bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic drug monitoring and safety of voriconazole in patients with liver dysfunction
Authors: Hu Lin , Su Yuan , Tang Xi , Li Yanfei , Feng Jinhui , He Gefei 
Published: October 2024

ABSTRACT

This study aims to describe the distribution characteristics of voriconazole (VRC) plasma trough concentrations (
C
trough
) in patients with liver dysfunction, identify factors influencing VRC
C
trough
, and provide recommendations for the use of VRC in this population. We retrospectively collected medical records of hospitalized patients with liver dysfunction who used VRC and underwent therapeutic drug monitoring (TDM) at the First Hospital of Changsha. The severity of liver dysfunction was assessed by the Child–Pugh (CP) score. Multiple linear regression was employed to explore factors affecting VRC
C
trough
in these patients. A total of 147
C
trough
from 102 patients with liver dysfunction were analyzed. Patients were categorized into a control group (
n
= 40), CP-A (
n
= 39), CP-B (
n
= 11), and CP-C group (
n
= 12). The initial probability of target attainment of
C
trough
was 70.6%, with 6.9% of patients obtaining subtherapeutic
C
trough
and 22.5% obtaining supertherapeutic
C
trough
. The initial
C
trough
in CP-A and B were 5.05 (0.64–9.57) mg/L and 5.37 (0.26–10.01) mg/L, respectively, significantly higher than the control group (
P
= 0.021 and
P
= 0.010). The proportion of VRC
C
trough
of >5.5 mg/L in CP-A and B was 33.3% and 45.5%, respectively. Multiple linear regression analysis revealed that factors such as age ≥70 years, CP class, C-reactive protein (CRP), and direct bilirubin were significantly related to the initial VRC
C
trough
. Among all measurements, patients with severe inflammation (CRP >100 mg/L), aged ≥70 years, and albumin levels of <30 or <25 g/L had significantly higher VRC
C
trough
. The treatment success rate of VRC was 69.6% (71 of 102), and the rate of VRC-related adverse drug reactions was 29.4% (30 of 102). The recommended half-maintenance dose may lead to elevated VRC
C
trough
in patients with CP-A and CP-B. TDM is essential for patients with advanced age, severe infections, or hypoalbuminemia to prevent excessive VRC trough levels.
Mechanisms leading to
in vivo
ceftazidime/avibactam resistance development during treatment of GES-5-producing
Pseudomonas aeruginosa
infections
Authors: Herrera Cristhian , Gomis-Font Maria A. , López-Causapé Carla , Díez-Aguilar María , Fraile-Ribot Pablo A. , Cardeñoso Laura M. , Oliver Antonio 
Published: October 2024

ABSTRACT

The mechanisms underlying ceftazidime/avibactam resistance development in four ceftazidime/avibactam susceptible/resistant pairs of GES-5-producing ST235
Pseudomonas aeruginosa
clinical isolates were investigated. In three of the cases, ceftazidime/avibactam resistance was driven by a single mutation leading to GES-27 (P162Q), GES-29 (P162A), or the novel GES-60 (N136S), as confirmed through cloning experiments. Moreover, these mutations were associated with increased cefiderocol MICs but reduced carbapenem, particularly imipenem/relebactam, resistance. Understanding the complexity of resistance mechanisms to the growing repertoire of antipseudomonal β-lactams is crucial to guide optimized treatments and antimicrobial stewardship measures.
Addressing the need to facilitate undergraduate research experiences for community college transfer students in science
Authors: Goodwin Emma C. , Cooper Katelyn M. , Gin Logan E. , Brownell Sara E. 
Published: October 2024

ABSTRACT

Community college transfer students face numerous challenges, including gaining access to undergraduate research experiences. In this Perspectives piece, we articulate the benefits of undergraduate research experiences for community college transfer students, some of the common barriers for engaging transfer students in undergraduate research, and how 4-year institutions can address these problems through the development of transfer-specific programs. We specifically discuss the LEAP Scholars program, which we designed for low-income community college transfer students. The LEAP Scholars program helped students learn about undergraduate research through their participation in a science education course-based undergraduate research experience and facilitated student access to undergraduate research experiences in science faculty member research labs.
Lytic promoter activity during herpes simplex virus latency is dependent on genome location
Authors: Singh Navneet , Zachariah Sherin , Phillips Aaron T. , Tscharke David 
Published: October 2024

