Fungal pathogens overcome antifungal drug therapy by classic resistance mechanisms, such as increased efflux or changes to the drug target. However, even when a fungal strain is susceptible, trailing ...or persistent microbial growth in the presence of an antifungal drug can contribute to therapeutic failure. This trailing growth is caused by adaptive physiological changes that enable the growth of a subpopulation of fungal cells in high drug concentrations, in what is described as drug tolerance. Mechanistically, antifungal drug tolerance is incompletely understood. Here we report that the transcriptional activator Rpn4 is important for drug tolerance in the human fungal pathogen Candida albicans. Deletion of RPN4 eliminates tolerance to the commonly used antifungal drug fluconazole. We defined the mechanism and show that Rpn4 controls fluconazole tolerance via two target pathways. First, Rpn4 activates proteasome gene expression, which enables sufficient proteasome capacity to overcome fluconazole-induced proteotoxicity and the accumulation of ubiquitinated proteins targeted for degradation. Consistently, inhibition of the proteasome with MG132 eliminates fluconazole tolerance and resistance, and phenocopies the rpn4Δ/Δ mutant for loss of tolerance. Second, Rpn4 is required for wild type expression of the genes required for the synthesis of the membrane lipid ergosterol. Our data indicates that this function of Rpn4 is required for mitigating the inhibition of ergosterol biosynthesis by fluconazole. Based on our findings, we propose that Rpn4 is a central hub for fluconazole tolerance in C. albicans by coupling the regulation of protein homeostasis (proteostasis) and lipid metabolism to overcome drug-induced proteotoxicity and membrane stress.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Inactivating mutations of the Ten-Eleven Translocation 2 (TET2) gene were first identified in myeloid malignancies and more recently in peripheral T-cell lymphomas (PTCLs). In the present study, we ...investigated the presence of TET2 coding sequence mutations and their clinical relevance in a large cohort of 190 PTCL patients. TET2 mutations were identified in 40 of 86 (47%) cases of angioimmunoblastic T-cell lymphoma (AITL) and in 22 of 58 (38%) cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), but were absent in all other PTCL entities, with the exception of 2 of 10 cases of enteropathy-associated T-cell lymphoma. Among PTCL-NOS, a heterogeneous group of lymphoma-comprising cases likely to derive from Th follicular (TFH) cells similarly to AITL, TET2 mutations were more frequent when PTCL-NOS expressed TFH markers and/or had features reminiscent of AITL (58% vs 24%, P = .01). In the AITL and PTCL-NOS subgroups, TET2 mutations were associated with advanced-stage disease, thrombocytopenia, high International Prognostic Index scores, and a shorter progression-free survival.
Background
The number of displaced midshaft clavicle fractures treated surgically is increasing and plate fixation is often the treatment modality of choice. The study quality and scientific levels ...of evidence at which possible complications of this treatment are presented vary greatly in literature.
Purposes
The purpose of this systematic review is to assess the prevalence of complications concerning plate fixation of dislocated midshaft clavicle fractures.
Methods
A computer-based search was carried out using EMBASE and PUBMED/MEDLINE. Studies included for review reported complications after plate fixation alone or in comparison to either treatment with intramedullary pin fixation and/or nonoperative treatment. Two quality assessment tools were used to assess the methodological quality of the studies. Included studies were ranked according to their levels of evidence.
Results
After study selection and reading of the full texts, 11 studies were eligible for final quality assessment. Nonunion and malunion rates were less than 10% in all analysed studies but one. The vast majority of complications seem to be implant related, with irritation or failure of the plate being consistently reported on in almost every study, on average ranging from 9 to 64%.
Conclusion
The quantity of relevant high evidence studies is low. With low nonunion and malunion rates, plate fixation can be a safe treatment option for acute dislocated midshaft clavicle fractures, but complications related to the implant material requiring a second operation are frequent. Future prospective trials are needed to analyse the influence of various plate types and plate position on implant-related complications.
PlasticSurgery Branford, Olivier A; Kamali, Parisa; Rohrich, Rod J ...
Plastic and reconstructive surgery (1963),
2016-December, 2016-Dec, 2016-12-00, 20161201, Letnik:
138, Številka:
6
Journal Article
Recenzirano
BACKGROUND:Social media use is growing inexorably, and there is public appetite for evidence-based information. Little is known about engagement by plastic surgeons with social media. The aim of this ...study was to examine posting about plastic surgery on Twitter, to best inform how board-certified plastic surgeons could use the hashtag #PlasticSurgery as a tool to educate patients and the public.
METHODS:A prospective analysis of 2880 “tweets” containing the words “plastic surgery” was performed. The following were assessedidentity of author, use of the hashtag #PlasticSurgery, subject matter, whether link to study was provided, and whether posts by surgeons were self-promotional or educational.
RESULTS:Social media posting about plastic surgery is dominated by the public, accounting for 70.6 percent of posts versus only 6.0 percent by plastic surgeons. Only 5.4 percent of all tweets contained the hashtag #PlasticSurgery, although almost half of those that did were by plastic surgeons. Of these, 61.3 percent of posts by plastic surgeons were about aesthetic surgery; additional posts were about basic science, patient safety, and reconstruction (13.9, 4.0, and 2.3 percent, respectively). Eighteen scientific articles were referenced, with a link to the Journal site posted in two tweets. Of posts by plastic surgeons, 37.0 percent were self-promotional.
