Optimizing working space in laparoscopy: CT-measurement of the effect of neuromuscular blockade and its reversal in a porcine model

Objective: The objective of this paper was to determine the effect of neuromuscular blockade (NMB) on working space in a porcine laparoscopy model. Background: Conflicting results on the effect of NMB on laparoscopic working space are found in literature. Almost all studies are limited by absence of objective assessment of working space or use surrogate outcomes. Methods: In a standardized porcine laparoscopy model, laparoscopic working-space dimensions with and without NMB were investigated in 16 animals using computed tomography at intra-abdominal pressures of 0, 5, 10, and 15 mmHg during multiple runs of abdominal insufflation. Results: No statistically significant effect of NMB on abdominal dimensions and laparoscopic working-space volume was found during CO2 pneumoperitoneum. In contrast, the effect of pre-stretching of the abdominal wall by a previous abdominal insufflation was found to be significant. Conclusions: This experimental study confirms the results from several clinical studies that NMB does not influence laparoscopic working space. Studies dealing with working space during laparoscopy should take note of pre-stretching bias

Impact damage characteristics of carbon fibre metal laminates : experiments and simulation

In this work, the impact response of carbon fibre metal laminates (FMLs) was experimentally and numerically studied with an improved design of the fibre composite lay-up for optimal mechanical properties and damage resistance. Two different stacking sequences (Carall 3–3/2–0.5 and Carall 5–3/2–0.5) were designed and characterised. Damage at relatively low energy impact energies (≤30 J) was investigated using Ultrasonic C-scanning and X–ray Computed Tomography (X-RCT). A 3D finite element model was developed to simulate the impact induced damage in both metal and composite layers using Abaqus/Explicit. Cohesive zone elements were introduced to capture delamination occurring between carbon fibre/epoxy plies and debonding at the interfaces between aluminium and the composite layers. Carall 5–3/2–0.5 was found to absorb more energy elastically, which indicates better resistance to damage. A good agreement is obtained between the numerically predicted results and experimental measurements in terms of force and absorbed energy during impact where the damage modes such as delamination was well simulated when compared to non-destructive techniques (NDT)

Bacteriophage DNA glucosylation impairs target DNA binding by type I and II but not by type V CRISPR-Cas effector complexes

Prokaryotes encode various host defense systems that provide protection against mobile genetic elements. Restriction-modification (R-M) and CRISPR-Cas systems mediate host defense by sequence specific targeting of invasive DNA. T-even bacteriophages employ covalent modifications of nucleobases to avoid binding and therefore cleavage of their DNA by restriction endonucleases. Here, we describe that DNA glucosylation of bacteriophage genomes affects interference of some but not all CRISPR-Cas systems. We show that glucosyl modification of 5-hydroxymethylated cytosines in the DNA of bacteriophage T4 interferes with type I-E and type II-A CRISPR-Cas systems by lowering the affinity of the Cascade and Cas9-crRNA complexes for their target DNA. On the contrary, the type V-A nuclease Cas12a (also known as Cpf1) is not impaired in binding and cleavage of glucosylated target DNA, likely due to a more open structural architecture of the protein. Our results suggest that CRISPR-Cas systems have contributed to the selective pressure on phages to develop more generic solutions to escape sequence specific host defense systems

S-Nitrosoglutathione is a component of wound- and salicylic acid-induced systemic responses in Arabidopsis thaliana

S-Nitrosoglutathione (GSNO) is a bioactive, stable, and mobile reservoir of nitric oxide (NO), and an important player in defence responses to herbivory and pathogen attack in plants. It has been demonstrated previously that GSNO reductase (GSNOR) is the main enzyme responsible for the in vivo control of intracellular levels of GSNO. In this study, the role of S-nitrosothiols, in particular of GSNO, in systemic defence responses in Arabidopsis thaliana was investigated further. It was shown that GSNO levels increased rapidly and uniformly in injured Arabidopsis leaves, whereas in systemic leaves GSNO was first detected in vascular tissues and later spread over the parenchyma, suggesting that GSNO is involved in the transmission of the wound mobile signal through the vascular tissue. Moreover, GSNO accumulation was required to activate the jasmonic acid (JA)-dependent wound responses, whereas the alternative JA-independent wound-signalling pathway did not involve GSNO. Furthermore, extending previous work on the role of GSNOR in pathogenesis, it was shown that GSNO acts synergistically with salicylic acid in systemic acquired resistance activation. In conclusion, GSNOR appears to be a key regulator of systemic defence responses, in both wounding and pathogenesis

