bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating the importance of selected surface-exposed loops in HpuB for hemoglobin binding and utilization by
Neisseria gonorrhoeae
Authors: Awate Olivia A. , Ng Dixon , Stoudenmire Julie L. , Moraes Trevor F. , Cornelissen Cynthia N. 
Published: June 2024

ABSTRACT

Neisseria gonorrhoeae
is the etiological agent of the sexually transmitted infection gonorrhea. The pathogen is a global health challenge since no protective immunity results from infection, and far fewer treatment options are available with increasing antimicrobial resistance. With no efficacious vaccines, researchers are exploring new targets for vaccine development and innovative therapeutics. The outer membrane TonB-dependent transporters (TdTs) produced by
N. gonorrhoeae
are considered promising vaccine antigens as they are highly conserved and play crucial roles in overcoming nutritional immunity. One of these TdTs is part of the hemoglobin transport system comprised of HpuA and HpuB. This system allows
N. gonorrhoeae
to acquire iron from hemoglobin (hHb). In the current study, mutations in the
hpuB
gene were generated to better understand the structure–function relationships in HpuB. This study is one of the first to demonstrate that
N. gonorrhoeae
can bind to and utilize hemoglobin produced by animals other than humans. This study also determined that when HpuA is absent, mutations targeting extracellular loop 7 of HpuB led to defective hHb binding and utilization. However, when the lipoprotein HpuA is present, these loop 7 mutants recovered their ability to bind hHb, although the growth phenotype remained significantly impaired. Interestingly, loop 7 contains putative heme-binding motifs and a hypothetical α-helical region, both of which may be important for the use of hHb. Taken together, these results highlight the importance of loop 7 in the functionality of HpuB in binding hHb and extracting and internalizing iron.
CRISPR-Cas9 high-throughput screening to study drug resistance in
Leishmania infantum
Authors: Queffeulou Marine , Leprohon Philippe , Fernandez-Prada Christopher , Ouellette Marc , Mejía-Jaramillo Ana María 
Published: June 2024

ABSTRACT

Parasites of the genus
Leishmania
pose a global health threat with limited treatment options. New drugs are urgently needed, and genomic screens have the potential to accelerate target discovery, mode of action, and resistance mechanisms against these new drugs. We describe here our effort in developing a genome-wide CRISPR-Cas9 screen in
Leishmania
, an organism lacking a functional nonhomologous end joining system that must rely on microhomology-mediated end joining, single-strand annealing, or homologous recombination for repairing Cas9-induced double-stranded DNA breaks. A new vector for cloning and expressing single guide RNAs (sgRNAs) was designed and proven to be effective in a small pilot project while enriching specific sgRNAs during drug selection. We then developed a whole-genome library of 49,754 sgRNAs, targeting all the genes of
Leishmania infantum
. This library was transfected in
L. infantum
expressing Cas9, and these cells were selected for resistance to two antileishmanials, miltefosine and amphotericin B. The sgRNAs the most enriched in the miltefosine screen targeted the miltefosine transporter gene, but sgRNAs targeting genes coding for a RING-variant protein and a transmembrane protein were also enriched. The sgRNAs the most enriched by amphotericin B targeted the sterol 24 C methyltransferase genes and a hypothetical gene. Through gene disruption experiments, we proved that loss of function of these genes was associated with resistance. This study describes the feasibility of carrying out whole-genome CRISPR-Cas9 screens in
Leishmania
provided that a strong selective pressure is applied. Such a screen can be used for accelerating the development of urgently needed antileishmanial drugs.

IMPORTANCE

Leishmaniasis, a global health threat, lacks adequate treatment options and drug resistance exacerbates the challenge. This study introduces a CRISPR-Cas9 screening approach in
Leishmania infantum
, unraveling mechanisms of drug resistance at a genome-wide scale. Our screen was applied against two main antileishmanial drugs, and guides were enriched upon drug selection. These guides targeted known and new targets, hence validating the use of this screen against
Leishmania
. This strategy provides a powerful tool to expedite drug discovery as well as potential therapeutic targets against this neglected tropical disease.
Candida parapsilosis
candidemia in children admitted to a tertiary hospital in Turkey: clinical features and antifungal susceptibility
Authors: Çetin Fatma Tuğba , Çay Ümmühan , Polat Murat , Kılınç Fatma , Ünal Asena , Tapaç Nisa Nur , Gündeşlioğlu Özlem Özgür , Alabaz Derya , Bilen Sevcan , Kibar Filiz , Totik Nazlı 
Published: June 2024

