bluuebunny/crossref_metadata_2025 huggingface dataset:
Chronic N‐acetyl cysteine treatment does not improve respiratory system performance in the mdx mouse model of Duchenne muscular dystrophy
Authors: Maxwell Michael N. , Marullo Anthony L. , Valverde‐Pérez Esther , Slyne Aoife D. , Murphy Ben T. , O'Halloran Ken D.
Published: June 2024

Duchenne muscular dystrophy (DMD) is characterised by respiratory muscle injury, inflammation, fibrosis and weakness, ultimately culminating in respiratory failure. The dystrophin‐deficient mouse model of DMD (mdx) shows evidence of respiratory muscle remodelling and dysfunction contributing to impaired respiratory system performance. The antioxidant N‐acetylcysteine (NAC) has been shown to exert anti‐inflammatory and anti‐fibrotic effects leading to improved respiratory muscle performance in a range of animal models of muscle dysfunction, including mdx mice, following short‐term administration (2 weeks). We sought to build on previous work by exploring the effects of chronic NAC administration (3 months) on respiratory system performance in mdx mice. One‐month‐old male mdx mice were randomised to receive normal drinking water (n = 30) or 1% NAC in the drinking water (n = 30) for 3 months. At 4 months of age, we assessed breathing in conscious mice by plethysmography followed by ex vivo assessment of diaphragm force‐generating capacity. Additionally, diaphragm histology was performed. In separate studies, in anaesthetised mice, respiratory electromyogram (EMG) activity and inspiratory pressure across a range of behaviours were determined, including assessment of peak inspiratory pressure‐generating capacity. NAC treatment did not affect force‐generating capacity of the mdx diaphragm. Collagen content and immune cell infiltration were unchanged in mdx + NAC compared with mdx diaphragms. Additionally, there was no significant effect of NAC on breathing, ventilatory responsiveness, inspiratory EMG activity or inspiratory pressure across the range of behaviours from basal conditions to peak system performance. We conclude that chronic NAC treatment has no apparent beneficial effects on respiratory system performance in the mdx mouse model of DMD suggesting limited potential of NAC treatment alone for human DMD.
Impact of Stacking Sequence and Size Effects on Open Hole Compressive Performance
Authors: McDonald Joseph , Lee Donyeong , Taketa Ichiro
Published: June 2024

Open hole compression testing is one of the most common evaluations of aerospace-grade composite materials and serves as an important allowable design value. The test utilizes quasi-isotropic laminates. Test results for these laminates are influenced by ply count and stacking sequence changes. Previous studies have focused on the impact of ply vs sub-laminate scaling on notched specimen size effects and resulting strength predictions. Studies analyzing OHC and other compressive testing with stress intensifications have observed the impacts of 0- & 90-degree ply location, however only when considering one thickness of specimen. Resulting in a reference base where altered locations of 0- & 90-degree plies within the laminates are not considered simultaneously to size effects. This study focused evaluating both size and center ply effects on OHC performance using the Toray T1100G/3960 toughened prepreg system. Quasi-isotropic laminates of [+45/0/−45/90]NS and [+45/90/−45/0]NS, with N ranging from 1–4, were chosen to create a varied range of thicknesses still commonly seen in test campaigns. Each laminate composition had four panels manufactured for testing two sets of specimens at two test conditions. The first sample for each laminate type was tested to full failure. The second sample had specimens tested to increasing percentages of the average failure load for that laminate type. Interrupted test coupons were analyzed to evaluate damage propagation for test condition, ply count and stacking sequence variations. Using both the compressive strength results from complete testing and damage area analysis from interrupted testing, a deeper understanding of size and stacking sequence effects can be gained. The repetition of tests for both room temperature ambient and elevated temperature wet conditioned coupons expands the observation of stacking sequence and size effects is to the most common test conditions. The data collected provides an important overall evaluation of these factors on past test campaigns as choices in ply count and stacking sequence choices varied over time.
Physics of a Flexible Panel Subject to Shock Wave/Boundary Layer Interactions
Authors: Ramkumar S. , Gogulapati Abhijit , Sinha Krishnendu
Published: June 2024

Supersonic flows involve shock waves across which pressure steeply rises. The adverse pressure gradient across a shock wave can lead to significant distortion of boundary layer profile, eventually causing flow separation. Further, the phenomenon is unsteady, especially in turbulent boundary layers. This is owing to the turbulent fluctuations within the boundary layer, which induce low frequency shock foot oscillations and separation region pulsations. The shock oscillation frequencies are typically in resonance with the fundamental vibration modes of the aircraft structure. The coupled mechanism eventually results in shock induced limit cycle oscillations (LCOs) and flutter. This work investigates into this phenomenon by analytically deriving an equation for the low frequency shock foot oscillations over any elastic panel. Suitable approximations are used, with supporting evidence from CFD results using RANS. The derived equation shows the panel flexibility to be a forcing as well as a damping term for the shock foot motions.
Accurate Prediction of Process-Induced Deformations in Composites Using Layer-Wise Models and Theory-Guided Probabilistic Machine Learning
Authors: Schoenholz Caleb , Zappino Enrico , Petrolo Marco , Zobeiry Navid
Published: June 2024

