bluuebunny/crossref_metadata_2025_split huggingface dataset:
The riboflavin biosynthetic pathway as a novel target for antifungal drugs against
Candida
species
Authors: Nysten Jana , Peetermans Arne , Vaneynde Dries , Jacobs Stef , Demuyser Liesbeth , Van Dijck Patrick 
Published: October 2024

ABSTRACT

In recent decades, there has been an increase in the occurrence of fungal infections; yet, the arsenal of drugs available to fight invasive infections remains very limited. The development of new antifungal agents is hindered by the restricted number of molecular targets that can be exploited, given the shared eukaryotic nature of fungi and their hosts which often leads to host toxicity. In this paper, we examine the riboflavin biosynthetic pathway as a potential novel drug target. Riboflavin is an essential nutrient for all living organisms. Its biosynthetic pathway does not exist in humans, who obtain riboflavin through their diet. Our findings demonstrate that all enzymes in the pathway are essential for
Candida albicans
,
Candida glabrata,
and
Saccharomyces cerevisiae.
Auxotrophic strains, which mimic a drug targeting the biosynthesis pathway, experience rapid mortality in the absence of supplemented riboflavin. Furthermore,
RIB1
is essential for virulence in both
C. albicans
and
C. glabrata
in a systemic mouse model. The fungal burden of a
RIB1
deletion strain is significantly reduced in the kidneys and brain of infected mice, and this reduction becomes more pronounced over time. Nevertheless, auxotrophic cells can still take up external riboflavin when supplemented. We identified Orf19.4337 as the riboflavin importer in
C. albicans
and named it Rut1. We found that Rut1 only facilitates growth at external riboflavin concentrations that exceed the physiological concentrations in the human body. This suggests that riboflavin uptake is unlikely to serve as a resistance mechanism against drugs targeting the biosynthesis pathway. Interestingly, the uptake system in
S. cerevisiae
is more effective than in
C. albicans
and
C. glabrata,
enabling an auxotrophic
S. cerevisiae
strain to outcompete an auxotrophic
C. albicans
strain in lower riboflavin concentrations.

IMPORTANCE

Candida
species are a common cause of invasive fungal infections.
Candida albicans
, in particular, poses a significant threat to immunocompromised individuals. This opportunistic pathogen typically lives as a commensal on mucosal surfaces of healthy individuals but it can also cause invasive infections associated with high morbidity and mortality. Currently, there are only three major classes of antifungal drugs available to treat these infections. In addition, the efficacy of these antifungal agents is restricted by host toxicity, suboptimal pharmacokinetics, a narrow spectrum of activity, intrinsic resistance of fungal species, such as
Candida glabrata
, to certain drugs, and the acquisition of resistance over time. Therefore, it is crucial to identify new antifungal drug targets with novel modes of action to add to the limited armamentarium.
Microbial diversification is maintained in an experimentally evolved synthetic community
Authors: Al-Tameemi Zahraa , Rodríguez-Verdugo Alejandra 
Published: October 2024

ABSTRACT

Microbial communities are incredibly diverse. Yet, the eco-evolutionary processes originating and maintaining this diversity remain understudied. Here, we investigate the patterns of diversification for
Pseudomonas putida
evolving in isolation and with
Acinetobacter johnsonii
leaking resources used by
P. putida
. We experimentally evolved four experimental replicates in monoculture and co-culture for 200 generations. We observed that
P. putida
diversified into two distinct morphotypes that differed from their ancestor by single-point mutations. One of the most prominent mutations hit the
fleQ
gene encoding the master regulator of flagella and biofilm formation. We experimentally confirmed that
fleQ
mutants were unable to swim and formed less biofilm than their ancestor, but they also produced higher yields. Interestingly, the
fleQ
genotype and other mutations swept to fixation in monocultures but not in co-cultures. In co-cultures, the two lineages stably coexisted for approximately 150 generations. We hypothesized that
A. johnsonii
modulates the coexistence of the two lineages through frequency-dependent selection. However, invasion experiments with two genotypes in monoculture and co-culture did not support this hypothesis. Finally, we conducted an evolutionary “replay” experiment to assess whether the presence or absence of
A. johnsonii
influenced the coexistence of morphotypes at the population level. Interestingly,
A. johnsonii
had a stabilizing effect on the co-culture. Overall, our study suggests that interspecies interactions play an important role in shaping patterns of diversification in microbial communities.