ABSTRACT

In recent years, the incidence and drug resistance of
Candida parapsilosis
have increased. Our study aimed to determine the antifungal sensitivity of
C. parapsilosis
and the clinical and demographic characteristics of children with candidemia. Two hundred pediatric patients with
C. parapsilosis
candidemia were included in the study between 1 January 2010 and 1 August 2023. Clinical samples were evaluated on a BACTEC-FX-40 automatic blood culture device (Becton Dickinson, USA). Yeast isolates were identified to the species level via identification cards (YST) using the VITEK 2 Compact (bioMeriéux, France) system. Antifungal susceptibility was performed using antifungal cell cards (AST-YST01). Approval for the study was received from the “University Faculty of Medicine” Hospital Clinical Research Ethics Committee. Non-catheter candidemia was detected in 127 (63.5%) patients, and catheter-related candidemia was detected in 73 (36.5%) patients. It was observed that the patients’ history of malignancy, mechanical ventilation, urinary catheter, nasogastric tube, and intensive care unit stay was associated with
C. parapsilosis
mortality. The mortality rate from candidemia was 9.5%. The most frequently preferred antifungal agents were amphotericin B and fluconazole. The fluconazole drug resistance rate was found to be 6%, and the amphotericin B drug resistance rate was 4%. Because
C. parapsilosis
candidemia mortality rates can be high depending on risk factors and clinical characteristics, it is important to initiate appropriate and timely antifungal therapy. We think that our study can provide important information about the clinical profiles, distributions, susceptibility profiles, and control of antifungal resistance of
C. parapsilosis
isolates.

IMPORTANCE

It has been observed that the frequency and antifungal resistance of
Candida parapsilosis
have increased recently. In our study, we aimed to determine the antifungal sensitivity of
C. parapsilosis
and the clinical and demographic characteristics of children with candidemia. It was observed that the patients’ history of malignancy, mechanical ventilation, urinary catheter, nasogastric tube, and intensive care stay was associated with
C. parapsilosis
mortality. The mortality rate from candidemia was 9.5%. The most frequently preferred antifungal agents were amphotericin B and fluconazole. The fluconazole drug resistance rate was found to be 6%, and the amphotericin B drug resistance rate was 4%. Because
C. parapsilosis
candidemia mortality rates can be high depending on risk factors and clinical characteristics, it is important to initiate appropriate and timely antifungal therapy.
Association between neutrophil-to-eosinophil ratio and efficacy outcomes with avelumab plus axitinib or sunitinib in patients with advanced renal cell carcinoma: post hoc analyses from the JAVELIN Renal 101 trial
Authors: Tucker Matthew , Chen Yu-Wei , Voss Martin H , McGregor Bradley A , Bilen Mehmet A , Grimm Marc-Oliver , Nathan Paul , Kollmannsberger Christian , Tomita Yoshihiko , Huang Bo , Amezquita Robert , Mariani Mariangela , di Pietro Alessandra , Rini Brian 
Published: June 2024

