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"Mitchell, P"
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Fungal Biofilms
[...]Pneumocystis species do not produce hyphal structures as part of their biofilms [6]. [...]hyphal formation is not a uniform feature of fungal biofilms. Genetic Determinants of Fungal Biofilm Formation Transcription factors play fundamental roles in both positive and negative regulation of biofilm formation through regulation of hyphal formation and cell surface proteins responsible for adherence [1]. Cell wall proteins are of particular interest in biofilm formation. Besides its expected role in adherence, the cell wall may have a sensory role that promotes adherence-induced responses [23].
Journal Article
Disclosing information about the self is intrinsically rewarding
Humans devote 30–40% of speech output solely to informing others of their own subjective experiences. What drives this propensity for disclosure? Here, we test recent theories that individuals place high subjective value on opportunities to communicate their thoughts and feelings to others and that doing so engages neural and cognitive mechanisms associated with reward. Five studies provided support for this hypothesis. Self-disclosure was strongly associated with increased activation in brain regions that form the mesolimbic dopamine system, including the nucleus accumbens and ventral tegmental area. Moreover, individuals were willing to forgo money to disclose about the self. Two additional studies demonstrated that these effects stemmed from the independent value that individuals placed on self-referential thought and on simply sharing information with others. Together, these findings suggest that the human tendency to convey information about personal experience may arise from the intrinsic value associated with self-disclosure.
Journal Article
Inferences about mental states
Human social cognition relies on an ability to predict what others will think, feel or do in novel situations. Research in social neuroscience has consistently observed several brain regions that contribute ubiquitously to these abilities, including medial prefrontal cortex and aspects of lateral and medial parietal cortex. Interestingly, parallel work has suggested that this same network of regions subserves several seemingly distinct phenomena-notably, the abilities to remember the past, imagine the future and visualize spatial layouts-suggesting the existence of a common set of cognitive processes devoted to projecting oneself into worlds that differ mentally, temporally or physically from one's current experience. This use of self-projection to understand others' minds requires perceivers to solve three distinct cognitive challenges: (i) generating a simulated facsimile of one's own hypothetical mental states in a given situation, (ii) suppressing one's own current mental states, and (iii) deciding on the appropriateness of simulated states for understanding a particular other person. The present paper reviews recent psychology and neuroscience research aimed at understanding the underlying mechanisms that allow humans to solve each of these cognitive challenges to use self-projection to predict and understand the mental states of others.
Journal Article
High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy
Among many populations of blood cells, high dimensional analysis using mass cytometry reveals classical monocyte frequency as strong predictors of response to PD-1 blockade therapy of melanoma.
Immune-checkpoint blockade has revolutionized cancer therapy. In particular, inhibition of programmed cell death protein 1 (PD-1) has been found to be effective for the treatment of metastatic melanoma and other cancers. Despite a dramatic increase in progression-free survival, a large proportion of patients do not show durable responses. Therefore, predictive biomarkers of a clinical response are urgently needed. Here we used high-dimensional single-cell mass cytometry and a bioinformatics pipeline for the in-depth characterization of the immune cell subsets in the peripheral blood of patients with stage IV melanoma before and after 12 weeks of anti-PD-1 immunotherapy. During therapy, we observed a clear response to immunotherapy in the T cell compartment. However, before commencing therapy, a strong predictor of progression-free and overall survival in response to anti-PD-1 immunotherapy was the frequency of CD14
+
CD16
−
HLA-DR
hi
monocytes. We confirmed this by conventional flow cytometry in an independent, blinded validation cohort, and we propose that the frequency of monocytes in PBMCs may serve in clinical decision support.
Journal Article
Reinforcement amid genetic diversity in the Candida albicans biofilm regulatory network
Biofilms of the fungal pathogen
Candida albicans
include abundant long filaments called hyphae. These cells express hypha-associated genes, which specify diverse virulence functions including surface adhesins that ensure biofilm integrity. Biofilm formation, virulence, and hypha-associated gene expression all depend upon the transcription factor Efg1. This transcription factor has been characterized extensively in the
C
.
albicans
type strain SC5314 and derivatives, but only recently has its function been explored in other clinical isolates. Here we define a principal set of Efg1-responsive genes whose expression is significantly altered by an
efg1
Δ/Δ mutation across 17 clinical isolates. This principal gene set includes 68 direct Efg1 targets, whose 5’ regions are bound by Efg1 in five clinical isolates, and 42 indirect Efg1 targets, whose 5’ regions are not detectably bound by Efg1. Three direct Efg1 target genes encode transcription factors—
BRG1
,
UME6
, and
WOR3
–whose increased expression in an
efg1
Δ/Δ mutant restores expression of multiple indirect and direct principal targets, as well as biofilm formation ability. Although
BRG1
and
UME6
are well known positive regulators of hypha-associated genes and biofilm formation,
WOR3
is best known as an antagonist of Efg1 in the sexual mating pathway. We confirm the positive role of
WOR3
in biofilm formation with the finding that a
wor3
Δ/Δ mutation impairs biofilm formation in vitro and in an in vivo biofilm model. Positive control of Efg1 direct target genes by other Efg1 direct target genes–
BRG1
,
UME6
, and
WOR3
–may buffer principal Efg1-responsive gene expression against the impact of genetic variation in the
C
.
albicans
species.
