bluuebunny/crossref_metadata_2025 huggingface dataset:
Functionalisms and the Philosophy of Action
Authors: Vargas Manuel
Published: January 2024

Focusing on the recent work of Michael Bratman as emblematic of several important developments in the philosophy of action, I raise four questions that engage with a set of interlocking concerns about systemic functionalism in the philosophy of action. These questions are: (i) Are individual and institutional intentions the same kind of thing? (ii) Can the risk of proliferation of systemic functional explanations be managed? (iii) Is there an appealing basis for the apparent methodological individualism in our theories of action and agency? and (iv) Why not, instead, pursue a methodologically anti‐individualist and ecological approach to action and agency? The latter alternative, I suggest, offers a promising way to retain many of the core insights of the Bratmanian project while avoiding the difficulties inherent to some of the methodological presumptions of some strands of contemporary philosophy of action.
Alpine travellers in the Carpathians: The story of two rock‐dwelling snails told by genes and fossils
Authors: Horsáková Veronika , Divíšek Jan , Líznarová Eva , Kubíková Kateřina , Juřičková Lucie , Horsák Michal
Published: January 2024

Aim

Various species distributed in the Alps have their disjunct occurrences in the Carpathians. Fossil evidence for some woodland snails of Alpine distribution suggests that they colonized the Carpathians during the Holocene forest optimum or later. Here, we focus on disjunct Carpathian populations of the rock‐dwelling alpine snail Pyramidula saxatilis. As it occupies very stable habitats, that is, high‐elevation limestone rocks, one can assume its potential survival in Carpathian refugia over the glacial period(s). For comparison, the more widespread and warm‐climate P. pusilla is analysed.

Location

Europe.

Taxon

Pyramidula saxatilis and P. pusilla.

Methods

We analysed the genetic diversity of P. saxatilis and P. pusilla populations across their entire ranges using mitochondrial DNA and nuclear DNA markers. Seven fossil mollusc successions from the area where P. saxatilis occurs in the Carpathians were analysed and dated using the radiocarbon method. Habitat suitability models of both species were calculated for selected time periods since the Last Glacial Maximum.

Results

All Carpathian P. saxatilis populations were genetically homogeneous and similar to those from the Eastern Alps. In P. pusilla, we found a genetically distinct lineage in the southern Western Carpathians. Both species were found in three fossil profiles since the Middle Holocene, and in one already in the Late Glacial. Habitat suitability models suggested the fluctuations of suitable conditions in the Carpathians driven by summer precipitation, especially for P. saxatilis.

Main Conclusions

Our results suggest that the Carpathian populations of P. saxatilis represent a post‐LGM colonization from the Eastern Alps triggered by climatic changes, mainly by the increase in summer precipitation during the Late Glacial interstadials and Middle Holocene. The evidence for P. pusilla is similar, but also suggests rare long‐term survival in the Carpathian microrefugia. The palaeoecological evidence indicates a possible threat to high‐elevation species from future fluctuations in precipitation regimes.
L‐ascorbyl‐2‐phosphate alleviates white matter injury caused by chronic hypoxia through the PRMT5/P53/NF‐κB pathway
Authors: Ding Bingqing , Lou Jia , Qin Tianqi , Xie Weiwei , Li Di , Li Peijun , Wang Xingyun , Lin Zhenlang , Guo Xiaoling , Zhu Jianghu
Published: January 2024

White matter injury (WMI) is one of the most serious complications associated with preterm births. Damage to oligodendrocytes, which are the key cells involved in WMI pathogenesis, can directly lead to myelin abnormalities. L‐ascorbyl‐2‐phosphate (AS‐2P) is a stable form of vitamin C. This study aimed to explore the protective effects of AS‐2P against chronic hypoxia‐induced WMI, and elucidate the underlying mechanisms. An in vivo chronic hypoxia model and in vitro oxygen–glucose deprivation (OGD) model were established to explore the effects of AS‐2P on WMI using immunofluorescence, immunohistochemistry, western blotting, real‐time quantitative polymerase chain reaction, Morris water maze test, novel object recognition test, beaming‐walking test, electron microscopy, and flow cytometry. The results showed that AS‐2P resulted in the increased expression of MBP, Olig2, PDGFRα and CC1, improved thickness and density of the myelin sheath, and reduced TNF‐α expression and microglial cell infiltration to alleviate inflammation in the brain after chronic hypoxia. Moreover, AS‐2P improved the memory, learning and motor abilities of the mice with WMI. These protective effects of AS‐2P may involve the upregulation of protein arginine methyltransferase 5 (PRMT5) and downregulation of P53 and NF‐κB. In conclusion, our study demonstrated that AS‐2P attenuated chronic hypoxia‐induced WMI in vivo and OGD‐induced oligodendrocyte injury in vitro possibly by regulating the PRMT5/P53/NF‐κB pathway, suggesting that AS‐2P may be a potential therapeutic option for WMI.
Intent to stay, moral distress, and nurse practice environment among long‐term care nurses: A cross‐sectional questionnaire survey study
Authors: Tan Amil Kusain , Capezuti Elizabeth , Samuels William Ellery , Backhaus Ramona , Wagner Laura M.
Published: January 2024

Background

Many long‐term care facilities in the United States face significant problems with nurse retention and turnover. These challenges are attributed, at least in part, to moral distress and a negative nurse practice environment.

