bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi‐omics analyses reveal the importance of chromoplast plastoglobules in carotenoid accumulation in citrus fruit
Authors: Liu Yun , Ye Junli , Zhu Man , Atkinson Ross G. , Zhang Yingzi , Zheng Xiongjie , Lu Jiao , Cao Zhen , Peng Jun , Shi Chunmei , Xie Zongzhou , Larkin Robert M. , Nieuwenhuizen Niels J. , Ampomah‐Dwamena Charles , Chen Chuanwu , Wang Rui , Luo Xiaozhou , Cheng Yunjiang , Deng Xiuxin , Zeng Yunliu
Published: October 2023

Chromoplasts act as a metabolic sink for carotenoids, in which plastoglobules serve as versatile lipoprotein particles. PGs in chloroplasts have been characterized. However, the features of PGs from non‐photosynthetic plastids are poorly understood. We found that the development of chromoplast plastoglobules (CPGs) in globular and crystalloid chromoplasts of citrus is associated with alterations in carotenoid storage. Using Nycodenz density gradient ultracentrifugation, an efficient protocol for isolating highly purified CPGs from sweet orange (Citrus sinensis) pulp was established. Forty‐four proteins were defined as likely comprise the core proteome of CPGs using comparative proteomics analysis. Lipidome analysis of different chromoplast microcompartments revealed that the nonpolar microenvironment within CPGs was modified by 35 triacylglycerides, two sitosterol esters, and one stigmasterol ester. Manipulation of the CPG‐localized gene CsELT1 (esterase/lipase/thioesterase) in citrus calli resulted in increased lipids and carotenoids, which is further evidence that the nonpolar microenvironment of CPGs contributes to carotenoid accumulation and storage in the chromoplasts. This multi‐feature analysis of CPGs sheds new light on the role of chromoplasts in carotenoid metabolism, paving the way for manipulating carotenoid content in citrus fruit and other crops.
Numerical and Experimental Investigation of a Volumetric Resistance Blower Performance and Its Optimization for Portable Computing Device Applications
Authors: Kumar Amit , Majumder Ayan , Cardenas Ruander , MacDonald Mark , Bhattacharya Anandaroop
Published: October 2023

In this paper, we present our results on a relatively new kind of blower called Volumetric Resistance Blower (VRB) for cooling of portable computing platforms like laptop computers. The VRB performance was modeled numerically and compared to traditional bladed blowers. The sources of noise, dominant in bladed blower, are absent in case of VRB, because it uses a continuous porous disk instead of discrete blades. Thus, even though at iso-rpm, VRB yielded lower flowrate, its iso-acoustic performance could be superior. Hence, further analysis was crucial to quantify the potential benefit. The acoustics experiments for bladed blower and VRB were conducted in a hemi-anechoic chamber in accordance with ECMA-74 and ECMA TR/99 standards. Iso-acoustics pressure versus volume flowrate plot for both bladed blower and VRB are compared. VRB was found to have superior performance as compared to bladed blower. The volume flowrate at open flow condition for bladed blower and VRB are comparable, but as back pressure increased the flowrate yielded by VRB kept increasing and at stagnation condition, VRB showed around 79% higher static pressure. In the second part of the work, the experimentally validated numerical model for VRB was used for numerical optimization using a design of experiments (DOE) approach and varying the geometrical parameters. Rotor distance (minimum distance from the axis of rotation of impeller to the cutwater surface) was found to be the most important parameter, and an optimum value was found. A second DOE elucidated the optimal rotor hub center location in the two-dimensional space inside the casing as when the rotor is tucked back into the casing as much as possible and when the rotor distance is above 20.15 mm. A partial P–Q curve is generated (up to 20 Pa) for optimal geometry configuration. Based on the numerical and experimental evidence, VRB is found to have the potential to replace traditional bladed design in portable computing devices. In addition, due to absence of blades, it creates lower tonal noise, giving a much more comfortable experience to the end user.
A Numerical Study of Cyclist-Cyclist Aerodynamic Interaction towards Efficient Overtaking Strategy
Authors: Cantos Sinforiano , Mok Kwan Pui , Zhou Peng , Jiang Hanbo , Mao Xiaochen , Zhong Siyang , Zhang Xin
Published: October 2023

In cycling races, overtaking is a crucial maneuver that involves drafting behind and moving to the side of another cyclist. The flow interaction between the cyclists has a very significant impact on the aerodynamic performance. Previous experimental and numerical studies have shown the aerodynamic drag changes at certain relative positions between cyclists. This study aims at providing a comprehensive aerodynamic power contour along a complete overtaking path, detailing the power at different relative positions to develop efficient overtaking strategies. The aerodynamic results are obtained with numerical simulations, the accuracy of which is validated against wind tunnel experiments. Improved sampling and data-fitting approaches are employed to enhance previous findings. The results show that starting the overtaking maneuver closest to the leading cyclist and overtaking with a larger lateral separation is the most aerodynamically efficient strategy. These findings provide valuable insights into developing optimal overtaking strategies in competitive cycling races.
A Computational Study to Predict the Seakeeping Performance of a Surfaced Submarine in Irregular Waves
Authors: Jung Doojin , Kim Sanghyun
Published: October 2023

