Antimicrobial peptides: agents of border protection for companion animals.

Over the past 20 years, there have been significant inroads into understanding the roles of antimicrobial peptides in homeostatic functions and their involvement in disease pathogenesis. In addition to direct antimicrobial activity, these peptides participate in many cellular functions, including chemotaxis, wound healing and even determination of canine coat colour. Various biological and genetic approaches have helped to elucidate the role of antimicrobial peptides with respect to innate immunity and host defense. Associations of antimicrobial peptides with various skin diseases, including psoriasis, rosacea and atopic dermatitis, have been documented in humans. In the longer term, therapeutic modulation of antimicrobial peptide expression may provide effective new treatments for disease. This review highlights current knowledge about antimicrobial peptides of the skin and circulating leukocytes, with particular focus on relevance to physiology and disease in companion animals

Variable response in alpine tree-ring stable isotopes following volcanic eruptions in the tropics and iceland

The importance of the stable isotopes in tree rings for the study of the climate variations caused by volcanic eruptions is still unclear. We studied δ18O, δD, δ13C stable isotopes of larch and cembran pine cellulose around four major eruptions with annual resolution, along with a superposed epoch analysis of 34 eruptions with 5-year resolution. Initial analysis of the tropical Tambora (1815 CE) and Samalas (1257 CE) eruptions showed a post-eruption decrease in δ18O values attributed to post-volcanic cooling and increased summer precipitation in Southern Europe, as documented by observations and climate simulations. The post-volcanic cooling was captured by the δD of speleothem fluid inclusion. The δ18O decrease was also observed in the analysis of 34 major tropical eruptions over the last 2000 years. In contrast, the eruptions of c. 750, 756, and 764 CE attributed to Icelandic volcanoes left no significant responses in the cellulose isotopes. Further analysis of all major Icelandic eruptions in the last 2000 years showed no consistent isotopic fingerprints, with the exception of lower post-volcanic δ13C values in larch. In summary, the δ18O values of cellulose can provide relevant information on climatic and hydroclimatic variations following major tropical volcanic eruptions, even when using the 5-year resolution wood samples of the Alpine Tree-Ring Isotope Record database

The Hrs/Stam Complex Acts as a Positive and Negative Regulator of RTK Signaling during Drosophila Development

BACKGROUND: Endocytosis is a key regulatory step of diverse signalling pathways, including receptor tyrosine kinase (RTK) signalling. Hrs and Stam constitute the ESCRT-0 complex that controls the initial selection of ubiquitinated proteins, which will subsequently be degraded in lysosomes. It has been well established ex vivo and during Drosophila embryogenesis that Hrs promotes EGFR down regulation. We have recently isolated the first mutations of stam in flies and shown that Stam is required for air sac morphogenesis, a larval respiratory structure whose formation critically depends on finely tuned levels of FGFR activity. This suggest that Stam, putatively within the ESCRT-0 complex, modulates FGF signalling, a possibility that has not been examined in Drosophila yet. PRINCIPAL FINDINGS: Here, we assessed the role of the Hrs/Stam complex in the regulation of signalling activity during Drosophila development. We show that stam and hrs are required for efficient FGFR signalling in the tracheal system, both during cell migration in the air sac primordium and during the formation of fine cytoplasmic extensions in terminal cells. We find that stam and hrs mutant cells display altered FGFR/Btl localisation, likely contributing to impaired signalling levels. Electron microscopy analyses indicate that endosome maturation is impaired at distinct steps by hrs and stam mutations. These somewhat unexpected results prompted us to further explore the function of stam and hrs in EGFR signalling. We show that while stam and hrs together downregulate EGFR signalling in the embryo, they are required for full activation of EGFR signalling during wing development. CONCLUSIONS/SIGNIFICANCE: Our study shows that the ESCRT-0 complex differentially regulates RTK signalling, either positively or negatively depending on tissues and developmental stages, further highlighting the importance of endocytosis in modulating signalling pathways during development

Murine cytomegalovirus protein pM79 is a key regulator for viral late transcription

Herpesvirus genes are temporally expressed during permissive infections, but how their expression is regulated at late times is poorly understood. Previous studies indicate that the human cytomegalovirus (CMV) gene, UL79, is required for late gene expression. However, the mechanism remains to be fully elucidated, and UL79 homologues in other CMVs have not been studied. Here, we characterized the role of the conserved murine CMV (MCMV) gene M79. We showed that M79 encoded a protein (pM79) which was expressed with early-late kinetics and localized to nuclear viral replication compartments. M79 transcription was significantly decreased in the absence of viral DNA synthesis but markedly stimulated by pM79. To investigate its role, we created the recombinant virus SMin79, in which pM79 expression was disrupted. While marker-rescued virus grew efficiently in fibroblasts, SMin79 failed to produce infectious progeny but was rescued by pM79 expression in trans. During SMin79 infection, representative viral immediate-early and early gene products as well as viral DNA accumulated sufficiently. Formation of viral replication compartments also appeared normal. Pulsed-field gel electrophoresis analysis indicated that the overall structure of replicating viral DNA was indistinguishable between wild-type and SMin79 infection. Viral tiled array and quantitative PCR analysis revealed that many late transcripts sensitive to a viral DNA synthesis inhibitor (phosphonoacetic acid) were markedly reduced by pM79 mutation. This study indicates that cytomegaloviruses use a conserved mechanism to promote transcription at late stages of infection and that pM79 is a critical regulator for at least a subset of viral DNA synthesis-dependent transcripts