Objective

The purpose of the study was divided into two parts: first, to investigate the relationships among nurse practice environment, moral distress, and intent to stay; second, to explore the potential mediating effect of the nurse practice environment on the intent to stay among those with high levels of moral distress.

Design

This study was a descriptive, cross‐sectional survey using targeted sampling.

Participants

A total of 215 participants completed the surveys. Participants were nationally representative of long‐term care nurses by age, years of experience, employment status, and type of health setting.

Methods

This study was an online national survey of long‐term care nurses' perceptions of their intent to stay, moral distress level (Moral Distress Questionnaire), and nurse practice environment (Direct Care Staff Survey). Structural equation modeling analysis explored intent to stay, moral distress, and the nurse practice environment among long‐term care nurses.

Results

The mean moral distress score was low, while the mean nurse practice environment and intent to stay scores were high. Moral distress had a significant, moderately negative association with the nurse practice environment (β = −0.41), while the nurse practice environment had a significant, moderately positive association with intent to stay (β = 0.46). The moral distress had a significant, moderately negative association with intent to stay (β = −0.20). The computed structural equation modeling suggested a partially mediated model (indirect effect = −0.19, p = 0.001).

Conclusion

Since the nurse practice environment partially mediates the relationship between moral distress and intent to stay, interventions to improve the nurse practice environment are crucial to alleviating moral distress and enhancing nurses' intent to stay in their jobs, organizations, and the nursing profession.

Clinical Relevance

Our study demonstrated that the nurse practice environment mediates moral distress and intent to stay.

Interventions to improve the nurse practice environment are crucial to alleviating moral distress and enhancing nurses' intent to stay in their jobs, organizations, and the nursing profession.
Comparing quality of life, anxiety, depression, sleep disturbance, and associated factors in vitiligo and alopecia areata patients
Authors: Ghalamkarpour Fariba , Araghi Farnaz , Tabari Mohammadreza , Moslemi Haghighi Shima , Pourgholi Elnaz
Published: January 2024

Introduction and Objectives

Vitiligo and alopecia areata (AA) are two autoimmune skin diseases that affect patients' quality of life (QoL) and give rise to psychosocial complications, such as depression, negative self‐image, less joyful social engagements, and low self‐esteem. These two disorders have common and uncommon characteristics. Therefore, in this study, we tried to evaluate the similarities and differences in the psychological parameters including quality of life, sleep disturbance, anxiety, and depression levels between, vitiligo and AA patients.

Materials and Methods

Patients with either vitiligo or AA visiting the outpatient dermatology clinic from November 2017 to December 2020 have been included in this study. Persian versions of three questionnaires including the dermatology life quality index (DLQI), hospital anxiety and depression scale (HADS), and Pittsburgh sleep quality index (PSQI), have been used to assess the QoL, sleep disturbance, anxiety, and depression levels in patients.

Results

In total, 188 patients, including 94 (50%) cases of AA and 94 (50%) patients with vitiligo, met the criteria. In AA patients, a significantly higher DLQI score was found (p‐value = 0.002) compared to the vitiligo cases, which means a better QoL in vitiligo patients. Additionally, AA patients had higher scores of anxiety (P‐value<0.001) and depression (p‐Value<0.001). However, sleep disturbance (64.9% of AA patients vs. 59.3% of vitiligo patients; p‐Value = 0.4888) was not significantly different between the two groups.

Conclusions

Our data showed lower QoL and higher levels of anxiety and depression in AA patients compared to vitiligo cases, but no difference was seen in sleep disturbance in the PSQI‐P score.
Positive and Negative Sorting in Team Contests*
Authors: Fu Qiang , Wu Zenan , Zhang Hanyao , Zhou Yangfan
Published: January 2024

This paper investigates the formation of teams in a contest. A manager sorts four workers—who differ in their productivity—into two teams. Workers on each team join forces to produce team output, and one team wins a prize; for example, a bonus package. Two sorting patterns are possible: Positive sorting requires that each team consist of players of same caliber and negative sorting the opposite. We characterize the optimum. We further extend the model to allow the manager to set a prize schedule for the workers on each team upon a win, allocate productive resources between teams, and pick the level of competition of the contest.
Sex differences in development of functional connections in the face processing network
Authors: Nowling Duncan , Crum Kathleen I. , Joseph Jane
Published: January 2024

Background and Purpose

Understanding sex differences in typical development of the face processing network is important for elucidating disruptions during atypical development in sex‐linked developmental disorders like autism spectrum disorder. Based on prior sex difference studies in other cognitive domains, this study examined whether females show increased integration of core and extended face regions with age for face viewing, while males would show increased segregation.

Methods

This study used a cross‐sectional design with typically developing children and adults (n = 133) and a functional MRI face localizer task. Psychophysiological interaction (PPI) analysis examined functional connectivity between canonical and extended face processing network regions with age, with greater segregation indexed by decreased core‐extended region connectivity with age and greater integration indexed by increased core‐extended region connectivity with age.

