The natural antibiotic teixobactin kills pathogenic bacteria without detectable resistance. The difficult synthesis and unfavourable solubility of teixobactin require modifications, yet insufficient ...knowledge on its binding mode impedes the hunt for superior analogues. Thus far, teixobactins are assumed to kill bacteria by binding to cognate cell wall precursors (Lipid II and III). Here we present the binding mode of teixobactins in cellular membranes using solid-state NMR, microscopy, and affinity assays. We solve the structure of the complex formed by an improved teixobactin-analogue and Lipid II and reveal how teixobactins recognize a broad spectrum of targets. Unexpectedly, we find that teixobactins only weakly bind to Lipid II in cellular membranes, implying the direct interaction with cell wall precursors is not the sole killing mechanism. Our data suggest an additional mechanism affords the excellent activity of teixobactins, which can block the cell wall biosynthesis by capturing precursors in massive clusters on membranes.
Over the past two decades, magnetic hyperthermia and photothermal therapy are becoming very promising supplementary techniques to well-established cancer treatments such as radiotherapy and ...chemotherapy. These techniques have dramatically improved their ability to perform controlled treatments, relying on the procedure of delivering nanoscale objects into targeted tumor tissues, which can release therapeutic killing doses of heat either upon AC magnetic field exposure or laser irradiation. Although an intense research effort has been made in recent years to study, separately, magnetic hyperthermia using iron oxide nanoparticles and photothermal therapy based on gold or silver plasmonic nanostructures, the full potential of combining both techniques has not yet been systematically explored. Here we present a proof-of-principle experiment showing that designing multifunctional silver/magnetite (Ag/Fe3O4) nanoflowers acting as dual hyperthermia agents is an efficient route for enhancing their heating ability or specific absorption rate (SAR). Interestingly, the SAR of the nanoflowers is increased by at least 1 order of magnitude under the application of both an external magnetic field of 200 Oe and simultaneous laser irradiation. Furthermore, our results show that the synergistic exploitation of the magnetic and photothermal properties of the nanoflowers reduces the magnetic field and laser intensities that would be required in the case that both external stimuli were applied separately. This constitutes a key step toward optimizing the hyperthermia therapy through a combined multifunctional magnetic and photothermal treatment and improving our understanding of the therapeutic process to specific applications that will entail coordinated efforts in physics, engineering, biology, and medicine.
We present the results of a blind exercise to test the recoverability of stellar rotation and differential rotation in Kepler light curves. The simulated light curves lasted 1000 d and included ...activity cycles, Sun-like butterfly patterns, differential rotation and spot evolution. The range of rotation periods, activity levels and spot lifetime were chosen to be representative of the Kepler data of solar-like stars. Of the 1000 simulated light curves, 770 were injected into actual quiescent Kepler light curves to simulate Kepler noise. The test also included five 1000-d segments of the Sun's total irradiance variations at different points in the Sun's activity cycle. Five teams took part in the blind exercise, plus two teams who participated after the content of the light curves had been released. The methods used included Lomb–Scargle periodograms and variants thereof, autocorrelation function and wavelet-based analyses, plus spot modelling to search for differential rotation. The results show that the ‘overall’ period is well recovered for stars exhibiting low and moderate activity levels. Most teams reported values within 10 per cent of the true value in 70 per cent of the cases. There was, however, little correlation between the reported and simulated values of the differential rotation shear, suggesting that differential rotation studies based on full-disc light curves alone need to be treated with caution, at least for solar-type stars. The simulated light curves and associated parameters are available online for the community to test their own methods.