Carbon fiber-reinforced polymer (CFRP) composites are integral to high-performance aerospace applications, offering many exceptional properties such as high specific strength and stiffness. However, despite widespread use, several challenges persist during manufacturing, one of the most prevalent being the mitigation of residual stresses and process-induced deformations (PIDs). Shortcomings of traditional process simulation-based methods commonly employed to predict PIDs often contribute to these challenges. As a result, manufacturers often grapple with inaccurate PID predictions, component mismatches during assembly, increased production times, and compromised mechanical performance. This paper proposes an alternative method for accurately predicting PIDs in composite parts. First, a finite element (FE) solution scheme based on one-dimensional (1D) models and the Carrera Unified Formulation (CUF), is employed to predict PIDs for L-shaped laminates in a defined design space. Then, the virtual simulation data is mapped to a reduced-order theory-guided domain and modeled using Gaussian Process Regression (GPR), a probabilistic machine learning technique. The GPR model is then iteratively retrained to calibrate simulation predictions by incorporating limited real-world experimental data and creating an adaptive probabilistic model with a data-driven uncertainty structure. The effectiveness of the proposed method is demonstrated by accurately predicting the cured deformed shape of an L-shaped cross-ply laminate using just five experiments. The method provides a cost-efficient framework for predicting, understanding, and potentially mitigating PIDs in composite parts.
High-Acceleration Mechanical Shock Characteristics of an Industrial Marine Fender
Authors: N. V. David , M. R. Noor Dhahiyyah Shafia
Published: June 2024

The ability of an object to withstand the effects of mechanical shock on its structural integrity defines its crashworthiness. This paper presents the simulation study of the crashworthiness characteristics of a pre-used commercial marine fender including their peak accelerations (Gpeak) and shock energy absorptions. Three test specimens of thicknesses 10 mm, 20 mm and 30 mm are modeled using HyperMesh™. The peak acceleration responses of the specimens under half-sine shock waves at 50G, 60G and 70G are numerically determined using the LS-DYNA® solver tool under linear dynamic loading. The shock waves are generated by dropping a 5-kg payload from heights ranging between 50 mm and 300 mm onto a padded shock seat for a pulse duration from 5 to 8 ms. The Gpeak of the specimens are also experimentally measured and analytically computed to validate the numerical results. The shock energy absorptions (SEA) of the test specimens are calculated using analytical formulations in relation to the measured and simulated Gpeak. The effects of introducing tubular perforations in the specimens on the resulting Gpeak and thereby the shock energy absorbing capacities are also investigated. It is found that the perforated specimens have generally lower Gpeak than their solid counterparts. The numerically determined Gpeak agree well with the experimental values. The predicted SEA, however, is sensitive to the thickness (or the corresponding mass) of the specimen. The accuracy of the predicted SEA improves by 84% with the increase in specimen thickness from 10 mm to 30 mm.
Reduced Order Modeling and Image Processing Based Structural Analysis of Tow Steered Composite Laminates Considering Gaps/Overlaps
Authors: Dutta Soumik , Mahdi Mohammed Abir , Zhao Wei
Published: June 2024

Variable angle tow (VAT) steered laminate can increase the structural buckling performance of any structure by tailoring the in-plane stress distribution. Consequently, the present study investigates the thermal buckling analysis of a sixteen-layer composite plate containing VAT fibers by the developed finite element (FEM) code. The study found that VAT composite laminate significantly increases the critical buckling temperature compared to conventional quasi-isotropic laminate. Moreover, it is observed that curvilinear VAT laminates are more effective at redistributing in-plane stress from the center toward the support edges of the plate. Unfortunately, these laminates are susceptible to manufacturing defects, which are extremely difficult to detect. Thus, this study explored the effect of manufacturing defects such as gaps and overlaps on structural performance and critical thermal buckling temperature. In the methodology, defects are identified by applying a developed image processing code from the fiber-based prepreg tape image. Despite this, the high-resolution image of the prepreg tape model for the entire laminate results in a very dense mesh, which leads to an expensive structural analysis and requires substantial computational time. Therefore, this study employed the proper orthogonal decomposition (POD) based reduced-order modeling algorithm for efficient structural analysis. As a result, the computational time for the static analysis has been significantly reduced.
Parametric Stability Analysis With Variable Fidelity Beam Formulations
Authors: Filippi Matteo , Carrera Erasmo
Published: June 2024

In this study, we will utilize low and high-fidelity finite beam elements to assess instability thresholds for various structural configurations subjected to periodic excitations. The finite element formulations, based on arbitrary kinematic models, are obtained using an indicial formalism known as Carrera Unified Formulation. By appropriately selecting the expansions for kinematic assumptions, either equivalent-single layer or layer-wise approaches can be automatically derived. Specifically, Taylor- and Lagrange-type expansions are adopted for deriving the displacement field. Both methods will be employed to investigate the instability regions by solving the Mathieu-Hill equation for structures made of either composite or metallic materials. Using these advanced modeling techniques, we aim to enhance the accuracy and reliability of predicting dynamic instability in a broader range of structural systems.
Acute and Chronic Weight-Making Practice in Professional Mixed Martial Arts Athletes: An Analysis of 33 Athletes Across 80 Fights
Authors: Reale Reid , Wang Junzhu , Hu Stull Charles , French Duncan , Amasinger Dean , Wang Ran
Published: June 2024