ABSTRACT

Herpes simplex virus 1 (HSV-1) is a significant pathogen that establishes lifelong latent infections with intermittent episodes of resumed disease. In mouse models of HSV infection, sporadic low-level lytic gene expression has been detected during latency in the absence of reactivation events that lead to production of new viruses. This viral activity during latency has been reported using a sensitive Cre-marking model for several lytic gene promoters placed in one location in the HSV-1 genome. Here, we extend these findings in the same model by examining first, the activity of an ectopic lytic gene promoter in several places in the genome and second, whether any promoters might be active in their natural context. We found that
Cre
expression was detected during latency from ectopic and native promoters, but only in locations near the ends of the unique long genome segment. This location is significant because it is in close proximity to the region from which latency-associated transcripts (LATs) are derived. These results show that native HSV-1 lytic gene promoters can produce protein products during latency, but that this activity is only detectable when they are located close to the LAT locus.

IMPORTANCE
HSV is a significant human pathogen and the best studied model of mammalian virus latency. Traditionally, the active (lytic) and inactive (latent) phases of infection were considered to be distinct, but the notion of latency being entirely quiescent is evolving due to the detection of some lytic gene expression during latency. Here, we add to this literature by finding that the activity can be found for native lytic gene promoters as well as for constructs placed ectopically in the HSV genome. However, this activity was only detectable when these promoters were located close by a region known to be transcriptionally active during latency. These data have implications for our understanding of HSV gene regulation during latency and the extent to which transcriptionally active regions are insulated from adjacent parts of the viral genome.
Rab6a enables BICD2/dynein-mediated trafficking of human papillomavirus from the
trans-
Golgi network during virus entry
Authors: Choi Jeongjoon , Speckhart Kaitlyn , Tsai Billy , DiMaio Daniel 
Published: October 2024

ABSTRACT

Rab GTPases control intracellular vesicular transport, including retrograde trafficking of human papillomavirus (HPV) during cell entry, guiding the virus from the endosome to the
trans-
Golgi network (TGN), the Golgi apparatus, and eventually the nucleus. Rab proteins have been identified that act prior to the arrival of HPV at the TGN, but Rab proteins operating in later stages of entry remain elusive. Here, we report that knockdown of Rab6a impairs HPV entry by preventing HPV exit from the TGN and impeding intra-Golgi transport of the incoming virus. Rab6a supports HPV trafficking by facilitating the association of HPV with dynein, a motor protein complex, and BICD2, a dynein adaptor, in the TGN. L2 can bind directly to GTP-Rab6a
in vitro
, and excess of either GTP-Rab6a or GDP-Rab6 inhibits HPV entry, suggesting that cycling between GDP-Rab6 and GTP-Rab6 is critical. Notably, Rab6a is crucial for HPV-BICD2 and HPV-dynein association in the TGN of infected cells but not in the endosome. Our findings reveal important features of the molecular basis of HPV infection, including the discovery that HPV uses different mechanisms to engage dynein at different times during entry, and identify potential targets for therapeutic approaches to inhibit HPV infection.

IMPORTANCE

Human papillomaviruses (HPVs) are small, non-enveloped DNA viruses that cause approximately 5% of human cancer. Like most other DNA viruses, HPV traffics to the nucleus during virus entry to successfully infect cells. We show here that HPV utilizes a cellular enzyme, Rab6a, during virus entry to engage the dynein molecular motor for transport along microtubules. Rab6a is required for complex formation between the HPV L2 capsid protein, dynein, and the dynein adaptor BICD2 in the
trans
-Golgi network (TGN). This complex is required for transport of the incoming virus out of the TGN as it journeys to the nucleus. Our findings identify potential targets for therapeutic approaches.
Draft genome sequences of
Listeria monocytogenes
strains from human listeriosis in Sweden harboring premature stop codons in the virulence determinant
inlA
Authors: Lee Sangmi , Brown Phillip , Tham Wilhelm , Danielsson-Tham Marie-Louise , Lopez-Valladares Gloria , Ward Todd , Elhanafi Driss , Chen Yi , Kathariou Sophia 
Published: October 2024

