bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vaccine-induced NA immunity decreases viral shedding, but does not disrupt chains of airborne transmission for the 2009 pandemic H1N1 virus in ferrets
Authors: Septer K. M. , Heinly T. A. , Sim D. G. , Patel D. R. , Roder A. E. , Wang W. , Chung M. , Johnson K. E. E. , Ghedin E. , Sutton T. C. 
Published: September 2024

ABSTRACT

Split-virion-inactivated influenza vaccines are formulated based on viral hemagglutinin content. These vaccines also contain the viral neuraminidase (NA) protein, but NA content is not standardized and varies between manufacturers. In clinical studies and animal models, antibodies directed toward NA reduced disease severity and viral load; however, the impact of vaccine-induced NA immunity on airborne transmission of influenza A viruses is not well characterized. Therefore, we evaluated if vaccination against NA could disrupt chains of airborne transmission for the 2009 pandemic H1N1 virus in ferrets. Immunologically naïve donor ferrets were infected with the 2009 pandemic H1N1 virus and then paired in transmission cages with mock- or NA-vaccinated respiratory contacts. The mock- and NA-vaccinated animals were then monitored daily for infection, and once infected, these animals were paired with a naive secondary respiratory contact. In these studies, all mock- and NA-vaccinated animals became infected; however, NA-vaccinated animals shed significantly less virus for fewer days relative to mock-vaccinated animals. For the secondary contacts, 6/6 and 5/6 animals became infected after exposure to mock- and NA-vaccinated animals, respectively. To determine if vaccine-induced immune pressure selected for escape variants, we sequenced viruses recovered from ferrets. No mutations in NA became enriched during transmission. These findings indicate that despite reducing viral load, vaccine-induced NA immunity does not prevent infection during continuous airborne exposure and subsequent onward airborne transmission of the 2009 pandemic H1N1 virus.

IMPORTANCE
In humans and animal models, immunity against neuraminidase (NA) reduces disease severity and viral replication during influenza infection. However, we have a limited understanding of the impact of NA immunity on viral transmission. Using chains of airborne transmission in ferrets as a strategy to simulate a more natural route of infection, we assessed if vaccine-induced NA immunity could disrupt transmission of the 2009 pandemic H1N1 virus. The 2009 pandemic H1N1 virus transmitted efficiently through chains of transmission in the presence of NA immunity, but NA-vaccinated animals shed significantly less virus and had accelerated viral clearance. To determine if immune pressure led to the generation of escape variants, viruses in ferret nasal wash samples were sequenced, and no mutations in NA were identified. These findings demonstrate that vaccine-induced NA immunity is not sufficient to prevent infection via airborne exposure and onward airborne transmission of the 2009 pandemic H1N1 virus.
A plasmid-mediated type III secretion system associated with invasiveness and diarrheagenicity of
Providencia rustigianii
Authors: Hassan Jayedul , Hinenoya Atsushi , Hatanaka Noritoshi , Awasthi Sharda Prasad , Manjunath Goutham Belagula , Rahman Nahid , Yamate Jyoji , Nakamura Shota , Motooka Daisuke , Nagita Akira , Faruque Shah M. , Yamasaki Shinji 
Published: September 2024

ABSTRACT

We have recently described a clinical isolate of
Providencia rustigianii
strain JH-1 carrying the genes for cytolethal distending toxin (CDT) in a conjugative plasmid. A
cdtB
mutant of strain JH-1, which lost CDT activity, was still found to retain invasiveness and diarrheagenicity. The strain was subjected to phenotypic and genetic analyses including whole genome sequencing (WGS) to explore the genetic determinants of the observed invasiveness and diarrheagenic properties. Analysis and annotation of WGS data revealed the presence of two distinct type III secretion systems (T3SS) in strain JH-1, one of which was located on the chromosome designated as cT3SS (3,992,833 bp) and the other on a mega-plasmid designated as pT3SS (168,819 bp). Comparative genomic analysis revealed that cT3SS is generally conserved in
Providencia
spp. but pT3SS was limited to a subset of
Providencia
spp., carrying
cdt
genes. Strain JH-1 was found to invade HeLa cells and induce fluid accumulation with characteristic pathological lesions in rabbit ileal loops. Remarkably, these phenomena were associated with the pT3SS but not cT3SS. The plasmid could be transferred by conjugation from strain JH-1 to other strains of
P. rustigianii
,
Providencia rettgeri
, and
Escherichia coli
with concomitant transfer of these virulence properties. This is the first report of a functional and mobile T3SS in
P. rustigianii
and its association with invasiveness and diarrheagenicity of this bacterium. These data suggest that
P. rustigianii
and other CDT-producing
Providencia
strains might carry T3SS and exert their diarrheagenic effect by exploiting the T3SS nano-machinery.

