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Although the Marijuana Problems Index (MPI) is widely used in studies with college student samples to reflect a unidimensional measure of cannabis-related problems, no studies have assessed the psychometric properties of the MPI in a college student population. The present study sought to resolve this gap in a sample of 879 college students reporting past-year cannabis use. Confirmatory factor analyses were used to test the factor structure of the unidimensional 23- and 18-item MPI and measurement invariance across gender. Bivariate correlations between the final factors, cannabis use history/frequency, and other substance use outcomes were used to examine concurrent and discriminant validities (i.e., vs. noncannabis outcomes). The 18-item (but not the 23-item) MPI demonstrated good model fit, measurement invariance across gender, adequate internal reliability, as well as concurrent and discriminant validities. Results support the use of the 18-item MPI over the 23-item MPI for conceptualizing problematic cannabis use, including the testing of gender-specific differences, among college students. Findings also reinforce the importance of evaluating the psychometric properties of widely used measures across samples. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Arthrodesis of the first metatarsal phalangeal joint (MTPJ) is a widely utilized surgical procedure for a wide array of metatarsal pathologies. This study aims to explore the functional limitations following first MTPJ arthrodesis, overall satisfaction and patient's abilities to achieve activities of daily living (ADL). This prospective cohort study assessed functional limitations as well as footwear and lifestyle restrictions using several questionnaires. One hundred and three participants who had a first MTPJ arthrodesis under the care of a single surgeon were recruited. Pre- and postoperative patient-reported outcome measures were recorded. The American Orthopaedic Foot and Ankle Score (AOFAS) and the Manchester-Oxford Foot Questionnaire were also used to further examine functional status. Hallux valgus angle (HVA) and intermetatarsal angle (IMA) were compared using preoperative and postoperative weightbearing radiographs and successful fusion was recorded. Complications were documented and are discussed in detail. The duration of follow-up was more than 12 months. There was one nonunion in the cohort while 2 patients experienced delay to fusion. Approximately 97% of patients were very satisfied with the procedure and their ability to achieve ADLs post operatively. A further 82.5% of patients were able to return to wearing nonadaptive footwear. The mean reduction in HVA and IMA was 21.78° and 6.84°, respectively. This study demonstrates the safe and successful use of a compression screw/locking plate construct for arthrodesis of the first MTPJ. Furthermore, the study provides clear evidence of high levels of functionality after the procedure with statistically significant differences (p value.05) in all 4 facets of the AOFAS questionnaire as well as several notable differences in activity levels and footwear restrictions pre and postoperatively.

OBJECTIVE Evidence suggests that social anxiety (SA) is a risk factor for problematic alcohol and cannabis use, particularly during states of social stress. Unfortunately, laboratory studies to date have overlooked decision-making mechanisms (e.g., use willingness) and contextual features of commonly used social stress tasks that may clarify what is driving these links. The current study begins to address this gap by testing the effects of SA and laboratory-induced peer rejection on acute alcohol and cannabis use willingness within a simulated party setting. METHOD 80 emerging adults (18-25 years; 70% women) endorsing lifetime alcohol and cannabis use were randomly assigned to experience rejection or neutral social cues. They rated their willingness to use alcohol and cannabis before and after cue exposure within the simulated party. A hierarchical regression tested the main and interaction effects of SA symptoms and experimental condition (Rejection vs. Neutral) on alcohol and cannabis use willingness, controlling for past-year use frequency and willingness to accept any offers (e.g., food and nonalcoholic drinks). RESULTS There were statistically significant main (but not interaction) effects of SA and experimental condition on cannabis use willingness. Higher SA and Rejection exposure were each associated with greater cannabis use willingness. There were neither main nor interaction effects on alcohol willingness. CONCLUSIONS Results suggest that elevated SA increases cannabis use willingness across social contexts, regardless of Rejection exposure, while Rejection exposure increases use willingness similarly across levels of SA. Together, findings reinforce the need to consider social-contextual factors and polysubstance use in laboratory settings. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

SARS-CoV-2 infection is controlled by the opening of the spike protein receptor binding domain (RBD), which transitions from a glycan-shielded 'down' to an exposed 'up' state to bind the human angiotensin-converting enzyme 2 receptor and infect cells. While snapshots of the 'up' and 'down' states have been obtained by cryo-electron microscopy and cryo-electron tomagraphy, details of the RBD-opening transition evade experimental characterization. Here over 130 µs of weighted ensemble simulations of the fully glycosylated spike ectodomain allow us to characterize more than 300 continuous, kinetically unbiased RBD-opening pathways. Together with ManifoldEM analysis of cryo-electron microscopy data and biolayer interferometry experiments, we reveal a gating role for the N-glycan at position N343, which facilitates RBD opening. Residues D405, R408 and D427 also participate. The atomic-level characterization of the glycosylated spike activation mechanism provided herein represents a landmark study for ensemble pathway simulations and offers a foundation for understanding the fundamental mechanisms of SARS-CoV-2 viral entry and infection.

Background Strongyloides stercoralis is a soil-transmitted helminth, endemic in remote Aboriginal and Torres Strait Islander communities in northern Australia with estimates of prevalences up to 60%. Hyperinfection in the setting of immunosuppression is a rare but well-recognised cause of significant morbidity and mortality. However, the morbidity associated with chronic uncomplicated infection is less well characterised. Methods This retrospective case-control study measured the prevalence of symptoms potentially attributable to S. stercoralis infection and their association with seropositivity. Records of primary healthcare presentations were reviewed for symptoms in the 12 months before and after an ivermectin mass drug administration (MDA) in a remote Aboriginal community. Results One hundred and seventy-five S. stercoralis seropositive cases were matched with 175 seronegative controls. The most frequently reported symptom overall in the 12 months prior to the MDA was cough followed by abdominal pain, weight loss/malnutrition, diarrhoea and pruritis. Seropositive cases were not more likely than matched controls to have symptoms typically attributed to strongyloidiasis. In the seropositive cohort, we found no difference in symptoms in the 12 months before and after an ivermectin MDA despite a reduction in seroprevalence. Conclusion We found no evidence to suggest that S. stercoralis seropositivity was associated with increased symptoms when compared to matched seronegative controls. Treatment with ivermectin did not reduce symptoms in seropositive cases. Without evidence to support that population-based screening or treatment programs reduce symptoms, the emphasis must remain on identifying and managing those few individuals with immunosuppression that predisposes them to potentially life-threatening hyperinfection. This article is protected by copyright. All rights reserved.