ABSTRACT

Premature stop codons in the internalin virulence determinant
inlA
are common in serotype 1/2a
Listeria monocytogenes
from food/food processing environments but rare among human clinical isolates. Here, we report the genome sequences of serotype 1/2a (STs 121 and 3258) human listeriosis isolates from Sweden harboring such mutations in
inlA
.
Human immunodeficiency virus-1 genome from patient with fever, Nepal
Authors: Tuladhar Eans Tara , Chalise Bimal Sharma , Khadka Binod , Tamang Mamta , Neupane Jenish , Poudel Shankar , Droit Lindsay , Mihindukulasuriya Kathie A. , Elong Ngono Annie , Basaula Yuba Nidhi , Shresta Sujan , Wang David , Manandhar Krishna Das 
Published: October 2024

ABSTRACT

A patient with fever presented to the referral infectious disease hospital in Kathmandu, Nepal. Metagenomic sequencing of the patient’s serum recovered a near-complete genome of human immunodeficiency virus-1 (HIV-1), distinct from previous HIV-1 genomes from Nepal in GenBank. It shared 92.48% nucleotide identity with an HIV-1 subtype C isolate from India.
Complete genome sequence of
Kozakia baliensis
LTH 7215, a newly isolated strain from grape must
Authors: Zipori Dor , Brychcy Merlin , Schmidt Herbert 
Published: October 2024

ABSTRACT

We report the complete genome sequence of the novel
Kozakia baliensis
strain LTH 7215, isolated from grape must. This strain exhibits a mucoid phenotype on solid medium, associated with exopolysaccharide production. The high-quality and full-length genome sequence was obtained using PacBio Sequencing technology, refined with Illumina sequencing.
Complete genome sequences of two
Paenibacillus
isolated from pegmatite in Fukushima, Japan
Authors: Yamamoto Phillip K. , Fujimoto Yuto , Warashina Tomoro , Arakawa Kazuharu 
Published: October 2024

ABSTRACT

The genus
Paenibacillus
comprises facultatively anaerobic, endospore-forming, Gram-positive eubacteria known for efficiently producing a diverse array of exoenzymes. We isolated and sequenced the complete genomes of two
Paenibacillus
bacteria from the pegmatite surface in the fourth ore body in the mine Wagu Kannon Mine, Fukushima Prefecture.
Strain variation in
Candida albicans
glycolytic gene regulation
Authors: Kim Min-Ju , White Amelia M. , Mitchell Aaron P. 
Published: October 2024

ABSTRACT

Central carbon metabolism is vital for the proliferation of
Candida albicans
, a fungus that is prominent as a commensal and pathogen. Glycolytic genes are activated by overlapping activities of the transcription factors Tye7 and Gal4, as shown by studies in the SC5314 genetic background. However, regulatory relationships can vary among
C. albicans
isolates. Here, we analyzed Tye7- and Gal4-related phenotypes in five diverse clinical isolates of
C. albicans
. We tested growth properties and gene expression impact through Nanostring profiling and, for the two strains SC5314 and P87, RNA sequencing. Our results lead to three main conclusions. First, the functional redundancy of Tye7 and Gal4 for glycolytic gene activation is preserved among all strains tested. Second, at the gene expression level, strain P87 is an outlier with regard to
tye7
Δ/Δ impact, and strain SC5314 is an outlier with regard to
gal4
Δ/Δ impact. Third, while Gal4 is well known to be dispensable for induction of the
GAL1
,
GAL7
, and
GAL10
galactose-specific metabolic genes, we find that
gal4
Δ/Δ mutants of several strains have a mild galactose fermentation defect, as assayed by growth on galactose with the respiration inhibitor antimycin A. Our findings indicate that even a central metabolic regulatory network is subject to strain variation and illustrates an unexpected genotype-phenotype relationship.

