bluuebunny/crossref_metadata_2025_split huggingface dataset:
MmpL3, Wag31, and PlrA are involved in coordinating polar growth with peptidoglycan metabolism and nutrient availability
Authors: Arejan Neda Habibi , Czapski Desiree R. , Buonomo Joseph A. , Boutte Cara C. 
Published: September 2024

ABSTRACT

Cell growth in mycobacteria involves cell wall expansion that is restricted to the cell poles. The DivIVA homolog Wag31 is required for this process, but the molecular mechanism and protein partners of Wag31 have not been described. In this study of
Mycobacterium smegmatis
, we identify a connection between
wag31
and trehalose monomycolate (TMM) transporter
mmpl3
in a suppressor screen and show that Wag31 and polar regulator PlrA are required for MmpL3’s polar localization. In addition, the localization of PlrA and MmpL3 is responsive to nutrient and energy deprivation and inhibition of peptidoglycan metabolism. We show that inhibition of MmpL3 causes delocalized cell wall metabolism but does not delocalize MmpL3 itself. We found that cells with an MmpL3 C-terminal truncation, which is defective for localization, have only minor defects in polar growth but are impaired in their ability to downregulate cell wall metabolism under stress. Our work suggests that, in addition to its established function in TMM transport, MmpL3 has a second function in regulating global cell wall metabolism in response to stress. Our data are consistent with a model in which the presence of TMMs in the periplasm stimulates polar elongation and in which the connection between Wag31, PlrA, and the C-terminus of MmpL3 is involved in detecting and responding to stress in order to coordinate the synthesis of the different layers of the mycobacterial cell wall in changing conditions.

IMPORTANCE

This study is performed in
Mycobacterium smegmatis
, which is used as a model to understand the basic physiology of pathogenic mycobacteria such as
Mycobacterium tuberculosis
. In this work, we examine the function and regulation of three proteins involved in regulating cell wall elongation in mycobacterial cells, which occurs at the cell tips or poles. We find that Wag31, a regulator of polar elongation, works partly through the regulation of MmpL3, a transporter of cell wall constituents and an important drug target. Our work suggests that, beyond its transport function, MmpL3 has another function in controlling cell wall synthesis broadly in response to stress.
Isolation of a
bla
NDM-1
-positive strain in Israel predating the earliest observations from India
Authors: Grenier Frédéric , Baby Vincent , Allard Sarah , Lévesque Simon , Papale François , Sullivan Richard , Landecker Hannah L. , Higgins Paul G. , Rodrigue Sébastien , Haraoui Louis-Patrick 
Published: September 2024

ABSTRACT

bla
NDM
, the most prevalent carbapenemase among carbapenem-resistant Enterobacteriaceae, is thought to have emerged in India, as its initial detection in 2008 was linked to this country, and subsequent retrospective surveys had so far established the earliest
bla
NDM
-positive strains to be isolated in India in 2005. Molecular dating and analyses suggest
bla
NDM
emerged within
Acinetobacter
species decades prior to 2005 on a Tn
125
transposon. Despite early reports of elevated rates of carbapenem-resistant
Acinetobacter
species in Israel starting in the 1990s, limited molecular data are available from this location. We searched for
bla
NDM
among
Acinetobacter
species isolated in Israel between 2001 and 2006. One
A. junii
strain, Ajun-H1-3, isolated in January 2004, carried
bla
NDM-1
within a Tn
125
-like transposon on a 49-kb plasmid, pNDM-Ajun-H1-3, making Ajun-H1-3 the earliest NDM-positive isolate observed to date. The pNDM-Ajun-H1-3 plasmid matched numerous BJ01-like NDM-positive plasmids identified from 2005 onward in
Acinetobacter
species as well as Enterobacterales. These results indicate the need for further retrospective work on global strain archives to shed light on the conditions favoring the emergence as well as subsequent evolution and spread of
bla
NDM
.