Mixed martial arts’ popularity has increased in recent years, alongside descriptive research and evidence-based performance recommendations. Guidelines for (both chronic and acute) weight making exist; however, how these translate in real-life scenarios and detailed investigations on practices in larger groups deserve attention. The present study examined the body mass (BM) and composition of 33 professional mixed martial arts athletes preparing for 80 fights. Athletes were supported by on-site dietitians, who encouraged evidence-based practices. Fasted BM was measured throughout the last ∼10 days before all bouts (acute weight management phase). A subset of athletes had body composition assessed before and after the chronic weight loss phase for 40 fights. Most athletes engaged in chronic BM loss, and all engaged in acute weight loss. Many lost fat-free mass (FFM) during the chronic phase, with rates of BM loss <0.5% best preserving FFM. Regardless of losses, the present athletes possessed greater FFM than other combat sport athletes and engaged in greater acute weight loss. Dehydration in the 24–48 hr before the weigh-in was not reflective of weight regain after the weigh-in, rather BM 7–10 days before the weigh-in was most reflective. These findings suggest that many mixed martial arts athletes could increase FFM at the time of competition by maintaining leaner physiques outside of competition and/or allowing increased time to reduce BM chronically. Acutely, athletes can utilize evidence-based protocols, eliminating carbohydrates, fiber, sodium, and finally fluid in a staged approach, before the weigh-in, reducing the amount of sweating required, thus theoretically better protecting health and preserving performance.
A Typology of Design Archetypes in Professional Football Leagues: Autonomy and Openness as Key Factors Explaining Design Variance
Authors: Hughes Grant , Billsberry Jon , Todres Mathew , Swanson Steve
Published: June 2024

Previous approaches to design archetypes in sport management have taken a single-country, multisport approach with a focus on National Sporting Organizations. While this line of research has provided significant breakthroughs for understanding sport organizations, there is a need to extend the boundaries of these investigations to explore variations within professional leagues in one sport and across multiple countries. Accordingly, the current study takes a single-sport, multicountry approach to explore how design archetypes vary and the factors influencing the variation. We analyzed the design archetypes of 104 professional football leagues using 44 organizational variables and identified four different design archetypes that can be used to categorize professional football leagues globally. Autonomy and openness were identified as the key factors determining design archetype structure in this environment. Our analysis of professional football league archetypes provides a foundation for understanding design archetype variation, and the insights can be used for comparison and analysis of meaningful change.
Rethinking quantum orthodoxy
Escape from Shadow Physics: The Quest to End the Dark Ages of Quantum Theory
Adam Forrest Kay
Basic Books, 2024. 496 pp.
Authors: Halpern Paul
Published: June 2024

A physicist makes the case for a deterministic alternative to quantum mechanics
In Science Journals
Authors: Lopez Bianca , Szuromi Phil , Nusinovich Yevgeniya , Walia Ankit , Grocholski Brent , Suleymanov Yury , Yeston Jake S. , Neuhofer Daniela , Alderton Gemma , Maroso Mattia , Funk Michael A. , Scanlon Seth Thomas , Ash Caroline , Smith Jesse , Ferrarelli Leslie K.
Published: June 2024

Highlights from the
Science
family of journals
In Other Journals
Authors: Simonti Corinne N. , Ash Caroline , Walia Ankit , McCartney Melissa , Suleymanov Yury , Vignieri Sacha , Szuromi Phil
Published: June 2024

Editors’ selections from the current scientific literature
Signs of science
Authors: Selibas Dimitri
Published: June 2024

CyberTracker, software developed in collaboration with Indigenous trackers, is enabling almost anyone to collect complex biodiversity data
Winners of prestigious Sackler prize call for name change
Authors: de Vrieze Jop
Published: June 2024

Biophysics prize from Tel Aviv University bears the family’s name despite its role in opioid epidemic
Manganese uptake by MtsABC contributes to the pathogenesis of human pathogen group A streptococcus by resisting host nutritional immune defenses
Authors: Makthal Nishanth , Saha Subhasree , Huang Elaine , John Juliane , Meena Himani , Aggarwal Shifu , Högbom Martin , Kumaraswami Muthiah
Published: June 2024

The interplay between host nutritional immune mechanisms and bacterial nutrient uptake systems has a major impact on the disease outcome. The host immune factor calprotectin (CP) limits the availability of essential transition metals, such as manganese (Mn) and zinc (Zn), to control the growth of invading pathogens. We previously demonstrated that the competition between CP and the human pathogen group A streptococcus (GAS) for Zn impacts GAS pathogenesis. However, the contribution of Mn sequestration by CP in GAS infection control and the role of GAS Mn acquisition systems in overcoming host-imposed Mn limitation remain unknown. Using a combination of
in vitro
and
in vivo
studies, we show that GAS-encoded
mtsABC
is a Mn uptake system that aids bacterial evasion of CP-imposed Mn scarcity and promotes GAS virulence. Mn deficiency caused by either the inactivation of
mtsC
or CP also impaired the protective function of GAS-encoded Mn-dependent superoxide dismutase. Our
ex vivo
studies using human saliva show that saliva is a Mn-scant body fluid, and Mn acquisition by MtsABC is critical for GAS survival in human saliva. Finally, animal infection studies using wild-type (WT) and
CP−/
− mice showed that MtsABC is critical for GAS virulence in WT mice but dispensable in mice lacking CP, indicating the direct interplay between MtsABC and CP
in vivo
. Together, our studies elucidate the role of the Mn import system in GAS evasion of host-imposed metal sequestration and underscore the translational potential of MtsABC as a therapeutic or prophylactic target.
VP1 is the primary determinant of neuropathogenesis in a mouse model of enterovirus D68 acute flaccid myelitis
Authors: Leser J. Smith , Frost Joshua L. , Wilson Courtney J. , Rudy Michael J. , Clarke Penny , Tyler Kenneth L.
Published: June 2024

