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Treatment of bacterial infections is one of the major challenges of our time due to the evolved resistance mechanisms of pathogens against antibiotics. To circumvent this problem, it is necessary to understand the mode of action of the drug and the mechanism of resistance of the pathogen. One of the most potent antibiotic targets is peptidoglycan (PGN) biosynthesis, as this is an exclusively occurring and critical feature of bacteria. Lipid II is an essential PGN precursor synthesized in the cytosol and flipped into the outer leaflet of the membrane prior to its incorporation into nascent PGN. Antimicrobial peptides (AMPs), such as nisin and colistin, targeting PGN synthesis are considered promising weapons against multidrug-resistant bacteria. However, human pathogenic bacteria that were also resistant to these compounds evolved by the expression of an ATP-binding cassette transporter of the bacitracin efflux (BceAB) type localized in the membrane. In the human pathogen Streptococcus agalactiae, the BceAB transporter SaNsrFP is known to confer resistance to the antimicrobial peptide nisin. The exact mechanism of action for SaNsrFP is poorly understood. For a detailed characterization of the resistance mechanism, we heterologously expressed SaNsrFP in Lactococcus lactis. We demonstrated that SaNsrFP conferred resistance not only to nisin but also to a structurally diverse group of antimicrobial PGN-targeting compounds such as ramoplanin, lysobactin, or bacitracin/(Zn)-bacitracin. Growth experiments revealed that SaNsrFP-producing cells exhibited normal behavior when treated with nisin and/or bacitracin, in contrast to the nonproducing cells, for which growth was significantly reduced. We further detected the accumulation of PGN precursors in the cytoplasm after treating the cells with bacitracin. This did not appear when SaNsrFP was produced. Whole-cell proteomic protein experiments verified that the presence of SaNsrFP in L. lactis resulted in higher production of several proteins associated with cell wall modification. These included, for example, the N-acetylmuramic acid-6-phosphate etherase MurQ and UDP-glucose 4-epimerase. Analysis of components of the cell wall of SaNsrFP-producing cells implied that the transporter is involved in cell wall modification. Since we used an ATP-deficient mutant of the transporter as a comparison, we can show that SaNsrFP and its inactive mutant do not show the same phenotype, albeit expressed at similar levels, which demonstrates the ATP dependency of the mediated resistance processes. Taken together, our data agree to a target protection mechanism and imply a direct involvement of SaNsrFP in resistance by shielding the membrane-localized target of these antimicrobial peptides, resulting in modification of the cell wall.

The assessment of water quality is critical to implement preventive and emergency interventions aimed to limit/avoid environmental contamination and human exposure to toxic compounds. While established high-resolution techniques allow quantitative and qualitative determination of contaminants, their widespread application is not feasible due to cost, time, and need for trained personnel. In this context, the development of easy-to-implement approaches for preliminary detection of contaminants is of the utmost importance. Herein, a portable self-powered microbial electrochemical sensor enabling online monitoring of Cr(VI) is reported. The biosensor employs a bio-inspired redox mediating system to allow extracellular electron transfer between a bacterial isolate from chromium-contaminated environments and the electrode, providing a clear response to Cr(VI) presence. The biosensor shows good linearity (R2 = 0.983) and a limit of detection of 2.4 mg L−1 Cr(VI), with a sensitivity of 0.31 ± 0.02 μA cm−2 mgCr(VI)−1 L. The presented microbial bioanode architecture enhanced biosensor performance thanks to the improved “electrical wiring” between biological entities and the abiotic electrode surface. This approach could be easily implemented in engineered electrode surfaces, such as paper-based multi-anodes that maximize bacterial colonization, further improving biosensor response.

