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During voluntary behaviors, animals need to disable any reflexes that could interfere with the intended movements. With the optomotor response, flies stabilize a straight flight path by correcting for unintended deviations sensed as the panoramic motion of the surround. HS cells of the fly are thought to mediate optomotor responses to horizontal motion. During spontaneous flight turns, an efference copy acts on HS cells with the right sign to counteract the visual input elicited by the fly's own behavior. Here, we investigated, whether looming-elicited turns in flying Drosophila have a similar effect on HS cells. We show that looming stimuli themselves can influence the processing of panoramic motion stimuli in HS cells and that an inhibitory efference copy suppresses excitatory motion responses during turns in both directions, but only in a subset of HS cells. Our findings support the notion that the processing of sensory information is finely tuned to behavioral context., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Cystobactamids are myxobacteria-derived topoisomerase inhibitors with potent anti-Gram-negative activity. They are formed by a non-ribosomal peptide synthetase (NRPS) and consist of tailored para-aminobenzoic acids, connected by a unique α-methoxy-L-isoasparagine or a β-methoxy-L-asparagine linker moiety. We describe the heterologous expression of the cystobactamid biosynthetic gene cluster (BGC) in Myxococcus xanthus. Targeted gene deletions produce several unnatural cystobactamids. Using in vitro experiments, we reconstitute the key biosynthetic steps of linker formation and shuttling via CysB to the NRPS. The biosynthetic logic involves a previously uncharacterized bifunctional domain found in the stand-alone NRPS module CysH, albicidin biosynthesis and numerous BGCs of unknown natural products. This domain performs either an aminomutase (AM) or an amide dehydratase (DH) type of reaction, depending on the activity of CysJ which hydroxylates CysH-bound L-asparagine. Furthermore, CysQ O-methylates hydroxyl-L-(iso)asparagine only in the presence of the AMDH domain. Taken together, these findings provide direct evidence for unique steps in cystobactamid biosynthesis.

To navigate through the world, animals must stabilize their path against disturbances and change direction to avoid obstacles and to search for resources [1, 2]. Locomotion is thus guided by sensory cues but also depends on intrinsic processes, such as motivation and physiological state. Flies, for example, turn with the direction of large-field rotatory motion, an optomotor reflex that is thought to help them fly straight [3-5]. Occasionally, however, they execute fast turns, called body saccades, either spontaneously or in response to patterns of visual motion such as expansion [6-8]. These turns can be measured in tethered flying Drosophila [3, 4, 9], which facilitates the study of underlying neural mechanisms. Whereas there is evidence for an efference copy input to visual interneurons during saccades [10], the circuits that control spontaneous and visually elicited saccades are not well known. Using two-photon calcium imaging and electrophysiological recordings in tethered flying Drosophila, we have identified a descending neuron whose activity is correlated with both spontaneous and visually elicited turns during tethered flight. The cell's activity in open- and closed-loop experiments suggests that it does not underlie slower compensatory responses to horizontal motion but rather controls rapid changes in flight path. The activity of this neuron can explain some of the behavioral variability observed in response to visual motion and appears sufficient for eliciting turns when artificially activated. This work provides an entry point into studying the circuits underlying the control of rapid steering maneuvers in the fly brain., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Stable L-forms are cell wall-deficient bacteria which are able to multiply and propagate indefinitely, despite the absence of a rigid peptidoglycan cell wall. We investigated whether L-forms of the intracellular pathogen L. monocytogenes possibly retain pathogenicity, and if they could trigger an innate immune response. While phagocytosis of L. monocytogenes L-forms by non-activated macrophages sometimes resulted in an unexpected persistence of the bacteria in the phagocytes, they were effectively eliminated by IFN-γ preactivated or bone marrow-derived macrophages (BMM). These findings were in line with the observed down-regulation of virulence factors in the cell-wall deficient L. monocytogenes. Absence of Interferon-β (IFN-β) triggering indicated inability of L-forms to escape from the phagosome into the cytosol. Moreover, abrogated cytokine response in MyD88-deficient dendritic cells (DC) challenged with L. monocytogenes L-forms suggested an exclusive TLR-dependent host response. Taken together, our data demonstrate a strong attenuation of Listeria monocytogenes L-form pathogenicity, due to diminished expression of virulence factors and innate immunity recognition, eventually resulting in elimination of L-form bacteria from phagocytes.

