Neuro-Immune Circuits Regulate Immune Responses in Tissues and Organ Homeostasis

The dense innervation of the gastro-intestinal tract with neuronal networks, which are in close proximity to immune cells, implies a pivotal role of neurons in modulating immune functions. Neurons have the ability to directly sense danger signals, adapt immune effector functions and integrate these signals to maintain tissue integrity and host defense strategies. The expression pattern of a large set of immune cells in the intestine characterized by receptors for neurotransmitters and neuropeptides suggest a tight neuronal hierarchical control of immune functions in order to systemically control immune reactions. Compelling evidence implies that targeting neuro-immune interactions is a promising strategy to dampen immune responses in autoimmune diseases such as inflammatory bowel diseases or rheumatoid arthritis. In fact, electric stimulation of vagal fibers has been shown to be an extremely effective treatment strategy against overwhelming immune reactions, even after exhausted conventional treatment strategies. Such findings argue that the nervous system is underestimated coordinator of immune reactions and underline the importance of neuro-immune crosstalk for body homeostasis. Herein, we review neuro-immune interactions with a special focus on disease pathogenesis throughout the gastro-intestinal tract

Predictors for surgical site infection in patients undergoing therapeutic or prophylactic intra-abdominal onlay mesh (IPOM) implantation in clean and contaminated surgical fields.

BACKGROUND Prophylactic intra-abdominal onlay mesh (IPOM) implantation has been shown to reduce the rate of fascial dehiscence and incisional hernia. However, surgical site infection (SSI) in presence of an IPOM remains a concern. The aim of this study was to assess predictors for SSI following IPOM placement in hernia and non-hernia abdominal surgery in clean and contaminated surgical fields. METHODS Observational study including patients undergoing IPOM placement at a Swiss tertiary care hospital 2007-2016. IPOM implantation was performed in hernia and non-hernia elective and emergency abdominal surgery, including contaminated and infected surgical fields. The incidence of SSI was prospectively assessed by Swissnoso according to CDC criteria. The effect of disease- and procedure-related factors on SSI was assessed in multivariable regression analysis, adjusting for patient-related factors. RESULTS A total of 1072 IPOM implantations were performed. Laparoscopy was performed in 415 patients (38.7%), laparotomy in 657 patients (61.3%). SSI occurred in 172 patients (16.0%). Superficial, deep, and organ space SSI were found in 77 (7.2%), 26 (2.4%), and 69 (6.4%) patients, respectively. Multivariable analysis revealed emergency hospitalization (OR 1.787, p = 0.006), previous laparotomy (1.745, p = 0.029), duration of operation (OR 1.193, p < 0.001), laparotomy (OR 6.167, p < 0.001), bariatric (OR 4.641, p < 0.001), colorectal (OR 1.941, p = 0.001), and emergency (OR 2.510, p < 0.001) surgery, wound class ≥ 3 (OR 3.878, p < 0.001), and non-polypropylene mesh (OR 1.818, p = 0.003) as independent predictors for SSI. Hernia surgery was independently associated with a lower risk for SSI (OR 0.165, p < 0.001). CONCLUSION This study revealed emergency hospitalization, previous laparotomy, duration of operation, laparotomy, as well as bariatric, colorectal, and emergency surgery, abdominal contamination or infection, and usage of non-polypropylene mesh as independent predictors for SSI. In contrast, hernia surgery was associated with a lower risk for SSI. The knowledge of these predictors will help to balance benefits of IPOM implantation against the risk for SSI

ILC3s restrict the dissemination of intestinal bacteria to safeguard liver regeneration after surgery.

