is a Gram-negative pathogen that has a large accessory genome of plasmids and chromosomal gene loci. This accessory genome divides
strains into opportunistic, hypervirulent, and multidrug-resistant ...groups and separates
from two closely related species,
and
. Some strains of
act as opportunistic pathogens, infecting critically ill and immunocompromised patients. These
are a common cause of health-care associated infections including pneumonia, urinary tract infections (UTIs), and bloodstream infections.
and
are often clinically indistinguishable from opportunistic
. Other strains of
are hypervirulent, infecting healthy people in community settings and causing severe infections including pyogenic liver abscess, endophthalmitis, and meningitis. A third group of
encode carbapenemases, making them highly antibiotic-resistant. These strains act as opportunists but are exceedingly difficult to treat. All of these groups of
and related species can colonize the gastrointestinal tract, and the accessory genome may determine if a colonizing strain remains asymptomatic or progresses to cause disease. This review will explore the associations between colonization and infection with opportunistic, antibiotic-resistant, and hypervirulent
strains and the role of the accessory genome in distinguishing these groups and related species. As
infections become progressively more difficult to treat in the face of antibiotic resistance and hypervirulent strains, an increased understanding of the epidemiology and pathogenesis of these bacteria is vital.
The changing epidemiology of SARS-CoV-2 Koelle, Katia; Martin, Michael A; Antia, Rustom ...
Science (American Association for the Advancement of Science),
03/2022, Volume:
375, Issue:
6585
Journal Article
Peer reviewed
Open access
We have come a long way since the start of the COVID-19 pandemic-from hoarding toilet paper and wiping down groceries to sending our children back to school and vaccinating billions. Over this ...period, the global community of epidemiologists and evolutionary biologists has also come a long way in understanding the complex and changing dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19. In this Review, we retrace our steps through the questions that this community faced as the pandemic unfolded. We focus on the key roles that mathematical modeling and quantitative analyses of empirical data have played in allowing us to address these questions and ultimately to better understand and control the pandemic.
We describe a case of chronic coronavirus disease 2019 (COVID-19) in a patient with lymphoma and associated B-cell immunodeficiency. Viral cultures and sequence analysis demonstrate ongoing ...replication of infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for at least 119 days. The patient had 3 admissions related to COVID-19 over a 4-month period and was treated twice with remdesivir and convalescent plasma with resolution of symptoms. The patient's lack of seroconversion and prolonged course illustrate the importance of humoral immunity in resolving SARS-CoV-2 infection. This case highlights challenges in managing immunocompromised hosts, who may act as persistent shedders and sources of transmission.
Insights from SARS-CoV-2 sequences Martin, Michael A; VanInsberghe, David; Koelle, Katia
Science (American Association for the Advancement of Science),
01/2021, Volume:
371, Issue:
6528
Journal Article
Peer reviewed
Open access
Analysis of viral sequences can tell us how SARS-CoV-2 spreads and adapts
As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread across the globe, so have efforts to sequence its ...RNA genome. More than 260,000 sequences are now available in public databases, about a year after the viral genome was first sequenced (
1
). These sequences and their associated metadata have allowed researchers to estimate the timing of SARS-CoV-2 spillover into humans, characterize the spread of the virus, and gauge virus adaptation to its new host. Such analyses rely on interpreting patterns of nucleotide changes that have occurred in the virus population over time and are brought into focus through the reconstruction of genealogical relationships between sampled viruses that are depicted in phylogenetic trees.
The amygdala plays key roles in fear and anxiety. Studies of the amygdala have largely focused on neuronal function and connectivity. Astrocytes functionally interact with neurons, but their role in ...the amygdala remains largely unknown. We show that astrocytes in the medial subdivision of the central amygdala (CeM) determine the synaptic and behavioral outputs of amygdala circuits. To investigate the role of astrocytes in amygdala-related behavior and identify the underlying synaptic mechanisms, we used exogenous or endogenous signaling to selectively activate CeM astrocytes. Astrocytes depressed excitatory synapses from basolateral amygdala via A
adenosine receptor activation and enhanced inhibitory synapses from the lateral subdivision of the central amygdala via A
receptor activation. Furthermore, astrocytic activation decreased the firing rate of CeM neurons and reduced fear expression in a fear-conditioning paradigm. Therefore, we conclude that astrocyte activity determines fear responses by selectively regulating specific synapses, which indicates that animal behavior results from the coordinated activity of neurons and astrocytes.
A reanalysis of SARS-CoV-2 deep sequencing data from donor-recipient pairs indicates that transmission bottlenecks are very narrow (one to three virions).