IMPORTANCE
In nature, bacteria live in microbial communities and interact with other species, for example, through the exchange of resources leaked into the external environment (i.e., cross-feeding interactions). The role that these cross-feeding interactions play in shaping patterns of diversification remains understudied. Using a simple bacterial system in which one species cross-feeds resources to a second species (commensal species), we showed that the commensal species diversified into two subpopulations that persisted only when the cross-feeder partner was present. We further observed loss-of-function mutations in flagellar genes that were fixed in monocultures but not in co-cultures. Our findings suggest that cross-feeding species influence patterns of diversification of other species. Given that nutrient leakage is pervasive in microbial communities, the findings from this study have the potential to extend beyond our specific bacterial system. Importantly, our study has contributed to answering the larger question of whether species evolved differently in isolation versus when interacting with other species.
Efficacy of CP-COV03 (a niclosamide-based inorganic nanohybrid product) against severe fever with thrombocytopenia syndrome virus in an
in vitro
model
Authors: Han Min , Lee Youn-Jung , Ahn Sang Min , Seong Jae Eun , Lee Jung Ah , Lee Yong Seop , Kim Jung Ho , Ahn Jin Young , Jeong Su Jin , Ku Nam Su , Yeom Joon Sup , Choi Jun Yong 
Published: October 2024

ABSTRACT

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne infectious disease caused by the SFTS virus (SFTSV). CP-COV03 is a novel antiviral candidate that significantly enhanced the bioavailability of niclosamide through inorganic-based drug delivery technology. The active pharmaceutical ingredient of CP-COV03, niclosamide, has been previously shown to possess broad-spectrum antiviral activity against over 30 different viruses in the
in vitro
tests. The aim of this study is to confirm the antiviral activity of CP-COV03 against the SFTSV in an
in vitro
model. Vero cells and SFTS viral stock NCCP43270, a 2015 Gangwon Province isolate, were used to obtain the 50% tissue culture infective dose of the virus. Vero cells seeded in 96-well plates were infected with SFTSV for 1 h. SFTSV-infected cells were treated with CP-COV03 at various concentrations of 0.1–100 μM and incubated for 7 days. On the seventh day of the culture, the cytopathic effect (CPE) of SFTSV was checked by microscopy and the cell viability was checked by using Cell Counting Kit-8 assay. The CPE reduced as the CP-COV03 concentration increased. The 50% inhibitory concentration (IC
50
) range of CP-COV03 was below 0.125 µM, as determined from the viral titers of culture supernatants collected on the third day posttreatment of CP-COV03. The plaque reduction assay showed that the IC
50
of CP-COV03 was 1.893 µM, as determined from the percentage reduction of plaque counts for each drug concentration on the second day posttreatment with CP-COV03. This study suggests that CP-COV03 could be used as a potential antiviral agent for SFTS.

IMPORTANCE

We demonstrated a concentration-dependent response and identified low a IC
50
of CP-COV03. This result is comparable to other antiviral drugs used against viruses like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We believe that our study makes a significant contribution to the literature as our findings suggest that CP-COV03 may serve as a potential treatment for SFTS, highlighting its importance in the field of antiviral research.
Prevalence and management of ectopic and molar pregnancies in 17 countries in Africa and Latin America and the Caribbean: a secondary analysis of the WHO multi-country cross-sectional survey on abortion
Authors: Cavalari Camila Ayume Amano , Mehrtash Hedieh , Brizuela Vanessa , Baguiya Adama , Adu-Bonsaffoh Kwame , Cecatti Jose Guilherme , Bahamondes Luis , Charles Charles M'poca , Govule Philip , Dossou Jean-Paul , Souza Renato T , Leão Luis Henrique , Filippi Veronique , Tunçalp Özge , Baccaro Luiz Francisco 
Published: October 2024