Journal Article
Intuitive Prosociality
Prosocial behavior is a central feature of human life and a major focus of research across the natural and social sciences. Most theoretical models of prosociality share a common assumption: Humans are instinctively selfish, and prosocial behavior requires exerting reflective control over these basic instincts. However, findings from several scientific disciplines have recently contradicted this view. Rather than requiring control over instinctive selfishness, prosocial behavior appears to stem from processes that are intuitive, reflexive, and even automatic. These observations suggest that our understanding of prosociality should be revised to include the possibility that, in many cases, prosocial behavior—instead of requiring active control over our impulses—represents an impulse of its own.
Journal Article
Genetic control of Candida albicans biofilm development
Key Points
Biofilm formation by
Candida albicans
on implanted medical devices is a major source of infection.
Advances in expression profiling and genetic manipulation have provided insights into the mechanisms and regulatory pathways that govern
C. albicans
biofilm formation and biofilm-based drug resistance. Major regulatory genes and their targets have been connected to biofilm formation. Relevant targets include many cell surface proteins; some are adhesins, but many are still not understood mechanistically. Identifying the regulators has provided insight into the signals that control biofilm development, including nutrients, hyphae formation and quorum sensing molecules.
Increasingly, mechanistic studies have focused on diverse biofilms, including mucosal infection models,
in vivo
implanted-device models and mixed-species biofilms. One of the common themes to emerge is the requirement for hyphae formation and for the transcription factor biofilm and cell wall regulator 1 (Bcr1).
Biofilm induction assays have shown a unique biological function for non-mating white cells in creating cohesive biofilms that promote mating, and have uncovered a hybrid signal transduction pathway that mediates this behaviour.
Biofilms of most species are associated with epigenetic resistance to antimicrobials. Resistance of
C. albicans
biofilms is conferred by multiple mechanisms that include drug binding by extracellular matrix material and the production of persisters.
Finally, the cells released from a preformed biofilm have unique properties that favour invasive infection. The dispersed cells are yeast-form cells, and their production depends on several regulators of the yeast–hypha transition.
The formation of
Candida albicans
biofilms on implanted medical devices is a major source of infection. Here, Finkel and Mitchell review the latest insights into the mechanisms and regulatory pathways that govern
C. albicans
biofilm formation and biofilm-based drug resistance.
Candida
species cause frequent infections owing to their ability to form biofilms — surface-associated microbial communities — primarily on implanted medical devices. Increasingly, mechanistic studies have identified the gene products that participate directly in the development of
Candida albicans
biofilms, as well as the regulatory circuitry and networks that control their expression and activity. These studies have uncovered new mechanisms and signals that govern
C. albicans
biofilm development and associated drug resistance, thus providing biological insight and therapeutic foresight.
Journal Article
Estimating the annual attack rate of seasonal influenza among unvaccinated individuals: A systematic review and meta-analysis
Seasonal influenza affects millions of people globally each year, causing significant morbidity and mortality. However, there remains substantial uncertainty about the attack rate (incidence) of influenza, particularly in unvaccinated individuals.
We undertook a systematic review of vaccine randomised controlled trials (RCTs) that reported on laboratory-confirmed seasonal influenza in the placebo arm. We calculated the influenza attack rate from included studies as the number of laboratory-confirmed positive seasonal influenza cases in the placebo arm divided by the total number of subjects in this arm. A random effects meta-analysis was conducted to estimate the influenza attack rate among unvaccinated individuals (both symptomatic only as well as symptomatic and asymptomatic combined).
We included 32 RCTs that had a total of 13,329 participants. The pooled estimates for symptomatic influenza were 12.7% (95%CI 8.5%, 18.6%) for children (<18 years), 4.4% (95%CI 3.0%, 6.3%) for adults, and 7.2% (95%CI 4.3%, 12.0%) for older people (65 years and above). The pooled estimates for symptomatic and asymptomatic influenza combined for all influenza were 22.5% (95%CI 9.0%, 46.0%) for children and 10.7% (95%CI 4.5%, 23.2%) for adults. Only one study was identified for symptomatic and asymptomatic combined in older people which had a rate of 8.8% (95%CI 7.0%, 10.8%). There was substantial heterogeneity between studies.
Overall, we found that approximately 1 in 5 unvaccinated children and 1 in 10 unvaccinated adults were estimated to be infected by seasonal influenza annually, with rates of symptomatic influenza roughly half of these estimates. Our findings help to establish the background risk of seasonal influenza infection in unvaccinated individuals.
Journal Article