Biotin deficiency in mice is associated with decreased serum availability of insulin-like growth factor-I

Background  Biotin deficiency leads to decreased weight and nose-rump length in mice. Aim of the study  The mechanisms underlying this impairment in body growth are yet unclear. Biotin restriction, however, could affect the availability of growth hormone (GH) and/or insulin like growth factor-I (IGF-I) since both hormones control body growth. We then conducted a correlative study aimed at establishing whether biotin dietary restriction is associated with decreased GH/IGF-I serum concentrations. Methods  Levels of GH and IGF-I were measured through ELISA in serum samples of male BALB/cAnN mice fed with: 1] standard chow diet (control diet); 2] 30% egg-white biotin-deficient diet; or 3] 30% egg-white diet supplemented with 16.4 μmol biotin per kilogram (biotin sufficient diet). Relative food consumption, as adjusted per gram of body weight, was also determined. GH and IGF-I measurements were taken individually for 20 weeks beginning at the postnatal week 3, when the animals started consuming the corresponding diets. In addition, femur’s weight and longitudinal growth and the organization of its growth plate were all analyzed as indicators of GH/IGF-I function. Results  No differences in relative food consumption were observed among the three groups of mice along the experimental period that was evaluated. IGF-I serum levels, but not GH ones, were decreased in biotin deficient mice. These animals also showed decreased femur’s longitudinal growth, speed of lengthening and weight gain, as well as shorter and disorganized growth plates. Conclusions  This study shows that biotin dietary restriction is indeed associated with decreased availability of IGF-I and diminished long bone growth and elongation. These conditions could explain the impairment of longitudinal body growth previously reported in biotin deficient mice. Although cause-effect studies are still needed, we believe our results support the notion that biotin might modulate the availability of IGF-I. This work was supported by grants from the Dirección General de Asuntos del Personal Académico (DGAPA), Universidad Nacional Autónoma de México (PAPIIT IN230905, IN200205, IN208605) and the Consejo Nacional de Ciencia y Tecnología, México (52746, 42568Q).     

CD94-NKG2A recognition of human leukocyte antigen (HLA)-E bound to an HLA class I leader sequence

The recognition of human leukocyte antigen (HLA)-E by the heterodimeric CD94-NKG2 natural killer (NK) receptor family is a central innate mechanism by which NK cells monitor the expression of other HLA molecules, yet the structural basis of this highly specific interaction is unclear. Here, we describe the crystal structure of CD94-NKG2A in complex with HLA-E bound to a peptide derived from the leader sequence of HLA-G. The CD94 subunit dominated the interaction with HLA-E, whereas the NKG2A subunit was more peripheral to the interface. Moreover, the invariant CD94 subunit dominated the peptide-mediated contacts, albeit with poor surface and chemical complementarity. This unusual binding mode was consistent with mutagenesis data at the CD94-NKG2A-HLA-E interface. There were few conformational changes in either CD94-NKG2A or HLA-E upon ligation, and such a "lock and key" interaction is typical of innate receptor-ligand interactions. Nevertheless, the structure also provided insight into how this interaction can be modulated by subtle changes in the peptide ligand or by the pairing of CD94 with other members of the NKG2 family. Differences in the docking strategies used by the NKG2D and CD94-NKG2A receptors provided a basis for understanding the promiscuous nature of ligand recognition by NKG2D compared with the fidelity of the CD94-NKG2 receptors.     

Lymph-migrating, tissue-derived dendritic cells are minor constituents within steady-state lymph nodes

Observations that dendritic cells (DCs) constitutively enter afferent lymphatic vessels in many organs and that DCs in some tissues, such as the lung, turnover rapidly in the steady state have led to the concept that a major fraction of lymph node DCs are derived from migratory DCs that enter the lymph node through upstream afferent lymphatic vessels. We used the lysozyme M–Cre reporter mouse strain to assess the relationship of lymph node and nonlymphoid organ DCs. Our findings challenge the idea that a substantial proportion of lymph node DCs derive from the upstream tissue during homeostasis. Instead, our analysis suggests that nonlymphoid organ DCs comprise a major population of DCs within lymph nodes only after introduction of an inflammatory stimulus.     

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Authors of papers published in Rockefeller University Press journals (The Journal of Cell Biology, The Journal of Experimental Medicine, or The Journal of General Physiology) now retain copyright to their published work. This permits authors to reuse their own work in any way, as long as they attribute it to the original publication. Third parties may use our published materials under a Creative Commons license, six months after publication.     