The purpose of this study was to evaluate the extent of constitutive activity among orphan class-A G protein coupled receptors within the cAMP signaling pathway. Constitutive signaling was revealed ...by changes in gene expression under control of the cAMP response element. Gene expression was measured in Chinese hamster ovary cells transiently co-transfected with plasmids containing a luciferase reporter and orphan receptor. Criteria adopted for defining constitutive activation were: 1) 200% elevation over baseline reporter gene expression; 2) 40% inhibition of baseline expression; and 3) 40% inhibition of expression stimulated by 3 μM forskolin. Five patterns of activity were noted: 1) inhibition under both baseline and forskolin stimulated expression (GPR15, GPR17, GPR18, GPR20, GPR25, GPR27, GPR31, GPR32, GPR45, GPR57, GPR68, GPR83, GPR84, GPR132, GPR150, GPR176); 2) no effect on baseline expression, but inhibition of forskolin stimulated expression (GPR4, GPR26, GPR61, GPR62, GPR78, GPR101, GPR119); 3) elevation of baseline signaling coupled with inhibition of forskolin stimulated expression (GPR6, GPR12); 4) elevation of baseline signaling without inhibition of forskolin stimulated expression (GPR3, GPR21, GPR52, GPR65); and 5) no effect on expression (GPR1, GPR19, GPR22, GPR34, GPR35, GPR39, GPR63, GPR82, GPR85, GPR87). Constitutive activity was observed in 75% of the orphan class-A receptors examined (30 of 40). This constitutive signaling cannot be explained by simple overexpression of the receptor. Inhibition of cAMP mediated expression was far more common (65%) than stimulation of expression (15%). Orphan receptors that were closely related based on amino acid homology tended to have similar effects on gene expression. These results suggest that identification of inverse agonists may be a fruitful approach for categorizing these orphan receptors and targeting them for pharmacological intervention.
Complete metastatic ablation of oligometastatic prostate cancer may provide an alternative to early initiation of androgen deprivation therapy (ADT).
To determine if stereotactic ablative ...radiotherapy (SABR) improves oncologic outcomes in men with oligometastatic prostate cancer.
The Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer (ORIOLE) phase 2 randomized study accrued participants from 3 US radiation treatment facilities affiliated with a university hospital from May 2016 to March 2018 with a data cutoff date of May 20, 2019, for analysis. Of 80 men screened, 54 men with recurrent hormone-sensitive prostate cancer and 1 to 3 metastases detectable by conventional imaging who had not received ADT within 6 months of enrollment or 3 or more years total were randomized.
Patients were randomized in a 2:1 ratio to receive SABR or observation.
The primary outcome was progression at 6 months by prostate-specific antigen level increase, progression detected by conventional imaging, symptomatic progression, ADT initiation for any reason, or death. Predefined secondary outcomes were toxic effects of SABR, local control at 6 months with SABR, progression-free survival, Brief Pain Inventory (Short Form)-measured quality of life, and concordance between conventional imaging and prostate-specific membrane antigen (PSMA)-targeted positron emission tomography in the identification of metastatic disease.
In the 54 men randomized, the median (range) age was 68 (61-70) years for patients allocated to SABR and 68 (64-76) years for those allocated to observation. Progression at 6 months occurred in 7 of 36 patients (19%) receiving SABR and 11 of 18 patients (61%) undergoing observation (P = .005). Treatment with SABR improved median progression-free survival (not reached vs 5.8 months; hazard ratio, 0.30; 95% CI, 0.11-0.81; P = .002). Total consolidation of PSMA radiotracer-avid disease decreased the risk of new lesions at 6 months (16% vs 63%; P = .006). No toxic effects of grade 3 or greater were observed. T-cell receptor sequencing identified significant increased clonotypic expansion following SABR and correlation between baseline clonality and progression with SABR only (0.082085 vs 0.026051; P = .03).
Treatment with SABR for oligometastatic prostate cancer improved outcomes and was enhanced by total consolidation of disease identified by PSMA-targeted positron emission tomography. SABR induced a systemic immune response, and baseline immune phenotype and tumor mutation status may predict the benefit from SABR. These results underline the importance of prospective randomized investigation of the oligometastatic state with integrated imaging and biological correlates.
ClinicalTrials.gov Identifier: NCT02680587.
CP and discrete flavour symmetries Holthausen, Martin; Lindner, Manfred; Schmidt, Michael A.
The journal of high energy physics,
04/2013, Volume:
2013, Issue:
4
Journal Article
Peer reviewed
Open access
A
bstract
We give a consistent definition of generalised CP transformations in the context of discrete flavour symmetries. Non-trivial consistency conditions imply that every generalised CP ...transformation can be interpreted as a representation of an automorphism of the discrete group. This allows us to give consistent generalised CP transformations of popular flavour groups. We are able to clear up issues concerning recent claims about geometrical CP violation in models based on
T
′
, clarify the origin of ”calculable phases” in Δ(27) and explain why apparently CP violating scalar potentials of
A
4
result in a CP conserving ground state.
PDF
