Sex-Specific Heterosis in Line Crosses of Mice Selectively Bred for High Locomotor Activity

When populations with similar histories of directional selection are crossed, their offspring may differ in mean phenotype as compared with the average for the parental populations, often exhibiting enhancement of the mean phenotype (termed heterosis or hybrid vigor). We tested for heterosis in a cross of two replicate lines of mice selectively bred for high voluntary wheel running for 53 generations. Mice were paired to produce four sets of F1 offspring: two purebred High Runner (HR) lines and the hybrid reciprocal crosses. The purebred HR showed statistically significant, sex-dependent differences in body mass, wheel revolutions, running duration, mean running speed, and (controlling for body mass) organ masses (heart ventricles, liver, spleen, triceps surae muscle). Hybrid males ran significantly more revolutions than the purebred males, mainly via increased running speeds, but hybrid females ran intermediate distances, durations, and speeds, as compared with the purebred females. In both sexes, ventricles were relatively smaller in hybrids as compared with purebred HR. Overall, our results demonstrate differential and sex-specific responses to selection in the two HR lines tested, implying divergent genetic architectures underlying high voluntary exercise

Treatment of Full-Thickness Acetabular Chondral Flaps during Hip Arthroscopy: Bone Marrow Aspirate Concentrate versus Microfracture

Background: The optimal treatment strategy for patients with full-thickness chondral flaps undergoing hip arthroscopy is controversial. Purpose: To compare functional outcomes of patients who underwent bone marrow aspirate concentrate (BMAC) application with those of patients who underwent microfracture. Study Design: Cohort study; Level of evidence, 3. Methods: This was a retrospective case series of prospectively collected data on patients who underwent arthroscopic acetabular labral repair by 1 surgeon between June 2014 and April 2020. The inclusion criteria for this study were age ≥18 years, preoperative radiographs of the pelvis, arthroscopic acetabular labral repair, exposed subchondral bone with overlying chondral flap seen at the time of hip arthroscopy, microfracture or BMAC to address this lesion, and completed patient-reported outcome measures (PROMs) (International Hip Outcome Tool-33 [iHOT-33], Hip Outcome Score-Activities of Daily Living [HOS-ADL], Hip Outcome Score-Sports Subscale [HOS-Sport], modified Harris Hip Score [mHHS], and visual analog scale [VAS] for pain) at enrollment and 12-month follow-up. Clinical outcomes were assessed using PROM scores. Results: A total of 81 hips with full-thickness chondral flaps were included in this study: 50 treated with BMAC and 31 treated with microfracture. There were no significant differences between groups in age, sex, body mass index, tear size, radiographic osteoarthritis, or radiographic femoroacetabular impingement. In the BMAC cohort, all PROM scores improved significantly from preoperatively to follow-up: 41.7 to 75.6 for iHOT-33, 67.6 to 91.0 for HOS-ADL, 41.5 to 72.3 for HOS-Sport, 59.4 to 87.2 for mHHS, and 6.2 to 2.2 for VAS pain (P \u3c .001 for all). In the microfracture cohort, the score improvements were 48.0 to 65.1 for iHOT-33 (P = .001), 80.5 to 83.3 for HOS-ADL (P = .275), 59.2 to 62.4 for HOS-Sport (P = .568), 70.4 to 78.3 for mHHS (P = .028), and 4.9 to 3.6 for VAS pain (P = .036). Regarding clinically meaningful outcomes, 77.6% of the BMAC group and 50.0% of the microfracture group met the minimal clinically important difference for iHOT-33 at the 12-month follow-up (P = .013). Conclusion: Patients with full-thickness chondral flaps at the time of hip arthroscopy experienced greater improvements in functional outcome scores at the 12-month follow-up when treated with BMAC as opposed to microfracture

Positional Cloning of “Lisch-like”, a Candidate Modifier of Susceptibility to Type 2 Diabetes in Mice

In 404 Lepob/ob F2 progeny of a C57BL/6J (B6) x DBA/2J (DBA) intercross, we mapped a DBA-related quantitative trait locus (QTL) to distal Chr1 at 169.6 Mb, centered about D1Mit110, for diabetes-related phenotypes that included blood glucose, HbA1c, and pancreatic islet histology. The interval was refined to 1.8 Mb in a series of B6.DBA congenic/subcongenic lines also segregating for Lepob. The phenotypes of B6.DBA congenic mice include reduced β-cell replication rates accompanied by reduced β-cell mass, reduced insulin/glucose ratio in blood, reduced glucose tolerance, and persistent mild hypoinsulinemic hyperglycemia. Nucleotide sequence and expression analysis of 14 genes in this interval identified a predicted gene that we have designated “Lisch-like” (Ll) as the most likely candidate. The gene spans 62.7 kb on Chr1qH2.3, encoding a 10-exon, 646–amino acid polypeptide, homologous to Lsr on Chr7qB1 and to Ildr1 on Chr16qB3. The largest isoform of Ll is predicted to be a transmembrane molecule with an immunoglobulin-like extracellular domain and a serine/threonine-rich intracellular domain that contains a 14-3-3 binding domain. Morpholino knockdown of the zebrafish paralog of Ll resulted in a generalized delay in endodermal development in the gut region and dispersion of insulin-positive cells. Mice segregating for an ENU-induced null allele of Ll have phenotypes comparable to the B.D congenic lines. The human ortholog, C1orf32, is in the middle of a 30-Mb region of Chr1q23-25 that has been repeatedly associated with type 2 diabetes

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Immune response to a Trichinella spiralis infection in house mice from lines selectively bred for high voluntary wheel running.