Background and Aims Bacterial swarming, a collective movement on a surface, has rarely been associated with human pathophysiology. This study aims to define a role for bacterial swarmers in amelioration of intestinal stress. Methods We developed a polymicrobial plate agar assay to detect swarming and screened mice and humans with intestinal stress and inflammation. From chemically induced colitis in mice, as well as humans with inflammatory bowel disease, we developed techniques to isolate the dominant swarmers. We developed swarm-deficient but growth and swim-competent mutant bacteria as isogenic controls. We performed bacterial reinoculation studies in mice with colitis, fecal 16S, and meta-transcriptomic analyses, as well as in vitro microbial interaction studies. Results We show that bacterial swarmers are highly predictive of intestinal stress in mice and humans. We isolated a novel Enterobacter swarming strain, SM3, from mouse feces. SM3 and other known commensal swarmers, in contrast to their mutant strains, abrogated intestinal inflammation in mice. Treatment of colitic mice with SM3, but not its mutants, enriched beneficial fecal anaerobes belonging to the family of Bacteroidales S24-7. We observed SM3 swarming associated pathways in the in vivo fecal meta-transcriptomes. In vitro growth of S24-7 was enriched in presence of SM3 or its mutants; however, because SM3, but not mutants, induced S24-7 in vivo, we concluded that swarming plays an essential role in disseminating SM3 in vivo. Conclusions Overall, our work identified a new but counterintuitive paradigm in which intestinal stress allows for the emergence of swarming bacteria; however, these bacteria act to heal intestinal inflammation.

Background Uncemented hemiarthroplasty (UHA) for displaced femoral neck fracture (FNF) is favored by some surgeons because of the reduced rate of perioperative mortality and operative time. However higher rates of intraoperative and postoperative periprosthetic fractures (PPFs) have been reported. The aim of the study was to review day-0, day-1, day-2, day-30, and one-year mortality as well as intraoperative and postoperative PPF after UHA for displaced FNF and compare this with cemented hemiarthroplasties (CHAs) performed. Secondary objectives were to assess whether femoral stem geometry and alignment were associated with PPF in UHA. Methods A retrospective observational study was conducted of patients treated with a hemiarthroplasty for a displaced FNF over an eleven-year period. Radiographic analysis was conducted of femoral geometry and stem alignment. Results Over the 11-year study period, 857 UHAs and 247 CHAs were performed. There were no on-table, day-0, day-1, or day-2 deaths in UHA. Intraoperative PPF occurred in 3.6% UHA and 2% CHA and postoperative PPF in 2.4% UHA and 4.8% CHA. Intraoperative PPF was not associated with increased mortality (P = .15), postoperative PPF, or all-cause revision in UHA. Valgus stem alignment was a risk factor for a postoperative PPF and additional surgery in UHA (P = .004). Conclusion UHA was associated with no perioperative deaths and a 30-day mortality rate of 5% in this series. It can be considered in patients with multiple medical comorbidities. Careful surgical planning and technique is important to optimize stem alignment particularly in Dorr C type femurs.

Gene discovery efforts in autism spectrum disorder have identified heterozygous defects in chromatin remodeller genes, the ‘readers, writers and erasers’ of methyl marks on chromatin, as major contributors to this disease. Despite this advance, a convergent aetiology between these defects and aberrant chromatin architecture or gene expression has remained elusive. Recently, data have begun to emerge that chromatin remodellers also function directly on the cytoskeleton. Strongly associated with autism spectrum disorder, the SETD2 histone methyltransferase for example, has now been shown to directly methylate microtubules of the mitotic spindle. However, whether microtubule methylation occurs in post-mitotic cells, for example on the neuronal cytoskeleton, is not known. We found the SETD2 α-tubulin lysine 40 trimethyl mark occurs on microtubules in the brain and in primary neurons in culture, and that the SETD2 C-terminal SRI domain is required for binding and methylation of α-tubulin. A CRISPR knock-in of a pathogenic SRI domain mutation (Setd2SRI) that disables microtubule methylation revealed at least one wild-type allele was required in mice for survival, and while viable, heterozygous Setd2SRI/wtmice exhibited an anxiety-like phenotype. Finally, whereas RNA-sequencing (RNA-seq) and chromatin immunoprecipitation-sequencing (ChIP-seq) showed no concomitant changes in chromatin methylation or gene expression in Setd2SRI/wtmice, primary neurons exhibited structural deficits in axon length and dendritic arborization. These data provide the first demonstration that microtubules of neurons are methylated, and reveals a heterozygous chromatin remodeller defect that specifically disables microtubule methylation is sufficient to drive an autism-associated phenotype.

Purpose: We investigated whether targeting chromatin stability through a combination of the curaxin CBL0137 with the histone deacetylase (HDAC) inhibitor, panobinostat, constitutes an effective multimodal treatment for high-risk neuroblastoma. Experimental Design: The effects of the drug combination on cancer growth were examined in vitro and in animal models of MYCN-amplified neuroblastoma. The molecular mechanisms of action were analyzed by multiple techniques including whole transcriptome profiling, immune deconvolution analysis, immunofluorescence, flow cytometry, pulsed-field gel electrophoresis, assays to assess cell growth and apoptosis, and a range of cell-based reporter systems to examine histone eviction, heterochromatin transcription, and chromatin compaction. Results: The combination of CBL0137 and panobinostat enhanced nucleosome destabilization, induced an IFN response, inhibited DNA damage repair, and synergistically suppressed cancer cell growth. Similar synergistic effects were observed when combining CBL0137 with other HDAC inhibitors. The CBL0137/panobinostat combination significantly delayed cancer progression in xenograft models of poor outcome high-risk neuroblastoma. Complete tumor regression was achieved in the transgenic Th-MYCN neuroblastoma model which was accompanied by induction of a type I IFN and immune response. Tumor transplantation experiments further confirmed that the presence of a competent adaptive immune system component allowed the exploitation of the full potential of the drug combination. Conclusions: The combination of CBL0137 and panobinostat is effective and well-tolerated in preclinical models of aggressive high-risk neuroblastoma, warranting further preclinical and clinical investigation in other pediatric cancers. On the basis of its potential to boost IFN and immune responses in cancer models, the drug combination holds promising potential for addition to immunotherapies.

Globally, at least 40% of bird species are in decline and one in eight species are at risk of extinction (Birdlife International 2018a). Owing to the complex and interconnected causes of species’ d...