Untersucht wird der empirische Zusammenhang zwischen Aufsichtsratsvergutung und vergutungsbasierten Masen der Effektivitat der Uberwachung des Vorstands. Vor diesem Hintergrund verwenden wir einen Datensatz bestehend aus Gesellschaften des deutschen Prime Standard und stellen im Wege des Fixed-Effects-Ansatzes den Erklarungsgehalt der Aufsichtsratsvergutungshohe und -struktur zur vorstandsvergutungsbezogenen Uberwachungseffektivitat (ubermasige Vorstandsvergutung und Pay for Performance-Sensitivitat) fest. Wir messen einen positiven Zusammenhang zwischen anreizorientierten (insb. leistungsorientierten) Aufsichtsratsvergutungssystemen und ubermasiger Vorstandsvergutung. Weiterhin moderieren anreizorientierte (insb. leistungsorientierte) Vergutungsbestandteile die Pay for Performance-Sensitivitat negativ. Wir schlussfolgern daraus einen positiven Zusammenhang zwischen Agency-Kosten und anreizorientierter Aufsichtsratsvergutung und argumentieren, dass entsprechende Aufsichtsratsvergutungsformen aus Sicht der Aktionare nicht Bestandteil eines optimalen Vergutungskontrakts sein konnen. Da fur langfristig erfolgsorientierte Aufsichtsratsvergutungsstrukturen teilweise gegenteilige Befunde festgestellt werden, schlagen wir die Aufnahme einer unmittelbaren Empfehlung dieser Entlohnungsform in den Deutschen Corporate Governance Kodex (DCGK) vor.

This paper discusses otorhinolaryngological symptoms associated with functional disorders of the upper cervical spine. Hints aimed to avoid misdiagnoses of cross-organ otorhinolaryngological symptoms as phobic or psychogenic disorders are presented. Clinically relevant neuroanatomical convergence of the upper cervical spine (occiput to C3) is fundamental for the interpretation of functional otorhinolaryngological symptoms. Based thereon, evidence for the most common cervical differential diagnoses of dizziness, tinnitus, dysphagia, and craniomandibular dysfunction is presented separately. The corresponding therapeutic options and their contraindications are discussed in the concluding chapter. The importance of interdisciplinary cooperation in related fields is emphasized.

Despite the relative successes in the surgical treatment of pharmacoresistant epilepsy, there is rather little research on the neural (re)organization that potentially subserves behavioral compensation. Here, we examined the post-surgical functional connectivity (FC) in children and adolescents who have undergone unilateral cortical resection and, yet, display remarkably normal behavior. Conventionally, FC has been investigated in terms of the mean correlation of the BOLD time courses extracted from different brain regions. Here, we demonstrated the value of segregating the voxel-wise relationships into mutually exclusive populations that were either positively or negatively correlated. While, relative to controls, the positive correlations were largely normal, negative correlations among networks were increased. Together, our results point to reorganization in the contralesional hemisphere, possibly suggesting competition for cortical territory due to the demand for representation of function. Conceivably, the ubiquitous negative correlations enable the differentiation of function in the reduced cortical volume following a unilateral resection.

The replacement of native species by invasive species is one of the most critical threats to the biodiversity of aquatic systems today. However, little is known about potential effects of species invasions on the genetic diversity of indigenous species in cases where the latter coexist with the invader. Here we present an example of the indigenous amphipod Gammarus roeselii, which has been partly replaced by the invasive Dikerogammarus villosus in Lake Constance (C-Europe) and now mostly exists in small, isolated populations. We compared the genetic diversity, population structure, indicators for bottlenecks and migrations rates of G. roeselii before and after the invasion event from samples collected between 1999 and 2013. We expected a genetic impoverishment in the reduced and segregated populations of G. roeselii. However, no genetic measure on G. roeselii differed temporally or spatially over the investigated period, which indicates that D. villosus has not yet had an impact on G. roeselii at the genetic scale. Hence, even though a decline in population size of G. roeselii was found in Lake Constance, our results on the genetic scale contribute to recent findings that the overall impact of D. villosus on native species is not as strong as often discussed.

A population of loaches (Barbatula spec.) from the Aach Cave in Germany represents the first cave fish in Europe and the northernmost cave fish worldwide. Reasons for the evolution of this fish may include that its cave is fed by surface water that percolates from the upper Danube and enhances the habitat. Cave Barbatula are evolutionarily young and may serve to generalize findings about the well-studied Mexican cave tetra (Astyanax mexicanus). published

