“Fitness Fingerprints” Mediate Physiological Culling of Unwanted Neurons in Drosophila

BACKGROUND: The flower gene has been previously linked to the elimination of slow dividing epithelial cells during development in a process known as "cell competition." During cell competition, different isoforms of the Flower protein are displayed at the cell membrane and reveal the reduced fitness of slow proliferating cells, which are therefore recognized, eliminated, and replaced by their normally dividing neighbors. This mechanism acts as a "cell quality" control in proliferating tissues. RESULTS: Here, we use the Drosophila eye as a model to study how unwanted neurons are culled during retina development and find that flower is required and sufficient for the recognition and elimination of supernumerary postmitotic neurons, contained within incomplete ommatidia units. This constitutes the first description of the "Flower Code" functioning as a cell selection mechanism in postmitotic cells and is also the first report of a physiological role for this cell quality control machinery. CONCLUSIONS: Our results show that the "Flower Code" is a general system to reveal cell fitness and that it may play similar roles in creating optimal neural networks in higher organisms. The Flower Code seems to be a more general mechanism for cell monitoring and selection than previously recognized.

c-{\it mos\/} RNA expression in somatic cells and its physiological significance in cell cycle progression

The c-mos proto-oncogene, which is expressed at relatively high levels in male and female germ cells, plays a key role in oocyte meiotic maturation. The c-mos gene product in oocytes (p39$\sp{\rm c-mos}$) is necessary and sufficient to initiate meiosis. p39$\sp{\rm c-mos}$ is also an essential component of the cytostatic factor, which is responsible for arresting vertebrate oocytes at the second meiotic metaphase by stabilizing the maturation promoting factor (MPF). MPF is a universal regulator of both meiosis and mitosis. Much less is understood about c-mos expression and function in somatic cells. In addition to gonadal tissues, c-Mos has been detected in some somatic tissues and non-germ cell lines including NIH 3T3 cells as a protein termed p43$\sp{\rm c-mos}$. Since c-mos RNA transcripts were not previously detected in this cell line by Northern blot or S1 protection analyses, a search was made for c-mos RNA in NIH 3T3 cells. c-mos transcripts were detected using the highly sensitive RNA-PCR method and RNase protection assays. Furthermore, cell cycle analyses indicated that expression of c-mos RNA is tightly controlled in a cell cycle dependent manner with highest levels of transcripts (approximately 5 copies/cell) during the G2 phase.^ In order to determine the physiological significance of c-mos RNA expression in somatic cells, antisense mos was placed under the control of an inducible promoter and introduced into either NIH 3T3 cells or C2 cells. It was found that a basal level of expression of antisense mos resulted in interference with mitotic progression and growth arrest. Several nuclear abnormalities were observed, especially the appearance of binucleated and multinucleated cells as well as the extrusion of microvesicles containing cellular material. These results indicate that antisense mos expression results in a block in cytokinesis. In summary, these results establish that c-mos expression is not restricted to germ cells, but instead indicate that c-mos RNA expression occurs during the G2 stage of the cell cycle. Furthermore, these studies demonstrate that the c-mos proto-oncogene plays an important role in cell cycle progression. As in meiosis, c-mos may have a similar but not identical function in regulating cell cycle events in somatic cells, particularly in controlling mitotic progression via activation/stabilization of MPF. ^

Physiological effects of mechanical pain stimulation at the lower back measured by functional near-infrared spectroscopy and capnography

The aim was to investigate the effect of mechanical pain stimulation at the lower back on hemodynamic and oxygenation changes in the prefrontal cortex (PFC) assessed by functional near-infrared spectroscopy (fNIRS) and on the partial pressure of end-tidal carbon dioxide ( PetCO 2) measured by capnography. 13 healthy subjects underwent three measurements (M) during pain stimulation using pressure pain threshold (PPT) at three locations, i.e., the processus spinosus at the level of L4 (M1) and the lumbar paravertebral muscles at the level of L1 on the left (M2) and the right (M3) side. Results showed that only in the M2 condition the pain stimulation elicited characteristic patterns consisting of (1) a fNIRS-derived decrease in oxy- and total hemoglobin concentration and tissue oxygen saturation, an increase in deoxy-hemoglobin concentration, (2) a decrease in the PetCO 2 response and (3) a decrease in coherence between fNIRS parameters and PetCO 2 responses in the respiratory frequency band (0.2-0.5 Hz). We discuss the comparison between M2 vs. M1 and M3, suggesting that the non-significant findings in the two latter measurements were most likely subject to effects of the different stimulated tissues, the stimulated locations and the stimulation order. We highlight that PetCO 2 is a crucial parameter for proper interpretation of fNIRS data in experimental protocols involving pain stimulation. Together, our data suggest that the combined fNIRS-capnography approach has potential for further development as pain monitoring method, such as for evaluating clinical pain treatment.