In general, submarines are designed to optimize operation below the water surface because they spend most of their time underwater. On the other hand, the performance in the free surface condition is also important because submarines face a variety of scenarios to complete operational missions, and the free surface condition is unavoidable for port departure and arrival. In the case of a submarine, the numerical accuracy of the potential theory for seakeeping analysis is excellent in submerged conditions, but it is poor in free surface conditions because of nonlinear effects near the free surface area. In this study, star-ccm+ was used as a Reynolds-averaged Navier–Stokes (RANS) solver to estimate the seakeeping performance of a Canadian Victoria Class submarine in irregular waves. The results were compared with those of model tests from a published paper. In addition, the potential theory code was also used to assess the seakeeping performance and compare it with computational fluid dynamics (CFD) results. From the calculation results, the motion responses in irregular waves using CFD showed similar trends to the experimental results. In contrast, motion responses from potential code showed significantly larger values than the experimental results. In conclusion, CFD simulations with irregular waves can be a good solution to predict the seakeeping performance of submarines in free surface conditions.
Data Informed Model Test Design With Machine Learning–An Example in Nonlinear Wave Load on a Vertical Cylinder
Authors: Tang Tianning , Ding Haoyu , Dai Saishuai , Chen Xi , Taylor Paul H. , Zang Jun , Adcock Thomas A. A.
Published: October 2023

Model testing is common in coastal and offshore engineering. The design of such model tests is important such that the maximal information of the underlying physics can be extrapolated with a limited amount of test cases. The design of experiments also requires considering the previous similar experimental results and the typical sea-states of the ocean environments. In this study, we develop a model test design strategy based on Bayesian sampling for a classic problem in ocean engineering—nonlinear wave loading on a vertical cylinder. The new experimental design strategy is achieved through a GP-based surrogate model, which considers the previous experimental data as the prior information. The metocean data are further incorporated into the experimental design through a modified acquisition function. We perform a new experiment, which is mainly designed by data-driven methods, including several critical parameters such as the size of the cylinder and all the wave conditions. We examine the performance of such a method when compared to traditional experimental design based on manual decisions. This method is a step forward to a more systematic way of approaching test designs with marginally better performance in capturing the higher-order force coefficients. The current surrogate model also made several “interpretable” decisions which can be explained with physical insights.
A Novel Method of Designing Random Rough Surface Considering Its Contact Force–Deformation Characteristic Requirement
Authors: Guo Xuxin , Liu Daxin , Liu Zhenyu , Tan Jianrong
Published: October 2023

The height probability distribution (HPD) of random rough surface topography has significant effect on its contact behaviors. In this paper, an optimization model to calculate the optimal HPD of random rough surface topography to make its contact force–deformation characteristic satisfy the given target force–deformation characteristic was established. In the solution to calculate the optimal HPD, using Bezier interpolation curve to represent the curve of HPD function and using the positions of the control points of the Bezier interpolation curve as optimization variables were proposed. The solution was validated by numerical simulations implemented using matlab. The effect of the number of control points on the minimum objective function value was investigated. Through analyzing the obtained result, we found the most appropriate number of the control points is 35. Comparison with the method using height parameters as optimization variables in literature was implemented. It was found that the proposed method is applicable to broader types of contact force–deformation characteristic requirements than the method using height parameters as optimization variables.
El espacio vivido del inconsciente en la cultura Secoya (Alta Amazonía Ecuatoriana)
Authors:   Universidad Rey Juan Carlos, García Labrador Julián
Published: October 2023

Las rápidas trasformaciones a que se ve abocada la Amazonía hacen necesaria la investigación sobre el papel de sus culturas en dichos contextos de interacción. Esta necesidad no puede apartarnos, empero, de la investigación sobre prácticas epistémicas que corren el riesgo real de desaparecer para siempre, toda vez que sus actores morirán en los próximos años. Los elementos míticos y su papel en el proceso de adquisición de conocimiento en la cultura Secoya son una de las asignaturas pendientes en el acercamiento epistémico a dicha cultura. El mito nos transporta a un tiempo y un espacio diferentes de los cotidianos. El tiempo mítico no ha desaparecido de la vida diaria, a pesar del tiempo del calendario. La cultura Secoya (Siekopaai) de la Alta Amazonía Ecuatoriana posee una riqueza conceptual que va ligada al uso pragmalingüístico de los mitos. El contexto mítico interrelaciona el “espacio” físico y el “espacio” mental. Dicho espacio mental, al cual acceden en ciertos ritos, les permite visitar e interactuar con los “tipos míticos” que se nutren del “espacio físico” y proporcionan significado sobre el puesto del hombre en la cultura y el cosmos. El presente trabajo se adentra y presenta estos espacios vividos y su repercusión en el aprendizaje de los Siekopaai
Note on bee mites of Sennertia Oudemans, 1905 (Sarcoptiformes, Astigmata, Chaetodactylidae) from Taiwan, with descriptions of two new species
Authors: Chao Chia-Hui , Lu Sheng-Shan , Sung I-Hsin
Published: October 2023