It is generally believed that environmental or cutaneous bacteria are the main origin of surgical infections. Therefore, measures to prevent postoperative infections focus on optimizing hygiene and improving asepsis and antisepsis. In a large cohort of patients with infections following major surgery, we identified that the causative bacteria are mainly of intestinal origin. Postoperative infections of intestinal origin were also found in mice undergoing partial hepatectomy. CCR6+ group 3 innate lymphoid cells (ILC3s) limited systemic bacterial spread. Such bulwark function against host invasion required the production of interleukin-22 (IL-22), which controlled the expression of antimicrobial peptides in hepatocytes, thereby limiting bacterial spread. Using genetic loss-of-function experiments and punctual depletion of ILCs, we demonstrate that the failure to restrict intestinal commensals by ILC3s results in impaired liver regeneration. Our data emphasize the importance of endogenous intestinal bacteria as a source for postoperative infection and indicate ILC3s as potential new targets

Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci

Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and 882 controls, and the follow-up investigation of the top GWA results was performed in independent Danish (1396 cases and 1803 controls) and German-Dutch (1169 cases, 3714 controls) samples. The SNPs most strongly associated in the single-marker analysis of the combined Danish samples were rs4757144 in ARNTL (P=3.78 × 10 -6) and rs8057927 in CDH13 (P=1.39 × 10 -5). Both genes have previously been linked to schizophrenia or other psychiatric disorders. The strongest associated SNP in the combined analysis, including Danish and German-Dutch samples, was rs12922317 in RUNDC2A (P=9.04 × 10 -7). A region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10 -7). This signal was replicated in the follow-up analysis (P=2.3 × 10 -2). Significant interaction with maternal CMV infection was found for rs7902091 (P SNP × CMV =7.

Evolution of Alternative Splicing Regulation: Changes in Predicted Exonic Splicing Regulators Are Not Associated with Changes in Alternative Splicing Levels in Primates

Alternative splicing is tightly regulated in a spatio-temporal and quantitative manner. This regulation is achieved by a complex interplay between spliceosomal (trans) factors that bind to different sequence (cis) elements. cis-elements reside in both introns and exons and may either enhance or silence splicing. Differential combinations of cis-elements allows for a huge diversity of overall splicing signals, together comprising a complex ‘splicing code’. Many cis-elements have been identified, and their effects on exon inclusion levels demonstrated in reporter systems. However, the impact of interspecific differences in these elements on the evolution of alternative splicing levels has not yet been investigated at genomic level. Here we study the effect of interspecific differences in predicted exonic splicing regulators (ESRs) on exon inclusion levels in human and chimpanzee. For this purpose, we compiled and studied comprehensive datasets of predicted ESRs, identified by several computational and experimental approaches, as well as microarray data for changes in alternative splicing levels between human and chimpanzee. Surprisingly, we found no association between changes in predicted ESRs and changes in alternative splicing levels. This observation holds across different ESR exon positions, exon lengths, and 5′ splice site strengths. We suggest that this lack of association is mainly due to the great importance of context for ESR functionality: many ESR-like motifs in primates may have little or no effect on splicing, and thus interspecific changes at short-time scales may primarily occur in these effectively neutral ESRs. These results underscore the difficulties of using current computational ESR prediction algorithms to identify truly functionally important motifs, and provide a cautionary tale for studies of the effect of SNPs on splicing in human disease

Are Hox Genes Ancestrally Involved in Axial Patterning? Evidence from the Hydrozoan Clytia hemisphaerica (Cnidaria)

Background: The early evolution and diversification of Hox-related genes in eumetazoans has been the subject of conflicting hypotheses concerning the evolutionary conservation of their role in axial patterning and the pre-bilaterian origin of the Hox and ParaHox clusters. The diversification of Hox/ParaHox genes clearly predates the origin of bilaterians. However, the existence of a "Hox code' predating the cnidarian-bilaterian ancestor and supporting the deep homology of axes is more controversial. This assumption was mainly based on the interpretation of Hox expression data from the sea anemone, but growing evidence from other cnidarian taxa puts into question this hypothesis. Methodology/Principal Findings: Hox, ParaHox and Hox-related genes have been investigated here by phylogenetic analysis and in situ hybridisation in Clytia hemisphaerica, an hydrozoan species with medusa and polyp stages alternating in the life cycle. Our phylogenetic analyses do not support an origin of ParaHox and Hox genes by duplication of an ancestral ProtoHox cluster, and reveal a diversification of the cnidarian HOX9-14 genes into three groups called A, B, C. Among the 7 examined genes, only those belonging to the HOX9-14 and the CDX groups exhibit a restricted expression along the oralaboral axis during development and in the planula larva, while the others are expressed in very specialised areas at the medusa stage. Conclusions/Significance: Cross species comparison reveals a strong variability of gene expression along the oral-aboral axis and during the life cycle among cnidarian lineages. The most parsimonious interpretation is that the Hox code, collinearity and conservative role along the antero-posterior axis are bilaterian innovations