IMPORTANCE

This study presents the earliest observation of
bla
NDM-1
, isolated in a geographical region distant from where it is believed to have originated. In doing so, this study provides novel insights into the emergence and spread of
bla
NDM
, the most prevalent carbapenemase among carbapenem-resistant Enterobacteriaceae, and its associated mobile genetic elements. It also sheds light on the conditions that foster the evolution of antimicrobial resistance, one of the greatest public health challenges we face.
Re-updating the taxonomy of
Kluyvera
genus for a better understanding of CTX-M β-lactamase origin
Authors: Rodriguez Maria Margarita , Gutkind Gabriel 
Published: September 2024

ABSTRACT

The taxonomic definitions within the
Kluyvera
genus are still unclear, as several deposits might belong to misidentified species or genus or genome assemblies comprehend large indeterminate nucleotide zones. In this study, we performed a comparative phylogenomic analysis of
Kluyvera
chromosomes and other selected
Enterobacterales
. We also included the genomic analysis of chromosomal
bla
CTX-M/KLU
from
Kluyvera
isolates and assigned the plasmid-encoded
bla
CTX/M
genes. The study allowed us to propose a new
Kluyvera
genomospecies and to better define
Kluyvera
genomosp. 5. Two new CTX-M sub-groups could also be suggested. Even if no chromosomal
bla
CTX-M/KLU
gene can be found in
K. intermedia
and
Kluyvera
genomosp. 6, accurate identification can be achieved by using these gene sequences in the remaining strains.

IMPORTANCE

The use of whole-genome sequencing (WGS) accelerated the identification of new
Kluyvera
species proposals, but a rigorous analysis of these sequences is needed for a better definition, including preexisting, and even established species.
Kluyvera
genomosp. 5 could be more clearly defined, and, among isolates that do not produce a chromosome-encoded CTX-M enzyme, true
K. intermedia
should be kept within the genus as well as a new genomospecies (
Kluyvera
genomosp. 6) different from
K. intermedia
. We could clean up true
Kluyvera
from those that deserved transfer to other genera, and some deposits as
K. ascorbata
,
K. cryocrescens
,
K. georgiana
, and several
Kluyvera
sp. to the real species. Two new sub-groups of CTX-M enzymes could be proposed. The accurate identification of the chromosome-encoded
bla
CTX-M/KLU
gene in
Kluyvera
isolates could be a useful taxonomic tool to guide the species classification.
Contributions to forearm desaturation during transient ischemia in healthy adult males and females across the lifespan
Authors: Perlet Michael R. , Traylor Miranda K. , Ransom Kyndall V. , Batman Genevieve B. , Hill Ethan C. , Weir Joseph P. , Keller Joshua L. 
Published: September 2024

This study investigated skeletal muscle tissue oxygenation (StO2) desaturation in males and females across the adult lifespan. One hundred-two individuals (51 females) of 41 young, 34 midlife, and 27 older adults completed a vascular occlusion test with near-infrared spectroscopy (NIRS + VOT). This included five minutes of arterial occlusion, inducing transient ischemia in the forearm flexor muscle group while recording StO2. The magnitude of desaturation (StO2mag) was quantified as the difference between baseline StO2 and the minimum StO2 value observed during ischemia. The rate of desaturation was also examined. Forearm adipose tissue thickness (ATT), forearm lean mass, and handgrip muscular strength were measured. A p ≤ 0.05 was considered significant. Two-way between factor Analysis of variance (ANOVAs) indicated that males exhibited significantly ( p < 0.001) less ATT than females (collapsed across age) and that forearm lean mass ( p < 0.001) and muscular strength ( p < 0.001) decreased across the lifespan independent of sex. Bivariate analyses revealed significant ( p < 0.05) associations for sex, age, ATT, forearm lean mass, and muscular strength with the desaturation metrics. The ATT values demonstrated the strongest relations with StO2mag and desaturation rate ( r = −0.620 and 0.618). Using a model comparison approach, ATT plus age offered the best predictive power for StO2mag and desaturation rate ( R2 = 0.456 and 0.438) such that the inclusion of sex did not improve the models. These findings suggested differences in desaturation were primarily explained by variations in ATT and, to a lesser extent, age, but biological sex had no meaningful effect. Future studies must determine what other factors influence desaturation during ischemia.
Commutativity of Cascaded Connected Fractional Order Linear Time-Varying Systems
Authors: Ibrahim Salisu , Isah Abdulnasir , Iqbal Mujahid , Chang Phang , Baleanu Dumitru 
Published: September 2024