Sensory feedback is a ubiquitous feature of guidance systems in both animals and engineered vehicles. For example, a common strategy for moving along a straight path is to turn such that the measured rate of rotation is zero. This task can be accomplished by using a feedback signal that is proportional to the instantaneous value of the measured sensory signal. In such a system, the addition of an integral term depending on past values of the sensory input is needed to eliminate steady-state error [proportional-integral (PI) control]. However, the means by which nervous systems implement such a computation are poorly understood. Here, we show that the optomotor responses of flying Drosophila follow a time course consistent with temporal integration of horizontal motion input. To investigate the cellular basis of this effect, we performed whole-cell patch-clamp recordings from the set of identified visual interneurons [horizontal system (HS) cells] thought to control this reflex during tethered flight. At high stimulus speeds, HS cells exhibit steady-state responses during flight that are absent during quiescence, a state-dependent difference in physiology that is explained by changes in their presynaptic inputs. However, even during flight, the membrane potential of the large-field interneurons exhibits no evidence for integration that could explain the behavioral responses. However, using a genetically encoded indicator, we found that calcium accumulates in the terminals of the interneurons along a time course consistent with the behavior and propose that this accumulation provides a mechanism for temporal integration of sensory feedback consistent with PI control.

Sensory systems provide abundant information about the environment surrounding an animal, but only a small fraction of that information is relevant for any given task. One example of this requirement for context-dependent filtering of a sensory stream is the role that optic flow plays in guiding locomotion. Flying animals, which do not have access to a direct measure of ground speed, rely on optic flow to regulate their forward velocity. This observation suggests that progressive optic flow, the pattern of front-to-back motion on the retina created by forward motion, should be especially salient to an animal while it is in flight, but less important while it is standing still. We recorded the activity of cells in the central complex of Drosophila melanogaster during quiescence and tethered flight using both calcium imaging and whole cell patch-clamp techniques. We observed a genetically identified set of neurons in the fan-shaped body that are unresponsive to visual motion while the animal is quiescent. During flight their baseline activity increases, and they respond to front-to-back motion with changes relative to this baseline. The results provide an example of how nervous systems selectively respond to complex sensory stimuli depending on the current behavioral state of the animal.

Important brain functions need to be conserved throughout organisms of extremely varying sizes. Here we study the scaling properties of an essential component of computation in the brain: the single neuron. We compare morphology and signal propagation of a uniquely identifiable interneuron, the HS cell, in the blowfly (Calliphora) with its exact counterpart in the fruit fly (Drosophila) which is about four times smaller in each dimension. Anatomical features of the HS cell scale isometrically and minimise wiring costs but, by themselves, do not scale to preserve the electrotonic behaviour. However, the membrane properties are set to conserve dendritic as well as axonal delays and attenuation as well as dendritic integration of visual information. In conclusion, the electrotonic structure of a neuron, the HS cell in this case, is surprisingly stable over a wide range of morphological scales.

Recent experiments have shown that motion detection in Drosophila starts with splitting the visual input into two parallel channels encoding brightness increments (ON) or decrements (OFF). This suggests the existence of either two (ON-ON, OFF-OFF) or four (for all pairwise interactions) separate motion detectors. To decide between these possibilities, we stimulated flies using sequences of ON and OFF brightness pulses while recording from motion-sensitive tangential cells. We found direction-selective responses to sequences of same sign (ON-ON, OFF-OFF), but not of opposite sign (ON-OFF, OFF-ON), refuting the existence of four separate detectors. Based on further measurements, we propose a model that reproduces a variety of additional experimental data sets, including ones that were previously interpreted as support for four separate detectors. Our experiments and the derived model mark an important step in guiding further dissection of the fly motion detection circuit., (Copyright © 2011 Elsevier Inc. All rights reserved.)

This study evaluated the Brief Rating of Aggression by Children and Adolescents-Preliminary Version (BRACHA 0.8), an actuarial method of assessing the risk of aggressive behavior by hospitalized children and adolescents. Licensed psychiatric social workers used a 16-item questionnaire to assess all patients seen in the emergency department (ED) of a major urban children's hospital. Over a six-month period, 418 patients (age range, 3.5-19.0 years) underwent psychiatric hospitalization after ED evaluation. The hospital nursing staff recorded the inpatients' behavior, with the Overt Aggression Scale (OAS). Inpatients were deemed aggressive if, during the first six days of their hospital stay, they scored one or higher on any OAS subscale. We evaluated questionnaire properties, items, and demographic covariates (e.g., age, sex, and living situation) by using factor analyses, logistic regression models, and receiver operating characteristic (ROC) methods. A total of 292 aggressive acts were committed by 120 (29% of 418) patients. Fourteen of the 16 items predicted (p < .007) inpatient aggression and showed good internal consistency (Cronbach's α = 0.837). Age was inversely related to probability of aggression and was incorporated into the final assessment instrument. Predictive power was comparable with other published risk assessment instruments (ROC areas of .75 for any aggression and .82 for aggression toward others). BRACHA 0.8 shows promise in rapidly assessing risk of inpatient aggression, but further studies are needed to establish the reliability and validity of the instrument.

