Modulation of social behavior by the agouti pigmentation gene

Agouti is a secreted neuropeptide that acts as an endogenous antagonist of melanocortin receptors. Mice and rats lacking agouti (called non-agouti) have dark fur due to a disinhibition of melanocortin signaling and pigment deposition in the hair follicle. Non-agouti animals have also been reported to exhibit altered behavior, despite no evidence for the expression of agouti outside the skin. Here we confirm that non-agouti mice show altered social behavior and uncover expression of agouti in the preputial gland, a sebaceous organ in the urinary tract that secretes molecules involved in social behavior. Non-agouti mice had enlarged preputial glands and altered levels of putative preputial pheromones and surgical removal of the gland reversed the behavioral phenotype. These findings demonstrate the existence of an autologous, out-of-skin pathway for the modulation of social behavio

Small Oscillatory Accelerations, Independent of Matrix Deformations, Increase Osteoblast Activity and Enhance Bone Morphology

A range of tissues have the capacity to adapt to mechanical challenges, an attribute presumed to be regulated through deformation of the cell and/or surrounding matrix. In contrast, it is shown here that extremely small oscillatory accelerations, applied as unconstrained motion and inducing negligible deformation, serve as an anabolic stimulus to osteoblasts in vivo. Habitual background loading was removed from the tibiae of 18 female adult mice by hindlimb-unloading. For 20 min/d, 5 d/wk, the left tibia of each mouse was subjected to oscillatory 0.6 g accelerations at 45 Hz while the right tibia served as control. Sham-loaded (n = 9) and normal age-matched control (n = 18) mice provided additional comparisons. Oscillatory accelerations, applied in the absence of weight bearing, resulted in 70% greater bone formation rates in the trabeculae of the metaphysis, but similar levels of bone resorption, when compared to contralateral controls. Quantity and quality of trabecular bone also improved as a result of the acceleration stimulus, as evidenced by a significantly greater bone volume fraction (17%) and connectivity density (33%), and significantly smaller trabecular spacing (−6%) and structural model index (−11%). These in vivo data indicate that mechanosensory elements of resident bone cell populations can perceive and respond to acceleratory signals, and point to an efficient means of introducing intense physical signals into a biologic system without putting the matrix at risk of overloading. In retrospect, acceleration, as opposed to direct mechanical distortion, represents a more generic and safe, and perhaps more fundamental means of transducing physical challenges to the cells and tissues of an organism

Laparoscopic treatment of intestinal malrotation in neonates and infants: retrospective study

Intestinal malrotation in neonates or infants may require urgent surgical treatment, especially when volvulus and vascular compromise of the midgut are suspected. Successful laparoscopic management of malrotation has been described in a number of case reports. It remains unclear, however, whether laparoscopy for the treatment of malrotation has a success rate equal to that of open surgery and what relative risks exist in terms of conversion and redo surgery in larger numbers of patients. This report describes a retrospective analysis of the clinical outcome for 45 children who underwent laparoscopic treatment of intestinal malrotation at the authors' institution. The 45 patients in this series, ages several days to 13 years, underwent a diagnostic laparoscopy for suspected intestinal malrotation. For 37 patients, malrotation with or without volvulus was diagnosed. All these patients underwent laparoscopic derotation and Ladd's procedure. Successful laparoscopic treatment of intestinal malrotation could be performed in 75% of the cases (n = 28), and conversion to an open procedure was necessary in 25% of the cases (n = 9). The median hospital stay was 11 days (range, 2-60 days). Postoperative clinical relapse due to recurrence of malrotation, volvulus, or both occurred for 19% of the laparoscopically treated patients (n = 7). These patients underwent laparoscopic (n = 1) or open (n = 6) redo surgery. Diagnostic laparoscopy is the procedure of choice when intestinal malrotation is suspected. If present, malrotation can be treated adequately with laparoscopic surgery in the majority of cases. Nevertheless, to prevent recurrence of malrotation or volvulus, a low threshold for conversion to an open procedure is mandated

Rescuing Loading Induced Bone Formation at Senescence

The increasing incidence of osteoporosis worldwide requires anabolic treatments that are safe, effective, and, critically, inexpensive given the prevailing overburdened health care systems. While vigorous skeletal loading is anabolic and holds promise, deficits in mechanotransduction accrued with age markedly diminish the efficacy of readily complied, exercise-based strategies to combat osteoporosis in the elderly. Our approach to explore and counteract these age-related deficits was guided by cellular signaling patterns across hierarchical scales and by the insight that cell responses initiated during transient, rare events hold potential to exert high-fidelity control over temporally and spatially distant tissue adaptation. Here, we present an agent-based model of real-time Ca2+/NFAT signaling amongst bone cells that fully described periosteal bone formation induced by a wide variety of loading stimuli in young and aged animals. The model predicted age-related pathway alterations underlying the diminished bone formation at senescence, and hence identified critical deficits that were promising targets for therapy. Based upon model predictions, we implemented an in vivo intervention and show for the first time that supplementing mechanical stimuli with low-dose Cyclosporin A can completely rescue loading induced bone formation in the senescent skeleton. These pre-clinical data provide the rationale to consider this approved pharmaceutical alongside mild physical exercise as an inexpensive, yet potent therapy to augment bone mass in the elderly. Our analyses suggested that real-time cellular signaling strongly influences downstream bone adaptation to mechanical stimuli, and quantification of these otherwise inaccessible, transient events in silico yielded a novel intervention with clinical potential