Enterovirus D68 (EV-D68) is an emerging pathogen that can cause severe respiratory and neurologic disease [acute flaccid myelitis (AFM)]. Intramuscular (IM) injection of neonatal Swiss Webster (SW) mice with US/IL/14-18952 (IL52), a clinical isolate from the 2014 EV-D68 epidemic, results in many of the pathogenic features of human AFM, including viral infection of the spinal cord, death of motor neurons, and resultant progressive paralysis. In distinction, CA/14-4231 (CA4231), another clinical isolate from the 2014 EV-D68 outbreak, does not cause paralysis in mice, does not grow in the spinal cord, and does not cause motor neuron loss following IM injection. A panel of chimeric viruses containing sequences from IL52 and CA4231 was used to demonstrate that VP1 is the main determinant of EV-D68 neurovirulence following IM injection of neonatal SW mice. VP1 contains four amino acid differences between IL52 and CA4231. Mutations resulting in substituting these four amino acids (CA4231 residues into the IL52 polyprotein) completely abolished neurovirulence. Conversely, mutations resulting in substituting VP1 IL52 amino acid residues into the CA4231 polyprotein created a virus that induced paralysis to the same degree as IL52. Neurovirulence following infection of neonatal SW mice with parental and chimeric viruses was associated with viral growth in the spinal cord.

IMPORTANCE

Emerging viruses allow us to investigate mutations leading to increased disease severity. Enterovirus D68 (EV-D68), once the cause of rare cases of respiratory illness, recently acquired the ability to cause severe respiratory and neurologic disease. Chimeric viruses were used to demonstrate that viral structural protein VP1 determines growth in the spinal cord, motor neuron loss, and paralysis following intramuscular (IM) injection of neonatal Swiss Webster (SW) mice with EV-D68. These results have relevance for predicting the clinical outcome of future EV-D68 epidemics as well as targeting retrograde transport as a potential strategy for treating virus-induced neurologic disease.
Stability of influenza A virus in droplets and aerosols is heightened by the presence of commensal respiratory bacteria
Authors: David Shannon C. , Schaub Aline , Terrettaz Céline , Motos Ghislain , Costa Laura J. , Nolan Daniel S. , Augugliaro Marta , Wynn Htet Kyi , Glas Irina , Pohl Marie O. , Klein Liviana K. , Luo Beiping , Bluvshtein Nir , Violaki Kalliopi , Hugentobler Walter , Krieger Ulrich K. , Peter Thomas , Stertz Silke , Nenes Athanasios , Kohn Tamar
Published: June 2024

Aerosol transmission remains a major challenge for control of respiratory viruses, particularly those causing recurrent epidemics, like influenza A virus (IAV). These viruses are rarely expelled alone, but instead are embedded in a consortium of microorganisms that populate the respiratory tract. The impact of microbial communities and inter-pathogen interactions upon stability of transmitted viruses is well-characterized for enteric pathogens, but is under-studied in the respiratory niche. Here, we assessed whether the presence of five different species of commensal respiratory bacteria could influence the persistence of IAV within phosphate-buffered saline and artificial saliva droplets deposited on surfaces at typical indoor air humidity, and within airborne aerosol particles. In droplets, presence of individual species or a mixed bacterial community resulted in 10- to 100-fold more infectious IAV remaining after 1 h, due to bacterial-mediated flattening of drying droplets and early efflorescence. Even when no efflorescence occurred at high humidity or the bacteria-induced changes in droplet morphology were abolished by aerosolization instead of deposition on a well plate, the bacteria remained protective.
Staphylococcus aureus
and
Streptococcus pneumoniae
were the most stabilizing compared to other commensals at equivalent density, indicating the composition of an individual’s respiratory microbiota is a previously unconsidered factor influencing expelled virus persistence.

