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Sonstige beteiligte Institutionen
- Department of Hematology and Oncology, Sana Hospital Hof, Hof, Germany (1)
- Department of Laboratory Medicine and Medicine Huddinge, Karolinska Institutet and University Hospital, Stockholm, Sweden (1)
- Department of Medicine A, University Hospital of Münster, Münster, Germany (1)
- IZKF Nachwuchsgruppe Geweberegeneration für muskuloskelettale Erkrankungen (1)
- Interdisciplinary Center for Clinical Research (1)
- Johns Hopkins School of Medicine (1)
- University of Bari Medical School, Bari, Italy (1)
The heterotrimeric protein kinase SNF1 plays a key role in the metabolic adaptation of the pathogenic yeast Candida albicans. It consists of the essential catalytic α-subunit Snf1, the γ-subunit Snf4, and one of the two β-subunits Kis1 and Kis2. Snf4 is required to release the N-terminal catalytic domain of Snf1 from autoinhibition by the C-terminal regulatory domain, and snf4Δ mutants cannot grow on carbon sources other than glucose. In a screen for suppressor mutations that restore growth of a snf4Δ mutant on alternative carbon sources, we isolated a mutant in which six amino acids between the N-terminal kinase domain and the C-terminal regulatory domain of Snf1 were deleted. The deletion was caused by an intragenic recombination event between two 8-bp direct repeats flanking six intervening codons. In contrast to truncated forms of Snf1 that contain only the kinase domain, the Snf4-independent Snf1\(^{Δ311 − 316}\) was fully functional and could replace wild-type Snf1 for normal growth, because it retained the ability to interact with the Kis1 and Kis2 β-subunits via its C-terminal domain. Indeed, the Snf4-independent Snf1\(^{Δ311 − 316}\) still required the β-subunits of the SNF1 complex to perform its functions and did not rescue the growth defects of kis1Δ mutants. Our results demonstrate that a preprogrammed in-frame deletion event within the SNF1 coding region can generate a mutated form of this essential kinase which abolishes autoinhibition and thereby overcomes growth deficiencies caused by a defect in the γ-subunit Snf4.
YAP and TAZ, downstream effectors of the Hippo pathway, are important regulators of proliferation. Here, we show that the ability of YAP to activate mitotic gene expression is dependent on the Myb-MuvB (MMB) complex, a master regulator of genes expressed in the G2/M phase of the cell cycle. By carrying out genome-wide expression and binding analyses, we found that YAP promotes binding of the MMB subunit B-MYB to the promoters of mitotic target genes. YAP binds to B-MYB and stimulates B-MYB chromatin association through distal enhancer elements that interact with MMB-regulated promoters through chromatin looping. The cooperation between YAP and B-MYB is critical for YAP-mediated entry into mitosis. Furthermore, the expression of genes coactivated by YAP and B-MYB is associated with poor survival of cancer patients. Our findings provide a molecular mechanism by which YAP and MMB regulate mitotic gene expression and suggest a link between two cancer-relevant signaling pathways.
In contrast to the plasma membrane, the vacuole membrane has not yet been associated with electrical excitation of plants. Here, we show that mesophyll vacuoles from Arabidopsis sense and control the membrane potential essentially via the K\(^+\)-permeable TPC1 and TPK channels. Electrical stimuli elicit transient depolarization of the vacuole membrane that can last for seconds. Electrical excitability is suppressed by increased vacuolar Ca\(^{2+}\) levels. In comparison to wild type, vacuoles from the fou2 mutant, harboring TPC1 channels insensitive to luminal Ca\(^{2+}\), can be excited fully by even weak electrical stimuli. The TPC1-loss-of-function mutant tpc1-2 does not respond to electrical stimulation at all, and the loss of TPK1/TPK3-mediated K\(^{+}\) transport affects the duration of TPC1-dependent membrane depolarization. In combination with mathematical modeling, these results show that the vacuolar K\(^+\)-conducting TPC1 and TPK1/TPK3 channels act in concert to provide for Ca\(^{2+}\)- and voltage-induced electrical excitability to the central organelle of plant cells.