Emotional ratings and skin conductance response to visual, auditory and haptic stimuli

The human emotional reactions to stimuli delivered by different sensory modalities is a topic of interest for many disciplines, from Human-Computer-Interaction to cognitive sciences. Different databases of stimuli eliciting emotional reaction are available, tested on a high number of participants. Interestingly, stimuli within one database are always of the same type. In other words, to date, no data was obtained and compared from distinct types of emotion-eliciting stimuli from the same participant. This makes it difficult to use different databases within the same experiment, limiting the complexity of experiments investigating emotional reactions. Moreover, whereas the stimuli and the participants’ rating to the stimuli are available, physiological reactions of participants to the emotional stimuli are often recorded but not shared. Here, we test stimuli delivered either through a visual, auditory, or haptic modality in a within participant experimental design. We provide the results of our study in the form of a MATLAB structure including basic demographics on the participants, the participant’s self-assessment of his/her emotional state, and his/her physiological reactions (i.e., skin conductance)

Ethanolamine phosphoglycerol attachment to eEF1A is not essential for normal growth of Trypanosoma brucei

Eukaryotic elongation factor 1A (eEF1A) is the only protein modified by ethanolamine phosphoglycerol (EPG). In mammals and plants, EPG is attached to conserved glutamate residues located in eEF1A domains II and III, whereas in the unicellular eukaryote, Trypanosoma brucei, a single EPG moiety is attached to domain III. A biosynthetic precursor of EPG and structural requirements for EPG attachment to T. brucei eEF1A have been reported, but the role of this unique protein modification in cellular growth and eEF1A function has remained elusive. Here we report, for the first time in a eukaryotic cell, a model system to study potential roles of EPG. By down-regulation of EF1A expression and subsequent complementation of eEF1A function using conditionally expressed exogenous eEF1A (mutant) proteins, we show that eEF1A lacking EPG complements trypanosomes deficient in endogenous eEF1A, demonstrating that EPG attachment is not essential for normal growth of T. brucei in culture

A protein functionalization platform based on selective reactions at methionine residues.

Nature has a remarkable ability to carry out site-selective post-translational modification of proteins, therefore enabling a marked increase in their functional diversity1. Inspired by this, chemical tools have been developed for the synthetic manipulation of protein structure and function, and have become essential to the continued advancement of chemical biology, molecular biology and medicine. However, the number of chemical transformations that are suitable for effective protein functionalization is limited, because the stringent demands inherent to biological systems preclude the applicability of many potential processes2. These chemical transformations often need to be selective at a single site on a protein, proceed with very fast reaction rates, operate under biologically ambient conditions and should provide homogeneous products with near-perfect conversion2-7. Although many bioconjugation methods exist at cysteine, lysine and tyrosine, a method targeting a less-explored amino acid would considerably expand the protein functionalization toolbox. Here we report the development of a multifaceted approach to protein functionalization based on chemoselective labelling at methionine residues. By exploiting the electrophilic reactivity of a bespoke hypervalent iodine reagent, the S-Me group in the side chain of methionine can be targeted. The bioconjugation reaction is fast, selective, operates at low-micromolar concentrations and is complementary to existing bioconjugation strategies. Moreover, it produces a protein conjugate that is itself a high-energy intermediate with reactive properties and can serve as a platform for the development of secondary, visible-light-mediated bioorthogonal protein functionalization processes. The merger of these approaches provides a versatile platform for the development of distinct transformations that deliver information-rich protein conjugates directly from the native biomacromolecules

Tandem synthesis of alternating polyesters from renewable resources

The vast majority of commodity materials are obtained from petrochemical feedstocks. These resources will plausibly be depleted within the next 100 years, and the peak in global oil production is estimated to occur within the next few decades. In this regard, biomass represents an abundant carbon-neutral renewable resource for the production of polymers. Here we report a new strategy, based on tandem catalysis, to obtain renewable materials. Commercially available complexes are found to be efficient catalysts for alternating polyesters from the cyclization of dicarboxylic acids followed by alternating copolymerization of the resulting anhydrides with epoxides. This operationally simple method is an attractive strategy for the production of new biodegradable polyesters