registrar or who were in their first year of being a medical registrar. Interviews were recorded, transcribed verbatim and analysed using an IPA approach.

Results

Six trainees participated in this study, four of whom were currently in SHO positions, with the remaining two in their first year of medical registrar. Two main themes emerged from data—perception of the medical registrar and barriers in transition. The role of the medical registrar was perceived to represent a strong leadership role, with barriers created due to increasing expectations, lack of support and uncertainties regarding the job.

Conclusion

The role of the medical registrar is a challenging one, representing periods of uncertainty, increased expectations and reduced supports. Within this, there is potential to further support SHOs in transitioning to the role of medical registrar.
THE INFLUENCE OF THE NON-SYMMETRIC PUNCHING PROCESS PARAMETER ON THE HOLE SHAPE AND QUALITY OF A COMMERCIALLY PURE TITANIUM SHEET
Authors: Mahardika Muslim , Kurniawan Yani , - Suyitno , Amrullah Muhammad Haritsah , Arifvianto Budi
Published: December 2023

Recently, punching technology has become one of the promising manufacturing techniques for a thin metallic sheet. The processing parameters used in this technique have been recognized to influence the hole shape produced in the working materials. Therefore, it is important to understand the effect of the punching process parameters on the hole shape and quality over the manufactured materials. This study aims to determine the influence of the punching process on the non-symmetrical hole shape and quality over a commercially pure titanium sheet. The effect of punch speed on the punch force and the sheared surface is also studied, by applying the punch velocities of 10, 35 and 70 mm/s. The sheared surface of the hole was examined at its four different sides, namely K (straight), L (outer radius), N (inner radius) and M (straight). The results show uneven distribution of punch strength as detected at the affected region of the non-symmetrical hole. In addition, the punch force increased with the increase of punch speed. Meanwhile, the sheared surfaces on each side were apparently different. The burnish height on the side of the radius was found to be about 0.038 mm higher than that on the straight side. The burnish height on the radius side increases by 0.43 mm with the increasing punch speed from 10 to 70 mm/s. However, the increased punch velocity did not always increase the burr height. The work hardening that occurs on the straight side is smaller by about 15% than the radius side.
COMPUTATIONAL FLUID DYNAMICS MODEL OF THE VENTILATION AIR FLOW FOR A PROTECTIVE ENVIRONMENT ROOM
Authors: Siron Mohd Hazzah Ahmad , Md Nor Md Amin
Published: December 2023

The outbreak of infectious diseases in the healthcare environment has prompted the need to study the efficacy of patients' protection inside a protective environment (PE) room. The main objective of this study is to develop a computational fluid dynamics model for a PE room. The development involved the selection of a turbulence equation and an optimum finite volume size. Prior to selecting the optimum finite volume size, grid convergence test was carried out on the model. Subsequently, the model was validated with a set of experimental data for the selection of the right turbulence equation. The results revealed that the optimum element size is 0.06 m with the realizable k-epsilon turbulence equation as a suitable equation for the room's air flow. The resultant model has laid an important foundation for future simulation studies on the PE room in any healthcare setting.
CLASSIFICATION OF ELECTRICAL FAULT SEVERITY IN A MODERN POWER SYSTEM OPERATING ENVIRONMENT
Authors: Ismaeel Khalel Saraa
Published: December 2023

Electrical power systems frequently experience different kinds of faults while they are used on a daily basis. Therefore, it is crucial to classify faults according to their severity in order to keep the system operating reliably. In this study, a novel method for categorising the severity of faults in the stability of the power system into three cases namely Minor, Moderate, and Major Fault was presented. This method is based on cutting-edge artificial intelligence algorithms. Under different types of faults, the suggested methodology was used in IEEE 9-bus. The study's findings give network operators important information that they can use to spot electrical system weaknesses during serious faults and maintain the power system's dependability and continuity of energy flow.
AN ENHANCED WALABI METHOD FOR EMERGENCY VEHICLE PRIORITY SYSTEM
Authors: Badiruzaman Ainulhuda , Ng Kok Mun , Mohamad Roslina
Published: December 2023