Five mites of the genus Sennertia Oudemans, 1905: Sennertia alfkeni (Oudemans, 1900), Sennertia eximius sp. nov., Sennertia horrida (Vitzthum, 1912), Sennertia lauta Klimov and OConnor, 2007, Sennertia taiwanensis sp. nov., which are phoretic on carpenter bees (Genus Xylocopa) from Taiwan and Kinmen area, are described and illustrated. The species delimitation among the five Sennertia species using phylogenetic tree and genetic K2P distance analyses is well-defined. The species groups to which these bee mites belong, and their hosts in this area, are as follows: S. alfkeni (japonica-group): Xylocopa (Alloxylocopa) nr. appediculata, X. (Alloxylocopa) phalothorax and X. (Koptortosoma) ruficeps; S. eximius sp. nov. (cerambycina-group): X. (Biluna) auripennis, X. (Zonohirsuta) dejeanii and X. (Biluna) tranquebarorum; S. horrida (horrida-group): X. (Biluna) auripennis and X. (Biluna) tranquebarorum; S. lauta (horrida-group): X. (Zonohirsuta) dejeanii and X. (Biluna) tranquebarorum; S. taiwanensis sp. nov. (horrida-group): X. (Bombioxylocopa) bomboides.
A phase I study of the safety, tolerability, and pharmacokinetics of contezolid acefosamil after intravenous and oral administration in healthy Chinese subjects
Authors: Yang Haijing , Jin Yi , Wang Hailin , Yuan Hong , Wang Jingjing , Li Size , Hu Yingying , Yang Huahui , Li Xin , Liang Hong , Wu Jufang , Cao Guoying , Zhang Jing
Published: October 2023

Contezolid acefosamil (also known as MRX-4), a prodrug of contezolid, is under development for treatment of multidrug-resistant Gram-positive bacterial infections. A phase I single ascending dose (SAD) and multiple-dose placebo-controlled study was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of contezolid acefosamil in healthy Chinese subjects following intravenous (IV) and oral administration. Adverse events (AEs) and PK parameters were assessed appropriately. All subjects (
n
= 70) completed the trial. Overall, 67 cases of treatment-emergent adverse events (TEAEs) were observed in 49.1% (27 of 55) of the subjects receiving contezolid acefosamil. All TEAEs were mild in severity. No serious AEs or deaths were reported. After IV SAD (500–2,000 mg), the corresponding
C
max
of the active drug contezolid increased from 1.95 ± 0.57 to 15.61 ± 4.88 mg/L, AUC
0–inf
from 40.25 ± 10.12 to 129.41 ± 38.30 h·mg/L, median
T
max
from 2.00 to 2.75 h, and mean
t
1/2
from 13.33 to 16.74 h. Plasma contezolid reached steady state on day 6 after multiple IV doses, with an accumulation ratio of 2.20–2.96. Oral SAD of 500 and 1,500 mg resulted in contezolid
C
max
of 8.66 ± 2.60 and 37.10 ± 8.66 mg/L, AUC
0–inf
of 30.44 ± 7.33 and 162.36 ± 47.08 h·mg/L, and median
T
max
of 2.50 and 2.98 h. Contezolid reached steady state on day 5 after multiple oral doses of 1,500 mg without significant accumulation. Contezolid
C
max
and AUC
0–inf
increased with the dose of contezolid acefosamil. The good safety and PK profiles in this SAD and multiple-dose study can support further clinical development of contezolid acefosamil.
Autoinducer-2 promotes adherence of
Aeromonas veronii
through facilitating the expression of MSHA type IV pili genes mediated by c-di-GMP
Authors: Li Yi , Han Shuo , Wang Yuqi , Qin Mengyuan , Lu Chengjin , Ma Yingke , Yang Wenqing , Liu Jiajia , Xia Xiaohua , Wang Hailei
Published: October 2023

Aeromonas veronii.
a ubiquitous of zoonotic disease pathogen, depends on adhesion as the crucial way to colonize the gastrointestinal tract of humans and animals, which further causes severe gastrointestinal diseases and parenteral infections. However, the adherence mechanism of
A. veronii
has not been fully characterized. Therefore, we investigate the effect of autoinducer-2 (AI-2) on adherence of
A. veronii
through facilitating the expression of mannose-sensitive hemagglutinin (MSHA) type IV pili genes mediated by cyclic diguanosine monophosphate (c-di-GMP). The deficiency of AI-2 significantly lowered the adherence of
A. veronii
to erythrocytes and intestinal mucus, and the complement of AI-2 could increase its adherence ability. The deficiency of AI-2 only limited the formation of pili, instead of outer-membrane proteins and lipopolysaccharide, through reducing the expression levels of MSHA type IV pili genes due to the decline of c-di-GMP. The addition of guanosine triphosphate (GTP) could increase the content of c-di-GMP and the expression of MSHA type IV pili genes, and further promote adherence of
A. veronii
. Therefore, this study reveals, for the first time, adherence mediated by c-di-GMP with MshE as the c-di-GMP receptor is positively regulated by AI-2 in
A. veronii
, which increases the understanding of colonization strategy of pathogen and may facilitate control of
A. veronii
infection to host.

IMPORTANCE

Aeromonas veronii
can adhere to host cells through different adherence factors including outer-membrane proteins (OMPs), lipopolysaccharide (LPS), and pili, but its adherence mechanisms are still unclear. Here, we evaluated the effect of autoinducer-2 (AI-2) on adherence of
A. veronii
and its regulation mechanism. After determination of the promotion effect of AI-2 on adherence, we investigated which adherence factor was regulated by AI-2, and the results show that AI-2 only limits the formation of pili. Among the four distinct pili systems, only the mannose-sensitive hemagglutinin (MSHA) type IV pili genes were significantly downregulated after deficiency of AI-2. MshE, an ATPase belonged to MSHA type IV pilin, was confirmed as c-di-GMP receptor, that can bind with c-di-GMP which is positively regulated by AI-2, and the increase of c-di-GMP can promote the expression of MSHA type IV pili genes and adherence of
A. veronii
. Therefore, this study confirms that c-di-GMP positively regulated by AI-2 binds with MshE, then increases the expression of MSHA pili genes, finally promoting adherence of
A. veronii
, suggesting a multilevel positive regulatory adhesion mechanism that is responsible for
A. veronii
adherence.
Tracking the fecal mycobiome through the lifespan of production pigs and a comparison to the feral pig
Authors: Prisnee Tausha L. , Rahman Rajibur , Fouhse Janelle M. , Van Kessel Andrew G. , Brook Ryan K. , Willing Benjamin P.
Published: October 2023