Abstract
To alleviate anti-cancer treatment burden in advanced breast cancer, patient-clinician communication strategies based on nocebo-effect mechanisms are promising. We assessed distinct/combined ...effects on psychological outcomes (e.g. anxiety; main outcome) and side-effect expectations of (1) nocebo information about the (non)pharmacological origin of side effects, and (2) clinician-expressed empathy through reassurance of continuing support. Furthermore, we explored whether information and empathy effects on side-effect expectations were mediated by decreased anxiety. In a two-by-two experimental video-vignette design, 160 cancer patients/survivors and healthy women watched one of four videos differing in level of nocebo information (±) and empathy (±). Regression and mediation analysis were used to determine effects of information/empathy and explore anxiety’s mediating role. Anxiety was not influenced by empathy or information (Stai-state: p = 0.281; p = 0.410, VAS p = 0.387; p = 0.838). Information improved (specific) side-effect coping expectations (p < 0.01). Empathy improved side-effect intensity expectations (p < 0.01 = specific; p < 0.05 = non-specific/partial) and specific side-effect probability expectations (p < 0.01), and increased satisfaction, trust, and self-efficacy (p < 0.001). No mediating effects were found of anxiety on expectations. Mainly empathy, but also nocebo information improved psychological outcomes and—mainly specific—side-effect expectations. Exploring the power of these communication elements in clinical practice is essential to diminish the anti-cancer treatment burden in advanced breast cancer.
Purpose
The aim of this study is to investigate whether total knee arthroplasty (TKA) patients who consulted an occupational medicine specialist (OMS) within 3 months after surgery, return to work ...(RTW) earlier than patients who did not consult an OMS.
Methods
A multi-center prospective cohort study was performed among working TKA patients, aged 18 to 65 years and intending to RTW. Time to RTW was analyzed using Kaplan Meier and Mann Whitney U (MWU), and multiple linear regression analysis was used to adjust for effect modification and confounding.
Results
One hundred and eighty-two (182) patients were included with a median age of 59 years IQR 54–62, including 95 women (52%). Patients who consulted an OMS were less often self-employed but did not differ on other patient and work-related characteristics. TKA patients who consulted an OMS returned to work later than those who did not (median 78 versus 62 days, MWU p < 0.01). The effect of consulting an OMS on time to RTW was modified by patients’ expectations in linear regression analysis (p = 0.05). A median decrease in time of 24 days was found in TKA patients with preoperative high expectations not consulting an OMS (p = 0.03), not in patients with low expectations.
Conclusions
Consulting an OMS within 3 months after surgery did not result in a decrease in time to RTW in TKA patients. TKA patients with high expectations did RTW earlier without consulting an OMS. Intervention studies on how OMSs can positively influence a timely RTW, incorporating patients’ preoperative expectations, are needed.
Forests are major components of the global carbon cycle, providing substantial feedback to atmospheric greenhouse gas concentrations. Our ability to understand and predict changes in the forest ...carbon cycle--particularly net primary productivity and carbon storage--increasingly relies on models that represent biological processes across several scales of biological organization, from tree leaves to forest stands. Yet, despite advances in our understanding of productivity at the scales of leaves and stands, no consensus exists about the nature of productivity at the scale of the individual tree, in part because we lack a broad empirical assessment of whether rates of absolute tree mass growth (and thus carbon accumulation) decrease, remain constant, or increase as trees increase in size and age. Here we present a global analysis of 403 tropical and temperate tree species, showing that for most species mass growth rate increases continuously with tree size. Thus, large, old trees do not act simply as senescent carbon reservoirs but actively fix large amounts of carbon compared to smaller trees; at the extreme, a single big tree can add the same amount of carbon to the forest within a year as is contained in an entire mid-sized tree. The apparent paradoxes of individual tree growth increasing with tree size despite declining leaf-level and stand-level productivity can be explained, respectively, by increases in a tree's total leaf area that outpace declines in productivity per unit of leaf area and, among other factors, age-related reductions in population density. Our results resolve conflicting assumptions about the nature of tree growth, inform efforts to undertand and model forest carbon dynamics, and have additional implications for theories of resource allocation and plant senescence.