ObjectiveWe report post hoc analyses of efficacy with first-line avelumab plus axitinib or sunitinib according to baseline neutrophil-to-eosinophil ratio (NER) in patients with advanced renal cell carcinoma (aRCC) from the JAVELIN Renal 101 phase 3 trial.Methods and analysisProgression-free survival (PFS), overall survival (OS) and objective response per baseline NER were analysed in the overall population and in patients with programmed death ligand 1 (PD-L1+) tumours. Multivariable Cox regression analyses to assess the effect of NER after adjustment for other baseline variables were conducted.ResultsIn NER <median versus ≥median subgroups of the avelumab plus axitinib arm, HRs for PFS and OS were 0.81 (95% CI 0.630 to 1.035) and 0.67 (95% CI 0.481 to 0.940), and objective response rates (ORRs) were 63.9% vs 55.2%, respectively. The HR for PFS in the PD-L1+ subgroup was 0.72 (95% CI 0.520 to 0.986). Comparing NER-defined subgroups in the sunitinib arm, HRs for PFS and OS were 0.93 (95% CI 0.728 to 1.181) and 0.57 (95% CI 0.424 to 0.779), and ORRs were 32.8% versus 30.8%, respectively. Within NER subgroups, analyses of PFS, OS and ORR favoured avelumab plus axitinib versus sunitinib treatment. Interaction tests that assessed the association between treatment and NER yielded conflicting results when NER was assessed as a dichotomised variable (median cut-off) or continuous variable.ConclusionHypothesis-generating analyses suggest that baseline NER may be prognostic for longer OS irrespective of treatment. Analyses of the association between NER level and treatment outcomes with avelumab plus axitinib versus sunitinib were inconclusive.Trial registration numberNCT02684006.
Assessing the treatment effect of cranberry type A proanthocyanidins on vulvovaginal candidiasis: a randomised controlled clinical interventional study
Authors: Wei Dongmei , Chen Yaoming , Chen Yueyue , Cui Tao , Niu Xiaoyu 
Published: June 2024

ObjectiveThis study aimed to evaluate the efficacy and safety of cranberry extracts: A-type proanthocyanidins (A-PACs) in the treatment and prevention of vulvovaginal candidiasis (VVC).MethodAn open, randomised, parallel-design study was conducted. A cohort of 300 eligible patients with VVC was recruited from the hospital. All participants were randomly divided into three groups according to a computer-generated randomisation list. Patients in group 1 were treated with standard antifungal therapy (oral single-dose fluconazole 150 mg and vaginal miconazole suppository 400 mg at bedtime for 3 days); patients in group 2 received oral A-PACs 16 mL two times per day for 6 days based on the treatment regimen of group 1; patients in group 3 were given oral A-PACs 16 mL two times per day for 6 days and vaginal miconazole suppository 400 mg at bedtime for 3 days. Patients who were clinically cured at the seventh day of follow-up in group 2 received maintenance therapy by oral A-PACs for 12 weeks.ResultAt the seventh day of follow-up, the vaginal mycological results of all patients in group 2 who initially tested positive for pseudohyphae exhibited negative results. The negative conversion rates of fungal spores and blastospores in group 2 were superior to those in both group 1 and group 3. The symptoms of patients in group 2 ameliorated conspicuously compared with those in group 1 (p<0.05). The clinical cure rate of VVC in both group 2 and group 3 was not inferior to group 1. Cox regression analysis showed maintenance therapy was not significantly associated with short-term recurrence (HR 0.44 (0.11, 1.67); p=0.23) but could significantly diminish the risk of long-term recurrence (HR 0.57 (0.33, 0.99); p<0.05).ConclusionThis study revealed that A-PACs in cranberry juice combined with azole antibiotics can be used as a novel therapeutic option for the treatment and prevention of long-term recurrence of VVC.Trial registration numberChiCTR2300076392.
Finite-temperature equations of state of compact stars with hyperons: three-dimensional tables
Authors: Tsiopelas Stefanos , Sedrakian Armen , Oertel Micaela 
Published: June 2024

AbstractWe construct tables of finite temperature equation of state (EoS) of hypernuclear matter in the range of densities, temperatures, and electron fractions that are needed for numerical simulations of supernovas, proto-neutron stars, and binary neutron star mergers and cast them in the format of CompOSE database. The tables are extracted from a model that is based on covariant density functional (CDF) theory that includes the full $$J^P=1/2^+$$

J
P

=
1
/

2
+

baryon octet in a manner that is consistent with the current astrophysical and nuclear constraints. We employ a parameterization with three different values of the slope of the symmetry energy $$L_\textrm{sym}=30$$