Emergency response time (ERT) is a critical emergency provider's performance indicator. Traffic congestion, particularly at traffic light system (TLS) intersections, substantially impacts the ERT of emergency vehicles (EVs). In order to achieve ERT, it is crucial to have an emergency vehicle priority (EVP) system. EVP with Walabi (EVP-Walabi) method has been introduced but the existing approach caused EV to slow down when approaching TLS. This is because the existing EVP-Walabi method is only able to allow a green signal when the EV joins the queue at the TLS intersection. Therefore, this research introduced an enhanced Walabi method (EVP-Enhanced Walabi) to enhance the EV movement through the intersections. The simulation setup in this research used a series of TLS intersections in Simulation of Urban Mobility (SUMO) operating under uncongested and congested traffic flows. According to the simulation results, the EVP-Enhanced Walabi method mitigated the effect of EV slowing in the lowest and most congested traffic, which TLS without EVP and the original Walabi cannot handle. This can be proven when the improvement percentage range for Time Taken (TT) to reach accident site by EVP-Enhanced Walabi is between 7.05% and 35.18%. In addition, the EV travels at a higher average speed through the intersections, indicating smoother movement to the accident site.
EXPERIMENTAL AND NUMERICAL STUDY ON THE BEHAVIOUR OF SILICA SAND SLOPE MODEL SUBJECTED TO SURCHARGE LOAD
Authors: Ahmad Ishak Aina Syahirah , Jelani Jestin , Wong Soon Yee , Suif Zuliziana , Ahmad Mazuki Ahmad Loqman
Published: December 2023

Natural disasters such as landslides are becoming more frequent due to global warming. Because of the more frequent occurrences of natural disasters, there is an urgent need for researchers in geotechnical engineering to conduct slope stability analysis. This paper presents the findings of a laboratory experiment and numerical analysis of the behaviour of silica sand under static loading conditions. The laboratory experiment modelled a small-scale slope in a 500mm wide, 1000mm high and 1500mm long acrylic box. The numerical modelling in the experiment employed, Finite Element Modelling (FEM), Plaxis 3D, and the Hardening Soil Model (HSM). The researchers conducted a consolidated-drained (CD) triaxial compression test to determine the parameters of the silica sand. The FEM results are similar to the test results for the maximum loading conditions of 9.6kN/m2. The experimental observation revealed that applying a surcharge load on the top of the slope surface resulted in deformation and bulging. These observations were consistent with and validated the experimental and numerical results. The results of this study will be used to investigate the application of a proposed prototype inclinometer sensor for slope monitoring technology.
PROPERTIES OF CONCRETE INCORPORATED WITH SELF-HEALING AND INTERNAL CURING AGENTS
Authors: Rathinam Kumutha , Murali Abishek , D Pershiya , S Kaviarasu
Published: December 2023

In this study, effects of collective addition of self-healing and internal curing agents on the strength and permeation properties of concrete were determined. The internal curing agent Polyethylene Glycol (PEG 400) was added at 2% of cement based on weight and a mixture of Bentonite, Quick lime and Magnesium oxide were replaced for cement at 5% each as self-healing agent. Six mixes were investigated which includes a control mix (water curing), a mix with PEG 400 (with and without water curing), a mix with self-healing agents (water curing) and a mix integrated PEG 400 and self-healing agents. (With and without water curing) The density of concrete and strength parameters like compressive, flexural and tensile strengths were found by conducting experiments using the procedures given in testing standards. Permeation features were also studied by subjecting the concrete to water absorption and sorptivity tests. Density values lowered because of internal curing agents. The integration of internal curing and self-healing agents have adverse effects on density, strengths, water absorption and sorptivity co-efficients but there is an improvement in the mentioned properties when the specimens were cured in water.
Definitions and measures of long COVID fatigue in adults: a scoping review protocol
Authors: Thomas Bethan , Pattinson Rachael , Edwards Deborah , Dale Carys , Jenkins Benjamin , Lande Helena , Bundy Christine , Davies Jennifer L.
Published: December 2023

Objective:

The aim of this scoping review is to investigate how fatigue is defined and measured in adults with long COVID.