Four lines of mice bred for high voluntary wheel running (HR lines) have high baseline circulating corticosterone levels and increased daily energy expenditure as compared with four non-selected control (C) lines. High corticosterone may suppress immune function and competing energy demands may limit ability to mount an immune response. We hypothesized that HR mice have a reduced immune response and therefore a decreased ability to fight an infection by Trichinella spiralis, an ecologically relevant nematode common in mammals. Infections have an acute, intestinal phase while the nematode is migrating, reproducing and traveling throughout the bloodstream, followed by a chronic phase with larvae encysted in muscles. Adult males (generation 55 of the selection experiment) were sham-infected or infected by oral gavage with ~300 J1 T. spiralis larvae. During the chronic phase of infection, mice were given wheel access for 6 days, followed by 2 days of maximum aerobic performance trials. Two weeks post-infection, infected HR had significantly lower circulating immunoglobulin E levels compared with infected C mice. However, we found no statistical difference between infected HR and C mice in numbers of encysted larvae within the diaphragm. As expected, both voluntary running and maximum aerobic performance were significantly higher in HR mice and lower in infected mice, with no line type-by-infection interactions. Results complement those of previous studies suggesting decreased locomotor abilities during the chronic phase of T. spiralis infection. However, despite reduced antibody production, breeding for high voluntary wheel exercise does not appear to have a substantial negative impact on general humoral function

Roles for the Canidae in food webs reviewed: Where do they fit?

The roles of the 37 species in the family Canidae (the dog family), are of great current interest. The Gray Wolf is the largest canid and their roles in food webs are much researched, as are those of Domestic Dogs, Coyotes and Red Foxes. Much less is known about the other canid species and their ecological roles. Here we describe general food web theory and the potential application of network theory to it; summarise the possible roles of predators in food webs; document the occurrence, diet and presumed functions that canids play in food webs throughout the world; give case studies of four threatened canid species of top, middle and basal trophic positions and six anthropogenically affected species; and identify knowledge limitations and propose research frameworks necessary to establish the roles of canids in food webs. Canids can be top-down drivers of systems or responsive to the availability of resources including suitable prey. They can be affected anthropogenically by habitat change, lethal control and changes to basic resource availability. They can be sustainable yield harvesters of their indigenous prey or passengers in complex ecosystems, and some are prey of larger canids and of other predators. Nevertheless, the roles of most canids are generally poorly studied and described, and some, e.g. Gray Wolves, Coyotes and Australian dingoes, are controversial. We advocate mensurative and experimental research into communities and ecosystems containing canids for a quantitative understanding of their roles in food webs and consequent development of better management strategies for ecosystems

Burden of Clostridium difficile

BACKGROUND: The magnitude and scope of Clostridium difficile infection in the United States continue to evolve. METHODS: In 2011, we performed active population- and laboratory-based surveillance across 10 geographic areas in the United States to identify cases of C. difficile infection (stool specimens positive for C. difficile on either toxin or molecular assay in residents ≥ 1 year of age). Cases were classified as community-associated or health care-associated. In a sample of cases of C. difficile infection, specimens were cultured and isolates underwent molecular typing. We used regression models to calculate estimates of national incidence and total number of infections, first recurrences, and deaths within 30 days after the diagnosis of C. difficile infection. RESULTS: A total of 15,461 cases of C. difficile infection were identified in the 10 geographic areas; 65.8% were health care-associated, but only 24.2% had onset during hospitalization. After adjustment for predictors of disease incidence, the estimated number of incident C. difficile infections in the United States was 453,000 (95% confidence interval [CI], 397,100 to 508,500). The incidence was estimated to be higher among females (rate ratio, 1.26; 95% CI, 1.25 to 1.27), whites (rate ratio, 1.72; 95% CI, 1.56 to 2.0), and persons 65 years of age or older (rate ratio, 8.65; 95% CI, 8.16 to 9.31). The estimated number of first recurrences of C. difficile infection was 83,000 (95% CI, 57,000 to 108,900), and the estimated number of deaths was 29,300 (95% CI, 16,500 to 42,100). The North American pulsed-field gel electrophoresis type 1 (NAP1) strain was more prevalent among health care-associated infections than among community-associated infections (30.7% vs. 18.8%, P&lt;0.001). CONCLUSIONS: C. difficile was responsible for almost half a million infections and was associated with approximately 29,000 deaths in 2011. (Funded by the Centers for Disease Control and Prevention.)