Viruses and transposable elements are major drivers of evolution and make up over half the sequences in the human genome. In some cases, these elements are co-opted to perform biological functions for the host. Recent studies made the surprising observation that the neuronal gene Arc forms virus-like protein capsids that can transfer RNA between neurons to mediate a novel intercellular communication pathway. Phylogenetic analyses showed that mammalian Arc is derived from an ancient retrotransposon of the Ty3/gypsy family and contains homology to the retroviral Gag polyproteins. The Drosophila Arc homologues, which are independently derived from the same family of retrotransposons, also mediate cell-to-cell signaling of RNA at the neuromuscular junction; a striking example of convergent evolution. Here we propose an Arc “life cycle”, based on what is known about retroviral Gag, and discuss how elucidating these biological processes may lead to novel insights into brain plasticity and memory.

Next generation sequencing (NGS) assays are state of the art for HLA genotyping. To sequence on an Illumina sequencer, the DNA of interest must be enriched, fragmented, and bookended with known oligonucleotide sequences, a process known as library construction. Many HLA genotyping assays enrich the target loci by long-range PCR (LR-PCR), prior to fragmentation. This PCR step has been reported to introduce errors in the DNA to be sequenced, including inaccurate replication of repeated sequences, and the in vitro recombination of alleles encoded on separate chromosomes. An alternative library construction method involves fragmentation of genomic DNA, followed by hybrid-capture (HC) enrichment of target HLA loci. This HC-based method involves PCR, but with far fewer cycles. Consequently, the HC method had significantly fewer PCR-induced errors, including more faithful replication of repeated sequences, and the near elimination of recombinant sequences. These improvements likely produce more accurate NGS sequencing data of HLA loci.

Background To determine the prevalence of enteric infections in Aboriginal children aged 0–2 years using conventional and molecular diagnostic techniques and to explore associations between the presence of pathogens and child growth. Methods Cross-sectional analysis of Aboriginal children (n = 62) residing in a remote community in Northern Australia, conducted from July 24th - October 30th 2017. Stool samples were analysed for organisms by microscopy (directly in the field and following fixation and storage in sodium-acetate formalin), and by qualitative PCR for viruses, bacteria and parasites and serology for Strongyloides-specific IgG. Child growth (height and weight) was measured and z scores calculated according to WHO growth standards. Results Nearly 60% of children had evidence for at least one enteric pathogen in their stool (37/62). The highest burden of infection was with adenovirus/sapovirus (22.9%), followed by astrovirus (9.8%) and Cryptosporidium hominis/parvum (8.2%). Non-pathogenic organisms were detected in 22.5% of children. Ten percent of children had diarrhea at the time of stool collection. Infection with two or more pathogens was negatively associated with height for age z scores (− 1.34, 95% CI − 2.61 to − 0.07), as was carriage of the non-pathogen Blastocystis hominis (− 2.05, 95% CI - 3.55 to − 0.54). Conclusions Infants and toddlers living in this remote Northern Australian Aboriginal community had a high burden of enteric pathogens and non-pathogens. The association between carriage of pathogens/non-pathogens with impaired child growth in the critical first 1000 days of life has implications for healthy child growth and development and warrants further investigation. These findings have relevance for many other First Nations Communities that face many of the same challenges with regard to poverty, infections, and malnutrition.

There has been a growing interest in the seed microbiome due to its important role as an end and starting point of plant microbiome assembly that can have consequences for plant health. However, the effect of abiotic conditions on the seed microbial community remains unknown. We performed a pilot study in a controlled growth chamber to investigate how the endophytic seed microbiome of the common bean (Phaseolus vulgaris L. (var. Red Hawk)) was altered under abiotic treatments relevant for crop management with changing climate. Bean plants were subjected to one of three treatments: 66% water withholding to simulate mild drought, 50% Hoagland nutrient solution to simulate fertilization, or control with sufficient water and baseline nutrition. We performed 16S rRNA gene amplicon sequencing and ITS1 amplicon sequencing of the endophytic DNA to assess seed bacterial/archaeal and fungal community structure, respectively. We found that variability in the seed microbiome structure was high while alpha diversity was low, with tens of taxa present. Water withholding and nutrient addition altered the seed microbiome structure for bacterial/archaeal communities as compared to the control, and each treatment resulted in a distinct microbiome structure. There were no statistically supported differences in the fungal microbiome across treatments. While we discuss several limitations of this study, the promising results suggest that further investigation is needed to better understand abiotic or stress-induced changes in the seed microbiome, the mechanisms that drive those changes, and their implications for the health and stress responses of the next plant generation.ImportanceSeed microbiome members initiate the assembly of plant-associated microbial communities, but the environmental drivers of endophytic seed microbiome composition are unclear. Here, we exposed plants to short-term drought and fertilizer treatments during early vegetative growth and quantified the microbiome composition of the seeds that were ultimately produced. We found that seeds produced by plants stressed by water limitation or receiving nutrient addition had statistically different endophytic bacterial/archaeal microbiome compositions from each other and from seeds produced by control plants. This work suggests that the abiotic experience of a parental plant can influence the composition of its seed microbiome, with unknown consequences for the next plant generation.

A Z-osteotomy is a commonly performed procedure to correct mild-moderate hallux valgus. It is an effective procedure with high patient satisfaction rates. However, it is not without its challenges. One of the most frequently encountered issues during a Z-osteotomy is troughing of the first metatarsal. We present a simple surgical technique to correct troughing if it is encountered without the need for additional soft tissue or bony procedures.