IMPORTANCE

It is known that respiratory infections such as coronavirus disease 2019 and influenza are transmitted by release of virus-containing aerosols and larger droplets by an infected host. The survival time of viruses expelled into the environment can vary depending on temperature, room air humidity, UV exposure, air composition, and suspending fluid. However, few studies consider the fact that respiratory viruses are not alone in the respiratory tract—we are constantly colonized by a plethora of bacteria in our noses, mouth, and lower respiratory system. In the gut, enteric viruses are known to be stabilized against inactivation and environmental decay by gut bacteria. Despite the presence of a similarly complex bacterial microbiota in the respiratory tract, few studies have investigated whether viral stabilization could occur in this niche. Here, we address this question by investigating influenza A virus stabilization by a range of commensal bacteria in systems representing respiratory aerosols and droplets.
Neuronal expression of herpes simplex virus-1 VP16 protein induces pseudorabies virus escape from silencing and reactivation
Authors: Hsu Zhi-Shan , Engel Esteban A. , Enquist Lynn W. , Koyuncu Orkide O.
Published: June 2024

Alpha herpesvirus (α-HV) particles enter their hosts from mucosal surfaces and efficiently maintain fast transport in peripheral nervous system (PNS) axons to establish infections in the peripheral ganglia. The path from axons to distant neuronal nuclei is challenging to dissect due to the difficulty of monitoring early events in a dispersed neuron culture model. We have established well-controlled, reproducible, and reactivateable latent infections in compartmented rodent neurons by infecting physically isolated axons with a small number of viral particles. This system not only recapitulates the physiological infection route but also facilitates independent treatment of isolated cell bodies or axons. Consequently, this system enables study not only of the stimuli that promote reactivation but also the factors that regulate the initial switch from productive to latent infection. Adeno-associated virus (AAV)-mediated expression of herpes simplex-1 (HSV-1) VP16 alone in neuronal cell bodies enabled the escape from silencing of incoming pseudorabies virus (PRV) genomes. Furthermore, the expression of HSV VP16 alone reactivated a latent PRV infection in this system. Surprisingly, the expression of PRV VP16 protein supported neither PRV escape from silencing nor reactivation. We compared transcription transactivation activity of both VP16 proteins in primary neurons by RNA sequencing and found that these homolog viral proteins produce different gene expression profiles. AAV-transduced HSV VP16 specifically induced the expression of proto-oncogenes including c-Jun and Pim2. In addition, HSV VP16 induces phosphorylation of c-Jun in neurons, and when this activity is inhibited, escape of PRV silencing is dramatically reduced.

IMPORTANCE

During latency, alpha herpesvirus genomes are silenced yet retain the capacity to reactivate. Currently, host and viral protein interactions that determine the establishment of latency, induce escape from genome silencing or reactivation are not completely understood. By using a compartmented neuronal culture model of latency, we investigated the effect of the viral transcriptional activator, VP16 on pseudorabies virus (PRV) escape from genome silencing. This model recapitulates the physiological infection route and enables the study of the stimuli that regulate the initial switch from a latent to productive infection. We investigated the neuronal transcriptional activation profiles of two homolog VP16 proteins (encoded by HSV-1 or PRV) and found distinct gene activation signatures leading to diverse infection outcomes. This study contributes to understanding of how alpha herpesvirus proteins modulate neuronal gene expression leading to the initiation of a productive or a latent infection.
Metabolic engineering of
Pseudomonas bharatica
CSV86
T
to degrade Carbaryl (1-naphthyl-
N
-methylcarbamate) via the salicylate-catechol route
Authors: Malhotra Harshit , Dhamale Tushar , Kaur Sukhjeet , Kasarlawar Sravanti T. , Phale Prashant S.
Published: June 2024

Pseudomonas bharatica
CSV86
T
displays the unique property of preferential utilization of aromatic compounds over simple carbon sources like glucose and glycerol and their co-metabolism with organic acids. Well-characterized growth conditions, aromatic compound metabolic pathways and their regulation, genome sequence, and advantageous eco-physiological traits (indole acetic acid production, alginate production, fusaric acid resistance, organic sulfur utilization, and siderophore production) make it an ideal host for metabolic engineering. Strain CSV86
T
was engineered for Carbaryl (1-naphthyl-
N
-methylcarbamate) degradation via salicylate-catechol route by expression of a Carbaryl hydrolase (CH) and a 1-naphthol 2-hydroxylase (1NH). Additionally, the engineered strain exhibited faster growth on Carbaryl upon expression of the McbT protein (encoded by the
mcb
T gene, a part of Carbaryl degradation upper operon of
Pseudomonas
sp. C5pp). Bioinformatic analyses predict McbT to be an outer membrane protein, and Carbaryl-dependent expression suggests its probable role in Carbaryl uptake. Enzyme activity and protein analyses suggested periplasmic localization of CH (carrying transmembrane domain plus signal peptide sequence at the N-terminus) and 1NH, enabling compartmentalization of the pathway. Enzyme activity, whole-cell oxygen uptake, spent media analyses, and qPCR results suggest that the engineered strain preferentially utilizes Carbaryl over glucose. The plasmid-encoded degradation property was stable for 75–90 generations even in the absence of selection pressure (kanamycin or Carbaryl). These results indicate the utility of
P. bharatica
CSV86
T
as a potential host for engineering various aromatic compound degradation pathways.