IMPORTANCE

The precise mechanism of virulence of
Providencia rustigianii
is unclear, although some strains produce cytolethal distending toxin as a putative virulence factor. We have detected the presence of a type III secretion system (T3SS) for the first time on a plasmid in a
P. rustigianii
strain. Plasmid-mediated T3SS seems to be directly involved in virulence of
P. rustigianii
and may serve as a means of horizontal transfer of T3SS genes. Our results may have implication in understanding the mechanism of emergence of new pathogenic strains of
P. rustigianii
.
Draft genome sequence of
Taiwanofungus gaoligongensis
strain YAF008 isolated from Gaoligong Mountain
Authors: Bao Yuanduo , Yuan Xiaolong , Chen Zihong , Yang Yuming , Zheng Yuan , Wang Yi 
Published: September 2024

ABSTRACT

The draft genome sequence of
Taiwanofungus gaoligongensis
YAF008 was reported. The genome size of
T. gaoligongensis
YAF008 was 34.7M bp with 50.72% GC content. The genome resource will support future research into potential secondary metabolite diversity of this fungus.
Draft genome sequence of a
spa
non-typeable
Staphylococcus aureus
USA300 isolate causing complicated bacteremia
Authors: Felton Emily A. , Diaz Vera Jesus , Katzman Ju Hee , Daniels Sara , Lima Amorce , Becker Deanna , Silbert Suzane , Kim Kami , Shaw Lindsey N. 
Published: September 2024

ABSTRACT

Spa-typing is a major genetic tool used to distinguish between
Staphylococcus aureus
strains. Interestingly, although rare, ~1%–2 of isolates are considered Spa-non-typeable . Herein, we present the draft genome sequence of just such a strain,
S. aureus
TGH1097, a USA300 isolate from a complex bacteremia infection.
Complete genome sequence of
Bacillus pumilus
LBUM494, a plant-beneficial strain isolated from the rhizosphere of a strawberry plant
Authors: Biessy Adrien , Filion Martin 
Published: September 2024

ABSTRACT

Here, we present the complete genome sequence of
Bacillus pumilus
LBUM494, a plant-beneficial bacterial strain isolated from the rhizosphere of a strawberry plant grown in an agricultural field located in Bouctouche, New Brunswick, Canada. The genome size is 3,699,913 bp with a GC content of 41.7%.
Potential of training of anti-
Staphylococcus aureus
therapeutic phages against
Staphylococcus epidermidis
multidrug-resistant isolates is restricted by inter- and intra-sequence type specificity
Authors: Kolenda Camille , Bonhomme Mélanie , Medina Mathieu , Pouilly Mateo , Rousseau Clara , Troesch Emma , Martins-Simoes Patricia , Stegger Marc , Verhoeven Paul O. , Laumay Floriane , Laurent Frédéric 
Published: September 2024

ABSTRACT

Phage therapy appears to be a promising approach to tackle multidrug-resistant bacteria, including staphylococci. However, most anti-staphylococcal phages have been characterized in
Staphylococcus aureus
, while a limited number of studies investigated phage activity against
S. epidermidis
. We studied the potential of phage training to extend the host range of two types of anti-
S
.
aureus
phages against
S. epidermidis
isolates. The Appelmans protocol was applied to a mixture of
Kayvirus
and a mixture of
Silviavirus
phages repeatedly exposed to seven
S
.
epidermidis
strains representative of nosocomial-associated sequence types (ST), including the world-wide disseminated ST2. We observed increased activity only for the
Kayvirus
mixture against two of these strains (ST2 or ST35). Phage subpopulations isolated from the training mixture using these two strains (five/strain) exhibited different evolved phenotypes, active only against their isolation strain or strains of the same ST. Of note, 16/47 ST2 strains were susceptible to one of the groups of trained phages. A comparative genomic analysis of ancestral and trained phage genomes, conducted to identify potential bacterial determinants of such specific activity, found numerous recombination events between two of the three ancestors. However, a small number of trained phage genes had nucleotide sequence modifications impacting the corresponding protein compared to ancestral phages, two to four of them per phage genome being specific of each group of phage subpopulations exhibiting different host range. The results suggest that anti-
S
.
aureus
phages can be adapted to
S. epidermidis
isolates but with inter- and intra-ST specificity.

