bluuebunny/crossref_metadata_2025_split huggingface dataset:
Toxoplasma gondii
PROP1 is critical for autophagy and parasite viability during chronic infection
Authors: Thaprawat Pariyamon , Wang Fengrong , Chalasani Shreya , Schultz Tracey L. , Di Cristina Manlio , Carruthers Vern B. 
Published: February 2025

ABSTRACT

Macroautophagy is an important cellular process involving lysosomal degradation of cytoplasmic components, facilitated by autophagy-related proteins. In the protozoan parasite
Toxoplasma gondii
, autophagy has been demonstrated to play a key role in adapting to stress and the persistence of chronic infection. Despite limited knowledge about the core autophagy machinery in
T. gondii
, two PROPPIN family proteins (TgPROP1 and TgPROP2) have been identified with homology to Atg18/WIPI. Prior research in acute-stage tachyzoites suggests that TgPROP2 is predominantly involved in a non-autophagic function, specifically apicoplast biogenesis, while TgPROP1 may be involved in canonical autophagy. Here, we investigated the distinct roles of TgPROP1 and TgPROP2 in chronic stage
T. gondii
bradyzoites, revealing a critical role for TgPROP1, but not TgPROP2, in bradyzoite autophagy. Conditional knockdown of TgPROP2 did not impair bradyzoite autophagy. In contrast, TgPROP1 KO parasites had impaired autolysosome formation, reduced cyst burdens in chronically infected mice, and decreased viability. Together, our findings clarify the indispensable role of TgPROP1 to
T. gondii
autophagy and chronic infection.

IMPORTANCE

It is estimated that up to a third of the human population is chronically infected with
Toxoplasma gondii
; however, little is known about how this parasite persists long term within its hosts. Autophagy is a self-eating pathway that has recently been shown to play a key role in parasite persistence, yet few proteins that carry out this process during
T. gondii
chronic infection are known. Here, we provide evidence for a non-redundant role of TgPROP1, a protein important in the early steps of the autophagy pathway. Genetic disruption of TgPROP1 resulted in impaired autophagy and chronic infection of mice. Our results reveal a critical role for TgPROP1 in autophagy and underscore the importance of this pathway in parasite persistence.
Gut microbiota development in very preterm infants following fortification of human milk
Authors: Yang Lin , Hui Yan , Sangild Per Torp , Kot Witold Piotr , Aunsholt Lise , Zachariassen Gitte , Jiang Ping-Ping , Nielsen Dennis Sandris 
Published: February 2025

ABSTRACT

Very preterm infants (VPIs) are born with an immature gut and predisposed to gut microbiota dysbiosis-related diseases, for example, necrotizing enterocolitis. Although fortification of human milk is required for these infants, the optimal fortifier remains uncertain. Bovine colostrum (BC), rich in protein and bioactive components, could serve as an alternative to conventional fortifiers (CF). The gut microbiota (GM) of 225 VPIs fed human milk fortified with either BC or CF (FortiColos study, NCT03537365) was profiled by 16S rRNA gene amplicon sequencing of fecal samples collected before, and after 1 and 2 weeks of fortification. Birth mode exhibited transient effects on the microbial community structure shortly after birth, with cesarean section-born VPIs dominated by
Firmicutes
, whereas vaginally born VPIs were dominated by
Proteobacteria
. This birth mode-derived difference diminished with age and disappeared around 1 month after birth. Fortifier type affected the microbial community structure to a modest extent, but no specific taxa significantly differed between the BC and CF groups. Fecal pH, increased by BC, was positively correlated with
Staphylococcus
and
Corynebacterium
and negatively with
Bifidobacterium
abundance. Change in the relative abundance of
Staphylococcus
was negatively correlated with body weight gain. Collectively, fortification of human milk with BC or CF does influence the GM of VPIs but only to a modest extent during early life. Birth mode appears to have a significant, but temporary influence on the GM during this period.

IMPORTANCE
Early life is a key period for gut microbiota (GM) establishment, where enteral feeding plays a significant role. This is also the case for infants born preterm, who, due to their immature gut, are at a high risk of developing GM dysbiosis-related diseases. Human milk is the optimal feed for preterm infants, but it requires fortification to reach adequate levels of especially protein. Only a few studies have investigated the impact of fortifiers on GM development in preterm infants. Here, we demonstrate that two different bovine milk-based fortifiers, bovine colostrum and a conventional fortifier based on mature bovine milk, exhibit limited effects on the microbial community structure of very preterm infants. These findings suggest that although great care in terms of optimally maturing the preterm infant GM should be taken, the choice of fortifier only has limited impact. In clinical practice, the choice of fortifier can thus be fully focussed on optimizing preterm infant nutrition.

