Social behaviour has a key role in animal survival across species, ranging from insects to primates and humans. However, the biological mechanisms driving natural interactions between multiple animals, over long-term periods, are poorly studied and remain elusive. Rigorous and objective quantification of behavioural parameters within a group poses a major challenge as it requires simultaneous monitoring of the positions of several individuals and comprehensive consideration of many complex factors. Automatic tracking and phenotyping of interacting animals could thus overcome the limitations of manual tracking methods. Here we report a broadly applicable system that automatically tracks the locations of multiple, uniquely identified animals, such as mice, within a semi-natural setting. The system combines video and radio frequency identified tracking data to obtain detailed behavioural profiles of both individuals and groups. We demonstrate the usefulness of these data in characterizing individual phenotypes, interactions between pairs and the collective social organization of groups.
A peptide based on the sequence of the complementarity determining region (CDR) 1 of a human monoclonal anti-DNA autoantibody that bears the 16/6 idiotype (16/6Id) was synthesized as a potential candidate for the treatment of SLE patients. The peptide, designated hCDR1, did not induce experimental SLE upon active immunization of mice. The ability of the peptide to treat an already established lupus that was either induced in BALB/c mice or developed spontaneously in (NZB x NZW)F1 mice was tested. Ten weekly injections of hCDR1 (200, 50 microg/mouse) given subcutaneously mitigated disease manifestations (e.g., leukopenia, proteinuria and kidney damage) and resulted in a prominent reduction in the dsDNA specific antibody titers. Furthermore, treatment with hCDR1 resulted in reduced secretion and expression of the "pathogenic" cytokines [i.e., INFgamma, IL-1beta, TNFalpha (in the induced model) and IL-10], whereas the immunosuppressive cytokine TGFbeta was up-regulated. Thus, the significant ameliorating effects of hCDR1 are manifested at least partially via the immunomodulation of the cytokine profile. These results suggest that hCDR1 is a potential candidate for a novel treatment of SLE patients.
The laboratory mouse serves as an important model system for studying gene, brain and behavioural interactions. Powerful methods of gene targeting have helped to decipher gene-function associations in human diseases. Yet, the laboratory mouse, obtained after decades of human-driven artificial selection, inbreeding, and adaptation to captivity, is of limited use for the study of fitness-driven behavioural responses that characterize the ancestral wild house mouse. Here, we demonstrate that the backcrossing of wild mice with knockout mutant laboratory mice retrieves behavioural traits exhibited exclusively by the wild house mouse, thereby unmasking gene functions inaccessible in the domesticated mutant model. Furthermore, we show that domestication had a much greater impact on females than on males, erasing many behavioural traits of the ancestral wild female. Hence, compared with laboratory mice, wild-derived mutant mice constitute an improved model system to gain insights into neuronal mechanisms underlying normal and pathological sexually dimorphic social behaviours.
BackgroundAtrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all‐cause mortality may guide interventions.Methods and ResultsIn the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose‐adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all‐cause mortality in the 14 171 participants in the intention‐to‐treat population. The median age was 73 years, and the mean CHADS 2 score was 3.5. Over 1.9 years of median follow‐up, 1214 (8.6%) patients died. Kaplan–Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all‐cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33–1.70, P<0.0001) and age ≥75 years (hazard ratio 1.69, 95% CI 1.51–1.90, P<0.0001) were associated with higher all‐cause mortality. Multiple additional characteristics were independently associated with higher mortality, with decreasing creatinine clearance, chronic obstructive pulmonary disease, male sex, peripheral vascular disease, and diabetes being among the most strongly associated (model C‐index 0.677).ConclusionsIn a large population of patients anticoagulated for nonvalvular atrial fibrillation, ≈7 in 10 deaths were cardiovascular, whereas <1 in 10 deaths were caused by nonhemorrhagic stroke or systemic embolism. Optimal prevention and treatment of heart failure, renal impairment, chronic obstructive pulmonary disease, and diabetes may improve survival.Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00403767.
The Golgi is a dynamic organelle whose correct assembly is crucial for cellular homeostasis. Perturbations in Golgi structure are associated with numerous disorders from neurodegeneration to cancer. However, whether and how dispersal of the Golgi apparatus is actively regulated under stress, and the consequences of Golgi dispersal, remain unknown. Here we demonstrate that 26S proteasomes are associated with the cytosolic surface of Golgi membranes to facilitate Golgi Apparatus-Related Degradation (GARD) and degradation of GM130 in response to Golgi stress. The degradation of GM130 is dependent on p97/VCP and 26S proteasomes, and required for Golgi dispersal. Finally, we show that perturbation of Golgi homeostasis induces cell death of multiple myeloma in vitro and in vivo, offering a therapeutic strategy for this malignancy. Taken together, this work reveals a mechanism of Golgi-localized proteasomal degradation, providing a functional link between proteostasis control and Golgi architecture, which may be critical in various secretion-related pathologies.
