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The lack of a specific biomarker makes preclinical diagnosis of Alzheimer's disease (AD) impossible, and it precludes assessment of therapies aimed at preventing or reversing the course of the disease. The development of a tool that enables direct, quantitative detection of the amyloid-β deposits found in the disease would provide an excellent biomarker. This article demonstrates the real-time biodistribution kinetics of an imaging agent in transgenic mouse models of AD. Using multiphoton microscopy, Pittsburgh compound B (PIB) was imaged with sub-µm resolution in the brains of living transgenic mice during peripheral administration. PIB entered the brain quickly and labeled amyloid deposits within minutes. The nonspecific binding was cleared rapidly, whereas specific labeling was prolonged. WT mice showed rapid brain entry and clearance of PIB without any binding. These results demonstrate that the compound PIB has the properties required for a good amyloid-imaging agent in humans with or at risk for AD.

The lack of a specific biomarker makes preclinical diagnosis of Alzheimer's disease (AD) impossible, and it precludes assessment of therapies aimed at preventing or reversing the course of the disease. The development of a tool that enables direct, quantitative detection of the amyloid-{beta} deposits found in the disease would provide an excellent biomarker. This article demonstrates the real-time biodistribution kinetics of an imaging agent in transgenic mouse models of AD. Using multiphoton microscopy, Pittsburgh compound B (PIB) was imaged with sub-µm resolution in the brains of living transgenic mice during peripheral administration. PIB entered the brain quickly and labeled amyloid deposits within minutes. The nonspecific binding was cleared rapidly, whereas specific labeling was prolonged. WT mice showed rapid brain entry and clearance of PIB without any binding. These results demonstrate that the compound PIB has the properties required for a good amyloid-imaging agent in humans with or at risk for AD. [PUBLICATION ABSTRACT]

ObjectiveThis study aimed to systematically review and meta-analyse the incidence and prevalence of hamstring injuries in field-based team sports. A secondary aim was to determine the impact of other potential effect moderators (match vs training; sport; playing surface; cohort age, mass and stature; and year when data was collected) on the incidence of hamstring injury in field-based team sports.DesignSystematic review and meta-analysis.Data sourcesCINAHL, Cochrane Library, MEDLINE Complete (EBSCO), Embase, Web of Science and SPORTDiscus databases were searched from database inception to 5 August 2020.Eligibility criteriaProspective cohort studies that assessed the incidence of hamstring injuries in field-based team sports.MethodFollowing database search, article retrieval and title and abstract screening, articles were assessed for eligibility against predefined criteria then assessed for methodological quality using the Critical Appraisal Tool for prevalence studies. Meta-analysis was used to pool data across studies, with meta-regression used where possible.ResultsSixty-three articles were included in the meta-analysis, encompassing 5952 injuries and 7 262 168 hours of exposure across six field-based team sports (soccer, rugby union, field hockey, Gaelic football, hurling and Australian football). Hamstring injury incidence was 0.81 per 1000 hours, representing 10% of all injuries. Prevalence for a 9-month period was 13%, increasing 1.13-fold for every additional month of observation (p=0.004). Hamstring injury incidence increased 6.4% for every 1 year of increased average cohort age, was 9.4-fold higher in match compared with training scenarios (p=0.003) and was 1.5-fold higher on grass compared with artificial turf surfaces (p<0.001). Hamstring injury incidence was not significantly moderated by average cohort mass (p=0.542) or stature (p=0.593), was not significantly different between sports (p=0.150) and has not significantly changed over the last 30 years (p=0.269).ConclusionHamstring injury represents 10% of all injuries in field-based team sports, with 13% of the athletes experiencing a hamstring injury over a 9-month period most commonly during matches. More work is needed to reduce the incidence of hamstring injury in field-based team sports.PROSPERO registration numberCRD42020200022.

The cytokine macrophage migration inhibitory factor (MIF) plays a critical role in inflammatory diseases and atherogenesis. We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF. MIF triggered G αi - and integrin-dependent arrest and chemotaxis of monocytes and T cells, rapid integrin activation and calcium influx through CXCR2 or CXCR4. MIF competed with cognate ligands for CXCR4 and CXCR2 binding, and directly bound to CXCR2. CXCR2 and CD74 formed a receptor complex, and monocyte arrest elicited by MIF in inflamed or atherosclerotic arteries involved both CXCR2 and CD74. In vivo , Mif deficiency impaired monocyte adhesion to the arterial wall in atherosclerosis-prone mice, and MIF-induced leukocyte recruitment required Il8rb (which encodes Cxcr2). Blockade of Mif but not of canonical ligands of Cxcr2 or Cxcr4 in mice with advanced atherosclerosis led to plaque regression and reduced monocyte and T-cell content in plaques. By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis. Targeting MIF in individuals with manifest atherosclerosis can potentially be used to treat this condition.