Extreme climatic events: impacts of drought and high temperature on physiological processes in agronomically important plants

Climate models predict more frequent and more severe extreme events (e.g., heat waves, extended drought periods, flooding) in many regions for the next decades. The impact of adverse environmental conditions on crop plants is ecologically and economically relevant. This review is focused on drought and heat effects on physiological status and productivity of agronomically important plants. Stomatal opening represents an important regulatory mechanism during drought and heat stress since it influences simultaneously water loss via transpiration and CO2 diffusion into the leaf apoplast which further is utilized in photosynthesis. Along with the reversible short-term control of stomatal opening, stomata and leaf epidermis may produce waxy deposits and irreversibly down-regulate the stomatal conductance and non-stomatal transpiration. As a consequence photosynthesis will be negatively affected. Rubisco activase—a key enzyme in keeping the Calvin cycle functional—is heat-sensitive and may become a limiting factor at elevated temperature. The accumulated reactive oxygen species (ROS) during stress represent an additional challenge under unfavorable conditions. Drought and heat cause accumulation of free amino acids which are partially converted into compatible solutes such as proline. This is accompanied by lower rates of both nitrate reduction and de novo amino acid biosynthesis. Protective proteins (e.g., dehydrins, chaperones, antioxidant enzymes or the key enzyme for proline biosynthesis) play an important role in leaves and may be present at higher levels under water deprivation or high temperatures. On the whole plant level, effects on long-distance translocation of solutes via xylem and phloem and on leaf senescence (e.g., anticipated, accelerated or delayed senescence) are important. The factors mentioned above are relevant for the overall performance of crops under drought and heat and must be considered for genotype selection and breeding programs.

Cognitive and physiological effects of an acute physical activity intervention in elementary school children

The aim of the present study was to investigate the effects of an acute physical activity intervention that included cognitive engagement on executive functions and on cortisol level in young elementary school children. Half of the 104 participating children (6–8 years old) attended a 20-min sport sequence, which included cognitively engaging and playful forms of physical activity. The other half was assigned to a resting control condition. Individual differences in children's updating, inhibition, and shifting performance as well as salivary cortisol were assessed before (pre-test), immediately after (post-test), and 40 min after (follow-up) the intervention or control condition, respectively. Results revealed a significantly stronger improvement in inhibition in the experimental group compared to the control group, while it appeared that acute physical activity had no specific effect on updating and shifting. The intervention effect on inhibition leveled out 40 min after physical activity. Salivary cortisol increased significantly more in the experimental compared to the control group between post-test and follow-up and results support partly the assumed inverted U-shaped relationship between cortisol level and cognitive performance. In conclusion, results indicate that acute physical activity that includes cognitive engagement may have immediate positive effects on inhibition, but not necessarily on updating and shifting in elementary school children. This positive effect may partly be explained through cortisol elevation after acute physical activity.

Endogenous α-calcitonin-gene-related peptide promotes exercise-induced, physiological heart hypertrophy in mice.

AIM It is unknown how the heart distinguishes various overloads, such as exercise or hypertension, causing either physiological or pathological hypertrophy. We hypothesize that alpha-calcitonin-gene-related peptide (αCGRP), known to be released from contracting skeletal muscles, is key at this remodelling. METHODS The hypertrophic effect of αCGRP was measured in vitro (cultured cardiac myocytes) and in vivo (magnetic resonance imaging) in mice. Exercise performance was assessed by determination of maximum oxygen consumption and time to exhaustion. Cardiac phenotype was defined by transcriptional analysis, cardiac histology and morphometry. Finally, we measured spontaneous activity, body fat content, blood volume, haemoglobin mass and skeletal muscle capillarization and fibre composition. RESULTS While αCGRP exposure yielded larger cultured cardiac myocytes, exercise-induced heart hypertrophy was completely abrogated by treatment with the peptide antagonist CGRP(8-37). Exercise performance was attenuated in αCGRP(-/-) mice or CGRP(8-37) treated wild-type mice but improved in animals with higher density of cardiac CGRP receptors (CLR-tg). Spontaneous activity, body fat content, blood volume, haemoglobin mass, muscle capillarization and fibre composition were unaffected, whereas heart index and ventricular myocyte volume were reduced in αCGRP(-/-) mice and elevated in CLR-tg. Transcriptional changes seen in αCGRP(-/-) (but not CLR-tg) hearts resembled maladaptive cardiac phenotype. CONCLUSIONS Alpha-calcitonin-gene-related peptide released by skeletal muscles during exercise is a hitherto unrecognized effector directing the strained heart into physiological instead of pathological adaptation. Thus, αCGRP agonists might be beneficial in heart failure patients.