Introduction:

Following COVID-19 infection, 10% to 20% of individuals experience persisting symptoms for a minimum of 3 months; this is commonly known as long COVID. Fatigue is one of the most prevalent symptoms of long COVID, but there is currently no consistently applied definition of long COVID fatigue. To advance our understanding of long COVID fatigue, we must first identify the current definitions and measures being used to describe and mesure this condition.

Inclusion criteria:

This review will consider published and unpublished studies involving adults (≥18 years) that define and/or measure long COVID fatigue. Papers using quantitative or qualitative designs will be included. Conference abstracts, editorials, and opinion papers will be excluded.

Methods:

Published studies from January 2020 onwards will be searched for across MEDLINE (Ovid), CINAHL (EBSCOhost), Embase (Ovid), Scopus, PsycINFO (Ovid), Web of Science Core Collection, Epistemonikos, and Cochrane Central Register of Controlled Trials (CENTRAL). Dimensions, Overton, and ProQuest Dissertations and Theses will be searched for unpublished literature. Eligible records will be de-duplicated, and 2 independent reviewers will carry out title, abstract, and full-text screening. A data extraction tool will be pilot tested on a small number of papers, then modified as necessary, with any modifications detailed in the scoping review. Findings will be presented in tables and charts, supported by a narrative summary.

Review registration:

Open Science Framework https://osf.io/hnf8z
On reading non-participation as refusal
Authors: Meziant Kahina
Published: December 2023

Within the UK (the United Kingdom) charity sector, challenges persist in involving asylum seekers, migrants, and refugees in shaping services aimed at supporting and facilitating their everyday experiences. In that context, the study reframes non-participation as refusals of two kinds: noncompliance and departure. It challenges traditional participation models by exposing non-participation as a form of non-explicit agency for marginalised people. Looking at refusals though the lens of a two-year immersive study involving institutional ethnography and participatory research, it emphasises nuanced micropolitical dynamics in a charity supporting migrants and refugees’ ‘integration’ in a city of Northeast England. By examining and reinterpreting what stands behind people’s non-participation, the paper argues that the charity’s engagement with its internal politics and social dynamics is essential if it wants to foster active participation. It suggests these insights can uncover participation paradoxes and offer alternative engagement approaches. Ultimately, the research illuminates the gap between organizational intent and outcomes, contributing to debates on migration, critical humanitarianism and charity, as well as participation.
Pharmacokinetics and cardiac safety of clofazimine in children with rifampicin-resistant tuberculosis
Authors: Ali Ali Mohamed , P. Solans Belén , Hesseling Anneke C. , Winckler Jana , Schaaf H. Simon , Draper Heather R. , van der Laan Louvina , Hughes Jennifer , Fourie Barend , Nielsen James , Wiesner Lubbe , Garcia-Prats Anthony J. , Savic Radojka M.
Published: December 2023

Clofazimine is recommended for the treatment of rifampicin-resistant tuberculosis (RR-TB), but there is currently no verified dosing guideline for its use in children. There is only limited safety and no pharmacokinetic (PK) data available for children. We aimed to characterize clofazimine PK and its relationship with QT-interval prolongation in children. An observational cohort study of South African children <18 years old routinely treated for RR-TB with a clofazimine-containing regimen was analyzed. Clofazimine 100 mg gelatin capsules were given orally once daily (≥20 kg body weight), every second day (10 to <20 kg), or thrice weekly (<10 kg). PK sampling and electrocardiograms were completed pre-dose and at 1, 4, and 10 hours post-dose, and the population PK and Fridericia-corrected QT (QTcF) interval prolongation were characterized. Fifty-four children contributed both PK and QTcF data, with a median age (2.5th–97.5th centiles) of 3.3 (0.5–15.6) years; five children were living with HIV. Weekly area under the time-concentration curve at steady state was 79.1 (15.0–271) mg.h/L compared to an adult target of 60.9 (56.0–66.6) mg.h/L. Children living with HIV had four times higher clearance compared to those without. No child had a QTcF ≥500 ms. A linear concentration-QTcF relationship was found, with a drug effect of 0.05 (0.027, 0.075) ms/µg/L. In some of the first PK data in children, we found clofazimine exposure using an off-label dosing strategy was higher in children versus adults. Clofazimine concentrations were associated with an increase in QTcF, but severe prolongation was not observed. More data are required to inform dosing strategies in children.
FlhF affects the subcellular clustering of WspR through HsbR in
Pseudomonas aeruginosa
Authors: Guan Congcong , Huang Yi , Zhou Yun , Han Yuqian , Liu Shuhui , Liu Shimin , Kong Weina , Wang Tietao , Zhang Yani
Published: December 2023

