Characterization of human-dog social interaction using owner report

Dog owners were surveyed for observations of social behaviors in their dogs, using questions adapted from the human Autism Diagnostic Observation Schedule (ADOS) pre-verbal module. Using 939 responses for purebred and mixed-breed dogs, three factors were identified: initiation of reciprocal social behaviors (INIT), response to social interactions (RSPNS), and communication (COMM). There were small or no effects of sex, age, breed group or training. For six breeds with more than 35 responses (Border Collie, Rough Collie, German Shepherd, Golden Retriever, Labrador Retriever, Standard Poodle), the behaviors eye contact with humans, enjoyment in interactions with human interaction, and name recognition demonstrated little variability across breeds, while asking for objects, giving/showing objects to humans, and attempts to direct humans’ attention showed higher variability across these breeds. Breeds with genetically similar backgrounds had similar response distributions for owner reports of dog response to pointing. When considering these breeds according to the broad categories of “herders” and “retrievers,” owners reported that the “herders” used more eye contact and vocalization, while the “retrievers” used more body contact. Information regarding social cognitive abilities in dogs provided by owner report suggest that there is variability across many social cognitive abilities in dogs and offers direction for further experimental investigations.     

The nucleotide sequence of the yeast ARG4 gene

The complete nucleotide sequence of a 2296-bp DNA fragment containing the yeast (Saccharomyces cerevisiae) ARG4 gene has been determined. This gene specifies the synthesis of the arginine biosynthetic enzyme, argininosuccinate lyase (EC 4.3.2.1). The sequence contains one major open reading frame of 463 codons, giving a calculated M_r of 52010 for the protein, in good agreement with the experimentally determined value of 53 000. The sequence upstream from the ARG4 gene shares structural features in common with other yeast genes subject to general amino acid control.     

Analysis of triquetral-lunate fusion

Fusion of the centers of the triquetral and lunate (the os lunato-triquetrum) was observed in 1.6% of 7,543 subjects primarily of African origin as compared with 0.1% of 11,663 persons of European origin. The fusion was twice as common in females as in males, multifactorial inheritance was suggested in the lineages studied, and a possible selective disadvantage was postulated after comparison with West African fusion frequencies.     

Identification of novel bifunctional calmodulin-binding and microtubule-stabilizing motifs in STOP proteins.

Although microtubules are intrinsically labile tubulin assemblies, many cell types contain stable polymers, resisting depolymerizing conditions such as exposure to the cold or the drug nocodazole. This microtubule stabilization is largely due to polymer association with STOP proteins. There are several STOP variants, some with capacity to induce microtubule resistance to both the cold and nocodazole, others with microtubule cold stabilizing activity only. These microtubule-stabilizing effects of STOP proteins are inhibited by calmodulin and we now demonstrate that they are determined by two distinct kinds of repeated modular sequences (Mn and Mc), both containing a calmodulin-binding peptide, but displaying different microtubule stabilizing activities. Mn modules induce microtubule resistance to both the cold and nocodazole when expressed in cells. Mc modules, which correspond to the STOP central repeats, have microtubule cold stabilizing activity only. Mouse neuronal STOPs, which induce both cold and drug resistance in cellular microtubules, contain three Mn modules and four Mc modules. Compared with neuronal STOPs, the non-neuronal F-STOP lacks multiple Mn modules and this corresponds with an inability to induce nocodazole resistance. STOP modules represent novel bifunctional calmodulin-binding and microtubule-stabilizing sequences that may be essential for the generation of the different patterns of microtubule stabilization observed in cells.     

Thienopyrimidine-based P2Y12 platelet aggregation inhibitors

Herein we describe the design and synthesis of a novel series of potent thienopyrimidine P2Y₁₂ inhibitors and the negative impact protein binding has on the inhibition of platelet aggregation.     

Intravascular heavy chain-modification of hyaluronan during endotoxic shock

During inflammation, the covalent linking of the ubiquitous extracellular polysaccharide hyaluronan (HA) with the heavy chains (HC) of the serum protein inter alpha inhibitor (IαI) is exclusively mediated by the enzyme tumor necrosis factor α (TNFα)-stimulated-gene-6 (TSG-6). While significant advances have been made regarding how HC-modified HA (HC-HA) is an important regulator of inflammation, it remains unclear why HC-HA plays a critical role in promoting survival in intraperitoneal lipopolysaccharide (LPS)-induced endotoxemia while exerting only a modest role in the outcomes following intratracheal exposure to LPS. To address this gap, the two models of intraperitoneal LPS-induced endotoxic shock and intratracheal LPS-induced acute lung injury were directly compared in TSG-6 knockout mice and littermate controls. HC-HA formation, endogenous TSG-6 activity, and inflammatory markers were assessed in plasma and lung tissue. TSG-6 knockout mice exhibited accelerated mortality during endotoxic shock. While both intraperitoneal and intratracheal LPS induced HC-HA formation in lung parenchyma, only systemically-induced endotoxemia increased plasma TSG-6 levels and intravascular HC-HA formation. Cultured human lung microvascular endothelial cells secreted TSG-6 in response to both TNFα and IL1β stimulation, indicating that, in addition to inflammatory cells, the endothelium may secrete TSG-6 into circulation during systemic inflammation. These data show for the first time that LPS-induced systemic inflammation is uniquely characterized by significant vascular induction of TSG-6 and HC-HA, which may contribute to improved outcomes of endotoxemia.     