Results

PPI analysis confirmed increased segregation for males—right fusiform face area (FFA) coupling to right inferior frontal gyrus (IFG) opercular when viewing faces and left amygdala when viewing objects decreased with age. Females showed increased integration with age (increased coupling of the right FFA to right IFG opercular region and right occipital face area [OFA] to right IFG orbital when viewing faces and objects, respectively) and increased segregation (decreased coupling with age of the right OFA with IFG opercular region when viewing faces).

Conclusions

Development of core and extended face processing network connectivity follows sexually dimorphic paths. These differential changes mostly occur across childhood and adolescence, with males experiencing segregation and females both segregation and integration changes in connectivity.
Body size shift in sympatric insects in response to distinct selective forces in fragmented urban environments
Authors: Jia B.‐Y. , Xu R.‐Y. , Shi Z.‐H. , Sun N.‐N. , Xu R. , Wu S.‐H. , Gao L.‐F. , Du B.
Published: January 2024

Phenotypic plasticity, which encompasses the diversification of both irreversible and reversible traits, has long been considered an adaptive response by animals to varying environmental conditions. However, the process by which irreversible and reversible traits are coordinated to form an adaptive response to the changing environment has yet to be clarified. Here, we investigated the variation in body size of two urban insect species in the context of habitat fragmentation. These species were the Chinese cricket Gryllus chinensis and the stove grasshopper Diestrammena japonica, which are sympatric in urban housing estates. Results indicated that both species changed in body size in patches of urban environment. However, their body size shifts showed opposite tendencies and were influenced by distinct selective forces: Chinese crickets increased their body size with the patch history and predation risk, whereas stove grasshoppers decreased their body size with the degree of fragmentation of the patches. Territorial and competitive Chinese crickets rarely experience resource scarcity during urban environment fragmentation. Thus, a larger body size was preferred in response to intraspecific competition among Chinese crickets. By contrast, stove grasshoppers are group‐living and scramble for resources as competitors, requiring a large territory to secure adequate food for supporting a group of individuals. Consequently, stove grasshoppers frequently experienced resource scarcity in the patchy habitat, favoring small body size to reduce individual requirements throughout the life cycle. Our findings indicate that the body size shift of sympatric insects may be subjected to distinct selective forces in fragmented habitats, depending primarily on their reversible traits.
Virtual education strategies in the context of sustainable health care and medical education: A topic modelling analysis of four decades of research
Authors: Lee Jihyun , Kim Hyeongjo , Kron Frederick
Published: January 2024

Background

The growing importance of sustainability has led to the current literature being saturated with studies on the necessity of, and suggested topics for, education for sustainable health care (ESH). Even so, ESH implementation has been hindered by educator unpreparedness and resource scarcity. A potential resolution lies in virtual education. However, research on the strategies needed for successfully implementing virtual education in the context of sustainable health care and medical education is sparse; this study aims to fill the gap.

Methods

Topic modelling, a computational text‐mining method for analysing recurring patterns of co‐occurring word clusters to reveal key topics prevalent across the texts, was used to examine how sustainability was addressed in research in medicine, medical education, and virtual education. A total of 17 631 studies, retrieved from Web of Science, Scopus and PubMed, were analysed.

Results

Sustainability‐related topics within health care, medical education and virtual education provided systematic implications for Sustainable Virtual Medical Education (SVME)–ESH via virtual platforms in a sustainable way. Analyses of keywords, phrases, topics and their associated networks indicate that SVME should address the three pillars of environmental, social and economic sustainability and medical practices to uphold them; employ different technologies and methods including simulations, virtual reality (VR), artificial intelligence (AI), cloud computing, distance learning; and implement strategies for collaborative development, persuasive diffusion and quality assurance.

Conclusions

This research suggests that sustainable strategies in virtual education for ESH require a systems approach, encompassing components such as learning content and objectives, evaluation, targeted learners, media, methods and strategies. The advancement of SVME necessitates that medical educators and researchers play a central and bridging role, guiding both the fields of sustainable health care and medical education in the development and implementation of SVME. In this way, they can prepare future physicians to address sustainability issues that impact patient care.
A national survey of current practice on patients with long term and additional needs in paediatric intensive care units
Authors: Cuevas‐Asturias Sofia , Arambepola Devika , Cunningham Helen , Fraser James
Published: January 2024

Background

Patients with long term and additional needs (LEAP) in paediatric intensive care units (PICUs) are a growing and heterogenous cohort that provide unique challenges to clinicians. Currently no standard approach to define and manage this cohort exists.

Aim

To analyse bed occupancy, examine current practice, and explore ideas to improve PICU care of patients with long term and additional needs.

Study Design

Patients with LEAP were defined as meeting two or more of the following criteria: length of stay >14 days; life limiting condition; ≥2 failed extubations; hospital stay >1 month prior to PICU admission; likely to require long‐term ventilation. An electronic survey was then sent to all UK PICUs, via the UK Paediatric Critical Care Society, to collect quantitative and qualitative data relating to bed occupancy, length of stay, multidisciplinary and family involvement, and areas of possible improvement. Data collection were occurred between 8 February 2022 and 14 March 2022. Quantitative data were analysed using Microsoft Excel 365 and SPSS Statistics version 28.0. Raw data and descriptive statistics were reported, including percentages and median with interquartile range for non‐parametric data. Qualitative raw data were examined using thematic analysis. Analysis was undertaken independently by two authors and results assessed for concordance.