Implications of high maternal weight during pregnancy

A high body weight on conception and during pregnancy can have health implications for both the mother and child. Obese mothers have an increased risk of developing gestational diabetes, pre-eclampsia, delivering via Caesarean section and giving birth to large-for-gestational-age infants or infants with congenital anomalies. Women need to be educated about the importance of achieving a healthy body weight before conception, to avoid complications during pregnancy and prevent perinatal perturbations.     

Artemisinin and a series of novel endoperoxide antimalarials exert early effects on digestive vacuole morphology

Artermisinin and its derivatives are now the mainstays of antimalarial treatment; however, their mechanism of action is only poorly understood. We report on the synthesis of a novel series of epoxy-endoperoxides that can be prepared in high yields from simple starting materials. Endoperoxides that are disubstituted with alkyl or benzyl side chains show efficient inhibition of the growth of both chloroquine-sensitive and -resistant strains of Plasmodium falciparum. A trans-epoxide with respect to the peroxide linkage increases the activity compared to that of its cis-epoxy counterpart or the parent endoperoxide. The novel endoperoxides do not show a strong interaction with artemisinin. We have compared the mechanism of action of the novel endoperoxides with that of artemisinin. Electron microscopy reveals that the novel endoperoxides cause the early accumulation of endocytic vesicles, while artemisinin causes the disruption of the digestive vacuole membrane. At longer incubation times artemisinin causes extensive loss of organellar structures, while the novel endoperoxides cause myelin body formation as well as the accumulation of endocytic vesicles. An early event following endoperoxide treatment is the redistribution of the pH-sensitive probe LysoSensor Blue from the digestive vacuole to punctate structures. By contrast, neither artemisinin nor the novel endoperoxides caused alterations in the morphology of the endoplasmic reticulum nor showed antagonistic antimalarial activity when they were used with thapsigargin. Analysis of rhodamine 123 uptake by P. falciparum suggests that disruption of the mitochondrial membrane potential occurs as a downstream effect rather than as an initiator of parasite killing. The data suggest that the digestive vacuole is an important initial site of endoperoxide antimalarial activity.     

"It is very hard": treatment for childhood lymphoma from the parents' perspective

This article presents the findings of a five-year longitudinal study exploring the treatment experience for families coping with leukemia and lymphoma to address the dearth of psycho-social research documenting the experience of childhood lymphoma patients. The participants noted that the predominant differences for lymphoma families, as compared with other childhood hematological conditions, center around the issues of, firstly, the intensity of treatment. While the treatment protocol is comparatively shorter, the parents perceive it to be more arduous due to the intense and continuous nature of treatment. Important issues noted in this regard were the negative impact of the toxicity of the chemotherapeutic drugs, the stress associated with the invasiveness of accessing the child's veins for blood samples and to inject medications and the experience of undergoing lumbar punctures. Secondly, the relatively rare occurrence of pediatric lymphoma was reported to result in feelings of isolation from other families with children with a hematological malignancy and the unavailability of information and support services focusing specifically on childhood lymphoma. Thirdly, the relatively high curative success rate of lymphomas can have the effect that the parents feel that their angst is somewhat trivialized by other parents at the hospital. Recommendations include the importance of the availability of the full range of supportive care services, attention to the difficult emotional states the child patients experience, clinical strategies that lessen the trauma of treatment, and the use of positive role models by way of contact with or information of children who have successfully completed treatment.     

The effect of the GENTLE/s robot-mediated therapy system on arm function after stroke

OBJECTIVE: To evaluate the effect of robot-mediated therapy on arm dysfunction post stroke. DESIGN: A series of single-case studies using a randomized multiple baseline design with ABC or ACB order. Subjects (n = 20) had a baseline length of 8, 9 or 10 data points. They continued measurement during the B - robot-mediated therapy and C - sling suspension phases.Setting: Physiotherapy department, teaching hospital. SUBJECTS: Twenty subjects with varying degrees of motor and sensory deficit completed the study. Subjects attended three times a week, with each phase lasting three weeks.Interventions: In the robot-mediated therapy phase they practised three functional exercises with haptic and visual feedback from the system. In the sling suspension phase they practised three single-plane exercises. Each treatment phase was three weeks long. MAIN MEASURES: The range of active shoulder flexion, the Fugl-Meyer motor assessment and the Motor Assessment Scale were measured at each visit. RESULTS: Each subject had a varied response to the measurement and intervention phases. The rate of recovery was greater during the robot-mediated therapy phase than in the baseline phase for the majority of subjects. The rate of recovery during the robot-mediated therapy phase was also greater than that during the sling suspension phase for most subjects. CONCLUSION: The positive treatment effect for both groups suggests that robot-mediated therapy can have a treatment effect greater than the same duration of non-functional exercises. Further studies investigating the optimal duration of treatment in the form of a randomized controlled trial are warranted.