Pockmarks are variably sized crater-like structures that occur in young continental margin sediments. They are formed by gas eruptions and/or long-term release of fluid or gas. So far no pockmarks were known from the Pacific coast of South America between 51°S and 55°S. This article documents an extensive and previously unknown pockmark field in the Seno Otway (Otway Sound, 52°S) with multibeam bathymetry and parametric echosounding as well as sediment drill cores. Up to 31 pockmarks per square kilometer occur in water depths of 50 to >100 m in late glacial and Holocene sediments. They are up to 150 m wide and 10 m deep. Below and near the pockmarks, echosounder profiles image acoustic blanking as well as gas chimneys often crosscutting the 20 to >30 m thick glacial sediments above the acoustic basement, in particular along fault zones. Upward-migrating gas is trapped within the sediment strata, forming dome-like features. Two 5 m long piston cores from inside and outside a typical pockmark give no evidence for gas storage within the uppermost sediments. The inside core recovered poorly sorted glacial sediment, indicating reworking and re-deposition after several explosive events. The outside core documents an undisturbed stratigraphic sequence since ~15 ka. Many buried paleo-pockmarks occur directly below a prominent seismic reflector marking the mega-outflow event of the Seno Otway at 14.3 ka, lowering the proglacial lake level by about 80 m. This decompression would have led to frequent eruptions of gas trapped in reservoirs below the glacial sediments. However, the sediment fill of pockmarks formed after this event suggests recurrent events throughout the Holocene until today. Most pockmarks occur above folded hydrocarbon-bearing Upper Cretaceous and Paleogene rocks near the western margin of the Magallanes Basin, constraining them as likely source rocks for thermogenic gas. This study was funded by Grant Ki-456/11 of the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG). We thank Willi Weinrebe (Geomar, Kiel) for his assistance in setting up the portable multi beam equipment, and Marcelo Arevalo for his encouragement during various cruises aboard the RV Gran Campo II since 2002, Dr. Carlos Ríos from the University of Magallanes for a multiple logistic support, and Francisco Ríos for assessing a preliminary version of the manuscript. Also acknowledged are very constructive suggestions from the journal editors and an anonymous reviewer. Peerreview

Leslie Gail Ungerleider, a distinguished experimental psychologist and neuroscientist, previously Chief of the Laboratory of Brain and Cognition at the National Institute of Mental Health, died suddenly on 11 December 2020. Friends, family, colleagues, and trainees all the world over mourn her passing, but also celebrate her life and extraordinary achievements.

Isoprenylated proteins are associated with membranes and their inter-compartmental distribution is regulated by solubilization factors, which incorporate lipid moieties in hydrophobic cavities and thereby facilitate free diffusion during trafficking. Here we report the crystal structure of a solubilization factor, the prenyl-binding protein (PrBP/δ), at 1.81 Å resolution in its ligand-free apo-form. Apo-PrBP/δ harbors a preshaped, deep hydrophobic cavity, capacitating apo-PrBP/δ to readily bind its prenylated cargo. To investigate the molecular mechanism of cargo solubilization we analyzed the PrBP/δ-induced membrane dissociation of rod photoreceptor phosphodiesterase (PDE6). The results suggest that PrBP/δ exclusively interacts with the soluble fraction of PDE6. Depletion of soluble species in turn leads to dissociation of membrane-bound PDE6, as both are in equilibrium. This “solubilization by depletion” mechanism of PrBP/δ differs from the extraction of prenylated proteins by the similar folded solubilization factor RhoGDI, which interacts with membrane bound cargo via an N-terminal structural element lacking in PrBP/δ., The prenyl-binding protein PrBP/δ is a solubilization factor involved in trafficking of prenylated proteins. Here the authors present the ligand-free apo-PrBP/δ structure and propose a "solubilization by depletion" mechanism, where PrBP/δ sequesters only soluble rod photoreceptor phosphodiesterase (PDE6), leading to a dissociation of membrane-bound PDE6.

We have analysed strain and flow kinematics in the footwall of the South Cyclades Shear Zone (SCSZ), an important tectonic boundary within the Attic-Cycladic Crystalline Complex exposed on Ios Island, Cyclades, Aegean Sea. Coarse-grained augen gneisses in the basement unit flooring the SCSZ and forming a metamorphic core complex are excellently suited to measure finite strain using the Fry method and estimate the vorticity number (Wk) of flow with the “blocked-object” method. The results show that Oligo-Miocene exhumation of the basement unit during extension brought approximately 70 % N–S crustal stretching and up to 40 % subvertical shortening in a plane strain environment (k = 0.99). Linear down-section strain decrease constrains a zone of contact deformation of the SCSZ of about 1.5 km thick. Kinematic vorticity number estimates suggest little deviation from pure shear (Wk = 0.26). Finite strain and Wk are not correlated, indicating that the Ios basement and the overlying cover units were stretched compatibly. While the SCSZ is a localized zone of high strain, net displacement, however, may be restricted to about ten kilometres. This has important repercussions on large-scale tectonic models for extension in the Aegean.