Synapse-associated protein 1 (Syap1) is the mammalian homologue of synapse-associated protein of 47 kDa (Sap47) in Drosophila. Genetic deletion of Sap47 leads to deficiencies in short-term plasticity and associative memory processing in flies. In mice, Syap1 is prominently expressed in the nervous system, but its function is still unclear. We have generated Syap1 knockout mice and tested motor behaviour and memory. These mice are viable and fertile but display distinct deficiencies in motor behaviour. Locomotor activity specifically appears to be reduced in early phases when voluntary movement is initiated. On the rotarod, a more demanding motor test involving control by sensory feedback, Syap1-deficient mice dramatically fail to adapt to accelerated speed or to a change in rotation direction. Syap1 is highly expressed in cerebellar Purkinje cells and cerebellar nuclei. Thus, this distinct motor phenotype could be due to a so-far unknown function of Syap1 in cerebellar sensorimotor control. The observed motor defects are highly specific since other tests in the modified SHIRPA exam, as well as cognitive tasks like novel object recognition, Pavlovian fear conditioning, anxiety-like behaviour in open field dark-light transition and elevated plus maze do not appear to be affected in Syap1 knockout mice.
Objectives
To investigate the feasibility, diagnostic image quality and radiation dose of 3\(^{rd}\) generation dual-source computed tomography (CT) using a tin-filtered 100 kV protocol in patients with suspected acute inflammatory sinus disease.
Methods
We retrospectively evaluated 109 consecutive patients who underwent CT (Siemens SOMATOM Force, Erlangen, Germany) of the paranasal sinus with a new tin-filtered scanprotocol (Sn100 kV; tube current 35 mAs) using iterative reconstruction. Two readers independently assessed subjective image quality using a five-point Likert scale (1 = excellent, 5 = non-diagnostic). Inter-observer agreement was calculated and expressed as percentage of agreement. Noise was determined for calculation of signal-to-noise-ratio (SNR). Effective radiation dose (ED) was calculated from the dose-length-product (DLP).
Results
All examinations showed diagnostic image quality regarding evaluation of inflammatory sinus disease. On average, subjective general image quality was rated moderate (= 3) with a percentage of agreement between the observers of 81%. The mean image noise was 14.3 HU. The calculated median SNR was 6.0 for intraorbital fat, and 3.6 for the vitreous body, respectively. The median DLP was 2.1 mGy*cm, resulting in a median ED of 0.012 mSv.
Conclusions
Taking the study limitations into account, ultra-low-dose tin-filtered CT of the paranasal sinus at a tube voltage of 100 kV utilizing an iterative reconstruction algorithm provides for reliable exclusion of suspected acute inflammatory sinus disease in 100% of the cases.
Background
Almost 90% of cancer patients suffer from symptoms of fatigue during treatment. Supporting treatments are increasingly used to alleviate the burden of fatigue. This study examines the short-term and long-term effects of yoga on fatigue and the effect of weekly reminder e-mails on exercise frequency and fatigue symptoms.
Methods
The aim of the first part of the study will evaluate the effectiveness of yoga for cancer patients with mixed diagnoses reporting fatigue. We will randomly allocate 128 patients to an intervention group (N = 64) receiving yoga and a wait-list control group (N = 64) receiving yoga 9 weeks later. The yoga therapy will be performed in weekly sessions of 60 min each for 8 weeks. The primary outcome will be self-reported fatigue symptoms. In the second part of the study, the effectiveness of reminder e-mails with regard to the exercise frequency and self-reported fatigue symptoms will be evaluated. A randomized allocated group of the participants (“email”) receives weekly reminder e-mails, the other group does not. Data will be assessed using questionnaires the beginning and after yoga therapy as well as after 6 months.