Tidal salt marsh ecosystems store copious amounts of carbon (C) within sediments. In order to predict how these C stores may be affected by environmental change, it is critical to assess current CO2 and CH4 production and efflux from these ecosystems. Production and efflux of these greenhouse gases (GHGs) are governed by coupled geochemical, hydrological, physical and biological processes in sediments that are sensitive to local conditions, which can result in large spatial and temporal heterogeneity of GHGs dynamics within the ecosystem. To understand how the drivers of GHGs dynamics vary across salt marsh ecosystems, we coupled solid-phase geochemistry to measurements of porewater chemistry (to ∼1 m), CO2 and CH4 production in sediments and efflux to the atmosphere in a temperate tidal salt marsh for over one year to capture seasonal patterns within two vegetation zones of the marsh landscape that have distinct biogeochemical and hydrologic conditions: Tall Spartina (TS) and Short Spartina (SS). The SS vegetation zone experienced nearly constant inundation, low redox values (−200 to 200 mV), porewater pH 6–7 that did not vary with depth or time, an enrichment of pyrite and goethite with depth and up to 3 mM porewater sulfide. In contrast, the TS vegetation zone on the natural levee proximal to a tidal channel experienced large water level oscillations due to spring-neap tides that resulted in variable but higher redox values (0–700 mV), porewater pH 6–7 at depth but surface (0–3 cm) as low as 4 in the spring, an enrichment of ferrihydrite and a depletion of pyrite at ∼30 cm, and up to 0.8 mM ferrous Fe in porewater. At 50–56 cm, solid phase analyses (STXM-NEXAFS) revealed differential C speciation between the two vegetation zones, with stronger C-Fe spatial association at TS and stronger C-Ca co-association at SS despite both having similar soil pH of 3–4. These results suggest that soil pH may not be strongly predictive of C-mineral control in flooded marsh sediments. Both vegetation zones showed consistent CO2 and CH4 emissions from sediments to the atmosphere throughout the study period with TS having ∼60% higher median CO2 and SS having ∼55% higher median CH4 efflux. Using depth profiling, unexpectedly high concentrations of CO2 (>200 μM) and CH4 (>200 μM) were observed at depths 50–75 cm at both zones that were higher for SS in these sulfate-rich (up to 17 mM) sediments, which suggests methylotrophic methanogenesis occurs deep within the profile of salt marsh sediments away from the tidal channel. Moreover, if we extrapolate our median depth values of CH4 and CO2 to the 5.3 Mha of global salt marshes, this could account for a conservative estimate of ∼70 Gg of unaccounted C stored in gaseous form (i.e., CH4 and CO2) in marsh sediments, which should be considered when attempting to understand the current patterns and future responses of carbon dynamics from these ecosystems.

Copyright © 2020 American Chemical Society. Group A Streptococcus (GAS) displays cell-surface proteins that resemble human collagen. We find that a fluorophore-labeled collagen mimetic peptide (CMP) labels GAS cells but not Escherichia coli or Bacillus subtilis cells, which lack such proteins. The CMP likely engages in a heterotrimeric helix with endogenous collagen, as the nonnatural d enantiomer of the CMP does not label GAS cells. To identify a molecular target, we used reverse genetics to "knock-in"the GAS genes that encode two proteins with collagen-like domains, Scl1 and Scl2, into B. subtilis. The fluorescent CMP labels the cells of these B. subtilis strains. Moreover, these strains bind tightly to a surface of mammalian collagen. These data are consistent with streptococcal collagen forming triple helices with damaged collagen in a wound bed and thus have implications for microbial virulence.

Selective chemical probes enable individual investigation of penicillin-binding proteins (PBPs) and provide critical information about their enzymatic activity with spatial and temporal resolution. To identify scaffolds for novel probes to study peptidoglycan biosynthesis inBacillus subtilis, we evaluated the PBP inhibition profiles of 21 β-lactam antibiotics from different structural subclasses using a fluorescence-based assay. Most compounds readily labeled PBP1, PBP2a, PBP2b or PBP4. Almost all penicillin scaffolds were co-selective for all or combinations of PBP2a, 2b and 4. Cephalosporins, on the other hand, possessed the lowest IC50values for PBP1 alone or along with PBP4 (ceftriaxone, cefoxitin), 2b (cefotaxime) or 2a, 2b and 4 (cephalothin). Overall, five selective inhibitors for PBP1 (aztreonam, faropenem, piperacillin, cefuroxime and cefsulodin), one selective inhibitor for PBP5 (6-aminopenicillanic acid) and various co-selective inhibitors for other PBPs inB. subtiliswere discovered. Surprisingly, carbapenems strongly inhibited PBP3, formerly shown to have low affinity for β-lactams and speculated to be involved in resistance inB. subtilis. To investigate the specific roles of PBP3, we developed activity-based probes based on the meropenem core and utilized them to monitor the activity of PBP3 in living cells. We showed that PBP3 activity localizes as patches in single cells and concentrates as a ring at the septum and the division site during the cell growth cycle. Our activity-based approach enabled spatial resolution of the transpeptidation activity of individual PBPs in this model microorganism, which was not possible with previous chemical and biological approaches.

Nanophthalmos and posterior microphthalmos are ocular abnormalities in which both eyes are abnormally small, and typically associated with extreme hyperopia. We recruited 40 individuals from 13 kindreds with nanophthalmos or posterior microphthalmos, with 12 probands subjected to exome sequencing. Nine probands (69.2%) were assigned a genetic diagnosis, with variants in MYRF, TMEM98, MFRP, and PRSS56. Two of four PRSS56 families harboured the previously described c.1066dupC variant implicated in over half of all reported PRSS56 kindreds, with different surrounding haplotypes in each family suggesting a mutational hotspot. Individuals with a genetic diagnosis had shorter mean axial lengths and higher hyperopia than those without, with recessive forms associated with the most extreme phenotypes. These findings detail the genetic architecture of nanophthalmos and posterior microphthalmos in a cohort of predominantly European ancestry, their relative clinical phenotypes, and highlight the shared genetic architecture of rare and common disorders of refractive error.

Plant root−microbe interactions influence plant productivity, health, and resistance to stress. Although there is evidence that plant species and even genotypes can alter soil microbial community structure, environmental conditions can potentially outweigh plant genetic effects. Here, we used a reciprocal transplant experiment to understand the contributions of the environment and the host plant to rhizosphere microbiome composition in locally adapted ecotypes of Mimulus guttatus (syn. Erythranthe guttata). Two genotypes of a coastal ecotype and two genotypes of an inland ecotype were planted at coastal and inland sites. After 3 months, we collected rhizosphere and bulk soil and assessed microbial communities by 16S rRNA gene sequencing. We found that local environment (coastal versus inland site) strongly influenced rhizosphere communities, at least in part due to distinct local microbial species pools. Host identity played a smaller role: at each site, the ecotypes exhibited remarkably similar composition of microbial communities at the class level, indicating that divergent M. guttatus ecotypes recruit phylogenetically similar rhizosphere communities, even in environments to which they are maladapted. Nevertheless, the two ecotypes significantly differed in community composition at both sites due, in part, to an exclusive set of taxa associated with each ecotype. They also differed in alpha diversity at the inland site. Although this indicates that locally adapted M. guttatus ecotypes are genetically diverged in factors shaping rhizosphere communities, our findings highlight the context-specific interactions between host identity and local environment that shape those communities. [Formula: see text] Copyright © 2020 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .

Bacteria have developed numerous protection strategies to ensure survival in harsh environments, with perhaps the most robust method being the formation of a protective biofilm. In biofilms, bacterial cells are embedded within a matrix that is composed of a complex mixture of polysaccharides, proteins, and DNA. The gram-positive bacterium Bacillus subtilis has become a model organism for studying regulatory networks directing biofilm formation. The phenotypic transition from a planktonic to biofilm state is regulated by the activity of the transcriptional repressor, SinR, and its inactivation by its primary antagonist, SinI. In this work, we present the first full-length structural model of tetrameric SinR using a hybrid approach combining high-resolution solution nuclear magnetic resonance (NMR), chemical cross-linking, mass spectrometry, and molecular docking. We also present the solution NMR structure of the antagonist SinI dimer and probe the mechanism behind the SinR-SinI interaction using a combination of biochemical and biophysical techniques. As a result of these findings, we propose that SinI utilizes a residue replacement mechanism to block SinR multimerization, resulting in diminished DNA binding and concomitant decreased repressor activity. Finally, we provide an evidence-based mechanism that confirms how disruption of the SinR tetramer by SinI regulates gene expression.

Drinking games (DGs) participation is prevalent among college-attending emerging adults. Research also suggests that student-athletes play DGs more frequently than non student-athletes, but what motivates student-athletes to participate in DGs is not well understood. Using data from a larger longitudinal study with Division III female athletes, we examined the test-retest reliability and minimal detectable change of the revised 7-factor Motives for Playing Drinking Games (MPDG) measure, and explored how its subscales were related to DGs behavior across two annual timepoints (n = 49). Results indicated that the MPDG shows adequate test-retest reliability over a one year period among student-athletes. Controlling for age and general alcohol consumption, conformity motives were positively associated with DG consumption at timepoint 1, whereas the DG motives of enhancement/thrills and boredom were positively related to DG consumption at timepoint 2. Implications for future research directions on motives for playing DGs and DGs behavior among student-athletes are discussed.

Summary Background A cluster of seven cases of skin and wound infections caused by a multiply resistant meticillin-resistant Staphylococcus aureus (MRSA) were detected in a small-town community in South Yorkshire. Initial microbiological investigations showed that all isolates belonged to a spa type observed rarely in England (t1476). Aim To describe the epidemiology of t1476 MRSA in South Yorkshire. Methods Retrospective and prospective case ascertainment was promoted through communication with local microbiology laboratories. Public health investigation included a detailed review of clinical notes for a subset of nine cases. Genomic and phylogenetic analysis was undertaken on t1476 MRSA. Findings Thirty-two cases of t1476 MRSA infection or colonization were identified between December 2014 and February 2018. Cases were older adults (aged 50–98 years). Healthcare exposures for a subset of nine cases indicated frequent contact with a team of district nurses, with all but one case receiving treatment on the same day as another case prior to their own diagnosis. No cases were admitted to hospital at the time of specimen collection. Despite detailed investigations, no carriers were detected among district nursing staff. A long-term carrier/super-shedder was not found. Phylogenetic analysis indicated that t1476 MRSA cases from South Yorkshire were monophyletic and distant from both MRSA of the same lineage from elsewhere in the UK (N = 15) and from publicly available sequences from Tanzania. Conclusion Genomic and epidemiological analyses indicate community-based transmission of a multiply resistant MRSA clone within South Yorkshire introduced around 2012–2013, prior to the detection of a spatial–temporal cluster associated with a distinct risk group. Surveillance data indicate continued circulation.

The aim of this study was to evaluate whether the surface modification of expanded polytetrafluoroethylene (ePTFE) using an n-heptylamine (HA) plasma polymer would allow for functional epithelial monolayer formation suitable for subretinal transplant into a non-dystrophic rat model. Freshly isolated iris pigment epithelial (IPE) cells from two rat strains (Long Evans [LE] and Dark Agouti [DA]) were seeded onto HA, fibronectin-coated n-heptylamine modified (F-HA) and unmodified ePFTE and fibronectin-coated tissue culture (F-TCPS) substrates. Both F-HA ePTFE and F-TCPS substrates enabled functional monolayer formation with both strains of rat. Without fibronectin coating, only LE IPE formed a monolayer on HA-treated ePTFE. Functional assessment of both IPE strains on F-HA ePTFE demonstrated uptake of POS that increased significantly with time that was greater than control F-TCPS. Surgical optimization using Healon GV and mixtures of Healon GV: phosphate buffered saline (PBS) to induce retinal detachment demonstrated that only Healon GV:PBS allowed F-HA ePTFE substrates to be successfully transplanted into the subretinal space of Royal College of Surgeons rats, where they remained flat beneath the neural retina for up to 4 weeks. No apparent substrate-induced inflammatory response was observed by fundus microscopy or immunohistochemical analysis, indicating the potential of this substrate for future clinical applications. Refereed/Peer-reviewed

Introduction Severe SARS-CoV-2 infection is associated with a dysregulated immune response. Inflammatory monocytes and macrophages are crucial, promoting injurious, proinflammatory sequelae. Immunomodulation is, therefore, an attractive therapeutic strategy and we sought to test licensed and novel candidate drugs. Methods and analysis The CATALYST trial is a multiarm, open-label, multicentre, phase II platform trial designed to identify candidate novel treatments to improve outcomes of patients hospitalised with COVID-19 compared with usual care. Treatments with evidence of biomarker improvements will be put forward for larger-scale testing by current national phase III platform trials. Hospitalised patients >16 years with a clinical picture strongly suggestive of SARS-CoV-2 pneumonia (confirmed by chest X-ray or CT scan, with or without a positive reverse transcription PCR assay) and a C reactive protein (CRP) ≥40 mg/L are eligible. The primary outcome measure is CRP, measured serially from admission to day 14, hospital discharge or death. Secondary outcomes include the WHO Clinical Progression Improvement Scale as a principal efficacy assessment. Ethics and dissemination The protocol was approved by the East Midlands-Nottingham 2 Research Ethics Committee (20/EM/0115) and given urgent public health status; initial approval was received on 5 May 2020, current protocol version (V.6.0) approval on 12 October 2020. The MHRA also approved all protocol versions. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications. Trial registration numbers EudraCT2020-001684-89,NCT40580903.