In this work, we present a comprehensive study of the commutativity of fractional-order linear time-varying systems (LTVSs). Commutativity is a fundamental property in the analysis and control of dynamic systems and is often used to simplify the design of controllers. Fractional-order systems, which are characterized by a noninteger-order derivative, have been widely studied in recent years due to their ability to model a wide range of phenomena. However, the commutativity of fractional-order LTVSs has not been widely explored. In this work, we present a comprehensive study of the commutativity of fractional-order LTVSs. We first provide a mathematical definition of commutativity for these systems and demonstrate that it is equivalent to the commutativity of their transfer functions. We then propose a method for verifying the general condition for commutativity of fractional-order LTVSs under zero initial conditions (ICs) and prove it mathematically. Based on our findings, we realized that the commutative requirements, properties, theories, and conditions are general for fractional-order LTVSs, please observed that some fractional-order LTVSs are commutative, some are not commutative, while some are commutative under certain conditions. Based on this fact, we can say that not all fractional-order LTVSs are commutative. We apply explicit commutative results to several examples of fractional-order LTVSs. Our theoretical and simulation results show a good agreement and prove that our fractional-order LTVSs are commutative under certain conditions, moreover, the commutativity property holds for certain conditions and classes of fractional-order LTVSs, but not for others. Because of the application of fraction commutativity in various fields of science and engineering, we find it necessary to come up with explicit results for the first time.
Intraoperative Guidance of Pancreatic Cancer Resection Using a Toll-like Receptor 2–Targeted Fluorescence Molecular Imaging Agent
Authors: Huynh Amanda S. , Cohen Allison S. , Doligalski Michael , Casagni Todd J. , Moberg Valerie E. , Huang Xuan , Morse Jennifer , Abrahams Dominique , Lloyd Mark C. , Centeno Barbara A. , Baldwin Margaret K. , McLaughlin Mark L. , Vagner Josef , Morse David L. 
Published: September 2024

Abstract

To increase the achievement of negative R0 surgical margins and increase the low survival rates of pancreatic cancer, improvements in assessing tumor margins during surgical resections are needed. This can be accomplished by using pancreatic cancer–targeted fluorescence molecular imaging agents to intraoperatively detect tumor margins in real time. Because Toll-like receptor 2 (TLR2) is broadly expressed among many cancer types including pancreatic adenocarcinomas, a high-affinity TLR2-targeted fluorescence molecular imaging agent (TLR2L-800) was developed. We investigate the potential for increased survival by employing real-time intraoperative tumor detection in a preclinical orthotopic human pancreatic xenograft tumor model using TLR2L-800. Three cohorts of nude mice bearing orthotopic human pancreatic xenograft tumors were intravenously injected with TLR2L-800. At 24 hours postinjection, one cohort underwent in vivo fluorescence-guided surgical removal of tumors using a real-time fluorescence imaging platform, a second cohort underwent visible light surgery (VLS), and a third cohort did not undergo surgery. A fourth, nontumor-bearing cohort was administered TLR2L-800 with no surgery. At 41 days postsurgery, the survival rates were 53% for the fluorescence-guided surgery (FGS) group and 0% for both the VLS and the tumor-bearing no-surgery group. The overall 200-day survival rate of 35% for the FGS group was significant compared with 0% for the VLS group (P value = 0.0018). This study demonstrates the potential of increasing disease-free survival for patients with pancreatic cancer by increasing the attainment of R0 margins using a novel tumor-targeted lipopeptide ligand-based fluorescence molecular imaging agent, TLR2L-800, during real-time FGS.

Significance:
Human TLR2 is broadly expressed among pancreatic adenocarcinomas, and the highly specific TLR2L-800 fluorescence molecular imaging agent has potential for use in fluorescence-guided surgery to increase R0 margins and improve patient survival.
A Precision Engineered Interleukin-2 for Bolstering CD8+ T- and NK-cell Activity without Eosinophilia and Vascular Leak Syndrome in Nonhuman Primates
Authors: Ma Lina , Acuff Nicole V. , Joseph Ingrid B. , Ptacin Jerod L. , Caffaro Carolina E. , San Jose Kristine M. , Aerni Hans R. , Carrio Roberto , Byers Anthony M. , Herman Rob W. , Pavlova Yelena , Pena Michael J. , Chen David B. , Buetz Christen , Ismaili Taylor K. , Pham Helene V. , Cucchetti Margot , Sassoon Ingrid , Koriazova Lilia K. , Leveque Joseph A. , Shawver Laura K. , Mooney Jill M. , Milla Marcos E. 
Published: September 2024

