Type 3 Secretion System (T3SS) is a highly conserved virulence structure that plays an essential role in the pathogenesis of many Gram-negative pathogenic bacteria, including Pseudomonas aeruginosa. ...Exotoxin T (ExoT) is the only T3SS effector protein that is expressed in all T3SS-expressing P. aeruginosa strains. Here we show that T3SS recognition leads to a rapid phosphorylation cascade involving Abl / PKCδ / NLRC4, which results in NLRC4 inflammasome activation, culminating in inflammatory responses that limit P. aeruginosa infection in wounds. We further show that ExoT functions as the main anti-inflammatory agent for P. aeruginosa in that it blocks the phosphorylation cascade through Abl / PKCδ / NLRC4 by targeting CrkII, which we further demonstrate to be important for Abl transactivation and NLRC4 inflammasome activation in response to T3SS and P. aeruginosa infection.
Objectives
The emergency medicine (EM) physician workforce is largely composed of white men. Despite recruitment efforts over the past decade, there has not been a significant increase of trainees ...with underrepresented racial and ethnic identities in EM (URM). Prior studies have focused on institutional strategies to improve diversity, equity, and inclusion (DEI) in EM residency recruitment but have been limited in describing URM trainees’ perspectives. We sought to assess URM trainees’ perspectives on DEI in the EM residency application and selection process.
Methods
This study was conducted at an urban academic medical center in the United States from November 2021 to March 2022. Junior residents were invited to participate in individual semistructured interviews. We used a combined deductive–inductive approach to categorize responses in predetermined areas of interest then elicit dominant themes within each category through consensus discussions. Thematic saturation was reached after eight interviews, indicating adequate sample size.
Results
Ten residents participated in semistructured interviews. All identified as racial or ethnic minorities. Three dominant themes emerged relating to authenticity, representation, and being treated as a learner first. Participants assessed the authenticity of a program's DEI efforts by evaluating the time frame and scope of DEI efforts. Participants reported a desire for representation of other URM colleagues in a residency program and training environment. While participants wanted their lived experience as URM trainees acknowledged, they were wary of being viewed solely through the lens of future DEI leaders rather than as learners first.
Conclusions
URM residents value multifaceted commitment to DEI efforts, representation, and being seen as learners first when assessing residency programs. Programs seeking to recruit URM residents should develop a department‐wide, multipronged, comprehensive DEI plan and showcase how their program will contribute to an applicant's professional development.
is a leading cause of infection in the United States, and due to the rapid development of resistance, new antibiotics are constantly needed.
-Translation is a particularly promising antibiotic target ...because it is conserved in many bacterial species, is critical for bacterial survival, and is unique among prokaryotes. We have investigated the potential of KKL-40, a small-molecule inhibitor of
-translation, and find that it inhibits both methicillin-susceptible and methicillin-resistant strains of
KKL-40 is also effective against Gram-positive pathogens, including a vancomycin-resistant strain of
,
, and
, although its performance with Gram-negative pathogens is mixed. KKL-40 synergistically interacts with the human antimicrobial peptide LL-37, a member of the cathelicidin family, to inhibit
but not other antibiotics tested, including daptomycin, kanamycin, or erythromycin. KKL-40 is not cytotoxic to HeLa cells at concentrations that are 100-fold higher than the effective MIC. We also find that
develops minimal resistance to KKL-40 even after multiday passage at sublethal concentrations. Therefore,
-translation inhibitors could be a particularly promising drug target against
, not only because of their ability to inhibit bacterial growth but also because of their potential to simultaneously render
more susceptible to host antimicrobial peptides.
The spiroindimicins are a unique class of chlorinated indole alkaloids characterized by three heteroaromatic rings structured around a congested spirocyclic stereocenter. Here, we report the first ...total synthesis of (+)-spiroindimicin A, which bears a challenging C-3′/C-5′′-linked spiroindolenine. We detail our initial efforts to effect a biomimetic oxidative spirocyclization from its proposed natural precursor, lynamicin D, and describe how these studies shaped our final abiotic 9-step solution to this complex alkaloid built around a key Pd-catalyzed asymmetric spirocyclization. Scalable access to spiroindimicins A, H, and their congeners has enabled discovery of their activity against several parasites relevant to human health, providing potential starting points for new therapeutics for the neglected tropical diseases leishmaniasis and African sleeping sickness.