Towards Improved Quantum Simulations and Sensing with Trapped 2D Ion Crystals via Parametric Amplification

Improving coherence is a fundamental challenge in quantum simulation and sensing experiments with trapped ions. Here we discuss, experimentally demonstrate, and estimate the potential impacts of two different protocols that enhance, through motional parametric excitation, the coherent spin-motion coupling of ions obtained with a spin-dependent force. The experiments are performed on 2D crystal arrays of approximately one hundred $^9$Be$^+$ ions confined in a Penning trap. By modulating the trapping potential at close to twice the center-of-mass mode frequency, we squeeze the motional mode and enhance the spin-motion coupling while maintaining spin coherence. With a stroboscopic protocol, we measure $5.4 \pm 0.9$ dB of motional squeezing below the ground-state motion, from which theory predicts a $10$ dB enhancement in the sensitivity for measuring small displacements using a recently demonstrated protocol [Science $\textbf{373}$, 673 (2021)]. With a continuous squeezing protocol, we measure and accurately calibrate the parametric coupling strength. Theory suggests this protocol can be used to improve quantum spin squeezing, limited in our system by off-resonant light scatter. We illustrate numerically the trade-offs between strong parametric amplification and motional dephasing in the form of center-of-mass frequency fluctuations for improving quantum spin squeezing in our set-up.Comment: 11 pages, 6 figure

Infarct-remodelled hearts with limited oxidative capacity boost fatty acid oxidation after conditioning against ischaemia/reperfusion injury

Aims Infarct-remodelled hearts are less amenable to protection against ischaemia/reperfusion. Understanding preservation of energy metabolism in diseased vs. healthy hearts may help to develop anti-ischaemic strategies effective also in jeopardized myocardium. Methods and results Isolated infarct-remodelled/sham Sprague-Dawley rat hearts were perfused in the working mode and subjected to 15 min of ischaemia and 30 min of reperfusion. Protection of post-ischaemic ventricular work was achieved by pharmacological conditioning with sevoflurane. Oxidative metabolism was measured by substrate flux in fatty acid and glucose oxidation using [3H]palmitate and [14C]glucose. Mitochondrial oxygen consumption was measured in saponin-permeabilized left ventricular muscle fibres. Activity assays of citric acid synthase, hydroxyacyl-CoA dehydrogenase, and pyruvate dehydrogenase and mass spectrometry for acylcarnitine profiling were also performed. Six weeks after coronary artery ligation, the hearts exhibited macroscopic and molecular signs of hypertrophy consistent with remodelling and limited respiratory chain and citric acid cycle capacity. Unprotected remodelled hearts showed a marked decline in palmitate oxidation and acetyl-CoA energy production after ischaemia/reperfusion, which normalized in sevoflurane-protected remodelled hearts. Protected remodelled hearts also showed higher β-oxidation flux as determined by increased oxygen consumption with palmitoylcarnitine/malate in isolated fibres and a lower ratio of C16:1+C16OH/C14 carnitine species, indicative of a higher long-chain hydroxyacyl-CoA dehydrogenase activity. Remodelled hearts exhibited higher PPARα-PGC-1α but defective HIF-1α signalling, and conditioning enabled them to mobilize fatty acids from endogenous triglyceride stores, which closely correlated with improved recovery. Conclusions Protected infarct-remodelled hearts secure post-ischaemic energy production by activation of β-oxidation and mobilization of fatty acids from endogenous triglyceride store

Spatio-temporally separated cortical flows and spindle geometry establish physical asymmetry in fly neural stem cells

Asymmetric cell division, creating sibling cells with distinct developmental potentials, can be manifested in sibling cell size asymmetry. This form of physical asymmetry occurs in several metazoan cells, but the underlying mechanisms and function are incompletely understood. Here we use Drosophila neural stem cells to elucidate the mechanisms involved in physical asymmetry establishment. We show that Myosin relocalizes to the cleavage furrow via two distinct cortical Myosin flows: at anaphase onset, a polarity induced, basally directed Myosin flow clears Myosin from the apical cortex. Subsequently, mitotic spindle cues establish a Myosin gradient at the lateral neuroblast cortex, necessary to trigger an apically directed flow, removing Actomyosin from the basal cortex. On the basis of the data presented here, we propose that spatiotemporally controlled Myosin flows in conjunction with spindle positioning and spindle asymmetry are key determinants for correct cleavage furrow placement and cortical expansion, thereby establishing physical asymmetry