Importance

S. epidermidis
is increasingly recognized as a threat for public health. Its clinical importance is notably related to multidrug resistance. Phage therapy is one of the most promising alternative therapeutic strategies to antibiotics. Nonetheless, only very few phages active against this bacterial species have been described. In the present study, we showed that phage training can be used to extend the host range of polyvalent
Kayvirus
phages within the
Staphylococcus
genera to include
S. epidermidis
species. In the context of rapid development of phage therapy,
in vitro
forced adaptation of previously characterized phages could be an appealing alternative to fastidious repeated isolation of new phages to improve the therapeutic potential of a phage collection.
Flagellum-deficient
Pseudomonas aeruginosa
is more virulent than non-motile but flagellated mutants in a cystic fibrosis mouse model
Authors: Moustafa Dina A. , Fantone Kayla M. , Tucker Samantha L. , McCarty Nael A. , Stecenko Arlene A. , Goldberg Joanna B. , Rada Balázs 
Published: September 2024

ABSTRACT

Loss of the flagellum marks the pathoadaptation of
Pseudomonas aeruginosa
to the cystic fibrosis (CF) airway environment during lung disease. Losing the flagellum is advantageous to the bacterium as the flagellum can be recognized by immune cells. The primary purpose of the flagellum is, however, to provide motility to the bacterium. Our goal was to determine whether the loss of flagellar motility or the loss of flagellum expression contributes to
P. aeruginosa
lung infection in CF. To address this, wild-type and gut-corrected FABP-human cystic fibrosis transmembrane conductance regulator (hCFTR) mice deficient in the murine
Cftr
gene were infected intratracheally with lethal doses of wild-type or flagellum-deficient
P. aeruginosa
. While there was no significant difference in the survival of wild-type mice after infection with either of the bacterial strains, a significantly higher mortality was observed in FABP-hCFTR mice infected with flagellum-deficient
P. aeruginosa
, compared to mice infected with their flagellated counterparts. When FABP-hCFTR mice were infected with isogenic, motility-deficient flagellated mutants, animal survival and lung bacterial titers were similar to those observed in mice infected with the wild-type bacterium. Airway levels of neutrophils and the amount neutrophil elastase were similar in mice infected with either the wild-type bacteria or the flagellum-deficient
P. aeruginosa
. Our results show that FABP-hCFTR mice have a different response to flagellum loss in
P. aeruginosa
compared to wild-type animals. The loss of flagellum expression, rather than the loss of motility, is the main driver behind the increased virulence of flagellum-deficient
P. aeruginosa
in CF. These observations provide new insight into
P. aeruginosa
virulence in CF.

IMPORTANCE

Pseudomonas aeruginosa
, a major respiratory pathogen in cystic fibrosis, is known to lose its flagellum during the course of infection in the airways. Here, we show that the loss of flagellum leads to a more enhanced virulence in Cftr-deficient cystic fibrosis mice than in control animals. Loss of flagellum expression, rather than the loss of flagellar swimming motility, represents the main driver behind this increased virulence suggesting that this appendage plays a specific role in
P. aeruginosa
virulence in cystic fibrosis airways.
Enclaves as mushy magma strain archives: New perspectives on composite magmatic fabrics in plutons
Authors: Latimer Ben , McCarthy William , Mattsson Tobias , Reavy John 
Published: September 2024

Abstract
Mineral fabrics within igneous intrusions can archive both tectonic and magmatic processes. However, whether magmatic state fabrics reflect primary magmatic processes or regional tectonic strain is often ambiguous. To investigate when fabrics are formed, one can compare the mineral fabrics to primary magmatic features, such as the interface between solidified magmas in mingling zones. The monzodioritic Fanad pluton shows a NNE-SSW–aligned petrofabric parallel to the strike of a nearby shear zone, with dioritic enclaves aligned parallel and oblique to this petrofabric. We therefore aimed to test if the enclaves' internal fabrics are passive and align with enclave morphology or result from progressive overprint by regional tectonic strain. Crystallographic preferred orientation and anisotropy of magnetic susceptibility data from all enclaves and the host monzodiorite revealed a NNE-SSW petrofabric parallel to the regional tectonomagmatic fabric. However, anisotropy of anhysteretic remanent magnetization data within petrofabric-oblique enclaves revealed a primary fabric parallel to the enclave long axis. Therefore, we interpret enclave morphologies to reflect earlier magmatic state deformation, with fabrics being realigned to regional tectonic deformation. These two distinct petrofabrics were interpreted in the context of the magmatic processes and the evolving late Caledonian paleostress field, with earlier magma processes distinguished from subsequent tectonic overprinting occurring in the magmatic state. Our new data show that multiple fabrics are preserved within enclaves even though all fabric development occurred within a magmatic state. Our results also show that enclaves can effectively record successive strain events, providing new insight with which to decipher tectonomagmatic processes.
Tumor-Infiltrating Lymphocytes in Necrotic Tumors after Melanoma Neoadjuvant Anti–PD-1 Therapy Correlate with Pathologic Response and Recurrence-Free Survival
Authors: Ma Kevin L. , Mitchell Tara C. , Dougher Meaghan , Sharon Cimarron E. , Tortorello Gabriella N. , Elder David E. , Morgan Eric E. , Gimotty Phyllis A. , Huang Alexander C. , Amaravadi Ravi K. , Schuchter Lynn M. , Flowers Ahron , Miura John T. , Karakousis Giorgos C. , Xu Xiaowei 
Published: September 2024