CONCLUSIONS:The American Society of Plastic Surgeons and its Journal have recognized that social media may be used to educate and engage. Board-certified plastic surgeons have a great opportunity to promote evidence-based plastic practice by means of #PlasticSurgery in the interests of supporting patients and the profession.
Ever since the first observation of all-optical switching of magnetization in the ferrimagnetic alloy GdFeCo using femtosecond laser pulses, there has been significant interest in exploiting this ...process for data-recording applications. In particular, the ultrafast speed of the magnetic reversal can enable the writing speeds associated with magnetic memory devices to be potentially pushed towards THz frequencies. This work reports the development of perpendicular magnetic tunnel junctions incorporating a stack of Tb/Co nanolayers whose magnetization can be all-optically controlled via helicity-independent single-shot switching. Toggling of the magnetization of the Tb/Co electrode was achieved using either 60 femtosecond-long or 5 picosecond-long laser pulses, with incident fluences down to 3.5 mJ/cm
, for Co-rich compositions of the stack either in isolation or coupled to a CoFeB-electrode/MgO-barrier tunnel-junction stack. Successful switching of the CoFeB-Tb/Co electrodes was obtained even after annealing at 250
C. After integration of the Tb/Co-based electrodes within perpendicular magnetic tunnel junctions yielded a maximum tunneling magnetoresistance signal of 41% and RxA value of 150 Ωμm
with current-in-plane measurements and ratios between 28% and 38% in nanopatterned pillars. These results represent a breakthrough for the development of perpendicular magnetic tunnel junctions controllable using single laser pulses, and offer a technologically-viable path towards the realization of hybrid spintronic-photonic systems featuring THz switching speeds.
The use of synthetic pesticides and repellents to target pests of veterinary and medical significance is becoming increasingly problematic. One alternative approach employs the bioactive attributes ...of plant-derived products (PDPs). These are particularly attractive on the grounds of low mammalian toxicity, short environmental persistence and complex chemistries that should limit development of pest resistance against them.Several pesticides and repellents based on PDPs are already available, and in some cases widely utilised, in modern pest management. Many more have a long history of traditional use in poorer areas of the globe where access to synthetic pesticides is often limited. Preliminary studies support that PDPs could be more widely used to target numerous medical and veterinary pests, with modes of action often specific to invertebrates.Though their current and future potential appears significant, development and deployment of PDPs to target veterinary and medical pests is not without issue. Variable efficacy is widely recognised as a restraint to PDPs for pest control. Identifying and developing natural bioactive PDP components in place of chemically less-stable raw or 'whole’ products seems to be the most popular solution to this problem. A limited residual activity, often due to photosensitivity or high volatility, is a further drawback in some cases (though potentially advantageous in others). Nevertheless, encapsulation technologies and other slow-release mechanisms offer strong potential to improve residual activity where needed.The current review provides a summary of existing use and future potential of PDPs against ectoparasites of veterinary and medical significance. Four main types of PDP are considered (pyrethrum, neem, essential oils and plant extracts) for their pesticidal, growth regulating and repellent or deterrent properties. An overview of existing use and research for each is provided, with direction to more extensive reviews given in many sections. Sections to highlight potential issues, modes of action and emerging and future potential are also included.
Appropriate cancer care requires a thorough understanding of the natural history of the disease, including the cell of origin, the pattern of clonal evolution, and the functional consequences of the ...mutations. Using deep sequencing of flow-sorted cell populations from patients with chronic lymphocytic leukemia (CLL), we established the presence of acquired mutations in multipotent hematopoietic progenitors. Mutations affected known lymphoid oncogenes, including BRAF, NOTCH1, and SF3B1. NFKBIE and EGR2 mutations were observed at unexpectedly high frequencies, 10.7% and 8.3% of 168 advanced-stage patients, respectively. EGR2 mutations were associated with a shorter time to treatment and poor overall survival. Analyses of BRAF and EGR2 mutations suggest that they result in deregulation of B-cell receptor (BCR) intracellular signaling. Our data propose disruption of hematopoietic and early B-cell differentiation through the deregulation of pre-BCR signaling as a phenotypic outcome of CLL mutations and show that CLL develops from a pre-leukemic phase.
The origin and pathogenic mechanisms of CLL are not fully understood. The current work indicates that CLL develops from pre-leukemic multipotent hematopoietic progenitors carrying somatic mutations. It advocates for abnormalities in early B-cell differentiation as a phenotypic convergence of the diverse acquired mutations observed in CLL.