Results

70.1% (17/24) PICUs responded. 25% (67/259) of PICU beds were occupied by patients with long term and additional needs. 29% (5/17) of responding units have tailored management plans to this cohort of patient. A further 11% (2/17) have guidelines for children with generic chronic illness. 12% (2/16) of responding units had a designated area and 81% (13/16) of responding units had designated professionals. The majority (68% and 62%) of responding units engaged families and community professionals in multidisciplinary meetings. When asked how the care of long term and additional needs patients might be improved five themes were identified: consistent, streamlined care pathways; designated transitional care units; designated funding and hospital‐to‐home commissioning; development of roles to facilitate collaboration between hospital and community teams; proactive discharge planning and parallel planning.

Conclusions

This survey provides a snapshot of UK practice for a cohort of patients that occupies a considerable proportion (29%) of PICU beds. While only a minority of responding PICUs offer specifically tailored management plans, the majority of units have designated professionals.

Relevance to Clinical Practice

Opportunities exist to improve PICU care in LEAP patients in areas such as: streamlined care pathways, designated clinical areas, designated funding, and development of defined collaborative roles. Next steps may involve working group convention to develop a consensus definition and share good practice examples.
Patronus charm: a comparison of benefactor plants and climate mediation effects on diversity
Authors: Lortie Christopher J. , Liczner Amanda , Ruttan Ally , Braun Jenna , Sotomayor Diego A. , Westphal Mike , King Rachel , Filazzola Alessandro
Published: January 2024

Deserts are subject to significant anthropogenic pressure. The capacity to buffer against changes in the local environment and biodiversity are critical for ecosystem functioning. Foundation species can be a solution to rapidly assess ecological function and provide a simple nature‐based solution to protect against continuing biodiversity losses. A foundation species is defined as a species that exerts and promotes a positive set of processes for the biotic network. Two different shrub species in the central drylands of California were used to assay a potential buffer for plant species richness and to examine the species‐specificity of foundation facilitation. A five‐year dataset in two distinct regions differing in aridity was used to test the hypothesis that the direct effects of foundation plants facilitate other plant species and buffer diversity losses to a changing climate. The predicted positive effects of both shrub species on species richness increased with increasing local temperatures sampled. Finally, projected temperature increases for the region in trained Bayesian models demonstrated that both shrub species can profoundly increase in their capacity to facilitate plant species richness. Colloquially, this positive ecological effect can be described as the patronus charm hypothesis because regardless of the form of the protector, shrub species provided a talisman against local loss of richness driven by temperature increases.
Ultrasound‐guided fascial plane blocks for post‐breast surgery pain syndrome
Authors: Ferreira‐Silva Nuno , Hurdle Mark Friedrich B. , Clendenen Steven R. , Gulati Amitabh , McLaughlin Sarah A. , Troyer Wesley , Rosario‐Concepción Raúl A.
Published: January 2024

Introduction

Persistent pain following breast surgery is common and may be challenging to treat. In patients refractory to conservative treatments, ultrasound‐guided fascial plane blocks of thoracic nerves can be a useful option.

Results

This type of neuro blockade technique provides advantages in terms of safety and efficacy that are convenient for physicians managing refractory and complex cases of post‐breast surgery syndrome.

Conclusion

This technical review aims to present an up‐to‐date summary of the most common ultrasound‐guided fascial plane blocks for chronic pain in post‐breast surgery patients, provide a detailed technical description of each intervention, and propose preferred injections based on the anatomical location of the pain.
Roles of ROS and redox in regulating cell‐to‐cell communication: Spotlight on viral modulation of redox for local spread
Authors: Alazem Mazen , Burch‐Smith Tessa M.
Published: January 2024

Reactive oxygen species (ROS) are important signalling molecules that influence many aspects of plant biology. One way in which ROS influence plant growth and development is by modifying intercellular trafficking through plasmodesmata (PD). Viruses have evolved to use PD for their local cell‐to‐cell spread between plant cells, so it is therefore not surprising that they have found ways to modulate ROS and redox signalling to optimise PD function for their benefit. This review examines how intracellular signalling via ROS and redox pathways regulate intercellular trafficking via PD during development and stress. The relationship between viruses and ROS‐redox systems, and the strategies viruses employ to control PD function by interfering with ROS‐redox in plants is also discussed.
A single‐blind randomised study comparing the efficacy of fluconazole and itraconazole for the treatment of Malassezia dermatitis in client‐owned dogs
Authors: Lee Hayoon , Koo Yoonhoi , Yun Taesik , Lee Dohee , Chae Yeon , Min Kyung‐Duk , Kim Hakhyun , Yang Mhan‐Pyo , Kang Byeong‐Teck
Published: January 2024

Background

No reports have compared the clinical therapeutic efficacy of fluconazole and itraconazole in canine Malassezia dermatitis.

Objectives

The study aimed to compare the clinical therapeutic efficacy of fluconazole and itraconazole and to evaluate the adverse effects of fluconazole in canine Malassezia dermatitis.

Animals

Sixty‐one client‐owned dogs with Malassezia dermatitis.