Fungi in the pig gastrointestinal tract (the mycobiome) are believed to be important for host health and development. However, studies profiling the mycobiome over a production cycle and of the feral pig are lacking. The objectives of this study were to profile the pig mycobiome over one production cycle and profile the mycobiome of feral pigs. A total of 24 pigs from 12 litters (
n
= 2 per litter) had fecal swabs taken at 11 days of age (D11), the day before weaning (W − 1), 7 days post-weaning (W + 7), and 119 days post-weaning (W + 119) in a research facility. Their dams (
n
= 12) and an additional eight sows from a commercial barn had fecal swabs taken 3 days after farrowing. A total of 20 feral pigs had intestinal contents collected from the ileum and cecum for a total of 24 samples. Samples were analyzed
via
amplicon sequencing of the internal transcribed spacer 2 rRNA gene. Piglets tended to cluster based on their mother’s
Kazachstania slooffiae
levels on D11 (
P
= 0.087) and significantly clustered on W + 119 (
P
= 0.046). Piglets clustered with their littermate on D11 (
P
= 0.006) and on W + 119 (
P
= 0.007). In summary, we found that pigs maintain the same
K. slooffiae
status as their mothers until the end of the production cycle and show that the feral pig has a complex and unique mycobiome largely represented by ingested fungal species.

IMPORTANCE

This work provides evidence that early-life fungal community composition, or host genetics, influences long-term mycobiome composition. In addition, this work provides the first comparison of the feral pig mycobiome to the mycobiome of intensively raised pigs.
The plant stress hormone jasmonic acid evokes defensive responses in streptomycetes
Authors: van der Meij Anne , Elsayed Somayah S. , Du Chao , Willemse Joost , Wood Thomas M. , Martin Nathaniel I. , Raaijmakers Jos M. , van Wezel Gilles P.
Published: October 2023

Actinobacteria are prevalent in the rhizosphere and phyllosphere of diverse plant species where they help to enhance tolerance of plants against biotic and abiotic stresses. Here, we show that the plant hormones jasmonic acid (JA) and methyl jasmonate (MeJA) affect the growth, development, and specialized metabolism of
Streptomyces
. Exposure of
Streptomyces coelicolor
to JA or MeJA led to enhanced production of the polyketide antibiotic actinorhodin. JA also exhibited toxicity toward
Streptomyces
and
Streptacidiphilus
at higher concentrations, whereby streptomycetes were more tolerant to JA than members of the genus
Streptacidiphilus
. Tolerance to JA could be linked to its conjugation by the bacteria with glutamine. Additionally, JA conjugates with valine, tyrosine, phenylalanine, and leucine/isoleucine were identified. In contrast to JA, synthetic JA conjugates failed to activate antibiotic production and showed significantly reduced toxicity. Thus, our findings provide insights into a previously unknown defense mechanism deployed by
Streptomycetaceae
to a plant hormone. The underlying mechanism encompasses the attachment of amino acids to JA, which in turn safeguards the bacteria against the harmful impacts of the plant hormone. This study adds to the growing body of evidence that plant hormones can have a significant impact on members of the plant microbiome by affecting their growth, development, and secondary metabolism.

IMPORTANCE

Microorganisms that live on or inside plants can influence plant growth and health. Among the plant-associated bacteria, streptomycetes play an important role in defense against plant diseases, but the underlying mechanisms are not well understood. Here, we demonstrate that the plant hormones jasmonic acid (JA) and methyl jasmonate directly affect the life cycle of streptomycetes by modulating antibiotic synthesis and promoting faster development. Moreover, the plant hormones specifically stimulate the synthesis of the polyketide antibiotic actinorhodin in
Streptomyces coelicolor
. JA is then modified in the cell by amino acid conjugation, thereby quenching toxicity. Collectively, these results provide new insight into the impact of a key plant hormone on diverse phenotypic responses of streptomycetes.
Multi-center clinical evaluation of the Panther Fusion SARS-CoV-2/Flu A/B/RSV assay in nasopharyngeal swab specimens from symptomatic individuals
Authors: Sasidharan Anjana , Selvarangan Rangaraj , Konrad Kennah , Faron Matthew L. , Shakir Salika M. , Hillyard David , McCall Robert K. , McHardy Ian H. , Goldberg David C. , Dunn James J. , Greninger Alexander L. , Lansang Christine , Bogh Rachel , Remillard Carmelle V.
Published: October 2023