L
sym

=
30

, 50 and 70 MeV and fixed skewness $$Q_\textrm{sat}= 400$$

Q
sat

=
400

MeV for above saturation matter. A model for the EoS of inhomogeneous matter is matched at sub-saturation density to the high-density hypernuclear EoS. We discuss the generic features of the resulting EoS and the composition of matter as a function of density, temperature, and electron fraction. The nuclear characteristics and strangeness fraction of these models are compared to the alternatives from the literature. The integral properties of static and rapidly rotating compact stars in the limit of zero temperature are discussed and confronted with the multimessenger astrophysical constraints.
A PDE3A-SLFN12 Molecular Glue Exhibits Significant Antitumor Activity in TKI-Resistant Gastrointestinal Stromal Tumors
Authors: Takaki Emiri O. , Kiyono Kunihiko , Obuchi Yutaka , Yamauchi Takeshi , Watanabe Takashi , Matsumoto Hideki , Karimine Miho , Kuniyoshi Yuki , Nishikori Shingo , Yokoyama Fumiharu , Nishimori Hikaru , Nabeshima Hiroshi , Nakamura Kazuhide 
Published: June 2024

Abstract

Purpose:
Gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor with KIT or PDGFRA driver mutations, is typically treated with tyrosine kinase inhibitors (TKI). However, resistance to TKIs due to secondary mutations is a common challenge in advanced GISTs. In addition, there are currently no effective therapies for several other molecular subtypes, such as succinate dehydrogenase–deficient GISTs. Therefore, novel therapeutic strategies are needed.

Experimental Design:
To address this need, we tested the efficacy of a novel non-TKI compound, OPB-171775, using patient-derived xenograft models of GISTs. In parallel, we sought to elucidate the mechanism of action of the compound.

Results:
Our study revealed that OPB-171775 exhibited significant efficacy against GISTs regardless of their KIT mutation status by inducing complex formation between phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12), which are highly expressed in GISTs, leading to SLFN12 RNase-mediated cell death. Furthermore, we identified the activation of general control non-derepressible 2 and its downstream response as an effector pathway of SLFN12 in mediating anticancer activity and revealed potential pharmacodynamic markers.

Conclusions:
These findings suggest that OPB-171775, with its significant efficacy, could potentially serve as a novel and effective treatment option for advanced GISTs, particularly those resistant to TKIs.
Animals, Atrocity, and Trivialization
Authors: Müller Nico Dario 
Published: June 2024

Abstract
Many philosophers have said that atrocities are being committed against animals, particularly in industrialized rearing and slaughter. But they have made little of this powerful description. This paper argues that atrocities call for a different response than minor wrongs or evils, including that one should not trivialize them. The paper offers a new framework for understanding the trivialization of atrocities against animals and discusses the moral difficulties that trivialization raises, in part because it is not always easy to avoid. It concludes discussing how animal advocates can avoid and challenge trivialization.
The Propagation, Evolution, and Rotation in Linear Storms (PERiLS) Project
Authors: Kosiba Karen A. , Lyza Anthony W. , Trapp Robert J. , Rasmussen Erik N. , Parker Matthew , Biggerstaff Michael I. , Nesbitt Stephen W. , Weiss Christopher C. , Wurman Joshua , Knupp Kevin R. , Coffer Brice , Chmielewski Vanna C. , Dawson Daniel T. , Bruning Eric , Bell Tyler M. , Coniglio Michael C. , Murphy Todd A. , French Michael , Blind-Doskocil Leanne , Reinhart Anthony E. , Wolff Edward , Schneider Morgan E. , Silcott Miranda , Smith Elizabeth , Aikins Joshua , Wagner Melissa , Robinson Paul , Wilczak James M. , White Trevor , Diedrichsen Madeline R. , Bodine David , Kumjian Matthew R. , Waugh Sean M. , Alford A. Addison , Elmore Kim , Kollias Pavlos , Turner David D. 
Published: June 2024

Abstract
Quasi-linear convective systems (QLCSs) are responsible for approximately a quarter of all tornado events in the United States, but no field campaigns have focused specifically on collecting data to understand QLCS tornadogenesis. The Propagation, Evolution, and Rotation in Linear Storms (PERiLS) project was the first observational study of tornadoes associated with QLCSs ever undertaken. Participants were drawn from more than 10 universities, laboratories, and institutes, with over 100 students participating in field activities. The PERiLS field phases spanned 2 years, late winters and early springs of 2022 and 2023, to increase the probability of intercepting significant tornadic QLCS events in a range of large-scale and local environments. The field phases of PERiLS collected data in nine tornadic and nontornadic QLCSs with unprecedented detail and diversity of measurements. The design and execution of the PERiLS field phase and preliminary data and ongoing analyses are shown.
Monsoonal MCS Initiation, Rainfall, and Diurnal Gravity Waves over the Bay of Bengal: Observation and a Linear Model
Authors: Peng Chin-Hsuan , Chen Xingchao 
Published: June 2024