The conversion of white adipose to the highly thermogenic beige adipose tissue has been proposed as a potential strategy to counter the unfavorable consequences of obesity. Three regulators of this conversion have recently emerged but information regarding their control is limited, and contradictory. We present two studies examining the control of these regulators. Study 1: In 10 young men, the plasma concentrations of irisin and fibroblast growth factor 21 (FGF21) were determined prior to and during activation of the sympathetic nervous system via hypoxic gas breathing (FIO2 = 0.11). The measurements were performed twice, once with and once without prior/concurrent sympathetic inhibition via transdermal clonidine administration. FGF21 was unaffected by basal sympathetic inhibition (338±113 vs. 295±80 pg/mL; P = 0.43; mean±SE), but was increased during hypoxia mediated sympathetic activation (368±135); this response was abrogated (P = 0.035) with clonidine (269±93). Irisin was unaffected by sympathetic inhibition and/or hypoxia (P>0.21). Study 2: The plasma concentration of irisin and FGF21, and the skeletal muscle protein content of fibronectin type III domain containing 5 (FNDC5) was determined in 19 young adults prior to and following three weeks of sprint interval training (SIT). SIT decreased FGF21 (338±78 vs. 251±36; P = 0.046) but did not affect FNDC5 (P = 0.79). Irisin was decreased in males (127±18 vs. 90±23 ng/mL; P = 0.045) and increased in females (139±14 vs. 170±18). Collectively, these data suggest a potential regulatory role of acute sympathetic activation pertaining to the browning of white adipose; further, there appears to be a sexual dimorphic response of irisin to SIT.

Hydrogel materials have emerged as versatile platforms for various biomedical applications. Notably, the engineered nanofiber-hydrogel composite (NHC) has proven effective in mimicking the soft tissue extracellular matrix, facilitating substantial recruitment of host immune cells and the formation of a local immunostimulatory microenvironment. Leveraging this feature, here we report an mRNA lipid nanoparticle (LNP)-incorporated NHC microgel matrix, termed LiNx, by incorporating LNPs loaded with mRNA encoding tumour antigens. Harnessing the high transfection efficiency of LNPs in antigen-presenting cells, LiNx demonstrates substantial levels of immune cell recruitment, antigen expression and presentation, and cellular interaction. These attributes collectively create an immunostimulating microenvironment and yield a potent immune response with a single dose at a level comparable to the conventional three-dose LNP immunization protocol. Further investigation reveals that the LiNx generates not only high levels of Th1 and Th2 responses, but also a distinct Type 17 T helper cell response critical for bolstering antitumour efficacy. Our findings elucidate the mechanism underlying LiNx’s role in potentiating antigen-specific immune responses, presenting a strategy for cancer immunotherapy. Hydrogel materials have emerged as versatile platforms for biomedical applications. Here this group reports an mRNA lipid nanoparticle-incorporated microgel matrix for immune cell recruitment/antigen expression and presentation/cellular interaction thereby eliciting antitumor efficacy with a single dose.

Background Interventions utilising the Nordic hamstring exercise (NHE) have resulted in reductions in the incidence of hamstring strain injury (HSI). Subsequently, quantifying eccentric knee flexor strength during performance of the NHE to identify an association with the occurrence of future HSI has become increasingly common; however, the data to date are equivocal. Objective To systematically review the association between pre-season eccentric knee flexor strength quantified during performance of the NHE and the occurrence of future HSI. Design Systematic review and meta-analysis. Data sources CINAHL, Cochrane Library, Medline Complete, Embase, Web of Science and SPORTDiscus databases were searched from January 2013 to January 10, 2020. Eligibility criteria for selecting studies Prospective cohort studies which assessed the association between pre-season eccentric knee flexor strength quantified during performance of the NHE and the occurrence of future HSI. Methods Following database search, article retrieval and title and abstract screening, articles were assessed for eligibility against pre-defined criteria then assessed for risk of bias. Meta-analysis was used to pool data across studies, with meta-regression utilised where possible. Results A total of six articles were included in the meta-analysis, encompassing 1100 participants. Comparison of eccentric knee flexor strength during performance of the NHE in 156 injured participants and the 944 uninjured participants revealed no significant differences, regardless of whether strength was expressed as absolute (N), relative to body mass (N kg −1 ) or between-limb asymmetry (%). Meta-regression analysis revealed that the observed effect sizes were generally not moderated by age, mass, height, strength, or sport played. Conclusion Eccentric knee flexor strength quantified during performance of the NHE during pre-season provides limited information about the occurrence of a future HSI.