The symptomology is overlapping for respiratory infections due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), influenza A/B viruses, and respiratory syncytial virus (RSV). Accurate detection is essential for proper medical management decisions. This study evaluated the clinical performance of the Panther Fusion SARS-CoV-2/Flu A/B/RSV assay in nasopharyngeal swab (NPS) specimens from individuals of all ages with signs and symptoms of respiratory infection consistent with COVID-19, influenza, or RSV. Retrospective known-positive and prospectively obtained residual NPS specimens were collected during two respiratory seasons in the USA. Clinical performance was established by comparing Panther Fusion SARS-CoV-2/Flu assay results to a three-molecular assay composite comparator interpretation for SARS-CoV-2 and to the FDA-cleared Panther Fusion Flu A/B/RSV assay results for all non-SARS-CoV-2 targets. A total of 1,900 prospective and 95 retrospective NPS specimens were included in the analyses. The overall prevalence in prospectively obtained specimens was 20.7% for SARS-CoV-2, 6.7% for influenza A, and 0.7% for RSV; all influenza B-positive specimens were retrospective specimens. The positive percent agreement of the Panther Fusion assay was 96.9% (378/390) for SARS-CoV-2, 98.0% (121/123) for influenza A virus, 95.2% (20/21) for influenza B virus, and 96.6% (57/59) for RSV. The negative percent agreement was ≥98.5% for all target viruses. Specimens with discordant Panther Fusion SARS/Flu/RSV assay results all had cycle threshold values of ≥32.4 (by comparator or by Panther Fusion SARS/Flu/RSV assay). Only five co-infections were detected in the study specimens. The Panther Fusion SARS-CoV-2/Flu/RSV assay provides highly sensitive and specific detection of SARS-CoV-2, influenza A virus, influenza B virus, and RSV in NPS specimens.
Vaccine-induced antibody Fc-effector functions in humans immunized with a combination Ad26.RSV.preF/RSV preF protein vaccine
Authors: Bartsch Yannic C. , Cizmeci Deniz , Yuan Dansu , Mehta Nickita , Tolboom Jeroen , De Paepe Els , van Heesbeen Roy , Sadoff Jerald , Comeaux Christy A. , Heijnen Esther , Callendret Benoit , Alter Galit , Bastian Arangassery Rosemary
Published: October 2023

An Ad26.RSV.preF/RSV preF protein combination vaccine demonstrated 80.0% vaccine efficacy for the prevention of respiratory syncytial virus (RSV)-mediated lower respiratory tract disease in a phase 2b study. In addition to neutralizing antibodies, Fc-effector functions are associated with protective immunity against RSV. Here, vaccine-induced Fc-effector functions were evaluated for the Ad26.RSV.preF/RSV preF protein vaccine in a subset of participants enrolled in a phase 1/2a study. RSV preF-specific antibody subclasses, isotypes, Fcγ receptor binding, and Fc-effector functions were evaluated on days 1 (pre-vaccination), 15, 29, and 183. Compared with Ad26.RSV.preF or RSV preF protein alone, the combination vaccine induced greater Fc-effector functions, including antibody-dependent neutrophil phagocytosis and antibody-dependent natural killer cell activation. Despite RSV pre-exposure, antibody-dependent neutrophil phagocytosis and antibody-dependent natural killer cell activation were not observed at baseline but were induced
de novo
following vaccination. Compared with the individual vaccine components, the combination vaccine induced a more polyfunctional antibody response.

IMPORTANCE

Respiratory syncytial virus (RSV) can cause serious illness in older adults (i.e., those aged ≥60 years). Because options for RSV prophylaxis and treatment are limited, the prevention of RSV-mediated illness in older adults remains an important unmet medical need. Data from prior studies suggest that Fc-effector functions are important for protection against RSV infection. In this work, we show that the investigational Ad26.RSV.preF/RSV preF protein vaccine induced Fc-effector functional immune responses in adults aged ≥60 years who were enrolled in a phase 1/2a regimen selection study of Ad26.RSV.preF/RSV preF protein. These results demonstrate the breadth of the immune responses induced by the Ad26.RSV.preF/RSV preF protein vaccine.
African swine fever virus B175L inhibits the type I interferon pathway by targeting STING and 2′3′-cGAMP
Authors: Ranathunga Lakmal , Dodantenna Niranjan , Cha Ji-Won , Chathuranga Kiramage , Chathuranga W. A. Gayan , Weerawardhana Asela , Subasinghe Ashan , Haluwana D. K. , Gamage Nuwan , Lee Jong-Soo
Published: October 2023

Type I interferon (IFN)-mediated responses operate a pivotal role in the first line of host immune defense against viruses. Upon DNA virus infection, DNA sensing cyclic GMP-AMP synthase-STING signal pathway is a key event in the IFN-mediated antiviral response and also a target of viral immune evasion. African swine fever (ASF) is a highly contagious, cross-border viral disease that often confers fatalities in domestic and feral pigs of all ages. African swine fever virus (ASFV), a causative agent of ASF, is a nucleocytoplasmic large DNA virus that masks critical elements of host immune system by several encoded proteins. In this study, we report a novel immune evasion mechanism of ASFV B175L to block type I IFN signaling by targeting STING and 2'3'-cyclic GMP-AMP (2′3′-cGAMP). We found that ASFV B175L significantly inhibited the DNA virus-induced IFN-β production and IFN-mediated signaling responses. The conserved zf-FCS motif of ASFV B175L competitively interacted with both cGAMP and the cyclic dinucleotide binding domain of STING. Remarkably, the R238 and Y240 amino acids of STING were crucial for interaction with ASFV B175L. Consequently, this interaction inhibits the interaction between cGAMP and STING, thereby inhibiting downstream signaling including STING polymerization and phosphorylation of TANK-binding kinase 1 and interferon regulatory factor 3 for antiviral signaling. Taken together, these results highlight the critical role of ASFV B175L in suppression of IFN responses and provide a new target to guide live-attenuated ASFV vaccine.