The COVID‐19 pandemic is one of the most serious global challenges to delivering affordable and equitable treatment to children with cancer we have witnessed in the last few decades. This Special Report aims to summarize general principles for continuing multidisciplinary care during the SARS‐CoV‐2 (COVID‐19) pandemic. With contributions from the leadership of the International Society for Pediatric Oncology (SIOP), Children's Oncology Group (COG), St Jude Global program, and Childhood Cancer International, we have sought to provide a framework for healthcare teams caring for children with cancer during the pandemic. We anticipate the burden will fall particularly heavily on children, their families, and cancer services in low‐ and middle‐income countries. Therefore, we have brought together the relevant clinical leads from SIOP Europe, COG, and SIOP‐PODC (Pediatric Oncology in Developing Countries) to focus on the six most curable cancers that are part of the WHO Global Initiative in Childhood Cancer. We provide some practical advice for adapting diagnostic and treatment protocols for children with cancer during the pandemic, the measures taken to contain it (e.g., extreme social distancing), and how to prepare for the anticipated recovery period.

During growth, bacteria increase in size and divide. Division is initiated by the formation of the Z-ring, an intense ring-like cytoskeletal structure formed by treadmilling protofilaments of the tubulin homolog FtsZ. FtsZ localization is thought to be controlled by the Min and Noc systems, and here, we explore why cell division fails at high temperature when the Min and Noc systems are simultaneously mutated. Microfluidic analysis of a minD noc double mutant indicated that FtsZ formed proto-Z-rings at periodic inter-chromosome locations but that the rings failed to mature and become functional. Extragenic suppressor analysis indicated that a variety of mutations restored high temperature growth to the minD noc double mutant, and while many were likely pleiotropic, others implicated the proteolysis of the transcription factor Spx. Further analysis indicated that a Spx-dependent pathway activated the expression of ZapA, a protein that primarily compensates for the absence of Noc. Additionally, an Spx-independent pathway increased the activity of the divisome to reduce the length of the cytokinetic period. Finally, we provide evidence of an as-yet-unidentified protein that is activated by Spx and governs the frequency of polar division and minicell formation.IMPORTANCEBacteria must properly position the location of the cell division machinery in order to grow, divide, and ensure each daughter cell receives one copy of the chromosome. In B. subtilis, cell division site selection is thought to depend on two systems called Min and Noc, and while neither is individually essential, cells fail to grow at high temperature when both are mutated. Here, we show that cell division fails in the absence of Min and Noc, not due to a defect in FtsZ localization, but rather a failure in the maturation of the cell division machinery. To understand what happens when the division machinery fails to mature, suppressor mutations that bypass the need for Min, Noc, or both were selected. Some of the mutants activated the Spx stress response pathway while others appeared to directly enhance divisome activity.

Swarming motility is flagellar-mediated movement over a solid surface and Bacillus subtilis cells require an increase in flagellar density to swarm. SwrB is a protein of unknown function required for swarming that is necessary to increase the number of flagellar hooks but not basal bodies. Previous work suggested that SwrB activates flagellar type III secretion but the mechanism by which it might perform this function is unknown. Here we show that SwrB likely acts sub-stoichiometrically as it localizes as puncta at the membrane in numbers fewer than that of flagellar basal bodies. Moreover the action of SwrB is likely transient as puncta of SwrB were not dependent on the presence of the basal bodies and rarely co-localized with flagellar hooks. Random mutagenesis of the SwrB sequence found that a histidine within the transmembrane segment was conditionally required for activity and punctate localization. Finally, three hydrophobic residues that precede a cytoplasmic domain of poor conservation abolished SwrB activity when mutated and caused aberrant migration during electrophoresis. Our data are consistent with a model in which SwrB interacts with the flagellum, changes conformation to activate type III secretion, and departs.IMPORTANCEType III secretion systems (T3SS) are elaborate nanomachines that form the core of the bacterial flagellum and injectisome of pathogens. The machines not only secrete proteins like virulence factors but also secrete the structural components for their own assembly. Moroever, proper construction requires complex regulation to ensure that the parts are roughly secreted in the order in which they are assembled. Here we explore a poorly understood activator the flagellar T3SS activation in Bacillus subtilis called SwrB. To aid mechanistic understanding, we determine the rules for subcellular punctate localization, the topology with respect to the membrane, and critical residues required for SwrB function.

Muscular dystrophies are disorders characterized by progressive muscle loss and weakness that are both genotypically and phenotypically heterogenous. Progression of muscle disease arises from impaired regeneration, plasma membrane instability, defective membrane repair, and calcium mishandling. The ferlin protein family, including dysferlin and myoferlin, are calcium-binding, membrane-associated proteins that regulate membrane fusion, trafficking, and tubule formation. Mice lacking dysferlin (Dysf), myoferlin (Myof), and both dysferlin and myoferlin (Fer) on an isogenic inbred 129 background were previously demonstrated that loss of both dysferlin and myoferlin resulted in more severe muscle disease than loss of either gene alone. Furthermore, Fer mice had disordered triad organization with visibly malformed transverse tubules and sarcoplasmic reticulum, suggesting distinct roles of dysferlin and myoferlin. To assess the physiological role of disorganized triads, we now assessed excitation contraction (EC) coupling in these models. We identified differential abnormalities in EC coupling and ryanodine receptor disruption in flexor digitorum brevis myofibers isolated from ferlin mutant mice. We found that loss of dysferlin alone preserved sensitivity for EC coupling and was associated with larger ryanodine receptor clusters compared to wildtype myofibers. Loss of myoferlin alone or together with a loss of dysferlin reduced sensitivity for EC coupling, and produced disorganized and smaller ryanodine receptor cluster size compared to wildtype myofibers. These data reveal impaired EC coupling in Myof and Fer myofibers and slightly potentiated EC coupling in Dysf myofibers. Despite high homology, dysferlin and myoferlin have differential roles in regulating sarcotubular formation and maintenance resulting in unique impairments in calcium handling properties.