Materials and Methods

The enrolled animals were randomly divided into groups receiving 5 mg/kg fluconazole (5FZ), 10 mg/kg fluconazole (10FZ) or 5 mg/kg itraconazole (5IZ). The drugs were orally administered once daily for 28 days. Cytological examination, clinical index score (CIS), pruritus Visual Analog Scale (PVAS) evaluation and blood analysis (for 5FZ only) were performed on Day (D)0, D14 and D28.

Results

On D14, significant reductions in mean yeast count (MYC), CIS and PVAS were observed in the 5FZ (n = 20, p < 0.01), 10FZ (n = 17, p < 0.01) and 5IZ (n = 16, p < 0.05) groups. In all three groups, a significant reduction (p < 0.001) in MYC, CIS and PVAS expression was observed on D28. There was no significant difference in the percentage reduction of MYC, CIS and PVAS among the groups. Moreover, there was a significant difference (p < 0.05) in each group between D14 and D28, except for the percentage reduction in MYC in the 10FZ and 5IZ groups. No adverse effects of fluconazole were observed in the 5FZ or 10FZ groups.

Conclusions and Clinical Relevance

This study indicates that 5FZ and 10FZ are as effective as itraconazole in canine Malassezia dermatitis.
Effects of cognitive behavioral therapy in patients with chronic obstructive pulmonary disease: A systematic review and meta‐analysis
Authors: Chen Xinming , Guo Yating , Zhang Tuoxin , Lin Jiamin , Ding Xintong
Published: January 2024

Background

Chronic obstructive pulmonary disease (COPD) causes airflow blockage and breathing‐related issues. This chronic disease impacts people worldwide. Substantial evidence supports the use of cognitive behavioral therapy (CBT) to help patients with chronic illnesses cope with worrisome and painful symptoms. However, the impact of CBT on COPD outcomes is less understood.

Objective

In this study, we systematically summarized the effects of CBT on lung function, anxiety and depressive symptoms, and quality of life of patients with COPD.

Methods

Six English‐language and four Chinese‐language databases were systematically searched for relevant randomized controlled trials published through April 15, 2023. Studies in which CBT was the only difference in treatment administered to experimental and control groups were included in the review. The studies' risk of bias was evaluated using the Cochrane Criteria.

Results

Sixteen studies (1887 participants) were included. The meta‐analysis showed that CBT improved the percent‐predicted forced expiratory volume in 1 second (FEV1%), forced vital capacity (FVC), FEV1/FVC ratio, maximal voluntary ventilation, peak expiratory flow, treatment compliance, and World Health Organization abbreviated quality of life, Self‐rating Anxiety and Depression Scale, and St George's Respiratory Questionnaire scores compared with the control (all p < .05).

Conclusion

This review demonstrated that CBT improves the lung function, anxiety and depressive symptoms, treatment compliance, and quality of life of patients with COPD and can be used widely in the clinical treatment of this disease.
On the noise reduction mechanisms of over-tip liners
Authors: Subramanyam Ramesh Raja , Palani Suresh , Chaitanya Paruchuri , Palleja-Cabre Sergi
Published: January 2024

The application of acoustic liners near/directly over a sound source has gained significant interest for the excess noise reduction achieved with Over-the-Rotor (OTR) liners compared to the conventional liner installations at the intake of an aero-engine. However, the mechanism of noise reduction achieved in the OTR liners is not clearly understood. This paper aims to explain this mechanism by considering a static monopole source placed over a finite liner insert with a zero background mean flow. This has been investigated numerically using COMSOL Multiphysics in a half-space domain and compared with reference analytical solutions for infinite lined walls. One of the key findings of the paper is the underlying physics of the source modification mechanism, which has been found to be the interference between the primary noise source and a secondary noise source forming on the liner surface. It is identified through an optimal impedance study that this back-reaction mechanism is dominant when the source is located for a normalised tip gap, e/λ<0.25, where e is the distance between the source and the liner surface and λ is the acoustic wavelength. Within this region, there exists an optimum normalised liner length, L / e providing a maximum insertion loss.
Guanosine diphosphate–mannose suppresses homologous recombination repair and potentiates antitumor immunity in triple-negative breast cancer
Authors: Ding Jia-Han , Xiao Yi , Yang Fan , Song Xiao-Qing , Xu Ying , Ding Xiao-Hong , Ding Rui , Shao Zhi-Ming , Di Gen-Hong , Jiang Yi-Zhou
Published: January 2024

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis. TNBCs with high homologous recombination deficiency (HRD) scores benefit from DNA-damaging agents, including platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, whereas those with low HRD scores still lack therapeutic options. Therefore, we sought to exploit metabolic alterations to induce HRD and sensitize DNA-damaging agents in TNBCs with low HRD scores. We systematically analyzed TNBC metabolomics and identified a metabolite, guanosine diphosphate (GDP)–mannose (GDP-M), that impeded homologous recombination repair (HRR). Mechanistically, the low expression of the upstream enzyme GDP-mannose-pyrophosphorylase-A (GMPPA) led to the endogenous up-regulation of GDP-M in TNBC. The accumulation of GDP-M in tumor cells further reduced the interaction between breast cancer susceptibility gene 2 (BRCA2) and ubiquitin-specific peptidase 21 (USP21), which promoted the ubiquitin-mediated degradation of BRCA2 to inhibit HRR. Therapeutically, we illustrated that the supplementation of GDP-M sensitized DNA-damaging agents to impair tumor growth in both in vitro (cancer cell line and patient-derived organoid) and in vivo (xenograft in immunodeficient mouse) models. Moreover, the combination of GDP-M with DNA-damaging agents activated STING-dependent antitumor immunity in immunocompetent syngeneic mouse models. Therefore, GDP-M supplementation combined with PARP inhibition augmented the efficacy of anti–PD-1 antibodies. Together, these findings suggest that GDP-M is a crucial HRD-related metabolite and propose a promising therapeutic strategy for TNBCs with low HRD scores using the combination of GDP-M, PARP inhibitors, and anti–PD-1 immunotherapy.
The metabolic slowdown caused by the deletion of
pspA
accelerates protein aggregation during stationary phase facilitating antibiotic persistence
Authors: Li Yingxing , Chen Xiao , Zhang Weili , Fang Kefan , Tian Jingjing , Li Fangyuan , Han Mingfei , Huang Jingjing , Sun Tianshu , Bai Fan , Cheng Mei , Xu Yingchun
Published: January 2024