Abstract

We have created a precisely pegylated IL-2 [SAR-444245 (SAR’245) or pegenzileukin, previously THOR-707] designed for proliferation of target CD8+ T and NK cells for anticancer activity, with minimal expansion of anti-target regulatory CD4+ T cells (Treg) that counter their action, or eosinophils that trigger vascular leak syndrome (VLS). We performed in vivo studies in nonhuman primates (NHP) to monitor the safety of SAR’245, pharmacokinetic profile, and pharmacodynamic parameters including expansion of peripheral CD8+ T and NK cells, and effects on Tregs and eosinophils. Studies included multiple ascending dosing and repeat dosing with different regimens (QW, Q2W, Q3W and Q4W). We also conducted ex vivo studies using human primary cells to further evaluate SAR’245 stimulation of target cells alone and in combination with programmed cell-death 1 (PD-1) checkpoint inhibitors. The pharmacokinetic profile of SAR’245 in NHP demonstrated dose-proportional exposure that was comparable with redosing. It elicited expansion of peripheral CD8+ T and NK cells that was comparable with each dose and with multiple dosing regimens. Once-weekly dosing showed no significant adverse effects, including no hallmark signs of VLS at dosing levels up to 1 mg/kg. Ex vivo, SAR’245 enhanced T-cell receptor responses alone and in combination with PD-1 inhibitors without inducing cytokines associated with cytokine release syndrome or VLS. Results support the clinical development of SAR’245 as a drug candidate for the treatment of solid tumors, alone or in combination with PD-1 inhibitory agents.

Significance:
SAR-444245 (SAR’245, pegenzileukin) is an extended half-life IL-2 that targets effector CD8+ T and NK cells, with little effect on regulatory T cells. We show that in the nonhuman primate model that closely approximates human immune function and response to IL-2, SAR’245 selectively activates CD8+ T and NK effectors without significant serious side effects (vascular leak syndrome or cytokine release syndrome), suggesting its potential for the treatment of solid tumors in humans.
Peripheral Blood IFN Responses to Toll-Like Receptor 1/2 Signaling Associate with Longer Survival in Men with Metastatic Prostate Cancer Treated with Sipuleucel-T
Authors: Brown Michael C. , D’Anniballe Vincent M. , Boczkowski David , Kandadi Harini , Sheikh Nadeem , Kornahrens William , Heath Elisabeth I. , Thakur Archana , Chen Wei , Lum Lawrence , Cackowski Frank C. , Boerner Julie , Gunn Michael D. , Armstrong Andrew J. , Nair Smita K. 
Published: September 2024

Abstract

Mounting evidence links systemic innate immunity with cancer immune surveillance. In advanced metastatic castration-resistant prostate cancer (mCRPC), Black patients have been found to have increased inflammatory markers and longer survival after sipuleucel-T (sip-T) therapy, an FDA-approved, autologous cell therapy. We hypothesized these differences may be explained by previously reported ancestral differences in pattern recognition receptor signaling, which broadly governs innate inflammation to control adaptive immune cell activation, chemotaxis, and functionality. We discovered that peripheral blood mononuclear cell IFN-β responses to Toll-like receptor 1/2 (TLR1/2), a sensor of bacterial and gut microbiome constituents, associated with significantly longer survival after sip-T therapy in two separate cohorts of men with mCRPC (discovery cohort: n = 106, HR = 0.12; P = 0.019; validation cohort: n = 28, HR &lt; 0.01; P = 0.047). Higher IFN-β induction after TLR1/2 stimulation was associated with lower HRs than biomarkers of vaccine potency and other prognostic factors in mCRPC. TLR1/2-dependent cytokine induction was stronger in Black individuals (1.2-fold higher for IFN-β; P = 0.04) but was associated with survival independently of race or numbers of vaccine-induced tumor antigen–specific T cells. IFN-β responses to TLR1/2 signaling correlated with increased numbers of IFN-γ producing T cells after broad, tumor antigen–independent stimulation. Thus, peripheral innate immunity differs by race, may predict survival after sip-T, and associates with peripheral T-cell functionality in men with mCRPC.