Motion vision is a major function of all visual systems, yet the underlying neural mechanisms and circuits are still elusive. In the lamina, the first optic neuropile of Drosophila melanogaster, photoreceptor signals split into five parallel pathways, L1-L5. Here we examine how these pathways contribute to visual motion detection by combining genetic block and reconstitution of neural activity in different lamina cell types with whole-cell recordings from downstream motion-sensitive neurons. We find reduced responses to moving gratings if L1 or L2 is blocked; however, reconstitution of photoreceptor input to only L1 or L2 results in wild-type responses. Thus, the first experiment indicates the necessity of both pathways, whereas the second indicates sufficiency of each single pathway. This contradiction can be explained by electrical coupling between L1 and L2, allowing for activation of both pathways even when only one of them receives photoreceptor input. A fundamental difference between the L1 pathway and the L2 pathway is uncovered when blocking L1 or L2 output while presenting moving edges of positive (ON) or negative (OFF) contrast polarity: blocking L1 eliminates the response to moving ON edges, whereas blocking L2 eliminates the response to moving OFF edges. Thus, similar to the segregation of photoreceptor signals in ON and OFF bipolar cell pathways in the vertebrate retina, photoreceptor signals segregate into ON-L1 and OFF-L2 channels in the lamina of Drosophila.

Background: Oral enteric contrast medium (ECM) is frequently administered to achieve visualization of the gastrointestinal tract during abdominal evaluation with computed tomography (CT). Administering oral ECM less than 2 hours before sedation/anesthesia violates the nothing-by-mouth guidelines and in theory may increase the risk of aspiration pneumonia. In this study we measured the residual gastric fluid when using a protocol in which ECM is administered up to 1 hour before anesthesia/sedation. We hypothesized that patients receiving ECM 1 hour before anesthesia/sedation would have residual gastric fluid volume (GFV) >0.4 mL/kg., Methods: Anesthesia and radiology reports, CT images, and department incident reports were reviewed between January 2005 and June 2009 for all patients who required sedation/anesthesia for abdominal CT. For each patient, the volume of contrast or stomach fluid was calculated using a region of interest outlining the stomach portion containing high-attenuation fluid and low-attenuation of other gastric contents. Information obtained from anesthesia/sedation reports included demographic characteristics, presenting pathology, drugs used for anesthesia/sedation induction and maintenance, airway interventions, method for securing endotracheal tube, and complications related to ECM administration, including oxygen desaturation, vomiting, coughing, bronchospasm, laryngospasm, and aspiration., Results: We identified 365 patients (mean age = 32 months; range = 0.66 to 211.10 months) who received oral/IV contrast material before anesthesia/sedation for abdominal CT and 47 patients (mean age = 52 months; range = 0.63 to 215.84 months) who received only IV contrast material and followed the traditional fast. For those who received oral contrast, the mean contrast volume administered was 18.10 mL/kg (range = 1.5 to 82.76 mL/kg). The median GVF 1 hour after completing the oral contrast was significantly higher than that in patients who received only IV contrast (0.38 mL/kg vs. 0.15 mL/kg, P = 0.0049). GFV exceeded 0.4 mL/kg in 189 patients (178 of 365 [49%] in the oral contrast group vs. 11 of 47 [23%] in the IV contrast group) (χ(2) = 10.7874, P = 0.0010). Among those who received oral contrast, 207 patients had general anesthesia and 158 patients had deep sedation. Two cases of vomiting were reported in the general anesthesia group with no evidence of pulmonary aspiration identified., Conclusion: For children receiving an abdominal CT, the residual GFV exceeded 0.4 mL/kg in 49% (178/365) of those who received oral ECM up to 1 hour before anesthesia/sedation in comparison with 23% (11/47) of those who received IV-only contrast.