Key messageThirteen potentially new leaf rust resistance loci were identified in a Vavilov wheat diversity panel. We demonstrated the potential of allele stacking to strengthen resistance against this important pathogen.Leaf rust (LR) caused by Puccinia triticina is an important disease of wheat (Triticum aestivum L.), and the deployment of genetically resistant cultivars is the most viable strategy to minimise yield losses. In this study, we evaluated a diversity panel of 295 bread wheat accessions from the N. I. Vavilov Institute of Plant Genetic Resources (St Petersburg, Russia) for LR resistance and performed genome-wide association studies (GWAS) using 10,748 polymorphic DArT-seq markers. The diversity panel was evaluated at seedling and adult plant growth stages using three P. triticina pathotypes prevalent in Australia. GWAS was applied to 11 phenotypic data sets which identified a total of 52 significant marker–trait associations representing 31 quantitative trait loci (QTL). Among them, 29 QTL were associated with adult plant resistance (APR). Of the 31 QTL, 13 were considered potentially new loci, whereas 4 co-located with previously catalogued Lr genes and 14 aligned to regions reported in other GWAS and genomic prediction studies. One seedling LR resistance QTL located on chromosome 3A showed pronounced levels of linkage disequilibrium among markers (r2 = 0.7), suggested a high allelic fixation. Subsequent haplotype analysis for this region found seven haplotype variants, of which two were strongly associated with LR resistance at seedling stage. Similarly, analysis of an APR QTL on chromosome 7B revealed 22 variants, of which 4 were associated with resistance at the adult plant stage. Furthermore, most of the tested lines in the diversity panel carried 10 or more combined resistance-associated marker alleles, highlighting the potential of allele stacking for long-lasting resistance.

The Nix-TB clinical trial evaluated a new 6 month regimen containing three oral drugs; bedaquiline (B), pretomanid (Pa), and linezolid (L) (BPaL regimen) for the treatment of tuberculosis (TB). This regimen achieved remarkable results as almost 90% of the multidrug-resistant or extensively drug-resistant TB participants were cured but many patients also developed severe adverse events (AEs). The AEs were associated with the long-term administration of the protein synthesis inhibitor linezolid. Spectinamide 1599 is also a protein synthesis inhibitor of Mycobacterium tuberculosis with an excellent safety profile, but it lacks oral bioavailability. Here, we propose to replace L in the BPaL regimen with spectinamide (S) administered via inhalation and we demonstrate that inhaled spectinamide 1599, combined with BPa ––BPaS regimen––has similar efficacy to that of the BPaL regimen while simultaneously avoiding the L-associated AEs. The BPaL and BPaS regimens were compared in the BALB/c and C3HeB/FeJ murine chronic TB efficacy models. After 4-weeks of treatment, both regimens promoted equivalent bactericidal effects in both TB murine models. However, treatment with BPaL resulted in significant weight loss and the complete blood count suggested the development of anemia. These effects were not similarly observed in mice treated with BPaS. BPaL and BPa, but not the BPaS treatment, also decreased myeloid to erythroid ratio suggesting the S in the BPaS regimen was able to recover this effect. Moreover, the BPaL also increased concentration of proinflammatory cytokines in bone marrow compared to mice receiving BPaS regimen. These combined data suggest that inhaled spectinamide 1599 combined with BPa is an effective TB regimen without L-associated AEs.

The Neopilionidae is a highly diversified harvestman family in New Zealand, comprising eight genera and 28 species. Although individuals of many species are abundant in the field, basic information on their natural history is absent. Here we describe the diet, predators, and defensive behaviors of 13 species across three genera, Forsteropsalis Taylor, 2013, Mangatangi Taylor, 2013, and Pantopsalis Simon, 1879. Using three years of field observations, we first identify food items for this family, finding that New Zealand neopilionids are opportunistic, generalist foragers with a diet composed of a wide variety of prey and scavenged soft-bodied invertebrates, including worms, amphipods, species from nine orders of insects, and two orders of arachnids (including conspecifics). We then describe the first known invertebrate predators of New Zealand harvestmen, including seven spider species, and conduct a review of the literature to collate a list of 32 species of native and non-native vertebrates (frogs, lizards, fish, birds, and mammals) that prey on harvestmen, including neopilionids. Finally, we describe the defensive behaviors of neopilionids, providing the first reports of autotomy and thanatosis in the family. In general, the diet of New Zealand neopilionids is similar to other harvestman species, and the list of predators includes mostly insectivorous taxa known to feed on harvestmen elsewhere. The defensive repertoire of neopilionids includes behaviors recorded for other species of Eupnoi, such as leg autotomy, but also unique behaviors that are only known for species of Dyspnoi and Laniatores, such as thanatosis.