IMPORTANCE

African swine fever virus (ASFV), the only known DNA arbovirus, is the causative agent of African swine fever (ASF), an acutely contagious disease in pigs. ASF has recently become a crisis in the pig industry in recent years, but there are no commercially available vaccines. Studying the immune evasion mechanisms of ASFV proteins is important for the understanding the pathogenesis of ASFV and essential information for the development of an effective live-attenuated ASFV vaccines. Here, we identified ASFV B175L, previously uncharacterized proteins that inhibit type I interferon signaling by targeting STING and 2′3′-cGAMP. The conserved B175L-zf-FCS motif specifically interacted with both cGAMP and the R238 and Y240 amino acids of STING. Consequently, this interaction interferes with the interaction of cGAMP and STING, thereby inhibiting downstream signaling of IFN-mediated antiviral responses. This novel mechanism of B175L opens a new avenue as one of the ASFV virulent genes that can contribute to the advancement of ASFV live-attenuated vaccines.
Alphavirus-induced transcriptional and translational shutoffs play major roles in blocking the formation of stress granules
Authors: Frolova Elena I. , Palchevska Oksana , Dominguez Francisco , Frolov Ilya
Published: October 2023

Alphavirus infections cause multiple alterations in the intracellular environment that can have both positive and negative effects on viral replication. The Old World alphaviruses, such as Sindbis (SINV), chikungunya (CHIKV), and Semliki Forest viruses, hinder the ability of vertebrate cells to form stress granules (SGs). Previously, this inhibitory function was attributed to the hypervariable domain (HVD) of nsP3, which sequesters the key SG components, G3BP1 and G3BP2, and to the nsP3 macro domain. The macro domain possesses ADP-ribosylhydrolase activity, which can diminish the ADP-ribosylation of G3BP1 during viral replication. However, our recent findings do not support the prevailing notions. We demonstrate that the interactions between SINV- or CHIKV-specific nsP3s and G3BPs, and the ADP-ribosylhydrolase activity are not major contributors to the inhibitory process, at least when nsP3 is expressed at biologically relevant levels. Instead, the primary factors responsible for suppressing SG formation are virus-induced transcriptional and translational shutoffs that rapidly develop within the first few hours post infection. Poorly replicating SINV variants carrying mutated nsP3 HVD still inhibit SG development even in the presence of sodium arsenite (NaAs). Conversely, SINV mutants lacking transcription and/or translation inhibitory functions lose their ability to inhibit SG formation, despite expressing high levels of wt nsP3. Moreover, we found that stable cell lines expressing GFP-nsP3 fusions retain the capacity to form SGs when exposed to NaAs. However, our results do not rule out the possibility that additional alphavirus-induced changes in cell biology may contribute to the suppression of SG formation.

IMPORTANCE

Our study highlights the mechanisms behind the cell’s resistance to stress granule (SG) formation after infection with Old World alphaviruses. Shortly after infection, the replication of these viruses hinders the cell’s ability to form SGs, even when exposed to chemical inducers such as sodium arsenite. This resistance is primarily attributed to virus-induced transcriptional and translational shutoffs, rather than interactions between the viral nsP3 and the key components of SGs, G3BP1/2, or the ADP-ribosylhydrolase activity of nsP3 macro domain. While interactions between G3BPs and nsP3 are essential for the formation of viral replication complexes, their role in regulating SG development appears to be small, if any. Cells harboring replicating viruses or replicons with lower abilities to inhibit transcription and/or translation, but expressing wild-type nsP3, retain the ability for SG development. Understanding these mechanisms of regulation of SG formation contributes to our knowledge of viral replication and the intricate relationships between alphaviruses and host cells.
3′UTR of ALV-J can affect viral replication through promoting transcription and mRNA nuclear export
Authors: Xu Moru , Qian Kun , Shao Hongxia , Yao Yongxiu , Nair Venugopal , Ye Jianqiang , Qin Aijian
Published: October 2023

3′ Untranslated regions (3′UTRs) play a crucial role in gene transcription and post-transcriptional regulation. During the past 30 years, subgroup J avian leukosis virus (ALV-J) had accumulated large-scale mutations in 3′UTRs of their proviral genome. In this study, we summarize five kinds of mutant 3′UTRs in ALV-J and analyzed their potential functions. Results indicated that ALV-J strains containing different 3′UTRs showed different replication ability, while this divergence is tissue preferential, especially in chicken embryonic liver cells and chicken endothelial cells. All 3′UTRs can assist intron-containing viral mRNA nuclear export, with no salient differences among the five forms. The half-life of ALV-J mRNA is not influenced by different 3′UTRs. However, 3′UTRs can drastically boost mRNA transcription in a cell-specific manner. These different 3′UTRs can promote foreign genes expression. Our results provide novel insight into the pathogenicity and life cycle of ALV-J.