Anxiety disorders are the most common mental illness in the USA affecting 18% of the population. The cause(s) of anxiety disorders is/are not completely clear, and research in the neurobiology of ...anxiety at the molecular level is still rather limited. Although mounting clinical and preclinical evidence now indicates that oxidative stress may be a major component of anxiety pathology, whether oxidative stress is the cause or consequence remains elusive. Studies conducted over the past few years suggest that anxiety disorders may be characterised by lowered antioxidant defences and increased oxidative damage to proteins, lipids, and nucleic acids. In particular, oxidative modifications to proteins have actually been proposed as a potential factor in the onset and progression of several psychiatric disorders, including anxiety and depressive disorders. Oxidised proteins are normally degraded by the proteasome proteolytic complex in the cell cytoplasm, nucleus, and endoplasmic reticulum. The Lon protease performs a similar protective function inside mitochondria. Impairment of the proteasome and/or the Lon protease results in the accumulation of toxic oxidised proteins in the brain, which can cause severe neuronal trauma. Recent evidence points to possible proteolytic dysfunction and accumulation of damaged, oxidised proteins as factors that may determine the appearance and severity of psychotic symptoms in mood disorders. Thus, critical interactions between oxidative stress, proteasome, and the Lon protease may provide keys to the molecular mechanisms involved in emotional regulation, and may also be of great help in designing and screening novel anxiolytics and antidepressants.
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Water contamination by multidrug resistant (MDR) enteric bacteria can be considered as the foremost cause of gastrointestinal infections and poses a threat to global public health. ...Therefore, there is an urgent need to pursue unorthodox techniques with potential of community scale applications for purging of water borne pathogenic bacteria. We communicate visible-light assisted photocatalytic disinfection (PCD) of an enteric MDR bacterium; Enterobacter sp. using Fe-doped ZnO nanoparticles impregnated on Kaolinite (Clay) (ZnO/K). ZnO/K was synthesized by co-precipitation technique and was found to be more effective than Fe-doped ZnO (ZnO) and Kaolinite for PCD process. Analysis from fluorescence microscopy and electron microscopy (FESEM) proposed complete bacterial cell death via PCD due to damage of bacterial cell membrane. Experimental evidences indicated that O2− could be acting as the most significant component in disinfection of MDR Enterobacter sp. in visible-light assisted PCD process in presence of ZnO/K. Considering the experimental data of Resazurin assay, it is proposed that reactive oxygen species (ROS) generated during PCD might have impeded the oxido-reductase enzyme system of the bacteria and hence trammeling its metabolic activity. Crystal structure and particle size of ZnO/K was found to be unaltered during the photocatalytic process indicating its potential for reusability. When ZnO/K was exposed to HCT-116 Human Colorectal Carcinoma cell lines, about 79% cell survivability was noticed. The synthesized material was successful in completely disinfecting the target microorganism in Zebra Fish model, without producing any adverse effects on the Fish itself, further reinforcing its biocompatibility factor. High effectiveness of PCD process using ZnO/K under visible light in disinfecting enteric MDR bacteria, might have promising outcome as an alternative water disinfection technology to prevent the spread of infectious and resistant bacteria without producing any adverse effect on non-specific flora and fauna.
Current staging methods for pancreatic cancer (PC) are inadequate, and biomarkers to aid clinical decision making are lacking. Despite the availability of the serum marker carbohydrate antigen 19.9 ...(CA19.9) for over two decades, its precise role in the management of PC is yet to be defined, and as a consequence, it is not widely used.
We assessed the relationship between perioperative serum CA19.9 levels, survival and adjuvant chemotherapeutic responsiveness in a cohort of 260 patients who underwent operative resection for PC.
By specifically assessing the subgroup of patients with detectable CA19.9, we identified potential utility at key clinical decision points. Low postoperative CA19.9 at 3 months (median survival 25.6 vs 14.8 months, P = 0.0052) and before adjuvant chemotherapy were independent prognostic factors. Patients with postoperative CA 19.9 levels >90 U/ml did not benefit from adjuvant chemotherapy (P = 0.7194) compared with those with a CA19.9 of ≤90 U/ml (median 26.0 vs 16.7 months, P = 0.0108). Normalization of CA19.9 within 6 months of resection was also an independent favorable prognostic factor (median 29.9 vs 14.8 months, P = 0.0004) and normal perioperative CA19.9 levels identified a good prognostic group, which was associated with a 5-year survival of 42%.
Perioperative serum CA19.9 measurements are informative in patients with detectable CA19.9 (defined by serum levels of >5 U/ml) and have potential clinical utility in predicting outcome and response to adjuvant chemotherapy. Future clinical trials should prioritize incorporation of CA19.9 measurement at key decision points to prospectively validate these findings and facilitate implementation.
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