A peptide based on complementarity-determining region (CDR)-1 of a monoclonal murine anti-DNA Ab that bears the common idiotype, 16͞6Id, was synthesized and characterized. The peptide, designated pCDR1, was found to be an immunodominant T-cell epitope in BALB͞c mice. The CDR1-based peptide was shown to be capable of inhibiting the in vivo priming of BALB͞c mice immunized with the peptide or with the whole anti-DNA 16͞6Id ؉ mAbs of either mouse or human origin. We show here that administration of pCDR1 (weekly, i.v., 100 g͞mouse) in aqueous solution for 5 weeks starting at the time of disease induction with the human 16͞6Id prevented the development of clinical manifestations of experimental systemic lupus erythematosus (SLE). Further, 10 weekly injections of pCDR1 to BALB͞c mice with an established experimental SLE down-regulated clinical manifestations of SLE (e.g., anti-DNA auto-Abs, leukopenia, proteinuria, immune complex deposits in the kidneys) in the treated mice. Prevention of SLE induction was shown to be associated mainly with a decrease in the levels of IL-2, INF␥, and the proinflammatory cytokine TNF␣. On the other hand, the secretion of the immunosuppressive cytokine TGF was elevated. Amelioration of the clinical manifestations of an already established experimental SLE correlated with a dramatic decrease in TNF␣ secretion, elevated levels of TGF, and immunomodulation of the Th1 and Th2 type cytokines to levels close to those observed in healthy mice. T he induction of experimental systemic lupus erythematosus (SLE) has been previously reported in our laboratory and was achieved by using the human monoclonal anti-DNA Ab that bears the common idiotype, designated 16͞6Id (1). This Ab could induce SLE in naive mice of different susceptible strains (2). The 16͞6Id-induced disease resembles SLE in human and is manifested by high levels of auto-Abs, which include anti-DNA and antinuclear protein Abs as well as 16͞6Id and anti-16͞6Id specific Abs (1). The 16͞6Id-immunized mice also develop lupus-associated clinical symptoms (e.g., leukopenia, proteinuria, and kidney damage). Experimental SLE can also be induced in mice after their immunization with either a murine anti-16͞6Id mAb (3) or a murine anti-DNA 16͞6Idϩ mAb, 5G12 (4), suggesting the importance of the 16͞6Id network in the disease. Furthermore, T-cell lines specific to the human anti-DNA 16͞6Id ϩ mAb were shown to be capable of inducing experimental SLE in syngeneic recipient mice indicating the role of T cells in the disease (5). Experimental SLE, although induced in mice that normally develop no symptoms of SLE, was found to share features with the SLE model of (NZBxNZW)F1 mice, which develop the disease spontaneously. Thus, sequencing of the variable regions coding for the heavy and light chains of anti-DNA mAb isolated from mice afflicted with experimental SLE show high homology with the variable regions of anti-DNA mAb isolated from (NZBxNZW)F1 mice (6).Two peptides based on the sequences of the complementaritydetermining regions (CDR) of the...
SUMMARYSystemic lupus erythematosus (SLE) is an autoimmune disease characterized by the increased production of autoantibodies and by systemic clinical manifestations and damage to multiple organs. The aim of the present study was to analyse matrix metalloproteinase (MMP)-9 activity in sera of patients with active and inactive SLE in order to evaluate its role in the pathogenesis and course of the disease, as well as its diagnostic value. We measured activity levels of MMP-9 and MMP-2, using both gel zymography and activity assay kits, in sera of 40 SLE patients and of 25 healthy controls. We found that MMP-9 activity, but not MMP-2 activity, is significantly elevated in the sera of SLE patients compared with sera samples of healthy controls. High activity levels of MMP-9 were determined in sera of 68% of the SLE patients. Elevated levels of MMP-9 were correlated with the presence of discoid rash, Raynaud phenomenon, pneumonitis, mucosal ulcers and anti-phospholipid antibodies. Changes in activity levels of MMP-9, but not of MMP-2, were observed in sera of the same patient at different periods of the disease course. High levels of MMP-9 did not correlate with disease activity index (SLEDAI, BILAG) in female patients, but correlated with SLE activity in the group of male patients. The results of the present study suggest that MMP-9 plays a role in the pathogenesis of SLE.
We studied 39 patients with thromboangiitis obliterans to determine their cellular and humoral immune responses to native human collagen Type I and Type III, which are constituents of blood vessels. Cell-mediated sensitivity to these collagens was measured by an antigen-sensitive thymidine-incorporation assay. The mean stimulation index--the ratio of thymidine incorporation in the presence of antigen to that in its absence--with both Type I and Type III collagens used as antigens was significantly higher in patients with thromboangiitis obliterans than in patients with arteriosclerosis obliterans or in healthy male controls. Lymphocytes from 77 per cent of the patients with thromboangiitis obliterans exhibited cellular sensitivity to human Type I or Type III collagens (or both). Furthermore, in 17 of 39 serum samples from the patients with thromboangiitis obliterans a low but significant level of anticollagen antibody activity was detected, whereas there was no antibody activity in serum samples from controls. These results suggest that there is a distinct etiologic factor in this disease and also raise the possibility of differentiating between thromboangiitis obliterans and arteriosclerosis obliterans by immunologic means.
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