CLINICAL TRIALS

This study is registered with ClinicalTrials.gov as
NCT03537365
.
Targeting efflux pumps prevents the multi-step evolution of high-level resistance to fluoroquinolone in
Pseudomonas aeruginosa
Authors: Yu Xiao-Quan , Yang Hao , Feng Han-Zhong , Hou Jun , Tian Jun-Qiang , Niu Shao-Min , You Chong-Ge , Tao Xuan-Yu , Zhang Si-Ping , Wang Zhi-Ping , He Yong-Xing 
Published: February 2025

ABSTRACT

Antibiotic resistance is emerging as a significant global health crisis, necessitating the urgent development of novel antibiotics or alternative therapies. Although it is recognized that bacteria require multiple mutations to develop resistance levels exceeding the mutant prevention concentration, the specific mutation combinations conferring high resistance have been largely undefined. Here, we investigated the multi-step evolution of fluoroquinolone resistance in
Pseudomonas aeruginosa
through experimental evolution and whole-genome sequencing coupled with proteomic approaches. We discovered that in low-dose and high-dose experimental evolution scenarios, combinations of mutations in the negative regulators of efflux pumps (
nfxB/mexR
) and DNA gyrases (
gyrA/gyrB
) contributed to the high-level resistance and some of these combinations were also prevalent in clinical isolates of
P. aeruginosa
. Notably, the selected
nfxB
mutation, which resulted in the overexpression of the MexCD-OprJ efflux pump, also exhibited collateral sensitivity to aminoglycosides and enhanced antibiotic tolerance. It was further revealed that the efflux pump inhibitor phenylalanine-arginine β-naphthylamide (PAβN) could effectively prevent evolution to high-level resistance for both laboratory and clinical
P. aeruginosa
strains. Our work highlights the critical role of efflux pump repressor-related mutations in the evolution of high-level antibiotic resistance and demonstrates the potential of targeting these mutations to impede the evolution toward high-level resistance.

IMPORTANCE

In this study, we examined the stepwise evolution of fluoroquinolone resistance in
Pseudomonas aeruginosa
using experimental evolution, whole-genome sequencing, and proteomic analyses. Our findings revealed that under both low-dose and high-dose conditions, mutations in efflux pump regulators (
nfxB
/
mexR
) and DNA gyrase genes (
gyrA
/
gyrB
) synergistically contributed to high-level resistance. These mutation combinations were not only observed in experimental settings but also detected in clinical isolates of
P. aeruginosa
. This work underscores the pivotal role of efflux pump repressor-related mutations in the progression to high-level antibiotic resistance. It also highlights the promise of targeting efflux pumps as a strategy to prevent the multi-step evolution of resistance in
P. aeruginosa
.
Demographic disparity in Wikipedia coverage: a global perspective
Authors: Yu Yulin , Li Xianglong , Li Tianyi , Dhillon Paramveer S. , Romero Daniel M. 
Published: February 2025

Abstract
Despite decades-long efforts to increase diversity, underrepresented social groups remain small minorities in many fields. Here, we ask whether disparities in global recognition exist for traditionally underrepresented demographic groups. We investigate whether a notable person’s demographic attributes are associated with their global recognition, considering both the global availability of public information about the person’s life and the consistency of such information. To track bibliographical information about notable people, we study Wikipedia, one of the most accessible knowledge bases on the Web. Using more than 1 million biographical articles from Wikipedia over ten years across the 12 largest language editions of Wikipedia, we study global gender and citizenship disparities in Wikipedia coverage. We measure global coverage in several ways, including the number of languages in which a person appears, the length of a person’s articles, and the global consensus about the person, which measures content similarity in the person’s articles across languages. We find that while females are broadly well-represented in terms of coverage in multiple languages starting from 2015, the quantity of the content of their articles and global consensus disparities persist consistently over time from 2010 to 2020. Additionally, some traditionally underrepresented nationalities are still covered less than their majority counterparts. Also, we observe an improvement on average in coverage while finding a persistent gender disparity in a specific domain, the global appearance of Olympic medal winners.
Graphene Oxide/CuO/ZnO Nanocomposite Combined Carbon Fibers as a Sensor for the Determination of Antibiotic Chloramphenicol
Authors: Shruthi S.M.G , KP Latha , Kumar Mohan , Revansiddappa Raghavendra R B , Reddy Sathish 
Published: February 2025