A strategy-based reading promotion program was implemented over a course of 8 months in 65 classes from grades 5 to 7 (student age M = 11.2 years, SD = 1.0). It was investigated whether teachers flexibly adapted their pedagogical content beliefs (PCBs) on the teaching of reading according to the instructional principles of the intervention. Fifteen teachers demonstrated the assumed PCB development curves, that is, an initial increase of direct-transmissive positions followed by an increase in the endorsement of constructivist beliefs. Students of teachers whose PCBs showed this belief development pattern demonstrated significantly larger reading achievement gains than students of the other teachers. Thus, teachers’ PCBs are—in principle—open to change which can turn out relevant for student achievement gains.

Behavioral responses to threat are critical to survival. Several cortical and subcortical brain regions respond selectively to threat. However, the relation of these neural responses and their underlying representations to behavior is unclear. We examined the contribution of lower-order subcortical representations to behavioral responses to threat in adult humans. In Experiments 1 and 2, participants viewed pairs of images presented to the same eye or to different eyes. We observed a monocular advantage, which indicates subcortical facilitation, for ancestral threats (snakes, spiders), but not for modern threats, positive images, or neutral images. In Experiment 3, we presented pairs of snakes or neutral images into the temporal or nasal hemifield. For snakes only, we observed a temporal hemifield advantage, which indicates facilitation by the retino-tectal subcortical pathway. These results advance the current understanding of processing of threat by adult humans by revealing the characteristics of behaviors driven by a lower-order neural mechanism that is specialized for the processing of ancestral threats. The results also contribute to ongoing debates concerning the biological generality of neural mechanisms for processing of complex, emotionally-relevant stimuli by providing evidence for conservation of lower-order neural mechanisms for processing of ancestral threats across both ontogeny and phylogeny.

Estrogen-related receptor alpha (ERRα) is an orphan nuclear factor that is a master regulator of cellular energy metabolism. ERRα is overexpressed in a variety of tumors, including ovarian, prostate, colorectal, cervical and breast, and is associated with a more aggressive tumor and a worse outcome. In breast cancer, specifically, high ERRα expression is associated with an increased rate of recurrence and a poor prognosis. Because of the common functions of ERRα and the mTORC1/S6K1 signaling pathway in regulation of cellular metabolism and breast cancer pathogenesis, we focused on investigating the biochemical relationship between ERRα and S6K1. We found that ERRα negatively regulates S6K1 expression by directly binding to its promoter. Downregulation of ERRα expression sensitized ERα-negative breast cancer cells to mTORC1/S6K1 inhibitors. Therefore, our results show that combinatorial inhibition of ERRα and mTORC1/S6K1 may have clinical utility in treatment of triple-negative breast cancer, and warrants further investigation.

λN-mediated processive antitermination constitutes a paradigmatic transcription regulatory event, during which phage protein λN, host factors NusA, NusB, NusE and NusG, and an RNA nut site render elongating RNA polymerase termination-resistant. The structural basis of the process has so far remained elusive. Here we describe a crystal structure of a λN–NusA–NusB–NusE–nut site complex and an electron cryo-microscopic structure of a complete transcription antitermination complex, comprising RNA polymerase, DNA, nut site RNA, all Nus factors and λN, validated by crosslinking/mass spectrometry. Due to intrinsic disorder, λN can act as a multiprotein/RNA interaction hub, which, together with nut site RNA, arranges NusA, NusB and NusE into a triangular complex. This complex docks via the NusA N-terminal domain and the λN C-terminus next to the RNA exit channel on RNA polymerase. Based on the structures, comparative crosslinking analyses and structure-guided mutagenesis, we hypothesize that λN mounts a multipronged strategy to reprogram the transcriptional machinery, which may include (1) the λN C terminus clamping the RNA exit channel, thus stabilizing the DNA:RNA hybrid; (2) repositioning of NusA and RNAP elements, thus redirecting nascent RNA and sequestering the upstream branch of a terminator hairpin; and (3) hindering RNA engagement of termination factor ρ and/or obstructing ρ translocation on the transcript. Structural characterization sheds mechanistic insights behind λN-dependent processive antitermination.