What happens when the upward in‐cloud (IC) breakdown transitions into horizontally expanding extension? Optical observations of this transition in IC lightning have not previously been reported. We ...identify the radio and optical signatures of this transition in low‐frequency (LF) magnetic, very high frequency interferometric and space‐borne optical measurements. For initial IC development in stratiform clouds, the ratio of 337/777.4 nm radiance is above unity prior to the transition but is almost always below unity after the transition. In particular, the 337 nm radiance drops significantly while the 777.4 nm radiance remains almost invariant after the transition, suggesting when the dominant illumination process of IC leaders changes from cold streamer discharges to a likely stepped leader. Furthermore, this transition in the LF and optical measurements resembles the reported changes in the cloud‐to‐ground measurements from initial leader to stepped leader, indicating that the initial leader may be physically different from the stepped leader.
Plain Language Summary
The development of negative leaders within clouds remains intriguing and merits optical observation imperatively. Here, we report the optical observations of initial in‐cloud (IC) leaders from a top view by a space‐borne Atmosphere‐Space Interactions Monitor on the International Space Station. After analyzing the dynamics of some upward IC flashes from very high frequency interferometry, we identify a clear transition in the initial development of IC leaders from upward propagation to sideways extension. We show that this transition also has repeatable signatures in the LF power density (1–300 kHz bandwidth) and optical waveforms. In our cases, the transition starts when the 337 (blue)/777.4 nm (red) brightness ratio drops significantly. The 337 nm radiance dominates the optical emissions prior to the transition but pronouncedly declines after the transition compared with the 777.4 nm radiance. The weakening of 337 nm radiance during the transition indicates a change in the dominant illumination processes of initial IC development. In addition, a similar variation identified from the observations of the initial IC and cloud‐to‐ground leaders suggests a connection between our transition and the reported transition from initial leader to stepped leader.
Key Points
Optical, very high frequency, and low‐frequency observations are combined to analyze the transition from upward to horizontal propagation of initial in‐cloud lightning
A drop in the optical blue‐to‐red ratio indicates when the dominant illumination process changes from streamers to likely stepped leader
We find for in‐cloud lightning that the upward initial leader and the horizontal stepped leader could be physically different
Bacteria belonging to the genus
Rickettsia
are known as causative agents of vector-borne zoonotic diseases, such as spotted fevers, epidemic typhus and endemic typhus. Different species of ticks, ...mites and fleas could act as reservoirs and arthropod vectors of different pathogenic
Rickettsia
species. The aim of this work was to establish active surveillance of
Rickettsia
spp. in mites, ticks and fleas collected from small mammals (rodents and shrews) in Eastern Slovakia. A total of 964 animal ear biopsies, 871 mites, 667 ticks and 743 fleas were collected from small mammals in the Košice region, Eastern Slovakia. All specimens were identified using specialized taxonomic keys, and were conserved in ethanol until DNA extraction was performed. After DNA extraction, identification of
Rickettsia
species was performed by PCR-based methods. The total prevalence of rickettsiae from ear biopsies was 4.6% (95% CI, 3.2–5.9), in tested mites 9.3% (95% CI, 7.4–11.2), 17.2% (95% CI, 14.3–20.1) in
I. ricinus
ticks and 3.5% (95% CI, 2.2–4.8) in fleas. Sequence analysis of the partial
gltA
gene and
Rickettsia helvetica
-,
Rickettsia slovaca
-,
Rickettsia raoultii
- species specific real-time PCR tests revealed the presence of
R. helvetica
,
R. slovaca
, unidentified
Rickettsia
and rickettsial endosymbionts. These pathogenic and symbiotic species were confirmed in the following ectoparasite species—
Laelaps jettmari
,
Haemogamasus nidi
,
Laelaps agilis
and
Eulaelaps stabularis
mites,
Ixodes ricinus
ticks,
Ctenophthalmus solutus
,
C. assimilis
and
Megabothris turbidus
fleas infesting host—
Apodemus agrarius
,
A. flavicollis
,
Microtus arvalis
and
Myodes glareolus
small mammals. These results confirm the circulation of
R. helvetica
,
R. slovaca
, unidentified
Rickettsia
and rickettsial endosymbionts in mites, ticks and fleas collected on small mammals in the Košice region, Eastern Slovakia.
The Psychometric Hepatic Encephalopathy Score (PHES) has previously been standardized in thirteen countries on three continents, confirming its status of gold standard test to detect minimal hepatic ...encephalopathy (MHE). In the meantime, performance has also been shown to vary with variables such as age, education, and barely sex. The present study aimed at standardizing the PHES in a French population. One hundred and ninety-six French healthy participants completed a French version of the paper-and-pencil PHES, involving five tests and six measures. Importantly, the balance was perfect between all levels of the three controlled factors, which were sex, age (seven decade-levels from 20–29 to 80–89 years), and education (two levels below or above 12 years of education). Raw measures were transformed to fit the normal distribution. ANOVAs on transformed variables showed no effect of sex, but an effect of age on all measures, and of education on five measures. Multiple or simple regressions were completed to build up normograms. Thorough analysis of variability within each test failed to find outliers that may bias the results. Comparison between French and seminal German data showed that they highly fitted though cultural and cognitive style specificities could be observed. This is the first study to standardize the PHES in a French population and to extensively explore the effects of sex, age and education using perfectly balanced samples. Subtle differences between countries of the same continent emphasize the need to build up normative data in each country to get accurate PHES in patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