In bacteria, the second messenger cyclic di-GMP (c-di-GMP) is synthesized and degraded by multiple diguanylate cyclases (DGCs) and phosphodiesterases. A high level of c-di-GMP induces biofilm formation and represses motility. WspR, a hybrid response regulator DGC, produces c-di-GMP when it is phosphorylated. FlhF, a signal recognition particle-type GTPase, is initially localized to the cell poles and is indispensable for polar flagellar localization in
Pseudomonas aeruginosa
. In this study, we report that deletion of
flhF
affected biofilm formation and the c-di-GMP level in
P. aeruginosa
. Phenotypic analysis of a
flhF
knockout mutant revealed increased biofilm formation, wrinkled colonies on Congo red agar, and an elevated c-di-GMP level compared to the wild-type strain, PAO1. Yeast and bacterial two-hybrid systems showed that FlhF binds to the response regulator HsbR, and HsbR binds to WspR. Deletion of
hsbR
or
wspR
in the Δ
flhF
background abolished the phenotype of Δ
flhF
. In addition, confocal microscopy demonstrated that WspR-GFP was distributed throughout the cytoplasm and formed a visible cluster at one cell pole in PAO1 and Δ
hsbR
, but it was mainly distributed as visible clusters at the lateral side of the periplasm and with visible clusters at both cell poles in Δ
flhF
. These findings suggest that FlhF influences the subcellular cluster and localization of WspR and negatively modulates WspR DGC activity in a manner dependent on HsbR. Together, our findings demonstrate a novel mechanism for FlhF modulating the lifestyle transition between motility and biofilm via HsbR to regulate the DGC activity of WspR.

IMPORTANCE

Cyclic di-GMP (c-di-GMP) is a second messenger that controls flagellum biosynthesis, adhesion, virulence, motility, exopolysaccharide production, and biofilm formation in bacteria. Recent research has shown that distinct diguanylate cyclases (DGCs) or phosphodiesterases (PDEs) produce highly specific outputs. Some DGCs and PDEs contribute to the total global c-di-GMP concentration, but others only affect local c-di-GMP in a microenvironment. However, the underlying mechanisms are unclear. Here, we report that FlhF affects the localization and DGC activity of WspR via HsbR and is implicated in local c-di-GMP signaling in
Pseudomonas aeruginosa
. This study establishes the link between the c-di-GMP signaling system and the flagellar localization and provides insight for understanding the complex regulatory network of c-di-GMP signaling.
Requirement of GrgA for
Chlamydia
infectious progeny production, optimal growth, and efficient plasmid maintenance
Authors: Lu Bin , Wang Yuxuan , Wurihan Wurihan , Cheng Andrew , Yeung Sydney , Fondell Joseph D. , Lai Zhao , Wan Danny , Wu Xiang , Li Wei Vivian , Fan Huizhou
Published: December 2023