The fungal commensal and pathogen
Candida albicans
rely upon metabolic flexibility to colonize and infect host niches. Central carbon metabolism is governed by two regulators, Tye7 and Gal4, as defined in the reference strain SC5314. Here, we have explored the impact of Tye7 and Gal4 on carbon utilization and gene expression across five diverse
C. albicans
clinical isolates. Novel aspects of this study are the finding that even a central metabolic regulatory network is subject to strain variation and the observation of an unexpected mutant phenotype.
Novel anti-virulence compounds disrupt exotoxin expression in MRSA
Authors: Balogh Halie , Anthony Amaiya K. , Stempel Robin , Vossen Lauren , Federico Victoria A. , Valenzano Gabriel Z. , Blackledge Meghan S. , Miller Heather B. 
Published: October 2024

ABSTRACT

Hemolysins are lytic exotoxins expressed in most strains of
S. aureus
, but hemolytic activity varies between strains. We have previously reported several novel anti-virulence compounds that disrupt the
S. aureus
transcriptome, including hemolysin gene expression. This report delves further into our two lead compounds, loratadine and a structurally related brominated carbazole, and their effects on hemolysin production in methicillin-resistant
S. aureus
(MRSA). To gain understanding into how these compounds affect hemolysis, we analyzed these exotoxins at the DNA, RNA, and protein level after
in vitro
treatment. While lysis of red blood cells varied between strains, DNA sequence variation did not account for it. We hypothesized that our compounds would modulate gene expression of multiple hemolysins in two hospital-acquired strains of MRSA, both with staphylococcal cassette chromosome
mec
(SCC
mec
) type II. RNA-seq analysis of differential gene expression in untreated and compound-treated cultures revealed hundreds of differentially expressed genes, with a significant enrichment in genes involved in hemolysis. The brominated carbazole and loratadine both displayed the ability to reduce hemolysis in strain 43300 but displayed differential activity in strain USA100. These results corroborate gene expression studies as well as western blots of alpha hemolysin. Together, this work suggests that small molecules may alter exotoxin production in MRSA but that the directionality and/or magnitude of the difference are likely strain dependent.

IMPORTANCE

Methicillin-resistant
S. aureus
(MRSA) is a deadly human pathogen. In addition to evading antibiotics, these bacteria produce a wide range of toxins that negatively affect the host. Our work aims to identify and characterize novel compounds that can decrease the pathogenic effects of MRSA. Two lead compounds investigated in this study triggered changes in the production of multiple toxins. These changes were specific to the strain of MRSA investigated. Specifically, this work sheds light on novel compounds that decrease MRSA’s ability to lyse host red blood cells. Importantly, it also highlights the importance of examining strain-specific differences in response to therapeutic interventions that could ultimately affect clinical outcomes.
New insights on gravity flow dynamics during submarine canyon flushing events
Authors: Ribó Marta , Mountjoy Joshu J. , Mitchell Neil , Watson Sally J. , Hoffmann Jasper J.L. , Woelz Susi 
Published: October 2024

Abstract
Millions of tons of material are flushed through submarine canyons during infrequent high-magnitude events, transporting coastal sediment to the deep ocean. However, observations related to individual canyon flushing events are challenging due to the destructive nature and infrequency of flushing events. The impacts of one of the largest gravity flows in the past decade were documented in Kaikōura Canyon, Aotearoa–New Zealand, where &gt;1 km3 of sediment was mobilized by the 2016 CE Kaikōura earthquake (Mw 7.8). We present new high-resolution (&lt;1 m) multibeam data collected with an autonomous underwater vehicle (AUV) along the Kaikōura Canyon axis, together with side-scan sonar and seafloor video imagery. These data sets reveal a wide range of erosional and depositional features that were not previously identified. Eroded bedrock and deep erosional structures are found in the upper canyon, including linear grooves, and rockfall debris (&gt;5-m-diameter boulders). This erosional area transitions downcanyon to coarse-grained depositional bedforms, including cyclic steps and gravel waves (average wavelengths of 250 m and wave heights of ~20 m), covering the mid- and lower canyon. Our observations provide high-resolution field-based evidence of (1) flow transformation, from a debris flow to a high-density turbidity current; and (2) variations of flow dynamics within turbidity currents both across- and downcanyon, during an infrequent, high-energy canyon flushing event. This research offers new insights into the processes that create and shape nearshore bedrock-incising submarine canyons.
Natural history of otitis media with effusion without hearing loss in children under 12 years: a systematic review
Authors: Paing Aye , Elliff-O’Shea Laura , Holland Brown Tamsin , Arnold Stephanie , Day John , Royds Jennifer , Kennedy Veronica 
Published: October 2024