IMPORTANCE

The current study describes engineering of Carbaryl metabolic pathway in
Pseudomonas bharatica
CSV86
T
. Carbaryl, a naphthalene-derived carbamate pesticide, is known to act as an endocrine disruptor, mutagen, cytotoxin, and carcinogen. Removal of xenobiotics from the environment using bioremediation faces challenges, such as slow degradation rates, instability of the degradation phenotype, and presence of simple carbon sources in the environment. The engineered CSV86-MEC2 overcomes these disadvantages as Carbaryl was degraded preferentially over glucose. Furthermore, the plasmid-borne degradation phenotype is stable, and presence of glucose and organic acids does not repress Carbaryl metabolism in the strain. The study suggests the role of outer membrane protein McbT in Carbaryl transport. This work highlights the suitability of
P. bharatica
CSV86
T
as an ideal host for engineering aromatic pollutant degradation pathways.
Reassessing ‘good’ medical practice and the climate crisis
Authors: Yassaie Rammina , Brooks Lucy
Published: June 2024

In August 2023, the General Medical Council released the latest update of Good Medical Practice, which sets out the standards of patient care and professional behaviour to be expected of UK doctors. These updated guidelines offer some environmental considerations that previous standards did not include. This paper explores these latest additions to Good Medical Practice through the healthcare ethics lens of non-maleficence, beneficence, justice and autonomy, alongside trust and physician well-being, to make the case that the latest updates to Good Medical Practice do not go far enough in specifying the duties for doctors in responding to climate and ecological emergencies to be seen as ethically justifiable.

The paper argues that given the health implications of the climate crisis and the harms associated with high-emission healthcare, as well as the co-benefits of climate action on health, there must be a stronger commitment from the medical regulator to ensure the groundwork is set for doctors to learn, understand and advocate for the importance and urgency of practicing sustainable healthcare. The case for this is strengthened by also examining the importance of maintaining public trust in the medical profession as advocates for public health, along with the notable societal and generational injustices that continue to deepen as the climate emergency escalates.

The paper concludes by arguing that doctors can and should be a part of writing a new chapter for health in the climate era, but our standards for practice need to offer a strengthened starting point of consensus for what is expected of the medical profession for that to come to fruition and raise questions as to what doctors can and should do when they have questions over their own regulators’ commitment to maintaining public health in relation to the climate and ecological crisis.
Other possible perspectives for solving the negative outcome penalty paradox in the application of artificial intelligence in clinical diagnostics
Authors: Ye Hongnan
Published: June 2024

Artificial intelligence (AI), represented by machine learning, artificial neural networks and deep learning, is impacting all areas of medicine, including translational research (from bench to bedside to health policy), clinical medicine (including diagnosis, treatment, prognosis and healthcare resource allocation) and public health. At a time when almost everyone is focused on how to better realise the promise of AI to transform the entire healthcare system, Dr Appel calls for public attention to the AI in medicine and the negative outcome penalty paradox. Proposing this topic has deepened our thinking about the application of AI in clinical diagnostics, and also prompted us to find more effective ways to integrate AI more effectively into future clinical practice. In addition to Dr Appel’s insightful advice, I hope to offer three other possible perspectives, including changing public perceptions, re-engineering clinical practice processes and introducing more stakeholders, to further the discussion on this topic.
Next-generation sequencing in Charcot-Marie-Tooth: a proposal for improvement of ACMG guidelines for variant evaluation
Authors: Geroldi Alessandro , Mammi Alessia , Gaudio Andrea , Patrone Serena , La Barbera Andrea , Origone Paola , Ponti Clarissa , Sanguineri Francesca , Massucco Sara , Marinelli Lucio , Grandis Marina , Schenone Angelo , Mandich Paola , Bellone Emilia , Gotta Fabio
Published: June 2024

Background

The application of massive parallel sequencing technologies in the molecular analysis of Charcot-Marie-Tooth (CMT) has enabled the rapid and cost-effective identification of numerous potentially significant variants for diagnostic purposes. The objective is to reduce the number of variants, focusing only on those with pathogenic significance. The 2015 American College of Medical Genetics and Genomics (ACMG) guidelines aid in achieving this goal, but it is now evident that a pathology or gene-specific review of these rules is essential to avoid misinterpretations that may result from blindly applying the criteria. This study demonstrates how revised ACMG criteria, combined with CMT-specific literature data and expertise, can alter the final classification of a variant.

Methods

We reviewed ACMG criteria based on current knowledge of CMT and provided suggestions for adapting them to the specificities of CMT.

Results

Of the 226 index patients analysed, a diagnostic yield of 20% was obtained. It is worth noting that the 9% of cases had their final diagnosis changed with the application of the revised criteria, often resulting in the loss of the pathogenic classification of a variant.

Conclusions

The widespread availability of high-throughput sequencing technologies has enabled genetic testing even for laboratories without specific disease expertise. Disease-specific ACMG criteria can be a valuable tool to prevent the proliferation of variants of uncertain significance and the misinterpretation of variants.
Unnecessary antibiotic use in men who have sex with men (MSM) with anogenital symptoms attending a sexual health clinic: a retrospective analysis
Authors: Wong Arthur , Applegate Tanya , Boettiger David Charles , Varma Rick , Guy Rebecca , Medland Nicholas
Published: June 2024

Objectives

To quantify the amount of unnecessary antibiotics, in particular ceftriaxone, given to men who have sex with men (MSM) with anogenital symptoms as part of presumptive management in an urban sexual health clinic and examine factors associated with unnecessary ceftriaxone.