IntroductionThere are limited global data on ectopic pregnancy (EP) and molar pregnancy (MP), making it important to understand their epidemiology and management across different regions. Our study aimed to describe their prevalence for both conditions, severity of their complications and management among women in selected health facilities across 17 countries in Africa and Latin America and the Caribbean (LAC).MethodsThis is a secondary analysis of the WHO multi-country survey on abortion. Data were collected from 280 healthcare facilities across 11 countries in Africa and 6 in LAC. Sociodemographic information, signs and symptoms, management and clinical outcomes were extracted from medical records. Facility-level data on post-abortion care (PAC) capabilities were also collected, and facilities were classified accordingly. χ2or Fisher’s exact tests were used to compare categorical data.ResultsThe total number of women with EP and MP across both regions was 9.9% (2 415/24 424) where EP accounted for 7.8% (1 904/24 424) and MP for 2.1% (511/24 424). EP presented a higher severity of complications than MP. At admission, 49.8% of EP had signs of peritoneal irritation. The most common surgical management for EP was laparotomy (87.2%) and for MP, uterine evacuation (89.8%). Facilities with higher scores in infrastructure and capability to provide PAC more frequently provided minimal invasive management using methotrexate/other medical treatment (34.9%) and laparoscopy (5.1%).ConclusionIn Africa and LAC, EP and MP cause significant maternal morbidity and mortality. The disparity in the provision of good quality care highlights the need to strengthen the implementation of evidence-based recommendations in the clinical and surgical management of EP and MP.
Electroosmotic peristaltic transport of magnetohydrodynamic Casson nanofluid in a non-uniform wavy porous asymmetric micro-channel
Authors: Ramki R. , Lakshminarayana P. 
Published: October 2024

Magnetohydrodynamics (MHD) have numerous engineering and biomedical applications such as sensors, MHD pumps, magnetic medications, MRI, cancer therapy, astronomy, cosmology, earthquakes, and cardiovascular devices. In view of these applications and current developments, we investigate the magnetohydrodynamic MHD electro-osmotic flow of Casson nanofluid during peristaltic movement in a non-uniform porous asymmetric channel. The effect of thermal radiation, heat source, and Hall current on the Casson fluid peristaltic pumping in a porous medium is taken into consideration. The effect of chemical reactions is also considered. The mass, momentum, energy, and concentration equations were constructed using the proper transformations and dimensionless variables to make them easier for non-Newtonian fluids. A lubricating strategy is used to make the system less complicated. The Boltzmann distribution of electric potential over an electric double layer is studied using the Debye–Huckel approximation. The temperature and concentration equations are addressed using the homotopy perturbation method (HPM), while the exact solution is determined for the velocity field. The study examines the performance of velocity, pressure rise, temperature, concentration, streamlines, Nusselt, and Sherwood numbers for the involved parameters using graphical illustrations and tables. Asymmetric channels exhibit varying behavior, with velocity declining near the left wall and accelerating towards the right wall while enhancing the Casson fluid parameter. The pumping rate boosts in the retrograde region due to the evolution of the permeability parameter value, while it declines in the augment region. The temperature profile optimizes as the value of the heat source parameter gets higher. The concentration profile significantly falls as the chemical reaction parameter rises. The size of the trapped bolus strengthens with a spike in the parameter for the Casson fluid.
Clinical Outcomes of a Trifocal Versus an Extended Depth of Field Intraocular Lens in Chinese Patients With Cataract: A Prospective Cohort Study
Authors: Chen Qingzhong , Zhang Guangbin 
Published: October 2024