IMPORTANCE

3′UTRs can affect gene transcription and post-transcriptional regulation in multiple ways, further influencing the function of proteins in a unique manner. Recently, ALV-J has been mutating and evolving rapidly, especially the 3′UTR of viral genome. Meanwhile, clinical symptoms caused by ALV-J have changed significantly. In this study, we found that the ALV-J strains containing △-r-TM-type 3′UTR are the most abundant. By constructing ALV-J infectious clones and subgenomic vectors containing different 3′UTRs, we prove that 3′UTRs directly affect viral tissue preference and can promote virus replication as an enhancer. ALV-J strain containing 3′UTR of △-r-TM proliferated fastest in primary cells. All five forms of 3′UTRs can assist intron-containing viral mRNA nuclear export, with similar efficiency. ALV-J mRNA half-life is not influenced by different 3′UTRs. Our results dissect the roles of 3′UTR on regulating viral replication and pathogenicity, providing novel insights into potential anti-viral strategies.
Real-life experience in two cases of secondary prophylaxis with letermovir for CMV infection in solid organ transplantation
Authors: Pérez Ana-Belén , Santos Bravo Marta , Vidal-Verdú Elisa , Páez-Vega Aurora , Vaquero-Barrios José-Manuel , Montero José-Luis , Marcos María-Ángeles , Torre-Cisneros Julián
Published: October 2023

The use of valganciclovir as secondary prophylaxis for cytomegalovirus (CMV) infection in solid organ transplantation (SOT) is the most prevalent therapeutic choice, but it has been dismissed by the presence of resistance and toxicity. Letermovir (LMV) is indicated as primary prophylaxis in hematopoietic stem cell transplantation, but there is scarce clinical data on its use as secondary prophylaxis in SOT. We present two cases of SOT recipients (lung, liver) who underwent LMV secondary prophylaxis. One patient developed the L595S (
UL97
)-resistant mutation to ganciclovir/valganciclovir and experienced several CMV relapses under LMV therapy, but no LMV resistance mutations were detected. The second patient developed the C325F (
UL56
)-resistant mutation to LMV under secondary prophylaxis which was rescued by foscarnet. This observation reviews previously published clinical data on LMV secondary prophylaxis and recommends a cautious use of LMV in the clinical practice due to the early development of
UL56
resistance mutations.

IMPORTANCE

This observation provides comprehensive data on the clinical correlates of both cytomegalovirus (CMV) genotypic follow-up and clinical monitoring and outcomes for two different solid organ transplantation recipients that received letermovir as secondary prophylaxis. Our study emphasizes that monitoring of CMV disease in the patient and early genotypic detection of resistance mutations are essential when using new antiviral drugs for off-label indication in patients experiencing CMV relapses or not responding to standard antiviral therapy. These cases and the bibliography reviewed can be helpful for other researchers and clinicians working in the field to optimize the use of new treatments for transplant recipients since drug-resistant CMV infection is an important emerging problem even with new developments in antiviral treatment.
Effect of short-term, climate-driven sediment deposition on tectonically controlled alluvial channel incision
Authors: Wang Xueliang , Clague John J. , Frattini Paolo , Qi Shengwen , Lan Hengxing , Zhang Wen , Li Lihui , Sun Juanjuan , Crosta Giovanni Battista
Published: October 2023

Debate about relations between rates of fluvial incision and time (the “Sadler effect”) continues, impeding the use of incision rates to infer tectonic and climatic processes. There is a dearth of detailed field evidence that can be used to explore the coupling between tectonics and climate in controlling alluvial channel geometry and incision rates over time scales of 102–105 yr. We present field data from the Rumei watershed of southeast Tibet, which we obtained by mapping and dating late Pleistocene (ca. 135 ka) fluvial terraces and related channels, measuring channel hydraulic geometry, and calculating channel steepness indexes and incision rates. The evidence indicates that climate forcing is the main driver of sediment production and delivery to streams in the watershed. New aggradation events altered alluvial valley and channel geometry and, coupled with tectonic uplift, affected the rate of channel incision in the catchment. We propose a conceptual model that links uplift-driven incision (II) to channel aggradation induced by climate change, which is valid in catchments and other areas. We conclude that the reduction in incision depth caused by climate-driven channel aggradation is significant on short time scales (102–105 yr), and its cumulative effect contributes to the “Sadler effect” on long time scales (>106 yr).
Specificities of the Fourier Transform Infrared Spectroscopic Methodology and Interpretation of Spectroscopic Data in Microbiological Analyses
Authors: Kamnev A. A. , Tugarova A. V.
Published: October 2023

In this mini-review, some of the most significant, from the authors’ point of view, features of the methodology of Fourier transform infrared (FTIR) spectroscopy and interpretation of experimentally obtained spectroscopic data are considered, as applied to the molecular spectrochemical analysis of microbiological objects using examples published in the specialised scientific literature mainly in recent years. Examples of typical inaccuracies and errors both of a methodological nature and arising in the interpretation of spectroscopic data are also presented and briefly discussed.
Serial lipase measurements in pancreatic panniculitis
Authors: El Brihi Jason , Chee Paul
Published: October 2023

Pancreatic panniculitis is a rare cutaneous manifestation of pancreatic disease with only scant case reports available to guide management. In this report, a woman in her 60s developed a painful, erythematous and indurated, nodular rash after an episode of acute pancreatitis postendoscopic retrograde cholangiopancreatography (ERCP). While clinically and radiologically the pancreatitis improved with standard conservative management, the panniculitis remained severely debilitating. Repeat testing of serum pancreatic enzymes revealed persistent and marked elevation. Octreotide was started to inhibit pancreatic enzyme release, and the lesions improved, with resolution of the panniculitis correlating with falling serum pancreatic enzyme levels. Hence, serial pancreatic enzyme testing may have utility in monitoring and management of pancreatic panniculitis.
Seat belt syndrome with caecal perforation and Chance fracture in an adolescent
Authors: Destinval Christelle , Larmure Olivier , Journeau Pierre , Lemelle Jean-Louis
Published: October 2023