Chlamydia
, an obligate intracellular bacterial pathogen, has a unique developmental cycle involving the differentiation of invading elementary bodies (EBs) to noninfectious reticulate bodies (RBs), replication of RBs, and redifferentiation of RBs into progeny EBs. Progression of this cycle is regulated by three sigma factors, which direct the RNA polymerase to their respective target gene promoters. We hypothesized that the
Chlamydia-
specific transcriptional regulator GrgA, previously shown to activate σ66 and σ28, plays an essential role in chlamydial development and growth. To test this hypothesis, we applied a novel genetic tool known as dependence on plasmid-mediated expression to create
Chlamydia trachomatis
with conditional GrgA deficiency. We show that GrgA-deficient
C. trachomatis
RBs have a growth rate that is approximately half of the normal rate and fail to transition into progeny EBs. In addition, GrgA-deficient
C. trachomatis
fails to maintain its virulence plasmid. Results of RNA-Seq analysis indicate that GrgA promotes RB growth by optimizing tRNA synthesis and expression of nutrient-acquisition genes, while it enables RB-to-EB conversion by facilitating the expression of a histone and outer membrane proteins required for EB morphogenesis. GrgA also regulates numerous other late genes required for host cell exit and subsequent EB invasion into host cells. Importantly, GrgA stimulates the expression of σ54, the third and last sigma factor, and its activator, AtoC, and thereby indirectly upregulating the expression of σ54-dependent genes. In conclusion, our work demonstrates that GrgA is a master transcriptional regulator in
Chlamydia
and plays multiple essential roles in chlamydial pathogenicity.

IMPORTANCE

Hallmarks of the developmental cycle of the obligate intracellular pathogenic bacterium
Chlamydia
are the primary differentiation of the infectious elementary body (EB) into the proliferative reticulate body (RB) and the secondary differentiation of RBs back into EBs. The mechanisms regulating these transitions remain unclear. In this report, we developed an effective novel strategy termed dependence on plasmid-mediated expression (DOPE) that allows for the knockdown of essential genes in
Chlamydia
. We demonstrate that GrgA, a
Chlamydia
-specific transcription factor, is essential for the secondary differentiation and optimal growth of RBs. We also show that GrgA, a chromosome-encoded regulatory protein, controls the maintenance of the chlamydial virulence plasmid. Transcriptomic analysis further indicates that GrgA functions as a critical regulator of all three sigma factors that recognize different promoter sets at developmental stages. The DOPE strategy outlined here should provide a valuable tool for future studies examining chlamydial growth, development, and pathogenicity.
The post-COVID-19 population has a high prevalence of cross-reactive antibodies to spikes from all
Orthocoronavirinae
genera
Authors: Singh Gagandeep , Abbad Anass , Kleiner Giulio , Srivastava Komal , Gleason Charles ,   PARIS Study Group, Carreño Juan Manuel , Simon Viviana , Krammer Florian , Andre Dalles , Bermúdez-González Maria C , Bielak Dominika , Cai Gianna , Cognigni Christian , Chen Yuexing , Fried Miriam , Kang Hyun Min , Lyttle Neko , Mauldin Jacob , Monahan Brian , Morris Sara , Nardulli Jessica , Oostenink Annika , Salimbangon Ashley-Beathrese , Sullivan Leeba , Van Kesteren Morgan , Yellin Temima
Published: December 2023

The Orthocoronavirinae subfamily is large comprising four highly divergent genera. Four seasonal coronaviruses were circulating in humans prior to the coronavirus disease 2019 pandemic. Infection with these viruses induced antibody responses that are relatively narrow with little cross-reactivity to spike proteins of other coronaviruses. Here, we report that infection with and vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces broadly cross-reactive binding antibodies to spikes from a wide range of coronaviruses including members of the sarbecovirus subgenus, other betacoronaviruses including Middle Eastern respiratory syndrome coronavirus, and extending to alpha-, gamma-, and delta-coronavirus spikes. These data show that the coronavirus spike antibody landscape in humans has profoundly been changed and broadened as a result of the SARS-CoV-2 pandemic. While we do not understand the functionality of these cross-reactive antibodies and their impact, there is the possibility that they may lead to enhanced resistance of the population to infection with newly emerging coronaviruses with pandemic potential.