Entering a dormant state is a prevailing mechanism used by bacterial cells to transiently evade antibiotic attacks and become persisters. The dynamic progression of bacterial dormancy depths driven by protein aggregation has been found to be critical for antibiotic persistence in recent years. However, our current understanding of the endogenous genes that affects dormancy depth remains limited. Here, we discovered a novel role of phage shock protein A (
pspA
) gene in modulating bacterial dormancy depth. Deletion of
pspA
of
Escherichia coli
resulted in increased bacterial dormancy depths and prolonged lag times for resuscitation during the stationary phase.
∆pspA
exhibited a higher persister ratio compared to the wild type when challenged with various antibiotics. Microscopic images revealed that
∆pspA
showed accelerated formation of protein aggresomes, which were collections of endogenous protein aggregates. Time-lapse imaging established the positive correlation between protein aggregation and antibiotic persistence of
∆pspA
at the single-cell level. To investigate the molecular mechanism underlying accelerated protein aggregation, we performed transcriptome profiling and found the increased abundance of chaperons and a general metabolic slowdown in the absence of
pspA
. Consistent with the transcriptomic results, the
∆pspA
strain showed a decreased cellular ATP level, which could be rescued by glucose supplementation. Then, we verified that replenishment of cellular ATP levels by adding glucose could inhibit protein aggregation and reduce persister formation in
∆pspA
. This study highlights the novel role of
pspA
in maintaining proteostasis, regulating dormancy depth, and affecting antibiotic persistence during stationary phase.
Improved characterization of aminoglycoside penetration into human lung epithelial lining fluid via population pharmacokinetics
Authors: Shin Eunjeong , Zhang Yongzhen , Zhou Jieqiang , Lang Yinzhi , Sayed Alaa R. M. , Werkman Carolin , Jiao Yuanyuan , Kumaraswamy Monika , Bulman Zackery P. , Luna Brian M. , Bulitta Jürgen B.
Published: January 2024

Aminoglycosides are important treatment options for serious lung infections, but modeling analyses to quantify their human lung epithelial lining fluid (ELF) penetration are lacking. We estimated the extent and rate of penetration for five aminoglycosides via population pharmacokinetics from eight published studies. The area under the curve in ELF vs plasma ranged from 50% to 100% and equilibration half-lives from 0.61 to 5.80 h, indicating extensive system hysteresis. Aminoglycoside ELF peak concentrations were blunted, but overall exposures were moderately high.
Escherichia coli
CadB is capable of promiscuously transporting muropeptides and contributing to peptidoglycan recycling
Authors: Simpson Brent W. , Gilmore Michael C. , McLean Amanda Briann , Cava Felipe , Trent M. Stephen
Published: January 2024

The bacterial peptidoglycan (PG) cell wall is remodeled during growth and division, releasing fragments called muropeptides. Muropeptides can be internalized and reused in a process called PG recycling.
Escherichia coli
is highly devoted to recycling muropeptides and is known to have at least two transporters, AmpG and OppBCDF, that import them into the cytoplasm. While studying mutants lacking AmpG, we unintentionally isolated mutations that led to the altered expression of a third transporter, CadB. CadB is normally upregulated under acidic pH conditions and is an antiporter for lysine and cadaverine. Here, we explored if CadB was altering PG recycling to assist in the absence of AmpG. Surprisingly, CadB overexpression was able to restore PG recycling when both AmpG and OppBCDF were absent. CadB was found to import freed PG peptides, a subpopulation of muropeptides, through a promiscuous activity. Altogether, our data support that CadB is a third transporter capable of contributing to PG recycling.