Bone mineral density increases in trans persons after 1 year of hormonal treatment : a multicenter prospective observational study

Sex steroids are important determinants of bone acquisition and bone homeostasis. Cross-sex hormonal treatment (CHT) in transgender persons can affect bone mineral density (BMD). The aim of this study was to investigate in a prospective observational multicenter study the first-year effects of CHT on BMD in transgender persons. A total of 231 transwomen and 199 transmen were included who completed the first year of CHT. Transwomen were treated with cyproterone acetate and oral or transdermal estradiol; transmen received transdermal or intramuscular testosterone. A dual-energy X-ray absorptiometry (DXA) was performed to measure lumbar spine (LS), total hip (TH), and femoral neck (FN) BMD before and after 1 year of CHT. In transwomen, an increase in LS (+3.67%, 95% confidence interval [CI] 3.20 to 4.13%, p < 0.001), TH (+0.97%, 95% CI 0.62 to 1.31%, p < 0.001), and FN (+1.86%, 95% CI 1.41 to 2.31%, p < 0.001) BMD was found. In transmen, TH BMD increased after 1 year of CHT (+1.04%, 95% CI 0.64 to 1.44%, p < 0.001). No changes were observed in FN BMD (–0.46%, 95% CI –1.07 to 0.16%, p = 0.144). The increase in LS BMD was larger in transmen aged ≥50 years (+4.32%, 95% CI 2.28 to 6.36%, p = 0.001) compared with transmen aged <50 years (+0.68%, 95% CI 0.19 to 1.17%, p = 0.007). In conclusion, BMD increased in transgender persons after 1 year of CHT. In transmen of postmenopausal age, the LS BMD increased more than in younger transmen, which may lead to the hypothesis that the increase in BMD in transmen is the result of the aromatization of testosterone to estradiol

Target and Tissue Selectivity Prediction by Integrated Mechanistic Pharmacokinetic-Target Binding and Quantitative Structure Activity Modeling

Selectivity is an important attribute of effective and safe drugs, and prediction of in vivo target and tissue selectivity would likely improve drug development success rates. However, a lack of understanding of the underlying (pharmacological) mechanisms and availability of directly applicable predictive methods complicates the prediction of selectivity. We explore the value of combining physiologically based pharmacokinetic (PBPK) modeling with quantitative structure-activity relationship (QSAR) modeling to predict the influence of the target dissociation constant (K D) and the target dissociation rate constant on target and tissue selectivity. The K D values of CB1 ligands in the ChEMBL database are predicted by QSAR random forest (RF) modeling for the CB1 receptor and known off-targets (TRPV1, mGlu5, 5-HT1a). Of these CB1 ligands, rimonabant, CP-55940, and Δ8-tetrahydrocanabinol, one of the active ingredients of cannabis, were selected for simulations of target occupancy for CB1, TRPV1, mGlu5, and 5-HT1a in three brain regions, to illustrate the principles of the combined PBPK-QSAR modeling. Our combined PBPK and target binding modeling demonstrated that the optimal values of the K D and k off for target and tissue selectivity were dependent on target concentration and tissue distribution kinetics. Interestingly, if the target concentration is high and the perfusion of the target site is low, the optimal K D value is often not the lowest K D value, suggesting that optimization towards high drug-target affinity can decrease the benefit-risk ratio. The presented integrative structure-pharmacokinetic-pharmacodynamic modeling provides an improved understanding of tissue and target selectivity.Medicinal Chemistr