Abstract

Purpose:
Neoadjuvant anti–PD-1 therapy in melanoma may increase tumor-infiltrating lymphocytes (TIL), and more TIL are associated with better treatment response. A major pathologic response (MPR) in melanoma after neoadjuvant anti–PD-1 therapy usually comprises tumor necrosis and fibrosis. The role of TIL in necrotic tumor necrosis (nTIL) has not been explored.

Experimental Design:
We performed CD3 and CD8 IHC stains on 41 melanomas with geographic necrosis. Of the 41, 14 were immunotherapy-naïve, and 27 had been treated with one dose of neoadjuvant anti–PD-1 in two clinical trials. CD3+ and CD8+ nTIL were graded as absent/minimal or moderate/brisk. The percentage of necrotic areas in the tumor bed before and after treatment was quantified. The endpoints were MPR and 5-year recurrence-free survival (RFS).

Results:
In the immunotherapy-naïve cohort, 3/14 (21%) specimens had moderate/brisk CD3+, and 2/14 (14%) had moderate/brisk CD8+ nTIL. In the treated cohort, 16/27 (59%) specimens had moderate/brisk CD3+, and 15/27 (56%) had moderate/brisk CD8+ nTIL, higher than those of the naïve cohort (CD3, P = 0.046; CD8, P = 0.018). Tumor necrosis was significantly increased after anti–PD-1 therapy (P = 0.007). In the treated cohort, moderate/brisk CD3+ and CD8+ nTIL correlated with MPR (P = 0.042; P = 0.019, respectively). Treated patients with moderate/brisk CD3+ nTIL had higher 5-year RFS than those with absent/minimal nTIL (69% vs. 0%; P = 0.006). This persisted on multivariate analysis (HR, 0.16; 95% confidence interval, 0.03–0.84; P = 0.03), adjusted for pathologic response, which was borderline significant (HR, 0.26; 95% confidence interval, 0.07–1.01; P = 0.051).

Conclusions:
CD3+ and CD8+ nTIL are associated with pathologic response and 5-year RFS in patients with melanoma after neoadjuvant anti–PD-1 therapy.
FDA Approval Summary: Belzutifan for Patients with Advanced Renal Cell Carcinoma
Authors: Fallah Jaleh , Heiss Brian L. , Joeng Hee-Koung , Weinstock Chana , Gao Xin , Pierce William F. , Chukwurah Benjamin , Bhatnagar Vishal , Fiero Mallorie H. , Amiri-Kordestani Laleh , Pazdur Richard , Kluetz Paul G. , Suzman Daniel L. 
Published: September 2024

Abstract
On December 14, 2023, the U.S. FDA approved belzutifan (Welireg, Merck & Co., Inc.) for patients with advanced renal cell carcinoma (RCC) following treatment with a PD-1/PD-L1 inhibitor and a VEGF tyrosine kinase inhibitor. The FDA granted traditional approval based on LITESPARK-005 (NCT04195750), an open-label, randomized, head-to-head trial of 746 patients with advanced RCC that progressed following treatment with both a PD-1/PD-L1 inhibitor and a VEGF tyrosine kinase inhibitor. Patients were randomized (1:1) to receive belzutifan or everolimus. The primary endpoints were progression-free survival (PFS) assessed by blinded independent central review and overall survival. A statistically significant improvement in PFS was demonstrated for belzutifan compared with everolimus [HR = 0.75; 95% confidence interval (CI), 0.63–0.90; one-sided P value = 0.0008]. Kaplan–Meier curves reflected nonproportional hazards with similar median PFS estimates of 5.6 months (95% CI, 3.9–7.0) in the belzutifan arm and 5.6 months (95% CI, 4.8–5.8) in the everolimus arm. Although not reaching full maturity, the overall survival results seemed to show a favorable trend in the belzutifan arm compared with the everolimus arm (HR, 0.88; 95% CI, 0.73–1.07). The confirmed objective response rate by blinded independent central review was 22% and 3.6% in the belzutifan and everolimus arms, respectively. Observed toxicities differed between treatment arms, but drug discontinuations and interruptions due to treatment-emergent adverse events were lower in the belzutifan arm compared with the everolimus arm, and a descriptive analysis of patient-reported symptom and functional outcomes was suggestive of favorable tolerability for belzutifan compared with everolimus.
Antiangiogenic Tyrosine Kinase Inhibitors have Differential Efficacy in Clear Cell Renal Cell Carcinoma in Bone
Authors: Maksimovic Stefan , Boscolo Nina C. , La Posta Ludovica , Barrios Sergio , Moussa Mohammad Jad , Gentile Emanuela , Pesquera Pedro I. , Li Wenjiao , Chen Jianfeng , Gomez Javier A. , Basi Akshay , Burks Jared K. , Alvarez-Breckenridge Christopher , Gao Jianjun , Campbell Matthew T. , Dondossola Eleonora 
Published: September 2024