Induced pluripotent stem cells generated from patients with geographic atrophy as well as healthy individuals were differentiated to retinal pigment epithelium (RPE) cells. By integrating transcriptional profiles of 127,659 RPE cells generated from 43 individuals with geographic atrophy and 36 controls with genotype data, we identified 439 expression Quantitative Trait (eQTL) loci in cis that were associated with disease status and specific to subpopulations of RPE cells. We identified loci linked to two genes with known associations with geographic atrophy - PILRB and PRPH2, in addition to 43 genes with significant genotype x disease interactions that are candidates for novel genetic associations for geographic atrophy. On a transcriptome-only level, we identified molecular pathways significantly upregulated in geographic atrophy-RPE including in extracellular cellular matrix reorganisation, neurodegeneration, and mitochondrial functions. We subsequently implemented a large-scale proteomics analysis, confirming modification in proteins associated with these pathways. We also identified six significant protein (p) QTL that regulate protein expression in the RPE cells and in geographic atrophy - two of which share variants with cis-eQTL. Transcriptome-wide association analysis identified genes at loci previously associated with age-related macular degeneration. Further analysis conditional on disease status, implicated statistically significant RPE-specific eQTL. This study uncovers important differences in RPE homeostasis associated with geographic atrophy.

Early-stage mammalian embryos survive within a low oxygen tension environment and develop into fully functional, healthy organisms despite this hypoxic stress. This suggests that hypoxia plays a regulative role in fetal development that influences cell mobilization, differentiation, proliferation, and survival. The long-term hypoxic environment is sustained throughout gestation. Elucidation of the mechanisms by which cardiovascular stem cells survive and thrive under hypoxic conditions would benefit cell-based therapies where stem cell survival is limited in the hypoxic environment of the infarcted heart. The current study addressed the impact of long-term hypoxia on fetal Islet-1+ cardiovascular progenitor cell clones, which were isolated from sheep housed at high altitude. The cells were then cultured in vitro in 1% oxygen and compared with control Islet-1+ cardiovascular progenitor cells maintained at 21% oxygen. RT-PCR, western blotting, flow cytometry, and migration assays evaluated adaptation to long term hypoxia in terms of survival, proliferation, and signaling. Non-canonical Wnt, Notch, AKT, HIF-2α and Yap1 transcripts were induced by hypoxia. The hypoxic niche environment regulates these signaling pathways to sustain the dedifferentiation and survival of fetal cardiovascular progenitor cells.

Ventral spinal cord progenitor cells, which express the basic helix loop helix transcription factor Olig2, sequentially produce motor neurons and oligodendrocyte precursor cells (OPCs). Following specification some OPCs differentiate as myelinating oligodendrocytes while others persist as OPCs. Though a considerable amount of work has described the molecular profiles that define motor neurons, OPCs, and oligodendrocytes, less is known about the progenitors that produce them. To identify the developmental origins and transcriptional profiles of motor neurons and OPCs, we performed single-cell RNA sequencing on isolated pMN cells from embryonic zebrafish trunk tissue at stages that encompassed motor neurogenesis, OPC specification, and initiation of oligodendrocyte differentiation. Downstream analyses revealed two distinct pMN progenitor populations: one that appears to produce neurons and one that appears to produce OPCs. This latter population, called Pre-OPCs, is marked by expression of GS Homeobox 2 (gsx2), a gene that encodes a homeobox transcription factor. Using fluorescent in situ hybridizations, we identified gsx2-expressing Pre-OPCs in the spinal cord prior to expression of canonical OPC marker genes. Our data therefore reveal heterogeneous gene expression profiles among pMN progenitors, supporting prior fate mapping evidence.HighlightsSingle-cell RNA sequencing reveals the developmental trajectories of neurons and glia that arise from spinal cord pMN progenitor cells in zebrafish embryosTranscriptionally distinct subpopulations of pMN progenitors are the apparent sources of neurons or oligodendrocytes, consistent with fate mapping datagsx2 expression marks pMN progenitors that produce oligodendrocyte lineage cells

To assess the transcriptomic profile of disease-specific cell populations, fibroblasts from patients with primary open-angle glaucoma (POAG) were reprogrammed into induced pluripotent stem cells (iPSCs) before being differentiated into retinal organoids and compared to those from healthy individuals. We performed single-cell RNA-sequencing of a total of 330,569 cells and identified cluster-specific molecular signatures. Comparing the gene expression profile between cases and controls, we identified novel genetic associations for this blinding disease. Expression quantitative trait mapping identified a total of 2,235 significant loci across all cell types, 58 of which are specific to the retinal ganglion cell subpopulations, which ultimately degenerate in POAG. Transcriptome-wide association analysis identified genes at loci previously associated with POAG, and analysis, conditional on disease status, implicated 54 statistically significant retinal ganglion cell-specific expression quantitative trait loci. This work highlights the power of large-scale iPSC studies to uncover context-specific profiles for a genetically complex disease.

SUMMARYChimeric antigen receptors (CARs) repurpose natural signaling components to retarget T cells to refractory cancers, but have shown limited efficacy against solid tumors. Here, we introduce ‘CAR Pooling’, a multiplexed approach to rapidly identify CAR designs with clinical potential. Forty CARs with diverse immune costimulatory domains were assessed in pooled assays for their ability to stimulate critical T cell effector functions during repetitive stimulation that mimics long-term tumor antigen exposure. Several non-native domains from the TNF receptor family exhibited enhanced proliferation (CD40) or cytotoxicity (BAFF-R and TACI) relative to clinical benchmarks, and fell into distinct states of memory, cytotoxicity, and metabolism. BAFF-R CAR T cells were enriched for a highly cytotoxic and NK-cell-like innate phenotype previously associated with positive clinical outcomes. ‘CAR Pooling’ enables efficient exploration of how CAR design affects cell activity and can be applied to optimize receptors across a range of applications and cell types.

Heteroclitic antibodies bind to a related antigen with higher affinity than to the immunizing antigen to which they were generated. This uncommon phenomenon is not well characterized for antibodies to HLA antigens. Here we analyzed allosera reactivity from two transplant recipients sensitized to mismatched donor alleles DQB1*06:01 and DQB1*06:02 respectively. Epitope analysis demonstrated the reactivity of both sera was restricted to DQB1*04, 05, and 06 alleles, with a specificity associated with the 55R eplet. Serum from one of these subjects (TE) was significantly more reactive with DQB1*04 alleles than the immunizing DQB1*06:01 or other alleles, a pattern not present in serum from the other patient. Antibody absorption/elution experiments using B cell lines expressing DQB1*06:01 or DQB1*04:02 alleles confirmed that the heteroclitic TE antibody eluted from cells carrying DQB1*06:01 was significantly more reactive with beads carrying the DQB1*04 alleles than with the DQB1*06 or other alleles. The significantly higher reactivity of the heteroclitic alloantibody with DQB1*04 specificity was explained structurally by variations of amino acid residues within 3.5 A of 55R. These findings have important implications for the interpretation of DQ alloantibody cross-reactivity frequently observed in transplant recipients.