Editorial: Induced resistance and priming against pests and pathogens

Due to the rapidly changing climate and increasingly restrictive regulations on the use of pesticides, there is an urgent need to discover and develop new and more sustainable strategies of crop protection that meet the present and future needs of a growing world population. Fundamental research on plant-microbe and plant-insect interactions – both pathogenic and beneficial – is of key importance to gain a better molecular, physiological and ecological understanding of these complex interactions and so generate the tools necessary to develop new crop protection strategies. Induced resistance (IR) develops after treatment of plants with pathogens, pests, beneficial microorganisms, chemical agents, physical wounding, or herbivory. Plants exposed to such stimuli increase their level of basal resistance against future attacks compared to non-stimulated plants. IR is often based on a priming of basal defense mechanisms, which enables a faster and/or stronger defense response upon secondary challenge. Given its long-lasting nature and broad-spectrum effectiveness, IR has long been recognized for its value in integrated pest and disease management approaches. This Research Topic highlights the latest advances in research on IR and priming presented at the IOBC-PR-IR2022 conference in Sheffield, UK, from 4th to 7th April 2022, which is organized by the working group of the International Organization for Biological Control. In addition to reviewing the scientific significance of this work, we discuss future challenges in IR research and the potential application of IR in future crop protection strategies

Contacts and contracts: Cross-level network dynamics in the development of an aircraft material

In this paper, we investigate how interorganizational networks and interpersonal networks interact over time. We present a retrospective longitudinal case study of the network system that developed a novel aircraft material and analyze changeepisodes from a structurationist perspective. We identify five types of episodes in which interpersonal and interorganizational networks interact (persistence, prospecting, consolidation, reconfiguration, and dissolution) and analyze conditionsfor these episodes and sequences among them. Our findings advance a cross-level perspective on embeddedness and show how individuals may draw on relational and structural embeddedness as distributed resources. The multiple levels of embeddedness impact network dynamics by introducing converging and diverging dialectics, thereby limiting path dependence and proactive network orchestration

Level of arterial ligation in total mesorectal excision (TME): an anatomical study

Introduction: High-tie ligation is a common practice in rectal cancer surgery. However, it compromises perfusion of the proximal limb of the anastomosis. This anatomical study was designed to assess the value of low-tie ligation in order to obtain a tension-free anastomosis. Materials and methods: Consecutive high- and low-tie resections were performed on 15 formalin-fixed specimens, with or without splenic flexure mobilization. If the proximal colon limb could reach the superior aspect of the symphysis pubis with more than 3 cm, the limb would be long enough for a tension-free colorectal anastomosis. Results: In 80% of cases, it was not necessary to perform high-tie ligation as sufficient length was gained with low-tie ligation. The descending branch of the left colic artery was the limiting factor in the other 20% of cases. Resecting half the sigmoid resulted in four times as many tension-free anastomoses after low-tie resection. Conclusion: In the majority of cases, it was not necessary to perform high-tie ligation in order to create a tension-free anastomosis. Low-tie ligation was applicable in 80% of cases and might prevent anastomotic leakage due to insufficient blood supply of the proximal colon limb

Dynamics of Responses in Compatible Potato - Potato virus Y Interaction Are Modulated by Salicylic Acid

To investigate the dynamics of the potato – Potato virus Y (PVY) compatible interaction in relation to salicylic acid - controlled pathways we performed experiments using non-transgenic potato cv. Désirée, transgenic NahG-Désirée, cv. Igor and PVYNTN, the most aggressive strain of PVY. The importance of salicylic acid in viral multiplication and symptom development was confirmed by pronounced symptom development in NahG-Désirée, depleted in salicylic acid, and reversion of the effect after spraying with 2,6-dichloroisonicotinic acid (a salicylic acid - analogue). We have employed quantitative PCR for monitoring virus multiplication, as well as plant responses through expression of selected marker genes of photosynthetic activity, carbohydrate metabolism and the defence response. Viral multiplication was the slowest in inoculated potato of cv. Désirée, the only asymptomatic genotype in the study. The intensity of defence-related gene expression was much stronger in both sensitive genotypes (NahG-Désirée and cv. Igor) at the site of inoculation than in asymptomatic plants (cv. Désirée). Photosynthesis and carbohydrate metabolism gene expression differed between the symptomatic and asymptomatic phenotypes. The differential gene expression pattern of the two sensitive genotypes indicates that the outcome of the interaction does not rely simply on one regulatory component, but similar phenotypical features can result from distinct responses at the molecular level