Purpose: To compare the standard outcomes between the PanOptix and Symfony multifocal intraocular lenses (MIOLs) in Chinese patients.Methods: This prospective observational cohort study enrolled patients with cataracts between April 2021 and December 2021 at Xiamen Eye Center Affiliated to Xiamen University. The patients were grouped in the PanOptix (TIOL group) and Symfony (EDF group) according to the IOLs implanted. Uncorrected distant, corrected distance, binocular uncorrected intermediate, and near visual acuity (UNVA), distance‐corrected intermediate and near VA (DCNVA) , defocus curve, spectacle independence, contrast sensitivity (CS), and visual disturbances were evaluated after 3 months.Results: Forty patients (80 eyes) were enrolled in the study (20/group). Three months after the operation, UNVA (0.13 ± 0.16) and DCNVA (0.08 ± 0.08) were better in the TIOL group than in the EDF group (0.22 ± 0.08 and 0.22 ± 0.08, respectively, p = 0.003 and p < 0.001, respectively). The TIOL group achieved a better‐than‐0.15‐logMAR VA from +0.5 D to −2.5 D (40 cm). VAs of the TIOL group from −1 D (100 cm) to −4 D (25 cm) were better than in the EDF group (p < 0.05). There were no significant differences in the intermediate and far vision outcomes (p > 0.05). Total near‐vision spectacle independence was higher in the TIOL group (80%) than in the EDF group (50%) (p = 0.039).Conclusion: Compared with EDF, TIOL leads to better near‐vision outcomes without significant differences for intermediate and distant vision outcomes.Trial Registration: ClinicalTrials.gov identifier: ChiCTR2100044558.
The USP1 Inhibitor KSQ-4279 Overcomes PARP Inhibitor Resistance in Homologous Recombination–Deficient Tumors
Authors: Cadzow Louise , Brenneman Jehrod , Tobin Erica , Sullivan Pamela , Nayak Sumeet , Ali Janid A. , Shenker Sol , Griffith Jim , McGuire Michael , Grasberger Paula , Mishina Yuji , Murray Morgan , Dodson Anne E. , Gannon Hugh , Krall Elsa , Hixon Jeff , Chipumuro Edmond , Sinkevicius Kerstin , Gokhale Prafulla C. , Ganapathy Suthakar , Matulonis Ursula A. , Liu Joyce F. , Olaharski Andrew , Sangurdekar Dipen , Liu Hanlan , Wilt Jeremy , Schlabach Michael , Stegmeier Frank , Wylie Andrew A. 
Published: October 2024

Abstract
Defects in DNA repair pathways play a pivotal role in tumor evolution and resistance to therapy. At the same time, they create vulnerabilities that render tumors dependent on the remaining DNA repair processes. This phenomenon is exemplified by the clinical activity of PARP inhibitors in tumors with homologous recombination (HR) repair defects, such as tumors with inactivating mutations in BRCA1 or BRCA2. However, the development of resistance to PARP inhibitors in BRCA-mutant tumors represents a high unmet clinical need. In this study, we identified deubiquitinase ubiquitin-specific peptidase-1 (USP1) as a critical dependency in tumors with BRCA mutations or other forms of HR deficiency and developed KSQ-4279, the first potent and selective USP1 inhibitor to enter clinical testing. The combination of KSQ-4279 with a PARP inhibitor was well tolerated and induced durable tumor regression across several patient-derived PARP-resistant models. These findings indicate that USP1 inhibitors represent a promising therapeutic strategy for overcoming PARP inhibitor resistance in patients with BRCA-mutant/HR-deficient tumors and support continued testing in clinical trials.
Significance: KSQ-4279 is a potent and selective inhibitor of USP1 that induces regression of PARP inhibitor–resistant tumors when dosed in combination with PARP inhibitors, addressing an unmet clinical need for BRCA-mutant tumors.
Causers, Causes, and Doers
Authors: Bianchi Robin T. 
Published: October 2024

Abstract
The view that to act is to cause change and that to be an agent is to be the causer of an action’s result has gained traction in the past twenty years or so. This view seems to have two significant corollaries. First, there is no distinction between doing an action and causing its result. Second, any two actions that have the same result will turn out to be identical. Ruben (2018) has recently used the first corollary to challenge the view, and the second corollary raises further problems for the view. This article aims to refine this view and defend it against the challenges that arise out of its two corollaries. It is argued that being the cause of an action’s result is not the same as being its causer and that doing an action is not just causing its result but causing it in a specific way.
Determinants of human-elephant conflict in tropical forest of South India
Authors: Ashokkumar Moharangan , Sakthivel Chinnaiyan , Sudhakar Kaliyaperumal 
Published: October 2024