Mechanical design of the optical modules intended for IceCube-Gen2

IceCube-Gen2 is an expansion of the IceCube neutrino observatory at the South Pole that aims to increase the sensitivity to high-energy neutrinos by an order of magnitude. To this end, about 10,000 new optical modules will be installed, instrumenting a fiducial volume of about 8 km3. Two newly developed optical module types increase IceCube’s current sensitivity per module by a factor of three by integrating 16 and 18 newly developed four-inch PMTs in specially designed 12.5-inch diameter pressure vessels. Both designs use conical silicone gel pads to optically couple the PMTs to the pressure vessel to increase photon collection efficiency. The outside portion of gel pads are pre-cast onto each PMT prior to integration, while the interiors are filled and cast after the PMT assemblies are installed in the pressure vessel via a pushing mechanism. This paper presents both the mechanical design, as well as the performance of prototype modules at high pressure (70 MPa) and low temperature (−40∘C), characteristic of the environment inside the South Pole ice

Direction reconstruction performance for IceCube-Gen2 Radio

The IceCube-Gen2 facility will extend the energy range of IceCube to ultra-high energies. The key component to detect neutrinos with energies above 10 PeV is a large array of in-ice radio detectors. In previous work, direction reconstruction algorithms using the forward-folding technique have been developed for both shallow (≲20 m) and deep in-ice detectors, and have also been successfully used to reconstruct cosmic rays with ARIANNA. Here, we focus on the reconstruction algorithm for the deep in-ice detector, which was recently introduced in the context of the Radio Neutrino Observatory in Greenland (RNO-G)

The next generation neutrino telescope: IceCube-Gen2

The IceCube Neutrino Observatory, a cubic-kilometer-scale neutrino detector at the geographic South Pole, has reached a number of milestones in the field of neutrino astrophysics: the discovery of a high-energy astrophysical neutrino flux, the temporal and directional correlation of neutrinos with a flaring blazar, and a steady emission of neutrinos from the direction of an active galaxy of a Seyfert II type and the Milky Way. The next generation neutrino telescope, IceCube-Gen2, currently under development, will consist of three essential components: an array of about 10,000 optical sensors, embedded within approximately 8 cubic kilometers of ice, for detecting neutrinos with energies of TeV and above, with a sensitivity five times greater than that of IceCube; a surface array with scintillation panels and radio antennas targeting air showers; and buried radio antennas distributed over an area of more than 400 square kilometers to significantly enhance the sensitivity of detecting neutrino sources beyond EeV. This contribution describes the design and status of IceCube-Gen2 and discusses the expected sensitivity from the simulations of the optical, surface, and radio components

Sensitivity of IceCube-Gen2 to measure flavor composition of Astrophysical neutrinos

The observation of an astrophysical neutrino flux in IceCube and its detection capability to separate between the different neutrino flavors has led IceCube to constraint the flavor content of this flux. IceCube-Gen2 is the planned extension of the current IceCube detector, which will be about 8 times larger than the current instrumented volume. In this work, we study the sensitivity of IceCube-Gen2 to the astrophysical neutrino flavor composition and investigate its tau neutrino identification capabilities. We apply the IceCube analysis on a simulated IceCube-Gen2 dataset that mimics the High Energy Starting Event (HESE) classification. Reconstructions are performed using sensors that have 3 times higher quantum efficiency and isotropic angular acceptance compared to the current IceCube optical modules. We present the projected sensitivity for 10 years of data on constraining the flavor ratio of the astrophysical neutrino flux at Earth by IceCube-Gen2