Abstract
A nano-composition of graphene oxide (GO), copper oxide (CuO), and zinc oxide (ZnO) was synthesized by utilizing the co-precipitation method and characterized by various methods. The synthesized GO/CuO/ZnO nanocomposite was utilized as a modifier combined with carbon fiber (CF) on the glassy carbon electrode (GO/CuO/ZnO@CF/GCE). The modified electrode was utilized to determine the antibiotic chloramphenicol (CAP), which risks public and environmental health by arising as residue, especially in food samples. Cyclic voltammetry and differential voltammetric techniques were used to investigate the electrochemical performance of CAP on the GO/CuO/ZnO@CF/GCE, and it established excellent electrocatalytic activity compared to bare glassy carbon electrode (BGCE). The electroactive surface area of BGCE and GO/CuO/ZnO@CF/GCE were found to be 0.03605 cm2 and 0.05215 cm2 respectively. Scan-rate studies reveal the diffusion-controlled electrode process at GO/CuO/ZnO@CF/GCE. The modified electrode showed a high sensitivity of 1.45 µA/µM cm2 with a low detection limit (13.3 µM). The prepared modified electrochemical sensor had well repeatability and reproducibility, adequate stability, and good selectivity toward the determination of CAP. Moreover, prepared (GO/CuO/ZnO@CF/GCE) was utilized to measure CAP in real samples such as milk and honey.
Inhibition of PIM kinase in tumor-associated macrophages suppresses inflammasome activation and sensitizes prostate cancer to immunotherapy
Authors: Clements Amber N. , Casillas Andrea L. , Flores Caitlyn E. , Liou Hope , Toth Rachel K. , Chauhan Shailender S. , Sutterby Kai , Deshmukh Sachin Kumar , Wu Sharon , Xiu Joanne , Farrell Alex , Radovich Milan , Nabhan Chadi , Heath Elisabeth I. , McKay Rana R. , Subah Noor , Centuori Sara , Wheeler Travis J. , Cress Anne E. , Rogers Gregory C. , Wilson Justin E. , Recio-Boiles Alejandro , Warfel Noel A. 
Published: February 2025

Abstract
Immune checkpoint inhibitors (ICIs) have changed the treatment paradigm for many cancers but have not shown benefit in prostate cancer (PCa). Chronic inflammation contributes to the immunosuppressive prostate tumor microenvironment (TME) and is associated with poor response to ICIs. The primary source of inflammatory cytokine production is the inflammasome. Here, we identify PIM kinases as regulators of inflammasome activation in tumor-associated macrophages (TAMs). Analysis of clinical data from a cohort of treatment naïve, hormone-responsive PCa patients revealed that tumors from patients with high PIM1/2/3 displayed an immunosuppressive TME characterized by high inflammation and a high density of repressive immune cells, most notably TAMs. Macrophage-specific knockout of PIM reduced tumor growth in syngeneic models of PCa. Transcriptional analyses indicated that eliminating PIM from macrophages enhanced the adaptive immune response and increased cytotoxic immune cells. Combined treatment with PIM inhibitors and ICIs synergistically reduced tumor growth. Immune profiling revealed that PIM inhibitors sensitized PCa tumors to ICIs by increasing tumor suppressive TAMs and increasing the activation of cytotoxic T cells. Our data implicate macrophage PIM as a driver of inflammation that limits ICI potency and provide preclinical evidence that PIM inhibitors are an effective strategy to improve the ICI efficacy in PCa.
Right-Wing Populists and the Politics of Renegotiating International Environmental Agreements
Authors: Huynh Nguyen Khoi 
Published: February 2025

Abstract
The rise of right-wing populist (RWP) parties across democracies who disparage and seek to dismantle international (environmental) agreements poses a grave threat to the liberal international order. Yet we know surprisingly little about how RWP parties influence the design of international agreements, including international environmental agreements (IEAs). This article addresses this lacuna by exploring the link between RWP parties and a key outcome in the design of IEAs—flexibility provisions used by democracies to reduce their obligations to curb environmental pollution. The theoretical framework first posits that RWP parties allege that IEAs hurt ordinary people to garner support from domestic constituents adversely affected by IEA environmental mandates. When a RWP party holds a majority of seats in its country’s legislature, it employs its legislative leverage in the international arena to negotiate and obtain maximum flexibility provisions from other member states to safeguard their constituents. Statistical results provide robust support for my theoretical predictions.
Proliferative retinopathy in a patient with mutation in the CLCN2 gene
Authors: Nasser Waseem , Pizem Hadas , Butbul Aviel Yonatan , Hershkovitz Tova , Tal Galit , Zayit-Soudry Shiri , Naaman Efrat 
Published: February 2025

