The relationship between consistency of propulsive cycles and maximum angular velocity during wheelchair racing

The purposes of this study were to examine the consistency of wheelchair athletes' upper-limb kinematics in consecutive propulsive cycles and to investigate the relationship between the maximum angular velocities of the upper arm and forearm and the consistency of the upper-limb kinematical pattern. Eleven elite international wheelchair racers propelled their own chairs on a roller while performing maximum speeds during wheelchair propulsion. A Qualisys motion analysis system was used to film the wheelchair propulsive cycles. Six reflective markers placed on the right shoulder, elbow, wrist joints, metacarpal, wheel axis, and wheel were automatically digitized. The deviations in cycle time, upper-arm and forearm angles, and angular velocities among these propulsive cycles were analyzed. The results demonstrated that in the consecutive cycles of wheelchair propulsion the increased maximum angular velocity may lead to increased variability in the upper-limb angular kinematics. It is speculated that this increased variability may be important for the distribution of load on different upper-extremity muscles to avoid the fatigue during wheelchair racing.     

The identification and optimisation of novel and selective diamide neuropeptide Y Y2 receptor antagonists

A novel small molecule NPY Y2 antagonist (3) identified from high throughput screening is described. A subsequent SAR study and optimisation programme based around this molecule is also described, leading to the identification of potent and soluble pyridyl analogue 36.     

AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias

AKT activation is associated with many malignancies, where AKT acts, in part, by inhibiting FOXO tumor suppressors. We show a converse role for AKT/FOXOs in acute myeloid leukemia (AML). Rather than decreased FOXO activity, we observed that FOXOs are active in ～40% of AML patient samples regardless of genetic subtype. We also observe this activity in human MLL-AF9 leukemia allele-induced AML in mice, where either activation of Akt or compound deletion of FoxO1/3/4 reduced leukemic cell growth, with the latter markedly diminishing leukemia-initiating cell (LIC) function in vivo and improving animal survival. FOXO inhibition resulted in myeloid maturation and subsequent AML cell death. FOXO activation inversely correlated with JNK/c-JUN signaling, and leukemic cells resistant to FOXO inhibition responded to JNK inhibition. These data reveal a molecular role for AKT/FOXO and JNK/c-JUN in maintaining a differentiation blockade that can be targeted to inhibit leukemias with a range of genetic lesions.     

Comparison of the results of surgical and non-surgical treatment of combat urogenital injuries in Bosnia war 1992-1995

Goal was to compare the results of surgical and non-surgical treatments of combat injuries of genitourinary system and to compare our data with data collected in the recent studies. The study was designed as a retrospective review of data collected in prospective databases. The data extracted from inpatients' medical records included demographics, mechanisms and type of injury, distribution of the lesions, clinical presentation features, applied diagnostic studies, treatment modalities, types of complication and results of treatment. Among 4.125 patients treated in the Mostar War Hospital, 111 had injury of genitourinary tract: 62 underwent a surgical and 49 non-surgical treatment. Mortality among operated patients was 16 (26%). Complications were noted in 47 patients (42%); in 33 (70%) were manifested as early complications, and 14 (30) as delayed ones (p = 0.006). Among the surgically treated patients, 40 (36%) had some complication, in comparison to 8 (7.2%) patients with complications among non-surgically treated patients; which represent a statistically significant difference (p < 0.05). In this study, there was a surprisingly high number of non-surgically treated patients, and this sub-group of UGT trauma patients had in some ways the superior treatment results in comparison with surgically treated patients. Conservatively treated patients had lower rate of complications, no mortality, and no patients with permanent disability.     

M-ORBIS: Mapping of mOleculaR Binding sItes and Surfaces

M-ORBIS is a Molecular Cartography approach that performs integrative high-throughput analysis of structural data to localize all types of binding sites and associated partners by homology and to characterize their properties and behaviors in a systemic way. The robustness of our binding site inferences was compared to four curated datasets corresponding to protein heterodimers and homodimers and protein–DNA/RNA assemblies. The Molecular Cartographies of structurally well-detailed proteins shows that 44% of their surfaces interact with non-solvent partners. Residue contact frequencies with water suggest that ∼86% of their surfaces are transiently solvated, whereas only 15% are specifically solvated. Our analysis also reveals the existence of two major binding site families: specific binding sites which can only bind one type of molecule (protein, DNA, RNA, etc.) and polyvalent binding sites that can bind several distinct types of molecule. Specific homodimer binding sites are for instance nearly twice as hydrophobic than previously described and more closely resemble the protein core, while polyvalent binding sites able to form homo and heterodimers more closely resemble the surfaces involved in crystal packing. Similarly, the regions able to bind DNA and to alternatively form homodimers, are more hydrophobic and less polar than previously described DNA binding sites.     

Coordination of Chimpanzees (<Emphasis Type="Italic">Pan troglodytes</Emphasis>) in a Stag Hunt Game

Group-living animals frequently face situations in which they must coordinate individual and sometimes conflicting goals. We assessed chimpanzees’ ability to coordinate in a Stag Hunt game. Dyads were confronted with a situation in which each individual was already foraging on a low-value food (hare) when a high-value food (stag) appeared that required collaboration for retrieval, with a solo attempt to get the stag resulting in a loss of both options. In one condition visibility between partners was open whereas in the other it was blocked by a barrier. Regardless of condition, dyads almost always (91%) coordinated to choose the higher valued collaborative option. Intentional communication or monitoring of the partner’s behavior before decision making—characteristic of much human coordination—were limited. Instead, all dyads adopted a leader–follower strategy in which one partner took the risk of going first, presumably predicting that this would induce the other to join in (sometimes communicating if she was slow to do so). These results show that humans’ closest primate relatives do not use complex communication to coordinate but most often use a less cognitively complex strategy that achieves the same end.     

Hepatitis B virus surface antigen assembly function persists when entire transmembrane domains 1 and 3 are replaced by a heterologous transmembrane sequence

Native hepatitis B surface antigen (HBsAg) spontaneously assembles into 22-nm subviral particles. The particles are lipoprotein micelles, in which HBsAg is believed to span the lipid layer four times. The first two transmembrane domains, TM1 and TM2, are required for particle assembly. We have probed the requirements for particle assembly by replacing the entire first or third TM domain of HBsAg with the transmembrane domain of HIV gp41. We found that either TM domain of HBsAg could be replaced, resulting in HBsAg-gp41 chimeras that formed particles efficiently. HBsAg formed particles even when both TM1 and TM3 were replaced with the gp41 domain. The results indicate remarkable flexibility in HBsAg particle formation and provide a novel way to express heterologous membrane proteins that are anchored to a lipid surface by their own membrane-spanning domain. The membrane-proximal exposed region (MPER) of gp41 is an important target of broadly reactive neutralizing antibodies against HIV-1, and HBsAg-MPER particles may provide a good platform for future vaccine development.