IMPORTANCE

As demonstrated by severe acute respiratory syndrome coronavirus 2, coronaviruses pose a significant pandemic threat. Here, we show that coronavirus disease 2019 mRNA vaccination can induce significant levels of cross-reactive antibodies against diverse coronavirus spike proteins. While these antibodies are binding antibodies that likely have little neutralization capacity and while their contribution to cross-protection is unclear, it is possible that they may play a role in protection from progression to severe disease with novel coronaviruses.
Inoviridae
prophage and bacterial host dynamics during diversification, succession, and Atlantic invasion of Pacific-native
Vibrio parahaemolyticus
Authors: Foxall Randi L. , Means Jillian , Marcinkiewicz Ashely L. , Schillaci Christopher , DeRosia-Banick Kristin , Xu Feng , Hall Jeffrey A. , Jones Stephen H. , Cooper Vaughn S. , Whistler Cheryl A.
Published: December 2023

The epidemiology of
Vibrio parahaemolyticus
, the leading cause of seafood-borne bacterial gastroenteritis of humans worldwide, dramatically changed in the United States following the establishment of a Pacific-native lineage called sequence type (ST) 36 in the Atlantic. In this study, we used phylogeography based on traceback to environmental source locations and comparative genomics to identify features that promoted evolution, dispersal, and competitive dominance of ST36. The major genomic differentiation and competitive success of ST36 were associated with a striking succession of filamentous prophage in the family
Inoviridae
(inoviruses), including loss of an inovirus prophage that had been maintained for decades in the endemic north Pacific population. Subsequently, at least five distinct progenitors arising from this diversification translocated from the Pacific into the Atlantic and established four geographically defined clonal subpopulations with remarkably low migration or mixing. Founders of two prevailing Atlantic subpopulations each acquired new stable and diagnostic inoviruses while other subpopulations that apparently declined did not. Broader surveys indicate inoviruses are common and active among the global population of
V. parahaemolyticus
, and though inovirus replacements, such as in ST36, appear to be infrequent, they are notable in pathogenic lineages that dispersed.

IMPORTANCE

An understanding of the processes that contribute to the emergence of pathogens from environmental reservoirs is critical as changing climate precipitates pathogen evolution and population expansion. Phylogeographic analysis of
Vibrio parahaemolyticus
hosts combined with the analysis of their
Inoviridae
phage resolved ambiguities of diversification dynamics which preceded successful Atlantic invasion by the epidemiologically predominant ST36 lineage. It has been established experimentally that filamentous phage can limit host recombination, but here, we show that phage loss is linked to rapid bacterial host diversification during epidemic spread in natural ecosystems alluding to a potential role for ubiquitous inoviruses in the adaptability of pathogens. This work paves the way for functional analyses to define the contribution of inoviruses in the evolutionary dynamics of environmentally transmitted pathogens.
Structural basis of increased binding affinities of spikes from SARS-CoV-2 Omicron variants to rabbit and hare ACE2s reveals the expanding host tendency
Authors: Shi Kaiyuan , Li Linjie , Luo Chunliang , Xu Zepeng , Huang Baihan , Ma Sufang , Liu Kefang , Yu Guanghui , Gao George F.
Published: December 2023

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has swept the globe and caused immense health and economic damage. SARS-CoV-2 has demonstrated a broad host range, indicating a high risk of interspecies transmission and adaptive mutation. Therefore, constant monitoring for potential hosts is of immense importance. In this study, we found that Omicron BA.4/5 and subsequent-emerged sub-variants exhibited enhanced binding to both rabbit and hare angiotensin-converting enzyme 2 (ACE2), and we elucidated the structural mechanism of their recognition. From the structure, we found that Q34, a unique residue of rabbit ACE2 compared to other ACE2 orthologs, plays an important role in ACE2 recognition. These results address the probability of rabbits/hares being potential hosts of SARS-CoV-2 and broaden our knowledge regarding the molecular mechanism of SARS-CoV-2 interspecies transmission.
Understanding Fc function for rational vaccine design against pathogens
Authors: Bowman Kathryn A. , Kaplonek Paulina , McNamara Ryan P.
Published: December 2023