Background: Dexmedetomidine has been increasingly used as an adjunct to opioid-propofol total intravenous anesthesia (TIVA). The authors tested the hypothesis and found that clinically relevant blood levels of dexmedetomidine do not produce significant attenuation of the amplitude of transcranial electric motor-evoked potentials either independently or by interaction with propofol in a dose-dependent manner., Methods: The authors planned to recruit 72 patients with idiopathic scoliosis who had posterior spine fusion surgery during propofol and remifentanil TIVA with dexmedetomidine as an adjunct. However, the authors terminated the study after enrolling 44 patients because of change in surgical technique. Before administering dexmedetomidine, baseline transcranial electric motor-evoked potentials were acquired during TIVA with remifentanil and propofol. Patients were randomized to varying targeted blood levels of dexmedetomidine (0.4, 0.6, and 0.8 ng/ml) and propofol (2.5, 3.75, and 5 microg/ml) using a factorial design. The primary outcome variable was amplitude of transcranial electric motor-evoked potential. The secondary outcome was amplitude of cortical somatosensory-evoked potentials., Results: Of the 44 recruited patients, 40 completed the study, and their data were analyzed. The administration of dexmedetomidine in increasing doses as an adjunct to propofol-based TIVA caused a clinically and statistically significant attenuation of amplitudes of transcranial electric motor-evoked potentials., Conclusion: The authors conclude that under the stimulation conditions used, dexmedetomidine as an anesthetic adjunct to propofol-based TIVA at clinically relevant target plasma concentrations (0.6-0.8 ng/ml) can significantly attenuate the amplitude of transcranial electric motor-evoked potentials.

Cell wall-deficient bacteria referred to as L-forms have lost the ability to maintain or build a rigid peptidoglycan envelope. We have generated stable, non-reverting L-form variants of the Gram-positive pathogen Listeria monocytogenes, and studied the cellular and molecular changes associated with this transition. Stable L-form cells can occur as small protoplast-like vesicles and as multinucleated, large bodies. They have lost the thick, multilayered murein sacculus and are surrounded by a cytoplasmic membrane only, although peptidoglycan precursors are still produced. While they lack murein-associated molecules including Internalin A, membrane-anchored proteins such as Internalin B are retained. Surprisingly, L-forms were found to be able to divide and propagate indefinitely without a wall. Time-lapse microscopy of fluorescently labelled L-forms indicated a switch to a novel form of cell division, where genome-containing membrane vesicles are first formed within enlarged L-forms, and subsequently released by collapse of the mother cell. Array-based transcriptomics of parent and L-form cells revealed manifold differences in expression of genes associated with morphological and physiological functions. The L-forms feature downregulated metabolic functions correlating with the dramatic shift in surface to volume ratio, whereas upregulation of stress genes reflects the difficulties in adapting to this unusual, cell wall-deficient lifestyle.

In the eye, visual information is segregated into modalities such as color and motion, these being transferred to the central brain through separate channels. Here, we genetically dissect the achromatic motion channel in the fly Drosophila melanogaster at the level of the first relay station in the brain, the lamina, where it is split into four parallel pathways (L1-L3, amc/T1). The functional relevance of this divergence is little understood. We now show that the two most prominent pathways, L1 and L2, together are necessary and largely sufficient for motion-dependent behavior. At high pattern contrast, the two pathways are redundant. At intermediate contrast, they mediate motion stimuli of opposite polarity, L2 front-to-back, L1 back-to-front motion. At low contrast, L1 and L2 depend upon each other for motion processing. Of the two minor pathways, amc/T1 specifically enhances the L1 pathway at intermediate contrast. L3 appears not to contribute to motion but to orientation behavior.

[reaction: see text] Biocatalytic racemization of a range of aliphatic, (aryl)aliphatic, and aromatic alpha-hydroxycarboxylic acids was accomplished by using whole resting cells of a range of Lactobacillus spp. The mild (physiological) reaction conditions ensured an essentially "clean" isomerization in the absence of side reactions, such as elimination or decomposition. Whereas straight-chain aliphatic 2-hydroxycarboxylic acids were racemized with excellent rates (up to 85% relative to lactate), steric hindrance was observed for branched-chain analogues. Good rates were observed for aryl-alkyl derivatives, such as 3-phenyllactic acid (up to 59%) and 4-phenyl-2-hydroxybutanoic acid (up to 47%). In addition, also mandelate and its o-chloro analogue were accepted at a fair rate (45%). This biocatalytic racemization represents an important tool for the deracemization of a number of pharmaceutically important building blocks.