ACL reconstruction with physiological graft tension by intraoperative adjustment of the anteroposterior translation to the uninjured contralateral knee.

PURPOSE Fixation of anterior cruciate ligament (ACL) substitutes with non-physiological anteroposterior translation (APT) worsens outcome. The aim was to present a technique for physiological APT adjustment of the transplant in ACL reconstruction and its outcome at midterm. METHODS In a consecutive series of 28 patients (age 32 ± 11 years, 24 male), chronic ACL deficiency was treated by bone-patella-tendon-bone reconstruction. Transplant APT was adjusted to that of the contralateral uninjured ACL, measured 3, 6, and 12 months postoperatively using the Rolimeter. At a median follow-up of 5.3 years (3-8 years), 82% of the patients were re-evaluated with APT measurement and using IKDC-, Tegner-, Lysholm-Scores, conventional radiographs and MRI. RESULTS No differences in APT (mean ± SD) between uninjured and reconstructed knees were observed after adjustment (6 ± 1 versus 6 ± 1 mm, n.s.). Three months postoperatively, a statistically significant increase in APT (7 ± 1 mm) and a further increase at midterm (9 ± 2 mm) were observed. Patients scored "normal" or "nearly normal", respectively, in 79% (IKDC) and 4 (3-9) points (Tegner; median, range) or 89 ± 9 points (Lysholm; mean ± SD). Radiological evaluation showed no, minimal or moderate joint degeneration in 5, 20 and 75% of patients, respectively. MRI confirmed intact ACL transplants in all patients. CONCLUSION ACL reconstruction using the presented technique was considered successful, as patients did not suffer from subjective instability, radiographic analysis did not provide evidence for graft rupture at midterm. However, APT increase and occurrence of degenerative changes in reconstructed knees at the midterm might not be prevented even by restoration of a physiological APT in ACL reconstruction. The Rolimeter can be used for quick and easy intraoperative indirect control of the applied tension to the ACL transplant by measuring the APT to obtain physiological tensioning resulting in a satisfying outcome at midterm. LEVEL OF EVIDENCE IV.

Teamwork reduces physiological stress in junior surgeons

Objective: The quality of teamwork depends not only on communication skills but also on team familiarity and hierarchical structures. The aim of the present study is to evaluate the physiological impact of close teamwork between senior and junior surgeons performing elective open abdominal surgery for six months in stable teams. Methods: Physiological measurements of the main and junior surgeons were taken in a total of 40 procedures. Cumulative stress was assessed by the mea- surements of urine catecholamines (Adrenaline, Noradrenaline, Dopamine, Metanephrine, Normetanephrine). Heart rate variability was measured to assess temporal aspects of stress. The procedures were observed by a trained team of work psychologists. Direct observations of distractors, team inter- actions and communication were performed. Specific questionnaires were filled by members of the surgical team that include surgeons, nurses and anesthetists. Results: In junior surgeons, physiological stress is reduced over a period of close collaboration. Case-related communication is not stressful. However, tension within the surgical team is associated with increased levels of cat- echolamine in the urine of the senior surgeon. The difficulty of the oper- ation impacts on heart-rate variability of the junior but not of the senior surgeon. Conclusion: Junior surgeons may require months of teamwork within one stable team in order to reduce levels of physiological stress. Senior surgeons are more resistant to stressful clinical situations compared to junior surgeons but are vulnerable to tension within the surgical team.

A highly sensitive TTF-functionalised probe for the determination of physiological thiols and its application in tumor cells

A tetrathiafulvalene (TTF)-fused piazselenole as a novel redox-active probe for highly sensitive determination of physiological thiols by electrochemical detection has been synthesised and successfully tested in intracellular non-protein thiol detection, reaching a detection limit of 10−10 M.

Loss of appetite in acutely ill medical inpatients: physiological response or therapeutic target?