Previous findings have shown that individuals with autism spectrum disorder (ASD) evince greater intra-individual variability (IIV) in their sensory-evoked fMRI responses compared to typical control participants. We explore the robustness of this finding with a new sample of high-functioning adults with autism. Participants were presented with visual, somatosensory and auditory stimuli in the scanner whilst they completed a one-back task. While ASD and control participants were statistically indistinguishable with respect to behavioral responses, the new ASD group exhibited greater IIV relative to controls. We also show that the IIV was equivalent across hemispheres and remained stable over the duration of the experiment. This suggests that greater cortical IIV may be a replicable characteristic of sensory systems in autism.

Following a salient cue that attracts attention to a specific spatial location, perceptual processing of information at that location is facilitated if the interval between the cue and target is brief, or, is inhibited if the interval between the cue and target is long. The mechanisms mediating these attentional dynamics continue to be the subject on ongoing debate. On one classic account, facilitation and inhibition of return (IOR) are two ends of a continuum, generated by the same underlying mechanism. Other accounts have postulated that these two attentional processes emerge from independent systems. To address these alternatives, we report data from three experiments in which a cue and its ensuing target are presented to the same or different eyes at varying cue-target intervals. Whereas the onset of facilitation was apparent earlier when the cue and target shared the eye-of-origin, the onset of IOR was not affected by the eye to which the cue and target were presented. This finding implicates at least some, if not full, independence in the system(s) that give rise to attentional facilitation and IOR, and, moreover, suggests that facilitation may be more reliant on subcortical levels of the visual pathways than IOR.

Muscle lymphoma (ML) is a relatively uncommon condition. On magnetic resonance imaging (MRI), ML can manifest with a broad spectrum of radiological features. The aim of this study was to demonstrate the features of DW images of muscle lymphoma (ML).In our database, ten patients (six women and four men) with ML were identified who were investigated by magnetic resonance imaging including acquisition of DW images. DW images were obtained using a multi-shot SE-EPI pulse sequence. Apparent diffusion constant (ADC) maps were also calculated. Furthermore, fusion images were generated manually from DW and HASTE or T2W images.On T2W images, all recognized lesions were hyperintense in comparison to unaffected musculature and on T1W images they were homogeneously hypointense. All lesions demonstrated low signal intensity on ADC images. The calculated ADC values ranged from 0.60 to 0.90 mm(2)s(-1) (mean value 0.76 ± 0.10; median value 0.78). On fusion images, all lesions showed high signal intensity.ML demonstrated low ADC values and high signal intensity on fusion images suggesting high cellularity of the lesions.

The state-of-the-art monitoring of drinking water hygiene is based on the cultivation and enumeration of indicator bacteria. Despite its proven reliability, this approach has the disadvantages of being (a) relatively slow and (b) limited to a small number of indicator bacteria. Ideally, alternative methods would be less time-consuming while providing information about a larger set of hygienically relevant microorganisms including viruses. In this paper, we present insights into the design of a modular concentration and detection system for bacteria, bacteriophages and viruses. Following further validation, this or similar techniques have the potential to extend and speed up the monitoring of raw and drinking water hygiene in the future. The system consists of different modules for the concentration of microorganisms, an amplification and detection unit that includes a module for the differentiation between live and dead microorganisms, and an automated system for decision support and self-diagnosis. The ongoing testing under controlled laboratory conditions and real-life conditions in the water supply industry yields further system improvements. Moreover, the increased sensitivity and broader range of microbiological parameters emphasize the need for a reconsideration of the currently used criteria for the assessment of (drinking) water hygiene.

Between 33°S and 47°S, the southern Chile forearc is affected by the subduction of the aseismic Juan Fernandez Ridge, several major oceanic fracture zones on the subducting Nazca Plate, the active Chile Ridge spreading centre, and the underthrusting Antarctic Plate. The heat flow through the forearc was estimated using the depth of the bottom simulating reflector obtained from a comprehensive database of reflection seismic profiles. On the upper and middle continental slope along the whole forearc, heat flow is about 30–60 mW m–2, a range of values common for the continental basement and overlying slope sediments. The actively deforming accretionary wedge on the lower slope, however, in places shows heat flow reaching about 90 mW m–2. This indicates that advecting pore fluids from deeper in the subduction zone may transport a substantial part of the heat there. The large size of the anomalies suggests that fluid advection and outflow at the seafloor is overall diffuse, rather than being restricted to individual fault structures or mud volcanoes and mud mounds. One large area with very high heat flow is associated with a major tectonic feature. Thus, above the subducting Chile Ridge at 46°S, values of up to 280 mW m–2 indicate that the overriding South American Plate is effectively heated by subjacent zero-age oceanic plate material.