Abstract
Previous observational studies have indicated that mesoscale convective systems (MCSs) contribute the majority of precipitation over the Bay of Bengal (BoB) during the summer monsoon season, yet their initiation and propagation remain incompletely understood. To fill this knowledge gap, we conducted a comprehensive study using a combination of 20-yr satellite observations, MCS tracking, reanalysis data, and a theoretical linear model. Satellite observations reveal clear diurnal propagation signals of MCS initiation frequency and rainfall from the west coast of the BoB toward the central BoB, with the MCS rainfall propagating slightly slower than the MCS initiation frequency. Global reanalysis data indicate a strong association between the offshore-propagating MCS initiation frequency/rainfall and diurnal low-level wind perturbations, implying the potential role of gravity waves. To verify the hypothesis, we developed a 2D linear model that can be driven by realistic meteorological fields from reanalysis. The linear model realistically reproduces the characteristics of offshore-propagating diurnal wind perturbations. The wind perturbations, as well as the offshore propagation signals of MCS initiation frequency and rainfall, are associated with diurnal gravity waves emitted from the coastal regions, which in turn are caused by the diurnal land–sea thermal contrast. The ambient wind speed and vertical wind shear play crucial roles in modulating the timing, propagation, and amplitude of diurnal gravity waves. Using the linear model and satellite observations, we further show that the stronger monsoonal flows lead to faster offshore propagation of diurnal gravity waves, which subsequently control the offshore propagation signals of MCS initiation and rainfall.

Significance Statement
Rainfall over the Bay of Bengal (BoB) is primarily contributed by large and organized rainfall systems in the summer monsoon season. During this season, these systems are commonly observed over the east coast of India around midnight, the western BoB in the morning, and the central BoB in the afternoon. This eastward rainfall propagation is confirmed by observations, reanalysis data, and a theoretical model to have a strong association with atmospheric diurnal gravity waves. These waves are caused by land–sea thermal contrast and can trigger rainfall systems over the offshore regions. We also found that the diurnal gravity waves, as well as their triggered rainfall systems, can be greatly modulated by the large-scale monsoonal flows. All the above findings improve our understanding of diurnal rainfall cycle over the BoB and may contribute to the future improvement of rainfall forecast over the region.
Near-Term Mediterranean Summer Temperature Climate Projections: A Comparison of Constraining Methods
Authors: Cos Pep , Marcos-Matamoros Raül , Donat Markus , Mahmood Rashed , Doblas-Reyes Francisco J. 
Published: June 2024

Abstract
There are several methods to constrain multimodel projections of future climate. This study assesses the quality of four constraining methods in representing the near-term summer temperature projections of the Mediterranean region. Three are based on phasing in ocean surface temperature variations based on observations or decadal predictions, and the method is based on the measuring performance and independence of the individual simulations. The comparison has been carried out with a new framework inspired by the forecast quality assessment of decadal predictions. The framework led to quality estimates of the constrained projection approaches obtained by producing 20-yr temperature estimates every year from 1970 to 2000 and computing quality metrics against observational references. The evaluation results show some differences between constraining approaches. The improvement or deterioration against quality measures of the full, unconstrained, phase 6 of the Coupled Model Intercomparison Project (CMIP6) ensemble shows strong spatial heterogeneity. From the analysis of the selection approaches it is found that the constraints based on sea surface temperature (SST) fields are affected not only by the variability but also by the warming trend. The weighting method generally shows small quality differences with respect to the full CMIP6 ensemble. Despite caveats of the different methods, there is potential to improve the near-term climate projections as some significant quality enhancements were found in some approaches according to the evaluation metrics used. This study suggests a good understanding of the constraining methods, and their forecast quality is required before using them to take informed decisions. Our study opens the door to optimizing these methods for the Mediterranean climate and highlights the need for evaluating the constraints through retrospective assessments against observational references.