Spiroindimicins A and H have been synthesized for the first time
via
a key palladium-catalyzed spirocyclization. Access to these alkaloids and several congeners has allowed the discovery of their antiparasitic properties.
Spontaneous intestinal perforations in the neonatal population are mostly associated with low birth weight, prematurity, and necrotizing enterocolitis. Spontaneous intestinal perforation in the ...absence of these risk factors is extremely rare and should raise clinical concern for an underlying bowel pathology. Here we present a unique case of a normal-weight, full-term girl with spontaneous intestinal perforation due to a spindle cell neoplasm with a novel
BRAF
mutation and infantile fibrosarcoma-like morphology. Though rare, malignancy should be considered in the differential diagnosis for bowel perforation in an otherwise healthy, term infant as complete surgical excision can be curative.
Compliance to step count and vegetable serve recommendations mediates weight gain prevention in mid-age, premenopausal women. Findings of the 40-Something RCT Hollis, Jenna L; Lauren T. WilliamsauthorNutrition and Dietetics, School of Health Sciences, Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW 2308, AustraliaPriority Research Centre in Physical Activity and Nutrition, The University of Newcastle, Callaghan, NSW 2308, AustraliaNutrition and Dietetics, School of Allied Health Sciences, Griffith University, Southport, QLD 4215, Australia; Myles D. YoungauthorPriority Research Centre in Physical Activity and Nutrition, The University of Newcastle, Callaghan, NSW 2308, AustraliaSchool of Education, Faculty of Education and Arts, The University of Newcastle, Callaghan, NSW 2308, Australia ...
2015
Journal Article
A taste of ethical consumption at a slow food festival Williams, Lauren T; John GermovauthorFaculty of Education and Arts, The University of Newcastle, Callaghan, NSW 2308, Australia; Sascha FullerauthorFaculty of Education and Arts, The University of Newcastle, Callaghan, NSW 2308, Australia ...
2015
Journal Article
Climatic warming following the Last Glacial Maximum caused the southern Laurentide Ice Sheet (LIS) to begin ∼2,000‐year cycles of retreat and readvance whose cause remains ambiguous. By developing a ...marine‐calibrated chronology of southern LIS position, we counterintuitively demonstrate that between 17.6 and 11.3 ka, ice advanced during times of northern‐hemisphere warming and retreated during times of northern‐hemisphere cooling. Here we propose a cyclical feedback: Meltwater from ice retreat cooled the northern hemisphere by weakening the Atlantic Meridional Overturning Circulation (AMOC). This eventually lead to ice‐sheet readvance, which reduced and rerouted meltwater discharge, and thereby allowed the AMOC to strengthen and the northern hemisphere to warm. Our data suggest that this antiphased ice–climate interaction, paced by ice‐sheet response time, was initiated by synchronous warming and ice retreat ∼18.7–17.6 ka (corresponding to the Erie “Interstade”) and reached its apex during the Younger Dryas.
Plain Language Summary
Twenty thousand years ago, a colder climate allowed glacial ice to flow from northern and eastern Canada into the Great Lakes region. But when climate began to warm, instead of simply melting from south to north, the margin of this ice front repeatedly retreated and re‐advanced in 2,000‐year cycles. First, we track these advances and retreats using records of ancient Gulf of Mexico water, stored in plankton shells retrieved from a sediment cores. Ice advance redirected water bearing “light” oxygen, with fewer neutrons, from Canada and the Great Lakes into the Mississippi River. When ice retreated, these waters found other courses to the sea, shifting Gulf of Mexico chemistry toward heavier oxygen (carrying more neutrons). Next, we ask why these ice‐margin cycles occurred during a time of monotonically increasing solar radiation to the northern hemisphere. We propose that ice‐sheet melt (during retreat) slowed Atlantic Ocean circulation, causing the northern hemisphere to cool and the ice sheet to gradually regrow. However, this same regrowth reduced meltwater flow to the ocean, causing the northern hemisphere to re‐warm and eventually leading the ice margin to retreat once more. This cycle persisted from approximately 17,600 to 11,300 years ago, until North American ice became too small to sustain this feedback.
Key Points
δ18O records from the Gulf of Mexico refine the chronology of Laurentide Ice Sheet advance and retreat through the Great Lakes
Counterintuitively, from 17.6 to 11.3 ka, ice advanced during times of warming and retreated during times of cooling
A feedback between meltwater, Atlantic Meridional Overturning Circulation strength, and temperature—paced by ice‐sheet response time—may have set this anticorrelation
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