Treatment with a sphingosine analog after the inception of house dust mite-induced airway inflammation alleviates key features of experimental asthma

Background

In vivo phosphorylation of sphingosine analogs with their ensuing binding and activation of their cell-surface sphingosine-1-phosphate receptors is regarded as the main immunomodulatory mechanism of this new class of drugs. Prophylactic treatment with sphingosine analogs interferes with experimental asthma by impeding the migration of dendritic cells to draining lymph nodes. However, whether these drugs can also alleviate allergic airway inflammation after its onset remains to be determined. Herein, we investigated to which extent and by which mechanisms the sphingosine analog AAL-R interferes with key features of asthma in a murine model during ongoing allergic inflammation induced by Dermatophagoides pteronyssinus.

Methods

BALB/c mice were exposed to either D. pteronyssinus or saline, intranasally, once-daily for 10 consecutive days. Mice were treated intratracheally with either AAL-R, its pre-phosphorylated form AFD-R, or the vehicle before every allergen challenge over the last four days, i.e. after the onset of allergic airway inflammation. On day 11, airway responsiveness to methacholine was measured; inflammatory cells and cytokines were quantified in the airways; and the numbers and/or viability of T cells, B cells and dendritic cells were assessed in the lungs and draining lymph nodes.

Results

AAL-R decreased airway hyperresponsiveness induced by D. pteronyssinus by nearly 70%. This was associated with a strong reduction of IL-5 and IL-13 levels in the airways and with a decreased eosinophilic response. Notably, the lung CD4⁺ T cells were almost entirely eliminated by AAL-R, which concurred with enhanced apoptosis/necrosis in that cell population. This inhibition occurred in the absence of dendritic cell number modulation in draining lymph nodes. On the other hand, the pre-phosphorylated form AFD-R, which preferentially acts on cell-surface sphingosine-1-phosphate receptors, was relatively impotent at enhancing cell death, which led to a less efficient control of T cell and eosinophil responses in the lungs.

Conclusion

Airway delivery of the non-phosphorylated sphingosine analog, but not its pre-phosphorylated counterpart, is highly efficient at controlling the local T cell response after the onset of allergic airway inflammation. The mechanism appears to involve local induction of lymphocyte apoptosis/necrosis, while mildly affecting dendritic cell and T cell accumulation in draining lymph nodes.     

How Could Hospitalisations at the End of Life Have Been Avoided? A Qualitative Retrospective Study of the Perspectives of General Practitioners,Nurses and Family Carers

Background

Although many patients prefer to stay and die at home at the end of life, many are hospitalised. Little is known about how to avoid hospitalisations for patients living at home.

Aim

To describe how hospitalisation at the end of life can be avoided, from the perspective of the GPs, nurses and family carers.

Method

A qualitative design with face-to-face interviews was used. Taking 30 cases of patients who died non-suddenly, 26 GPs, 15 nurses and 18 family carers were interviewed in depth. Of the 30 patients, 20 were hospitalised and 10 were not hospitalised in the last three months of life.

Results

Five key themes that could help avoid hospitalisation at the end of life emerged from the interviews. The key themes were: 1) marking the approach of death, and shifting the mindset; 2) being able to provide acute treatment and care at home; 3) anticipatory discussions and interventions to deal with expected severe problems; 4) guiding and monitoring the patient and family in a holistic way through the illness trajectory; 5) continuity of treatment and care at home. If these five key themes are adopted in an interrelated way, this could help avoid hospitalisations, according to GPs, nurses and family carers.

Conclusions

The five key themes described in this study can be seen as strategies that could help in avoiding hospitalisation at the end of life. It is recommended that for all patients residing at home, GPs and community nurses work together as a team from the moment that it is marked that death is approaching up to the end of life.     

Front-to-Rear Membrane Tension Gradient in Rapidly Moving Cells

Membrane tension is becoming recognized as an important mechanical regulator of motile cell behavior. Although membrane-tension measurements have been performed in various cell types, the tension distribution along the plasma membrane of motile cells has been largely unexplored. Here, we present an experimental study of the distribution of tension in the plasma membrane of rapidly moving fish epithelial keratocytes. We find that during steady movement the apparent membrane tension is ∼30% higher at the leading edge than at the trailing edge. Similar tension differences between the front and the rear of the cell are found in keratocyte fragments that lack a cell body. This front-to-rear tension variation likely reflects a tension gradient developed in the plasma membrane along the direction of movement due to viscous friction between the membrane and the cytoskeleton-attached protein anchors embedded in the membrane matrix. Theoretical modeling allows us to estimate the area density of these membrane anchors. Overall, our results indicate that even though membrane tension equilibrates rapidly and mechanically couples local boundary dynamics over cellular scales, steady-state variations in tension can exist in the plasma membranes of moving cells.