Discussion
Support of patients suffering from fatigue is an important goal in cancer patients care. If yoga therapy will reduce fatigue, this type of therapy may be introduced into routine practice. If the reminder e-mails prove to be helpful, new offers for patients may also develop from this.
Background:
Pedicled perforator flaps have expanded reconstructive options in extremity reconstruction. Despite preoperative mapping, intraoperative findings may require microvascular tissue transfer when no adequate perforators can be found. The free peroneal artery perforator flap may serve as a reliable back-up plan in small defects.
Methods:
In 16 patients with small soft tissue defects on the upper and lower extremities, perforator-based propeller flaps were planned. The handheld Doppler device was used to localize potential perforators for a propeller flap in close proximity to the defect. Perforators of the proximal peroneal artery were also marked to allow conversion to microvascular tissue transfer.
Results:
In 6 cases, no adequate perforators were found intraoperatively. In 4 patients, the peroneal artery perforator flap was harvested and transferred. The pedicle length did not exceed 4 cm. No flap loss occurred.
Conclusions:
When no adequate perforator capable of nourishing a propeller flap can be found intraoperatively, the free peroneal artery flap is a good option to reconstruct small soft tissue defects in the distal extremities. The short vascular pedicle is less ideal in cases with a large zone of injury requiring a more distant site of anastomosis or when recipient vessels are located in deeper tissue planes.
We report on a 14 months old toddler who sustained a traumatic hemipelvectomy by being crushed between a car and a stone wall. After stabilization in the resuscitation room he was treated operatively by laparotomy, osteosynthesis of the pelvic ring, reconstruction of the both external iliac vessels and the urethra and reposition of the testicles. After 66 days he was discharged into rehabilitation. Implants were removed after eight months. 20 months after the injury, the leg was plegic, initial radiological signs of femoral head necrosis showed up but the infant was able to walk with an orthesis and a walker.
Up to our knowledge, this is the youngest patient described in the literature with a survived traumatic hemipelvectomy and salvaged limb.
Dopaminergic neurons in the brain of the Drosophila larva play a key role in mediating reward information to the mushroom bodies during appetitive olfactory learning and memory. Using optogenetic activation of Kenyon cells we provide evidence that recurrent signaling exists between Kenyon cells and dopaminergic neurons of the primary protocerebral anterior (pPAM) cluster. Optogenetic activation of Kenyon cells paired with odor stimulation is sufficient to induce appetitive memory. Simultaneous impairment of the dopaminergic pPAM neurons abolishes appetitive memory expression. Thus, we argue that dopaminergic pPAM neurons mediate reward information to the Kenyon cells, and in turn receive feedback from Kenyon cells. We further show that this feedback signaling is dependent on short neuropeptide F, but not on acetylcholine known to be important for odor-shock memories in adult flies. Our data suggest that recurrent signaling routes within the larval mushroom body circuitry may represent a mechanism subserving memory stabilization.
Fin development and regeneration are complex biological processes that are highly relevant in teleost fish. They share genetic factors, signaling pathways and cellular properties to coordinate formation of regularly shaped extremities. Especially correct tissue structure defined by extracellular matrix (ECM) formation is essential. Gene expression and protein localization studies demonstrated expression of fndc3a (fibronectin domain containing protein 3a) in both developing and regenerating caudal fins of zebrafish (Danio rerio). We established a hypomorphic fndc3a mutant line (fndc3a\(^{wue1/wue1}\)) via CRISPR/Cas9, exhibiting phenotypic malformations and changed gene expression patterns during early stages of median fin fold development. These developmental effects are mostly temporary, but result in a fraction of adults with permanent tail fin deformations. In addition, caudal fin regeneration in adult fndc3a\(^{wue1/wue1}\) mutants is hampered by interference with actinotrichia formation and epidermal cell organization. Investigation of the ECM implies that loss of epidermal tissue structure is a common cause for both of the observed defects. Our results thereby provide a molecular link between these developmental processes and foreshadow Fndc3a as a novel temporal regulator of epidermal cell properties during extremity development and regeneration in zebrafish.