Methods

This is a retrospective cross-sectional analysis of electronic records from all visits involving MSM reporting symptoms of bacterial sexually transmitted infection (STI) and who received presumptive antibiotics at Sydney Sexual Health Centre. The following variables were extracted: demographic and sexual behaviour data, presenting symptoms, prior STI diagnoses, use of anoscopy, use of point-of-care microscopy, prescriptions of antibiotics and subsequent nucleic acid amplification testing (NAAT) results for chlamydia and gonorrhoea in all anatomical sites (urethra, pharynx and rectum). We defined unnecessary antibiotic as an agent prescribed to treat an STI organism that was subsequently not detected.

Results

Among 1061 visits in this analysis, 41.8% yielded negative NAAT results for both chlamydia and gonorrhoea in all anatomical sites. There were 44.3% of visits which had positive gonorrhoea NAAT result in at least one anatomical site. There were 187 courses of ceftriaxone prescribed in patients who tested negative for gonorrhoea in all anatomical sites and therefore were unnecessary. Unnecessary ceftriaxone prescribing occurred in 50.2% of visits with anorectal symptoms, 19.6% of scrotal symptoms and 7.3% of urethral symptoms. Microscopy was associated with significantly less unnecessary ceftriaxone in urethral but not anorectal or scrotal presentations. In multivariable analysis, the following factors were associated with a higher likelihood of unnecessary ceftriaxone use: anorectal symptoms, scrotal symptoms, gonorrhoea in the preceding year, contact of a bacterial STI and living with HIV.

Conclusions

This study highlights the significant amount of unnecessary ceftriaxone used for STI symptoms in MSM. A new pathway incorporating rapid point-of-care molecular testing in symptomatic patients may improve the precision of antibiotic prescribing and reduce unnecessary use.
Making sexual and reproductive healthcare environments safe and supportive for disclosure of sexual violence: interview findings from patients and healthcare professionals using a realist approach
Authors: Caswell Rachel J , Ross Jonathan DC , Bradbury-Jones Caroline
Published: June 2024

Objectives

Most people who have experienced sexual violence (SV) will disclose the event(s) to someone. Key recipients of disclosure are those working in healthcare. Telling someone in healthcare about experiences of SV can be an important step in accessing necessary medical care and being signposted to other services. While recognising healthcare settings are a key place for people to seek support, evidence is lacking about how best to create a safe environment for disclosure to take place, how services can make changes to better facilitate this experience and what changes matter most.

Design

This study used a realist approach to identify mechanisms that facilitate safe and supported disclosure. Data were generated through three focus groups with Sexual and Reproductive Health Services healthcare professionals in the UK, and one-to-one interviews with survivors of SV who attended healthcare settings (n=18).

Results

The analysis found that service users needed to feel empowered and recognised as appropriate candidates for care in the material used to promote sexual healthcare services after SV. This promotional material needs to address rape myths, stereotypes and silence surrounding SV, to ensure that all individuals and especially those from diverse groups are empowered to access care. Three fundamental mechanisms for safe and supported disclosure were identified: being listened to, being validated and having choice. Trauma-informed care was identified as being essential for implementing these mechanisms. Healthcare professionals who were confident and competent regarding enquiry about SV and response to disclosures of SV were key.

Conclusions

The development of services that are conducive to the disclosure of SV is needed to provide better support for those who have experienced SV and are ready to seek support. Use of appropriate promotional material, specific staff training and a trauma-informed approach are key elements to improve services.
Switching from cigarettes to IQOS: the relative importance of IQOS-associated reward, reinforcement and abstinence relief
Authors: Audrain-McGovern Janet , Wileyto E Paul , Klapec Olivia , Koita Fodie , Strasser Andrew A
Published: June 2024

Introduction

This study investigated whether IQOS, a heated tobacco product, can fully substitute for combustible cigarettes and the factors that promote substitution.

Methods

Adults who smoked cigarettes daily (N=90; 21–65 years) completed a baseline ad-lib smoking period (days 1–5), two laboratory visits (days 6–7) and a 2-week period where they were instructed to switch from smoking cigarettes to using IQOS 3.0 (days 8–21). Mixed-effect modelling estimated the changes in cigarettes per day (CPD) and the percentage of baseline CPD substituted by HeatSticks during the switch period. Predictors included IQOS-associated subjective reward, relative reinforcing value, craving relief and withdrawal relief.

Results

Participants reduced their CPD to about 30% of their baseline smoking rate by the end of the 14-day switch period (p<0001). A lower versus higher reinforcing value of smoking relative to IQOS (RRV; break point <5 vs ≥5) predicted greater reductions in CPD (β=−1.31 (95% CI −2.35 to −0.27) p=0.013). Initially, IQOS use was 72% of the baseline smoking rate (β=71.64 (95% CI 42.79 to 100.48) p<0.0001) and climbed by 0.8% per day (β=0.82 (95% CI 0.01 to 1.64) p=0.05), for an average substitution rate of 83%. The subjective reward of IQOS was the only predictor of a higher substitution rate (β=4.26 (95% CI 1.03 to 7.50) p=0.01).

Conclusions

IQOS fully substituted for cigarettes in ~20% of people who were not immediately interested in quitting smoking while the remainder significantly reduced their smoking. Positive reinforcing effects of IQOS foster use and the transition away from combustible cigarettes.