Abstract
Human-elephant conflict (HEC) is a global conservation issue that undermines the conservation of an endangered species. HEC and the factors influencing crop-raiding behaviour were studied in the tropical forests of south India from Nov 2006 to Mar 2008. Crop depredation, protection methods, and land use changes were studied at Mudumalai Tiger Reserve (TR). A total of 297 incidents of crop damage were recorded, with peaks in the raiding during the monsoon season. Spatial analysis of HEC showed peripheral farms are more vulnerable (1.51%) than village centers (0.18%). Temporally, cropping patterns have changed from food crops to commercial crops. The elephant-damaged area was positively correlated with the effective perimeter (pe-rimeter with crops), total cultivated area, and area of degradation around the village. Logistic regression of crop raiding incidence with independent predictors showed that the incidence of raiding was 95% greater in moist deciduous forests than in thorny forests. Palatable crops were likely to be raided more frequently (391 times). Crops with protection methods were 22 times less likely to be targets of raids. In the areas adjacent to the Mudumalai TR, crop species, improvements in protection, and land use change reduced the HEC. Relocating villages from the core reserve and existing corridors in the eastern region is essential for conserving elephants in the Nilgiris, Western Ghats landscape.
Analysis of Demographic Characteristics and Drinking Habits at a Southern College Provide Critical Information for Developing an Effective Prevention Program
Authors: Toland Rebecca M. , Rowan Tiera , Caballero Ivanna , Truong Dawn 
Published: October 2024

Importance To examine the associations of basic demographics (age, race, and gender identity) on alcohol consumption among college students at a mid-sized university. Objective To evaluate the drinking habits of students using the survey tool that will measure basic demographics to collect data. Design A cross-sectional study that included college students ages 17-21 at Columbus State University in the fall of 2021. Setting Columbus, Georgia. Participants University students (n = 260, mean age 20.5 ± 3.8). Analysis One-way ANOVA and independent t-tests were used to test differences in age on alcohol consumption and binge drinking. Chi-Square tests and Fisher’s Exact were used to estimate differences in proportions of binge drinking for race and gender. Results Underage students (57.7%) reported having consumed alcohol in the past. Frequency of alcohol consumption increased with age ( P = 0.004). Caucasian students reported drinking most frequently, with 14.8% (n = 12) drinking at least once a week, compared to 0 African American students reporting they drank at least once per week ( P < 0.001). There were no significant findings when examining differences in binge drinking for demographics assessed in this sample ( P > 0.05). Conclusion and Relevance: In this cross-sectional research study, the prevalence of underage drinking among college-aged students, there is a need for targeted prevention methods to reduce adverse health outcomes among this vulnerable population.
Assessing the stability of daptomycin in icodextrin-based peritoneal dialysis solution
Authors: Suzuki Hiroyuki , Kudo Kasumi , Uno Takashi , Konno Taisuke , Okada Kouji , Agatsuma Yasuyuki , Nakamura Hitoshi , Murai Yuriko 
Published: October 2024

Background The stability of antimicrobials in peritonitis during peritoneal dialysis (PD) solutions is a critical factor influencing treatment success. This study investigated the stability of daptomycin (DAP) when combined with icodextrin-based PD solution, by measuring DAP concentrations and observing any structural changes. Methods A dose of DAP (350 mg) was dissolved in 7 mL of saline in a clean bench. The solution was then injected into the large compartment (1,260 mL) of NICOPELIQ® Peritoneal Dialysis Solution and thoroughly mixed. Samples were collected at intervals ranging from 0 to 336 h (7 points in total). The concentration of DAP was quantified using high-performance liquid chromatography (HPLC). The structure of any unidentified peaks was determined using HPLC coupled with electrospray ionization tandem mass spectrometry. Results DAP maintained 90% of the initial concentration in NICOPELIC® for 72 h at room temperature and 12 h at 37 °C. Unidentified peaks, distinct from DAP, were detected during analysis. Further investigation indicated that these peaks corresponded to anhydrated DAP. Conclusions The findings from this stability study are expected to enhance the effectiveness of outpatient management and preparation for treating peritonitis using DAP.