IMPORTANCE

Bacteria produce a rigid mesh cell wall. During growth, the cell wall is remodeled, which releases cell wall fragments. If released into the extracellular environment, cell wall fragments can trigger inflammation by the immune system of a host. Gastrointestinal bacteria, like
Escherichia coli
, have dedicated pathways to recycle almost all cell wall fragments they produce.
E. coli
contains two known recycling transporters, AmpG and Opp, that we previously showed are optimized for growth in different environments. Here, we identify that a third transporter, CadB, can also contribute to cell wall recycling. This work expands our understanding of cell wall recycling and highlights the dedication of organisms like
E. coli
to ensure high recycling in multiple growth environments.
SNX32 is a host restriction factor that degrades African swine fever virus CP204L via the RAB1B-dependent autophagy pathway
Authors: Yang Wenping , Li Lingxia , Zhang Jing , Wu Junhuang , Kang Weifang , Wang Yue , Ding Haiyan , Li Dan , Zheng Haixue
Published: January 2024

African swine fever virus (ASFV) causes a highly contagious and deadly disease in domestic pigs and European wild boars, posing a severe threat to the global pig industry. ASFV CP204L, a highly immunogenic protein, is produced during the early stages of ASFV infection. However, the impact of CP204L protein-interacting partners on the outcome of ASFV infection is poorly understood. To accomplish this, coimmunoprecipitation and mass spectrometry analysis were conducted in ASFV-infected porcine alveolar macrophages (PAMs). We have demonstrated that sorting nexin 32 (SNX32) is a CP204L-binding protein and that CP204L interacted and colocalized with SNX32 in ASFV-infected PAMs. ASFV growth and replication were promoted by silencing SNX32 and suppressed by overexpressing SNX32. SNX32 degraded CP204L by recruiting the autophagy-related protein Ras-related protein Rab-1b (RAB1B). RAB1B overexpression inhibited ASFV replication, while knockdown of RAB1B had the opposite effect. Additionally, RAB1B, SNX32, and CP204L formed a complex upon ASFV infection. Taken together, this study demonstrates that SNX32 antagonizes ASFV growth and replication by recruiting the autophagy-related protein RAB1B. This finding extends our understanding of the interaction between ASFV CP204L and its host and provides new insights into exploring the relationship between ASFV infection and autophagy.

IMPORTANCE

African swine fever (ASF) is a highly contagious and acute hemorrhagic viral disease with a high mortality near 100% in domestic pigs. ASF virus (ASFV), which is the only member of the family
Asfarviridae
, is a dsDNA virus of great complexity and size, encoding more than 150 proteins. Currently, there are no available vaccines against ASFV. ASFV CP204L represents the most abundantly expressed viral protein early in infection and plays an important role in regulating ASFV replication. However, the mechanism by which the interaction between ASFV CP204L and host proteins affects ASFV replication remains unclear. In this study, we demonstrated that the cellular protein SNX32 interacted with CP204L and degraded CP204L by upregulating the autophagy-related protein RAB1B. In summary, this study will help us understand the interaction mechanism between CP204L and its host upon infection and provide new insights for the development of vaccines and antiviral drugs.
Palisade structure in intact vaccinia virions
Authors: Hernandez-Gonzalez Miguel , Calcraft Thomas , Nans Andrea , Rosenthal Peter B. , Way Michael
Published: January 2024

Poxviruses such as variola virus (smallpox) and monkeypox cause diseases in humans. Other poxviruses, including vaccinia and modified vaccinia Ankara, are used as vaccine vectors. Given their importance, a greater structural understanding of poxvirus virions is needed. We now performed cryo-electron tomography of purified intact vaccinia virions to study the structure of the palisade, a protein lattice that defines the viral core boundary. We identified the main viral proteins that form the palisade and their interaction surfaces and provided new insights into the organization of the viral core.
Dietary supplementation with
Lactiplantibacillus plantarum
P-8 improves the growth performance and gut microbiota of weaned piglets
Authors: Yu Jie , Zuo Bin , Li Qi , Zhao Feiyan , Wang Junjun , Huang Weiqiang , Sun Zhihong , Chen Yongfu
Published: January 2024

Weaning is a stressful event in the pig life cycle. We hypothesized that probiotics could be potential alternatives to antibiotics for promoting growth and ameliorating stress in weaning piglets via gut microbiota modulation and, thus, investigated the beneficial effects of dietary probiotic supplementation in weaning pigs. Ninety weaning piglets (Landrace × large white, 45 males and 45 females, 25 days of age) were randomized into three dietary treatments (30 piglets/treatment, divided into five replicates/treatment, i.e., six piglets/replicate) in this 28-day trial: control (C group, basal diet); probiotic [lactic acid bacteria (LAB) group, basal diet plus
Lactiplantibacillus plantarum
P-8]; and antibiotic (A group; basal diet plus chlortetracycline). The piglets’ growth performance [average daily gain, average daily feed intake (ADFI), and feed conversion ratio (FCR)], immune and antioxidant markers, ileal mucosal morphology, and ileal and colonic microbiomes were compared among treatment groups. Compared to the C and A groups, probiotic supplementation significantly decreased the ADFI, FCR, and ileal mucosal crypt depth while increasing the villus height-to-crypt depth ratio, hepatic glutathione peroxidase and catalase activities, and serum levels of interleukin-2. Both probiotic and antibiotic treatments modulated the piglets’ gut microbiomes, with more
L. plantarum
in the LAB group and more
Eubacterium rectale
and
Limosilactobacillus reuteri
in the A group. Probiotic supplementation significantly increased the relative abundance of genes encoding the acetylene, galactose, and stachyose degradation pathways, potentially enhancing nutrient absorption, energy acquisition, and growth performance. Probiotics are effective alternatives to antibiotics for promoting the health of piglets, possibly via gut microbiome modulation.