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney neoplasm; bone metastasis (BM) develops in 35% to 40% of metastatic patients and results in substantial morbidity and mortality, as well as medical costs. A key feature of ccRCC is the loss of function of the von Hippel–Lindau protein, which enhances angiogenesis via vascular endothelial growth factor release. Consequently, antiangiogenic tyrosine kinase inhibitors (TKI) emerged as a treatment for ccRCC. However, limited data about their efficacy in BM is available, and no systematic comparisons have been performed. We developed mouse models of bone and lung ccRCC tumors and compared their anticancer efficacy, impact on mouse survival, and mechanisms of action, including effects on tumor cells and both immune and nonimmune (blood vessels and osteoclasts) bone stromal components. This approach elucidates the efficacy of TKIs in ccRCC bone tumors to support rational interrogation and development of therapies.

Significance:
TKIs showed different efficacy in synchronous bone and lung metastases and did not eradicate tumors as single agents but induced extensive reprogramming of the BM microenvironment. This resulted in a significant decrease in neoangiogenic blood vessels, bone remodeling, and immune cell infiltration (including CD8 T cells) with altered spatial distribution.
Resistant Hypertension and Mortality: An Observational Cohort Study
Authors: de la Sierra Alejandro , Ruilope Luis M. , Staplin Natalie , Gorostidi Manuel , Vinyoles Ernest , Segura Julián , Armario Pedro , Oliveras Anna , Williams Bryan 
Published: September 2024

BACKGROUND:
Resistant hypertension is characterized by elevated blood pressure (BP) despite using 3 antihypertensive agents. Ambulatory BP monitoring (ABPM) detects the presence of white-coat resistant hypertension (24-hour BP <130/80 mm Hg). The aim of the study was to evaluate risks of death in resistant hypertension compared with controlled hypertension, as well as in ABPM-confirmed (24-hour BP ≥130 or 80 mm Hg), versus white-coat resistant hypertension.

METHODS:
We selected 8146 patients with controlled hypertension (office BP <140/90 mm Hg while being treated with ≤3 antihypertensive drugs) and 8577 with resistant hypertension (BP ≥140 or ≥90 mm Hg while being treated with ≥3 drugs). All-cause and cardiovascular mortalities (median follow-up, 9.7 years) were compared between groups, as well as between patients with white-coat (3289) and ABPM-confirmed (5288) resistant hypertension. Hazard ratios (HRs) from Cox models after adjustment for clinical confounders were used for comparisons.

RESULTS:
Compared with controlled hypertension, resistant hypertension was associated with an increased risk in all-cause (HR, 1.21 [95% CI, 1.12–1.30]) and cardiovascular mortalities (HR, 1.33 [95% CI, 1.17–1.51]) in confounder-adjusted models. Compared with white-coat, ABPM-confirmed resistant hypertension was associated with an increased risk of all-cause (HR, 1.45 [95% CI, 1.32–1.60]) and cardiovascular (HR, 1.68 [95% CI, 1.43–1.98]) mortalities. When ABPM-confirmed and white-coat resistant hypertension were separately compared with controlled hypertension, only the former was associated with an increased risk of death and cardiovascular death (HR, 1.36 [95% CI, 1.26–1.48] and 1.56 [95% CI, 1.36–1.79]), respectively.

CONCLUSIONS:
ABPM-confirmed resistant hypertension is associated with an increased risk of death and cardiovascular death with respect to both controlled hypertension and white-coat resistant hypertension.