Purpose CLCN2 is a gene that encodes the voltage-gated chloride channel protein 2 in the human brain and eyes. While mutations in this gene have been associated with leukoencephalopathy as well as ocular manifestations including optic neuropathy and choroidopathy, here we report for the first time a case of severe proliferative retinopathy in a patient with CLCN2 mutation. Observations A 12-year-old girl with Familial Mediterranean Fever (FMF) was referred due to blurred vision in both eyes. Ophthalmoscopic examination revealed mild vitreous hemorrhage, large neovascularization at the disc (NVD), extensive neovascularization along the arcades (i.e., NVE; neovascularization elsewhere), retinal arteriolar narrowing, silver sheathing of the veins and preretinal hemorrhages. Fluorescein angiography (FA) demonstrated prominent leakage from multiple large NVEs. A thorough and multidisciplinary evaluation ruled out metabolic, thrombotic, infectious, inflammatory, or autoimmune etiologies. Notably, however, brain magnetic resonance imaging (MRI) revealed leukodystrophy yet poorly correlated with her clinical manifestation. Strikingly, whole exome sequencing uncovered a homozygous mutation in the CLCN2 gene. She was treated with intravitreal injections of the anti-vascular endothelial growth factor (VEGF) antibody Bevacizumab and laser pan-retinal photocoagulation (PRP) with partial response. Conclusions This case suggests that CLCN2 mutation may possess a key role in an aggressive form of proliferative retinopathy with partial response to anti-VEGF therapy. We hypothesize that the potential underlying mechanism involves astrocyte dysfunction and retinal blood barrier disruption. Noteworthy, a comprehensive approach is unequivocally significant in evaluating such cases of proliferative retinopathy with unclear etiology to establish a diagnosis and management strategy.
Integrated metabolomics and transcriptomics reveal the potential of hydroxy-alpha-sanshool in alleviating insulin resistance
Authors: Zhu Yuping , Yang Pan , Ren Tingyuan , Chen Zhuqi , Tian Huanhuan , Wang Mingfen , Zhang Chunlin 
Published: February 2025

Abstract
Hydroxy-alpha-sanshool (HAS) has attracted attention because of its various biological activities, such as hypoglycemic, hypolipidemic, and antioxidant activities. In this study, we investigated the effects of HAS on insulin resistance (IR) and its mechanism. HAS reduced fasting blood glucose (FBG), promoted insulin (INS) secretion, significantly decreased levels of interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α and monocyte chemoattractant protein-1 (MCP-1), and increased the IL-2 level in serum of IR model mice. HAS regulated the mRNA levels of protein kinase B (Akt), B-cell lymphoma extra-large (Bcl-xL), stearoyl-CoA desaturase-1 (SCD1), nuclear factor kappa B (NF-κB), and eukaryotic translation initiation factor 4E (eIF4E). Additionally, differentially abundant metabolites in IR model mice treated with HAS were involved in these signaling pathways including prion disease, choline metabolism in cancer, regulation of lipolysis in adipocytes and the pentose phosphate pathway and positively regulated betaine abundance. In conclusion, HAS activated the phosphatidylinositol-3 kinase (PI3K)/Akt insulin and NF-κB signaling pathways to maintain glucose homeostasis and regulate IR.
Cost-effectiveness of nirsevimab and maternal RSVpreF for preventing respiratory syncytial virus disease in infants across Canada
Authors: Bugden Samara , Mital Shweta , Nguyen Hai V. 
Published: February 2025

Abstract

Background
Nirsevimab, a long-acting monoclonal antibody, and RSVpreF, a maternal vaccine, are newly approved respiratory syncytial virus (RSV) prophylactics for infants in Canada. Both have the potential to expand prevention efforts, but there is limited evidence regarding their cost-effectiveness and how it varies across the country, despite disparate hospitalisation rates and resource use among different populations.