IMPORTANCE

Weaning impacts piglet health, performance, and mortality. Antibiotic treatment during weaning can mitigate the negative effects on growth. However, antibiotic use in livestock production contributes to the emergence of antibiotic resistance, which is a threat to global public health. This comprehensive study describes the gut microbial composition and growth performance of weaned piglets after dietary supplementation with
Lactiplantibacillus plantarum
P-8 or antibiotics.
L. plantarum
P-8 ameliorated stress and improved antioxidant capacity and growth performance in weaned piglets, accompanied by gut microbiota improvement.
L. plantarum
P-8 is an effective substitute for antibiotics to promote the health of weaned piglets while avoiding the global concern of drug resistance.
SMR peptide antagonizes
Staphylococcus aureus
biofilm formation
Authors: Huang Ming-Bo , Brena Dara , Wu Jennifer Y. , Shelton Martin , Bond Vincent C.
Published: January 2024

The emergence and international dissemination of multi-drug resistant
Staphylococcus aureus
(
S. aureus
) strains challenge current antibiotic-based therapies, representing an urgent threat to public health worldwide. In the U.S. alone,
S
.
aureus
infections are responsible for 11,000 deaths and 500,000 hospitalizations annually. Biofilm formation is a major contributor to antibiotic tolerance and resistance-induced delays in empirical therapy with increased infection severity, frequency, treatment failure, and mortality. Developing novel treatment strategies to prevent and disrupt biofilm formation is imperative. In this article, we test the Secretion Modification Region (SMR) peptides for inhibitory effects on resistant
S. aureus
biofilm-forming capacity by targeting the molecular chaperone DnaK. The dose effect of SMR peptides on biofilm formation was assessed using microtiter plate methods and confocal microscopy. Interaction between the antagonist and DnaK was determined by immune precipitation with anti-Flag M2 Affinity and Western blot analysis. Increasing SMR peptide concentrations exhibited increasing blockade of
S. aureus
biofilm formation with significant inhibition found at 18 µM, 36 µM, and 72 µM. This work supports the potential therapeutic benefit of SMR peptides in reducing biofilm viability and could improve the susceptibility to antimicrobial agents.

IMPORTANCE

The development of anti-biofilm agents is critical to restoring bacterial sensitivity, directly combating the evolution of resistance, and overall reducing the clinical burden related to pervasive biofilm-mediated infections. Thus, in this study, the SMR peptide, a novel small molecule derived from the HIV Nef protein, was preliminarily explored for anti-biofilm properties. The SMR peptide was shown to effectively target the molecular chaperone DnaK and inhibit biofilm formation in a dose-dependent manner. These results support further investigation into the mechanism of SMR peptide-mediated biofilm formation and inhibition to benefit rational drug design and the identification of therapeutic targets.
Comparative reassessment of AcrB efflux inhibitors reveals differential impact of specific pump mutations on the activity of potent compounds
Authors: Schuster Sabine , Vavra Martina , Wirth Dave A. N. , Kern Winfried V.
Published: January 2024

Multidrug resistance poses global challenges, particularly with regard to Gram-negative bacterial infections. In view of the lack of new antibiotics, drug enhancers, such as efflux pump inhibitors (EPIs), have increasingly come into focus. A number of chemically diverse agents have been reported to inhibit AcrB, the main multidrug transporter in
Escherichia coli
, and homologs in other Gram-negative bacteria. However, due to the often varying methodologies used for their characterization, results remain difficult to compare. In this study, using a defined selection of antibiotics known to be efflux substrates, we reevaluated 38 published compounds for their
in vitro
EPI activity. When examined in an
E. coli
strain with stable wild-type AcrB overexpression, we found 17 compounds showing at least fourfold enhancing potency with more than 2 out of 10 test drugs (belonging to eight antibiotic classes). Pyranopyridines (MBX series) were confirmed as the most potent inhibitors among agents reported so far. A new and surprising finding was that their activity, unlike that of the pyridylpiperazine EPI BDM88855, was highly susceptible to the AcrB double-mutation G141D_N282Y, which had previously been shown to diminish drug enhancing of 1-(1-naphthylmethyl)piperazine in a predominantly substrate-specific manner. Conversely, transmembrane region mutation V411A, while eliminating the drug potentiating of the BDM compound, did not decrease the activity of the MBX EPIs. Besides comparative reassessment of the potency of reported EPIs, the study demonstrated the usefulness of mutagenesis approaches providing tools for an initial discrimination of EPIs regarding their mode of function.

IMPORTANCE

Infections with difficult-to-treat multidrug-resistant bacteria pose an urgent global threat in view of the stagnating development of new antimicrobial substances. Efflux pumps in Gram-negative pathogens are known to substantially contribute to multidrug resistance making them promising targets for chemotherapeutic interventions to restore the efficacy of conventional antibiotics. In the present study, the
in vitro
activity of previously reported efflux pump inhibitors was reassessed using standardized conditions. Relevant drug sensitizing activity could be proven for almost half of the tested compounds. Further characterization of potent inhibitors was achieved by investigating the impact of specific efflux pump mutations. A double-mutation previously known to decrease the activity of the arylpiperazine 1-(1-naphthylmethyl)piperazine also impaired that of the highly efficient pyranopyridine efflux pump inhibitors. Our findings provide direct comparability of reported efflux pump inhibitors and contribute to the elucidation of their mode of action.