Loss of appetite and ensuing weight loss is a key feature of severe illnesses. Protein-energy malnutrition (PEM) contributes significantly to the adverse outcome of these conditions. Pharmacological interventions to target appetite stimulation have little efficacy but considerable side effects. Therefore nutritional therapy appears to be the logical step to combat inadequate nutrition. However, clinical trial data demonstrating benefits are sparse and there is no current established standard algorithm for use of nutritional support in malnourished, acutely ill medical inpatients. Recent high-quality evidence from critical care demonstrating harmful effects when parenteral nutritional support is used indiscriminately has led to speculation that loss of appetite in the acute phase of illness is indeed an adaptive, protective response that improves cell recycling (autophagy) and detoxification. Outside critical care, there is an important gap in high quality clinical trial data shedding further light on these important issues. The selection, timing, and doses of nutrition should be evaluated as carefully as with any other therapeutic intervention, with the aim of maximising efficacy and minimising adverse effects and costs. In light of the current controversy, a reappraisal of how nutritional support should be used in acutely ill medical inpatients outside critical care is urgently required. The aim of this review is to discuss current pathophysiological concepts of PEM and to review the current evidence for the efficacy of nutritional support regarding patient outcomes when used in an acutely ill medical patient population outside critical care.

Only Neochordoplasty Achieves Physiological Trans-valvular Pressure Gradients After Repair Of Acute Posterior Leaflet Prolapse In Porcine Mitral Valves

Objective: Minimizing resection and preserving leaflet tissue has been previously shown to be beneficial for mitral valve function and leaflet kinematics after repair of acute posterior leaflet prolapse in porcine valves. We examined the effects of different additional methods of mitral valve repair (neochordoplasty, ring annuloplasty, edge-to-edge repair and triangular resection) on hemodynamics at different heart rates in an experimental model. Methods: Severe acute P2 prolapse was created in eight porcine mitral valves by resecting the posterior marginal chordae. Valve hemodynamics was quantified under pulsatile conditions in an in vitro heart simulator before and after surgical manipulation. Mitral regurgitation was corrected using four different methods of repair on the same valve: neochordoplasty with expanded polytetrafluoroethylene sutures alone and together with ring annuloplasty, edge-to-edge repair and triangular resection, both with non-restrictive annuloplasty. Residual mitral valve leak, trans-valvular pressure gradients, flow and cardiac output were measured at 60 and 80 beats/min. A validated statistical linear mixed model was used to analyze the effect of treatment. The p values were calculated using a two-sided Wald test. Results: Only neochordoplasty with expanded polytetrafluoroethylene sutures but without ring annuloplasty achieved similar hemodynamics compared to those of the native mitral valve (p range 0.071-0.901). Trans-valvular diastolic pressure gradients were within a physiologic range but significantly higher than those of the native valve following neochordoplasty with ring annuloplasty (p=0.000), triangular resection (p=0.000) and edge-to-edge repair (p=0.000). Neochordoplasty alone was significantly better in terms of hemodynamic than neochordoplasty with a ring annuloplasty (p=0.000). These values were stable regardless of heart rate or ring size. Conclusions: Neochordoplasty without ring annuloplasty is the only repair technique able to achieve almost native physiological hemodynamics after correction of leaflet prolapse in a porcine experimental model of acute chordal rupture.

The Sensitivity of Physiological Measures to Phobic and Nonphobic Fear Intensity

We investigated whether amygdala activation, autonomic responses, respiratory responses, and facial muscle activity (measured over the brow and cheek [fear grin] regions) are all sensitive to phobic versus nonphobic fear and, more importantly, whether effects in these variables vary as a function of both phobic and nonphobic fear intensity. Spider-phobic and comparably low spider-fearful control participants imagined encountering different animals and rated their subjective fear while their central and peripheral nervous system activity was measured. All measures included in our study were sensitive to variations in subjective fear, but were related to different ranges and positions on the subjective fear level continuum. Left amygdala activation, heart rate, and facial muscle activity over the cheek region captured fear intensity variations even within narrowly described regions on the fear level continuum (here within extremely low levels of fear and within considerable phobic fear). Skin conductance and facial muscle activity over the brow region did not capture fear intensity variations within low levels of fear: skin conductance mirrored only extreme levels of fear, and activity over the brow region distinguished phobic from nonphobic fear but also low-to-moderate and high phobic fear. Finally, respiratory measures distinguished phobic from nonphobic fear with no further differentiation within phobic and nonphobic fear. We conclude that a careful consideration of the measures to be used in an investigation and the population to be examined can be critical in order to obtain significant results.