Trial registration number

NCT05076708.
Macro Ethics Principles for Responsible AI Systems: Taxonomy and Directions
Authors: Woodgate Jessica , Ajmeri Nirav
Published: June 2024

Responsible AI must be able to make or support decisions that consider human values and can be justified by human morals. Accommodating values and morals in responsible decision making is supported by adopting a perspective of
macro ethics
, which views ethics through a holistic lens incorporating social context. Normative ethical principles inferred from philosophy can be used to methodically reason about ethics and make ethical judgements in specific contexts. Operationalising normative ethical principles thus promotes responsible reasoning under the perspective of macro ethics. We survey AI and computer science literature and develop a taxonomy of 21 normative ethical principles which can be operationalised in AI. We describe how each principle has previously been operationalised, highlighting key themes that AI practitioners seeking to implement ethical principles should be aware of. We envision that this taxonomy will facilitate the development of methodologies to incorporate normative ethical principles in reasoning capacities of responsible AI systems.
When Automated Program Repair Meets Regression Testing—An Extensive Study on Two Million Patches
Authors: Lou Yiling , Yang Jun , Benton Samuel , Hao Dan , Tan Lin , Chen Zhenpeng , Zhang Lu , Zhang Lingming
Published: June 2024

In recent years, Automated Program Repair (APR) has been extensively studied in academia and even drawn wide attention from the industry. However, APR techniques can be extremely time consuming since (1) a large number of patches can be generated for a given bug, and (2) each patch needs to be executed on the original tests to ensure its correctness. In the literature, various techniques (e.g., based on learning, mining, and constraint solving) have been proposed/studied to reduce the number of patches. Intuitively, every patch can be treated as a software revision during regression testing; thus, traditional Regression Test Selection (RTS) techniques can be leveraged to only execute the tests affected by each patch (as the other tests would keep the same outcomes) to further reduce patch execution time. However, few APR systems actually adopt RTS and there is still a lack of systematic studies demonstrating the benefits of RTS and the impact of different RTS strategies on APR. To this end, this article presents the first extensive study of widely used RTS techniques at different levels (i.e., class/method/statement levels) for 12 state-of-the-art APR systems on over 2M patches. Our study reveals various practical guidelines for bridging the gap between APR and regression testing, including: (1) the number of patches widely used for measuring APR efficiency can incur skewed conclusions, and the use of inconsistent RTS configurations can further skew the conclusions; (2) all studied RTS techniques can substantially improve APR efficiency and should be considered in future APR work; (3) method- and statement-level RTS outperform class-level RTS substantially and should be preferred; (4) RTS techniques can substantially outperform state-of-the-art test prioritization techniques for APR, and combining them can further improve APR efficiency; and (5) traditional Regression Test Prioritization (RTP) widely studied in regression testing performs even better than APR-specific test prioritization when combined with most RTS techniques. Furthermore, we also present the detailed impact of different patch categories and patch validation strategies on our findings.
Structural Damage Detection Using Mutual Information and Improved Reptile Search Algorithm for Fused Smooth Signals Affected by Coloured Noise
Authors: Hassani Sahar
Published: June 2024

Structural health monitoring (SHM) faces a significant challenge in accurately detecting damage due to noise in acquired signals in composite plates, which can adversely affect reliability. Specific noise reduction techniques tailored to SHM signals are developed to tackle this issue. Gaussian smoothing proves effective in reducing noise and enhancing signal features, thereby facilitating the identification of damage‐related information. Optimization algorithms play a crucial role in damage detection, especially when integrated with smoothing and fusion techniques, as they provide optimal solutions to SHM challenges. A model‐updating‐based optimization algorithm is proposed for detecting damage in structures using condensed frequency response functions (CFRFs), even in the presence of various types of noise and measurement errors. The CFRF signals are first smoothed using an optimized Gaussian smoothing technique as part of the proposed method. Then, the proposed methodology integrates diverse smoothed signals using a raw data fusion approach, including those from different excitations, frequency ranges, and sensor placements. Fused smoothed signals are then fed into a new objective function, incorporating mutual information (MI) and Gaussian smoothing to mitigate correlated coloured noise. The proposed objective function also introduces a hyperparameter tuning of Gaussian smoothing to enhance its performance. Optimization via the improved reptile search algorithm (IRSA) updates the objective function, optimizing damage and smoothing parameters. The hybrid method detects damage in numerical composite laminated plates with different layers and boundary conditions, demonstrating its effectiveness as an SHM technique. Comparative evaluations of other state‐of‐the‐art methods show that the proposed method outperforms its counterparts, making it a promising damage detection approach to address the noise challenge in the SHM field.
The 6th International Conference of Palaeogeography held in Nanjing, China
Authors: FANG XIANG
Published: June 2024

The 6th International Conference on Palaeogeography (ICP6), which took place in China’s Nanjing from the 17th to the 20th of May, 2024, was a great success. This prestigious conference was jointly sponsored by the International Society of Palaeogeography, the Palaeontological Society of China, and China University of Petroleum (Beijing), and the periodical Journal of Palaeogeography (English version) and was organised by Nanjing Institute of Geology and Palaeontology, Chinese Academy of Sciences.