Seat belt syndrome describes a combination of injuries a person restrained by a seat belt may have after a high-velocity motor vehicle crash. A seat belt-shaped bruise may be present across the torso. A Chance fracture is a horizontal vertebral fracture, resulting from spinal hyperflexion, and in disruption of the three columns of the vertebral bodies. Its association with intra-abdominal injury is rare in children. A male, in early adolescence, was involved in a high-energy car crash. A total-body CT scan highlighted lacerations of the anterolateral abdominal wall and an acute L4 Chance fracture. Another CT scan performed because of clinical deterioration, showed cecal perforation, caused by a mesenteric tear and non-displaced fracture of the left sacral ala. He underwent a right hemicolectomy with ileocolic anastomosis and protective ileostomy and was immobilised in a body jacket orthosis for 3 months. The ileostomy was closed 3 months later. At 2-year follow-up, he is well.
Haemorrhagic cholecystitis in a young patient, complicated by gallbladder perforation and choledocholithiasis
Authors: Harrison Nicholas L , Hepworth-Lloyd Freya , Briggs Patrick , Melling James
Published: October 2023

Haemorrhagic cholecystitis is a rare condition associated with a high risk of morbidity and mortality. Its pathophysiology is thought to be due to gallbladder wall erosion and infarction secondary to inflammation, which subsequently leads to haemorrhage into the gallbladder lumen or the peritoneal cavity. There is no current official guidance on optimal management of this condition. We describe a case of a female patient in her 40s who presented with right upper quadrant pain, followed by haematemesis. After CT scan, a diagnosis of haemorrhagic cholecystitis was made and initially managed conservatively. In this case, haemorrhagic cholecystitis was later complicated by gallbladder perforation and choledocholithiasis. Definitive management was with emergency open cholecystectomy. We believe this to be the first reported case of haemorrhagic cholecystitis complicated by gallbladder perforation and choledocholithiasis. This report highlights the need for early definitive management of haemorrhagic cholecystitis to prevent subsequent complications.
Effect of an electronic medical record nudge to improve quality improvement program tracking of neuraxial catheter replacements in obstetric patients
Authors: Fedoruk Kelly , Xie James , Wang Ellen , Fowler Cedar , Riley Edward , Carvalho Brendan
Published: October 2023

Background

Monitoring complications associated with medical procedures requires reliable and accurate record keeping. Nudge reminders executed by way of electronic medical record (EMR) alerts influence clinician behaviour. We hypothesised that the introduction of an EMR nudge would improve documentation of replaced neuraxial blocks by obstetric anaesthesiologists at our institution.

Methods

We developed an EMR nudge that would alert the physician to a replaced neuraxial block if two or more neuraxial procedure notes in a single patient encounter were detected. The nudge encouraged physicians to document neuraxial block replacements in our institution’s quality improvement database. We assessed the rate of physician adherence to replaced neuraxial block charting prior to the introduction of the nudge (January 2019–September 2019) and after the implementation (October 2019–December 2020).

Results

494 encounters during the chart review period, January 2019–December 2020, required a neuraxial block replacement, representing an actual neuraxial replacement rate of 6.3% prior to the introduction of the nudge in October 2019. This rate was largely unchanged (6.2%) after the introduction of the nudge (0.1% difference, 95% CI: −0.0119 to 0.0099). Prior to the introduction of the nudge, the proportion of correctly charted failed/replaced blocks in our quality improvement database was 80.0%, and after nudge introduction, the rate was 96.2% (p value <0.00001, OR=6.32, 95% CI: 3.15 to 12.66). A p-chart of the monthly adherence rate demonstrated sustained improvement over time.

Conclusions

EMR nudge technology significantly improved adherence with quality metric monitoring of neuraxial catheter replacement in obstetric patients. The results imply that data collection for quality metric databases of neuraxial block failures and replacements that rely on clinician memory without a nudge are likely under-reporting neuraxial block failures and replacements. This study supports widespread implementation of nudges in EMRs to improve quality metric reporting.
Associations between device-measured physical activity and performance-based physical function outcomes in adults: a systematic review and meta-analysis
Authors: Culverhouse Joshua , Hillsdon Melvyn , Metcalf Brad , Nunns Michael , Lear Rebecca , Brailey Gemma , Pulsford Richard
Published: October 2023

This systematic review and meta-analysis aimed to examine the association between device-measured physical activity (PA) and performance-based measures of physical function (PF). Databases searched included CINAHL, Embase, MEDLINE/PubMed, SPORTDiscus, and Web of Science (last search conducted on November 11, 2022). Observational studies (cross-sectional or prospective) reporting associations between wearable device-measured PA and PF outcomes in non-clinical adults were eligible. Forty-two studies with a pooled sample of 27 276 participants were eligible, with 34 studies reporting a standardised regression coefficient (β) between at least one of four PA measures and one of six PF outcomes. All measures of PA were positively associated with all measures of PF, except for step count with grip strength. Largest associations were seen with lower-body PF tests; gait speed (βs=0.11–0.26), walk tests (βs=0.18–0.41), chair-rise test (βs=0.10–0.26), balance (βs=0.07–0.24) and Timed Up-and-Go (βs=0.10–0.24) all p<0.01. Small or no association was seen with grip strength (βs=0.02–0.07). In observational studies of general adult populations, there were associations between multiple dimensions of PA and a broad range of PF measures. The findings provide provisional support for the use of device measures of movement to remotely monitor people for risk of low PF. Prospective designs are needed to determine the direction of the relationship. Future studies should also explore a broader range of PA metrics beyond simple aggregate measures of time spent at different acceleration values as there is evidence that the temporal distribution of activity is related to health and functional outcomes.