Significance:
The identification of factors that determine successful cancer immunotherapy, particularly in refractory tumor types like mCRPC, is urgently needed: both to identify patients that may benefit from such therapies and to uncover routes to sensitize patients with cancer to immunotherapy. Our work links functional peripheral immune responses with race and survival after cellular immunotherapy in men with mCRPC.
ENaCγ in Urinary Extracellular Vesicles as an Indicator of MR Signaling in Primary Aldosteronism
Authors: Hayama Yuto , Kuribayashi-Okuma Emiko , Fujii Norihiko , Ochiai-Homma Fumika , Yamazaki Osamu , Tsurutani Yuya , Nishikawa Tetsuo , Shibata Shigeru 
Published: September 2024

BACKGROUND:
Aldosterone and the MR (mineralocorticoid receptor) are important therapeutic targets for hypertension and cardiovascular diseases. However, biomarkers of tissue MR signaling are not fully established. Extracellular vesicles released from eukaryotic cells can provide information on tissue signaling. Using samples from patients with primary aldosteronism (PA), we explored the potential of urinary extracellular vesicles (uEVs) as a noninvasive indicator of MR signaling to guide treatment.

METHODS:
We analyzed proteins contained in PA uEVs by liquid chromatography tandem mass spectrometry. We narrowed down candidate biomarkers by referring to an existing database of urinary exosomes. The results were validated through Western blot analysis involving 63 patients with PA and 11 healthy volunteers.

RESULTS:

We identified a total of 1940 proteins in PA uEVs. Comparative analysis with the existing database narrowed down the pathways enriched in PA uEVs, which were related to diabetic complications, Rac1 signaling, and aldosterone-regulated sodium reabsorption. A closer look at the identified proteins revealed ENaCγ (epithelial Na
+
channel γ) peptides near the proteolytic cleavage sites, and Western blot analysis confirmed the predominant presence of cleaved ENaCγ, a marker of aldosterone signaling in renal tubules. In PA uEVs, cleaved ENaCγ showed a 4.8-fold increase compared with healthy volunteers and was significantly correlated with the aldosterone-to-renin ratio, aldosterone levels, and fractional excretion of K
+
. Targeted treatment in PA reduced the abundance of cleaved ENaCγ, suggesting a causal role for MR in its induction.

CONCLUSIONS:
This study provides a list of proteins contained in PA uEVs and suggests that ENaCγ in uEVs is a promising biomarker for renal MR signaling.
Characteristics of Young Women Presenting With Acute Myocardial Infarction: The Prospective, Multicenter, Observational Young Women Presenting Acute Myocardial Infarction in France Study
Authors: Manzo‐Silberman Stéphane , Couturaud Francis , Bellemain‐Appaix Anne , Vautrin Estelle , Gompel Anne , Drouet Ludovic , Marliere Stephanie , Sollier Claire Bal Dit , Uhry Sabrina , Eltchaninoff Hélène , Bergot Tessa , Motreff Pascal , Lahlou Najiba , Cottin Yves , Mounier‐Vehier Claire , Gilard Martine , Montalescot Gilles ,   for the WAMIF Investigators
Published: September 2024

Background
The percentage of women <50 years of age hospitalized with myocardial infarction is increasing. We describe the clinical, morphological, and biological characteristics, as well as the clinical outcomes of this population.

Methods and Results
This prospective, observational study included consecutive women <50 years of age admitted for myocardial infarction at 30 centers in France (May 2017–June 2019). The primary outcome was the composite of net adverse clinical events: all‐cause death, cardiovascular death, recurrent myocardial infarction, stent thrombosis, any stroke, or major bleeding occurring during hospitalization with a 12‐month follow up. Three hundred fourteen women were included. The mean age was 43.0 (±5.7) years, 60.8% presented with ST‐segment–elevation myocardial infarction, 75.5% were current smokers, 31.2% had a history of complicated pregnancy, and 55.1% reported recent emotional stress. Most (91.6%) women presented with typical chest pain. Of patients on an estrogen‐containing contraceptive, 86.0% had at least 1 contraindication. Of patients with ST‐segment–elevation myocardial infarction, 17.8% had myocardial infarction with nonobstructive coronary arteries and 14.6% had spontaneous coronary artery dissection, whereas 29.3% presented with multivessel vessel disease. During hospitalization, 11 net adverse clinical events occurred in 9 (2.8%) women, but no deaths or stent thromboses occurred. By 12 months, 14 net adverse clinical events occurred in 10 (3.2%) women; 2 (0.6%) died (from progressive cancer) and 25 (7.9%) had an ischemia‐driven repeat percutaneous coronary intervention.

Conclusions
Most young women with myocardial infarction reported typical chest pain and had modifiable cardiovascular risk factors. History of adverse pregnancy outcomes and prescription of combined oral contraceptive despite a contraindication were prevalent, emphasizing the need for comprehensive cardiological and gynecological evaluation and follow‐up.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03073447.