Methods
We developed a decision tree model to follow twelve monthly birth cohorts through their first year of life, incorporating risk differentiation based on Canadian region, prematurity, and comorbidities. The model tracked medically attended infections, including hospitalisations, intensive care unit admissions, and outpatient visits, comparing costs (in 2024 Canadian dollars) and effectiveness (in quality-adjusted life years (QALYs)) of nine different immunisation strategies compared to no intervention. The analysis was conducted from both healthcare and societal perspectives. We conducted threshold price analyses, varying the price-per-dose of each product to determine the threshold prices at which expanded coverage becomes cost-effective.

Results
At base case prices, the optimal strategy varies by region, but in all cases, the optimal strategy is both cost-saving and more effective than no intervention. In southern Canada, it is optimal to immunise only palivizumab-eligible infants (those born very prematurely or with high-risk comorbidities) with nirsevimab, resulting in cost savings of $4.14 and QALY gains of 0.000022 QALY per infant compared to no intervention. In the Northwest Territories, it is best to expand protection with nirsevimab to include all preterm infants (cost savings of $28.68 and QALY gains of 0.00007 per infant). In Nunavik and Nunavut, immunising all infants under 6 months and all infants under twelve months with nirsevimab are the best strategies, respectively (cost savings of $399.61 and QALY gains of 0.000821 per infant in Nunavik, and cost savings of $1067.03 and QALY gains of 0.000884 per infant in Nunavut). Universal, country-wide immunisation with nirsevimab would require a price-per-dose of under $112 to become the most cost-effective prevention strategy.

Conclusions
The optimal strategy for preventing respiratory syncytial virus disease in Canadian infants depends on product price and regional risk level and resource use. Canadian policy should account for these factors.
Effect of combination of multiple anti-inflammatory drugs strategy on postoperative delirium among older patients undergoing hip fracture surgery: a pilot randomized controlled trial
Authors: Nawan Ayixia , Wu Zilong , Jiang Bailin , Wang Geng , Zhang Wenchao , Feng Yi 
Published: February 2025

Abstract

Background
Postoperative delirium is the most common complication in older patients and is associated with surgery-induced inflammation. Although inflammation plays a key role in delirium, the potential benefits of a comprehensive anti-inflammatory approach to managing perioperative systemic inflammation remain underexplored. This study evaluated whether a perioperative anti-inflammatory bundle strategy, combining dexmedetomidine, glucocorticoids, ulinastatin, and nonsteroidal anti-inflammatory drugs, reduces the risk of postoperative delirium in older patients undergoing hip fracture surgery.

Methods
This dual-center, double-blind, placebo-controlled, parallel-group, pilot study was conducted from August 2023 to January 2024 at two tertiary university hospitals. A total of 132 patients aged ≥ 65 years with an American Society of Anesthesiologists physical status of 2 or 3 scheduled for elective hip fracture surgery were screened and randomized to receive either an anti-inflammatory drug bundle or a placebo. The primary outcome was postoperative delirium, identified within the first three postoperative days. Postoperative blood inflammatory markers and acute pain were measured for mediation analysis.

Results
Of the 132 patients randomized, 123 (93%) completed the trial (mean age, 82 years; 75% women). The prevalence of postoperative delirium was significantly lower in the anti-inflammatory bundle group (15%, 9/62) compared to the placebo group (44%, 27/61) (risk difference, − 30 percentage points [95% CI, − 45 to − 15]; relative risk [RR], 0.33 [95% CI, 0.17 to 0.64]; P = 0.001). No major adverse events were reported in either group. The postoperative CRP level in the anti-inflammatory bundle group was significantly lower (predicted mean difference: − 29.4 [95% CI: − 46.5, − 12.2] mg·L−1; adjusted P < 0.001). Mediation analysis showed a significant indirect association between the anti-inflammatory bundle and postoperative delirium through reduced systemic inflammation (odds ratio [OR], 0.61 [95% CI, 0.26 to 0.87]).

Conclusions
This study demonstrates that a perioperative anti-inflammatory bundle significantly reduces the prevalence of postoperative delirium in older patients undergoing hip fracture surgery, without major side effects. Systemic inflammation mediates the protective effect of the intervention. These findings provide preliminary evidence supporting the anti-inflammatory bundle strategy, paving the way for large-scale multicenter trials to optimize postoperative delirium prevention strategies.

Trial registration
This study was registered in the Chinese Clinical Trial Registry (ChiCTR2300074303) by Ayixia Nawan on August 3, 2023, prior to patient enrollment.