Antibodies represent the primary correlate of immunity following most clinically approved vaccines. However, their mechanisms of action vary from pathogen to pathogen, ranging from neutralization, to opsonophagocytosis, to cytotoxicity. Antibody functions are regulated both by antigen specificity (Fab domain) and by the interaction of their Fc domain with distinct types of Fc receptors (FcRs) present in immune cells. Increasing evidence highlights the critical nature of Fc:FcR interactions in controlling pathogen spread and limiting the disease state. Moreover, variation in Fc-receptor engagement during the course of infection has been demonstrated across a range of pathogens, and this can be further influenced by prior exposure(s)/immunizations, age, pregnancy, and underlying health conditions. Fc:FcR functional variation occurs at the level of antibody isotype and subclass selection as well as post-translational modification of antibodies that shape Fc:FcR-interactions. These factors collectively support a model whereby the immune system actively harnesses and directs Fc:FcR interactions to fight disease. By defining the precise humoral mechanisms that control infections, as well as understanding how these functions can be actively tuned, it may be possible to open new paths for improving existing or novel vaccines.
Variations in the oral microbiome and metabolome of methamphetamine users
Authors: Wang Dawei , Feng Yu , Yang Min , Sun Haihui , Zhang Qingchen , Wang Rongrong , Tong Shuqing , Su Rui , Jin Yan , Wang Yunshan , Lu Zhiming , Han Lihui , Sun Yundong
Published: December 2023

Drug addiction can seriously damage human physical and mental health, while detoxification is a long and difficult process. Although studies have reported changes in the oral microbiome of methamphetamine (METH) users, the role that the microbiome plays in the process of drug addiction is still unknown. This study aims to explore the function of the microbiome based on analysis of the variations in the oral microbiome and metabolome of METH users. We performed the 16S rRNA sequencing analysis based on the oral saliva samples collected from 278 METH users and 105 healthy controls (CTL). In addition, the untargeted metabolomic profiling was conducted based on 220 samples. Compared to the CTL group, alpha diversity was reduced in the group of METH users and the relative abundances of
Peptostreptococcus
and
Gemella
were significantly increased, while the relative abundances of
Campylobacter
and
Aggregatibacter
were significantly decreased. Variations were also detected in oral metabolic pathways, including enhanced tryptophan metabolism, lysine biosynthesis, purine metabolism, and steroid biosynthesis. Conversely, the metabolic pathways of porphyrin metabolism, glutathione metabolism, and pentose phosphate were significantly reduced. It was speculated that four key microbial taxa, i.e.,
Peptostreptococcus
,
Gemella
,
Campylobacter
, and
Aggregatibacter
, could be involved in the toxicity and addiction mechanisms of METH by affecting the above metabolic pathways. It was found that with the increase of drug use years, the content of tryptamine associated with neuropsychiatric disorders was gradually increased. Our study provides novel insights into exploring the toxic damage and addiction mechanisms underlying the METH addiction.

IMPORTANCE

It was found that with the increase of drug use years, the content of tryptamine associated with neuropsychiatric disorders gradually increased. The prediction models based on oral microbiome and metabolome could effectively predict the methamphetamine (METH) smoking. Our study provides novel insights into the exploration of the molecular mechanisms regulating the toxic damage and addiction of METH as well as new ideas for early prevention and treatment strategies of METH addiction.
Supplemental Material: Eocene crustal thickening in the Tethyan Himalaya: Insights from Barrovian metamorphism and granite geochemistry from the Ramba area
Authors: Shi Shuai , Jiang Yingde , et al.
Published: December 2023

Table S1: Summary of sample locations of granite and mica schist from the Ramba area. Table S2: Summary of LA-ICP-MS zircon standards U-Pb data. Table S3: Summary of LA-ICP-MS monazite standards U-(Th)-Pb data. Table S4: Major- and trace-elemental compositions of granite from the Ramba area and similar rocks from the region. Table S5: LA-ICP-MS zircon U-Pb isotopic data of the granite dikes from the Ramba area. Table S6: LA-ICP-MS monazite U-(Th)-Pb isotopic data of mica schists from the Ramba area. Table S7: Summary of monazite trace-elemental data of the mica schist from the Ramba dome.