Dead species remain dead. The diversity record of life is littered with examples of declines and radiations, yet no species has ever re-evolved following its true extinction. In contrast, functional traits can transcend diversity declines, often develop iteratively and are taxon-free allowing application across taxa, environments and time. Planktonic foraminifera have an unrivaled, near continuous fossil record for the past 200 million years making them a perfect test organism to understand trait changes through time, but the functional role of morphology in determining habitat occupation has been questioned. Here, we use single specimen stable isotopes to reconstruct the water depth habitat of individual planktonic foraminifera in the genus Subbotina alongside morphological measurements of the tests to understand trait changes through the Middle Eocene Climatic Optimum [MECO: ∼40 Myr ago (mega annum, Ma)]. The MECO is a geologically transient global warming interval that marks the beginning of widespread biotic reorganizations in marine organisms spanning a size spectrum from diatoms to whales. In contrast to other planktonic foraminiferal genera, the subbotinids flourished through this interval despite multiple climatic perturbations superimposed on a changing background climate. Through coupled trait and geochemical analysis, we show that Subbotina survival through this climatically dynamic interval was aided by trait plasticity and a wider ecological niche than previously thought for a subthermocline dwelling genus supporting a generalist life strategy. We also show how individually resolved oxygen isotopes can track shifts in depth occupancy through climatic upheaval. During and following the MECO, temperature changes were substantial in the thermocline and subthermocline in comparison to the muted responses of the surface ocean. In our post-MECO samples, we observe restoration of planktonic foraminifera depth stratification. Despite these changing temperatures and occupied depths, we do not detect a contemporaneous morphological response implying that readily available traits such as test size and shape do not have a clear functional role in this generalist genus. Modern imaging measurement technologies offer a promising route to gather more informative morphological traits for functional analysis, rather than the traditional candidates that are most easily measured.

Post-translational modifications to tubulin are important for many microtubule-based functions inside cells. It was recently shown that methylation of tubulin by the histone methyltransferase SETD2 occurs on mitotic spindle microtubules during cell division, with its absence resulting in mitotic defects. However, the catalytic mechanism of methyl addition to tubulin is unclear. We used a truncated version of human wild type SETD2 (tSETD2) containing the catalytic SET and C-terminal Set2–Rpb1–interacting (SRI) domains to investigate the biochemical mechanism of tubulin methylation. We found that recombinant tSETD2 had a higher activity toward tubulin dimers than polymerized microtubules. Using recombinant single-isotype tubulin, we demonstrated that methylation was restricted to lysine 40 of α-tubulin. We then introduced pathogenic mutations into tSETD2 to probe the recognition of histone and tubulin substrates. A mutation in the catalytic domain (R1625C) allowed tSETD2 to bind to tubulin but not methylate it, whereas a mutation in the SRI domain (R2510H) caused loss of both tubulin binding and methylation. Further investigation of the role of the SRI domain in substrate binding found that mutations within this region had differential effects on the ability of tSETD2 to bind to tubulin versus the binding partner RNA polymerase II for methylating histones in vivo, suggesting distinct mechanisms for tubulin and histone methylation by SETD2. Finally, we found that substrate recognition also requires the negatively charged C-terminal tail of α-tubulin. Together, this study provides a framework for understanding how SETD2 serves as a dual methyltransferase for both histone and tubulin methylation.

Bacteria move by a variety of mechanisms, but the best understood types of motility are powered by flagella ( 72 ). Flagella are complex machines embedded in the cell envelope that rotate a long extracellular helical filament like a propeller to push cells through the environment. The flagellum is one of relatively few biological machines that experience continuous 360° rotation, and it is driven by one of the most powerful motors, relative to its size, on earth. The rotational force (torque) generated at the base of the flagellum is essential for motility, niche colonization, and pathogenesis. This review describes regulatory proteins that control motility at the level of torque generation.

The "OECD Conference on Genome Editing: Applications in Agriculture-Implications for Health, Environment and Regulation" was held on the 28-29 June 2018 at the OECD headquarter and conference centre in Paris, France. It brought together policy makers, academia, innovators and other stakeholders involved in the topic, in order to take stock of the current technical developments and implementations of genome editing, as well as their applications in various areas of agriculture and the implications they give rise to (More information on the "OECD Conference on Genome Editing: Applications in Agriculture-Implications for Health, Environment and Regulation" can be found on the OECD Genome Editing hub: http://www.oecd.org/environment/genome-editing-agriculture/ ; the hub also contains the detailed conference programme, the biographies of all conference speakers, the detailed conference abstracts, and the presentations of the two-day conference). The conference aimed to provide a clearer understanding of the regulatory considerations raised by products of genome editing, pointing towards a coherent policy approach to facilitate innovations involving genome editing.

Background:\ud Surgical injury stimulates the systemic inflammatory response. The magnitude of the postoperative systemic inflammatory response has been shown to be significantly associated with short and long-term outcomes following surgery of varying severity. Different anesthetic techniques for surgery may have an impact on the postoperative systemic inflammatory response and on the rate of the postoperative infective complications.\ud \ud The aim of the present systematic review was to examine the relationship between perioperative anesthesia, the postoperative systemic inflammatory response and postoperative infective complications in patients undergoing surgery.\ud \ud Methods:\ud This was carried out using PubMed and other established databases from 1987 up to March 2018. In particular, randomized controlled studies and systemic inflammation markers, interleukin 6 and C-reactive protein were examined.\ud \ud Results:\ud Overall, 60 controlled, randomized clinical trials were included in the review. The mean or median values of both interleukin 6 and C-reactive protein were taken for each study and the mean value was calculated for each anesthetic group at sampling points of 12–24 and 24–72 hours for interleukin 6 and C-reactive protein respectively. When taking the magnitude of surgery into account, TIVA using propofol was significantly associated with a reduction in particular C-reactive protein (P = .04). However, there were no other specific anesthetic methods including general, regional and combined anesthetics that were associated with a reduction in either interleukin 6 or C-reactive protein.\ud \ud Conclusion:\ud There is some evidence that anesthetic regimens may reduce the magnitude of the postoperative systemic inflammatory response. However, the studies were heterogeneous and generally of low quality.\ud \ud Future, well conducted, adequately powered studies are required to clarify the effect of anesthesia on the postoperative systemic inflammatory response and infective complications.