Background: In the catheter laboratory there is a need for functional tests validating the hemodynamic significance of coronary artery stenosis., Objectives: It was the objective of our study to compare the long-term cardiac event rate and the clinical symptoms in patients with reduced coronary flow velocity reserve (CFVR) and standard PTCA with patients with normal CFVR and deferred angioplasty., Methods: Our study included 70 patients with intermediate coronary artery stenoses (13 f, 57 m; diameter stenosis >50%, <90%) and an indication for PTCA due to stable angina pectoris and/or signs of ischemia in noninvasive stress tests. CFVR was measured distal to the lesion after intracoronary administration of adenosine using 0.014 inch Doppler-tipped guide wires., Results: In 22 patients (31%), PTCA was deferred due to a CFVR > or = 2.0 (non-PTCA group). In the remaining 48 patients (69%) mean CFVR of 1.4+/-0.23 (p < 0.001) was measured (PTCA group). CFVR increased to 2.0+/-0.51 after angioplasty. During follow-up (average 15+/-6.0 months), the following major adverse cardiac events (MACE) occurred: in the PTCA group re-PTCA was performed in nine patients (18.8%) because of unstable angina, five patients (10.4%) suffered an acute myocardial infarction (MI) (two infarctions occurred during the angioplasty, three patients suffered an infarction during follow-up), two patients (4.2%) needed blood transfusions due to severe bleedings, two patients (4.2%) underwent bypass surgery and one patient (2.1%) died. In the non-PTCA group, angioplasty was necessary only in two cases (9.1%) during follow-up. We did not observe any MI in the non-PTCA group. The overall rate of MACE was significantly lower in the non-PTCA group compared to the PTCA group (9.1% vs. 33.3%, p < 0.01). However, only 40% of the patients of the non-PTCA group were free of angina pectoris at stress. In the PTCA group, 63% did not complain of any symptoms at follow-up (p < 0.05)., Conclusions: We conclude that determination of the CFVR is a valuable parameter for stratifying the hemodynamic significance of coronary artery stenosis. PTCA can safely be deferred in patients with significant coronary stenosis but a CFVR > or = 2.0. The total rate of MACE at follow-up was below 10% among these patients. However, if PTCA was deferred the number of patients who are free of angina is lower compared to those patients who underwent angioplasty.

My long-term goal is to prepare a study leading to a history of medieval German medical literature, from the beginnings to about 1500. This literature is largely missing from the standard histories of medicine, and it also seldom appears in histories of German literature. After reviewing the "überlieferungsgeschichtliche Ansatz", the method of examining texts in the historical and codicological contexts in which they are transmitted, I review the six German medical texts attested in twelfth century manuscripts (not counting individual recipes). These are: the, Prüller Kräuterbuch', the, Prüller Steinbuch', the 'Arzneibuch Ipocratis', the 'Capsula Eburnea', the 'Innsbrucker Arzneibuch', and the 'Frauengeheimnisse', all printed in Friedrich Wilhelm's collection of twelfth century texts. These texts are all from the second half of the century and from the Upper German language area, with Regensburg as the particular focus, and they are transmitted along with important theological and philosophical texts of the time.

During the 15th century a very great percentage (if not the major part) of German men of letters were physicians. This article concentrates on three of them, all of whom were born in Southern Germany, three of them studied in Italy, wrote during the second third of the century, and became widely renowned as physicians as well as poets or writers of prose. Johannes Hartlieb is well-known as author of a 'Kräuterbuch', but his fame is based mainly on his 'Alexanderroman'. The article tries to show a connection between the two aspects of Hartlieb's work, which have not been related to each other until now: the 'Alexanderroman' is, at least in its central theme, a novel that could only be written by a physician; the traces of the author's profession are obvious. The second part of the article deals with Hermann Schedel. It reconstructs his studies in Padua and then concentrates on five of his manuscripts, which reveal the names and professions of his patients. One may compare Hermann's cousin, Hartmann Schedel to Hartlieb. His 'Weltchronik', which is mainly famous for its illustrations, is the work of a physician, as was Hartlieb's 'Alexander'. Hartmann inserted biographical informations about 40 celebrities among his 'colleagues'. If the 15th century may rightly be called the 'century of the layman', it is because it was the 'century of the physician'.