ObjectiveThis study aimed to evaluate the natural history of otitis media with effusion (OME) without hearing loss in children under 12 years.MethodsWe performed a systematic search in Embase, CINAHL, MEDLINE, INAHTA database, CENTRAL, CDSR, Epistemonikos and PsycINFO to identify observational single group studies and comparative studies with untreated control arms published in English up to June 2022, reporting natural history of OME without hearing loss. The JBI (Joanna Briggs Institute) checklist and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology were used to assess risk of bias and overall quality of evidence, respectively.ResultsNineteen studies with samples ranging from 16 to 816 children met the inclusion criteria. The quality of evidence ranged from low to very low. Resolution of current episode of OME without hearing loss was 10–66% by 1 month, 3–93% by 3 months, 10–98% by 6 months, 20–92% by 9 months and 78–99% by 12 months, depending on populations and how resolution was defined across studies. Resolution of OME (defined as change from type B to non-B tympanogram) was only 10% by 6 months in Aboriginal infants. Recurrence of OME was 7% by 3 months, 8–18% by 6 months, 10–28% by 9 months and 8–35% by 12 months.ConclusionsThere was a trend towards greater resolution of OME without hearing loss and recurrence of OME over longer follow-up periods; however, they did not seem to follow a linear pattern, potentially due to differences in populations and definitions of resolution across studies.
An analysis of humanitarian and health aid harmonisation over a decade (2011–2019) of the Syrian conflict
Authors: Alkhalil Munzer , Ekzayez Abdulkarim , Meagher Kristen , Alaref Maher , Turkmani Rim , Abbara Aula , Al Zoubi Zedoun , El Achi Nassim , Patel Preeti 
Published: October 2024

IntroductionAid harmonisation is a key component of donor efforts to make aid more effective by improving coordination and simplifying and sharing information to avoid duplication. This study evaluates the harmonisation of health and humanitarian aid in Syria during acute humanitarian and health crises from 2011 to 2019.MethodsData on humanitarian and health aid for Syria between 2011 and 2019 was collected from the Organisation for Economic Cooperation and Development’s Creditor Reporting System to assess the harmonisation of aid. The data was linked to four key indicators of the conflict: the number of internally displaced persons; the number of people in need of humanitarian assistance; the number or frequency of internal movements (displacements) by individuals; and the decline in Syria’s population between 2011 and 2019. This was compared with data from highly fragile states and developing countries. Four focus group discussions, four key informants’ interviews and three consultations with humanitarian practitioners were also conducted.ResultsThe findings suggest that overall aid harmonisation did not occur and importantly did not correlate with increased humanitarian needs. During the first 5 years, humanitarian and health pooled funds (which endorse aid harmonisation) in Syria were nearly entirely absent, far less than those in developing countries and highly fragile states. However, from 2016 to 2019, a visible surge in humanitarian pooled funds indicated an increase in the harmonisation of donors’ efforts largely influenced by adopting the Whole of Syria approach in 2015 as a positive result of the cross-border United Nation (UN) Security Council resolution in 2014.ConclusionHarmonisation of aid within the Syrian crisis was found to have little correlation with the crisis parameters and population needs, instead aligning more with donor policies. Assessing fragmentation solely at the donor level is also insufficient. Aid effectiveness should be assessed with the inclusion of community engagement and aid beneficiary perspectives. Harmonisation mechanisms must be disentangled from international politics to improve aid effectiveness. In Syria, this study calls for finding and supporting alternative humanitarian coordination and funding mechanisms that are not dependent on the persistent limitations of the UN Security Council.