Convergent evolution of pain-inducing defensive venom components in spitting cobras.

Convergent evolution provides insights into the selective drivers underlying evolutionary change. Snake venoms, with a direct genetic basis and clearly defined functional phenotype, provide a model system for exploring the repeated evolution of adaptations. While snakes use venom primarily for predation, and venom composition often reflects diet specificity, three lineages of cobras have independently evolved the ability to spit venom at adversaries. Using gene, protein, and functional analyses, we show that the three spitting lineages possess venoms characterized by an up-regulation of phospholipase A2 (PLA2) toxins, which potentiate the action of preexisting venom cytotoxins to activate mammalian sensory neurons and cause enhanced pain. These repeated independent changes provide a fascinating example of convergent evolution across multiple phenotypic levels driven by selection for defense.

An optical neural chip for implementing complex-valued neural network.

Complex-valued neural networks have many advantages over their real-valued counterparts. Conventional digital electronic computing platforms are incapable of executing truly complex-valued representations and operations. In contrast, optical computing platforms that encode information in both phase and magnitude can execute complex arithmetic by optical interference, offering significantly enhanced computational speed and energy efficiency. However, to date, most demonstrations of optical neural networks still only utilize conventional real-valued frameworks that are designed for digital computers, forfeiting many of the advantages of optical computing such as efficient complex-valued operations. In this article, we highlight an optical neural chip (ONC) that implements truly complex-valued neural networks. We benchmark the performance of our complex-valued ONC in four settings: simple Boolean tasks, species classification of an Iris dataset, classifying nonlinear datasets (Circle and Spiral), and handwriting recognition. Strong learning capabilities (i.e., high accuracy, fast convergence and the capability to construct nonlinear decision boundaries) are achieved by our complex-valued ONC compared to its real-valued counterpart.

Near-ideal spontaneous photon sources in silicon quantum photonics.

While integrated photonics is a robust platform for quantum information processing, architectures for photonic quantum computing place stringent demands on high quality information carriers. Sources of single photons that are highly indistinguishable and pure, that are either near-deterministic or heralded with high efficiency, and that are suitable for mass-manufacture, have been elusive. Here, we demonstrate on-chip photon sources that simultaneously meet each of these requirements. Our photon sources are fabricated in silicon using mature processes, and exploit a dual-mode pump-delayed excitation scheme to engineer the emission of spectrally pure photon pairs through inter-modal spontaneous four-wave mixing in low-loss spiralled multi-mode waveguides. We simultaneously measure a spectral purity of 0.9904 ± 0.0006, a mutual indistinguishability of 0.987 ± 0.002, and  >90% intrinsic heralding efficiency. We measure on-chip quantum interference with a visibility of 0.96 ± 0.02 between heralded photons from different sources.

Perinatal inflammation influences but does not arrest rapid immune development in preterm babies.

Infection and infection-related complications are important causes of death and morbidity following preterm birth. Despite this risk, there is limited understanding of the development of the immune system in those born prematurely, and of how this development is influenced by perinatal factors. Here we prospectively and longitudinally follow a cohort of babies born before 32 weeks of gestation. We demonstrate that preterm babies, including those born extremely prematurely (<28 weeks), are capable of rapidly acquiring some adult levels of immune functionality, in which immune maturation occurs independently of the developing heterogeneous microbiome. By contrast, we observe a reduced percentage of CXCL8-producing T cells, but comparable levels of TNF-producing T cells, from babies exposed to in utero or postnatal infection, which precedes an unstable post-natal clinical course. These data show that rapid immune development is possible in preterm babies, but distinct identifiable differences in functionality may predict subsequent infection mediated outcomes.

Multimodality treatment of intracranial arteriovenous malformations in South Island, New Zealand.

Treatment of intracranial arteriovenous malformations is complex and multidisciplinary. This article presents the treatment model utilized in Christchurch, New Zealand which provides cerebrovascular surgery and interventional neuroradiology to the entire south island (approximate population of 1.1 million). A total of 40 patients treated over a 10 year period (2004-2014) are analysed here. Nine patients were managed surgically and complete resection was achieved in 100% of cases. Permanent mortality was 0% and permanent morbidity was 22% however median mRS improved from 3.0 preoperatively to 1.0 at follow up. Embolisation was utilized in 31 patients (mean age 40), of which 45% presented with haemorrhage, 39% with seizures, 10% with a headache only, and 6% with a deficit. None were found incidentally. The Spetzler-Martin grade 1 cases accounted for 10% of the cohort, 23% were grade II, 42% grade III, 23% grade IV and 3% grade V. A single aneurysm was present in 42% of cases, and multiple in 13%. The nidus was obliterated in 9.6% of cases with a morbidity rate of 6.5% and mortality rate of 3%. Modified Rankin scale improved marginally from 0.9 at diagnosis to 0.88 at final follow up (mean 22 months). There were no cases of recanalization. The total nidus obliteration rate using our algorithm of surgery alone for small accessible lesions, then staged embolization for larger lesions with adjuvant radiosurgery reserved for cases with residual nidus, was 50%.

Demonstration of Single-Barium-Ion Sensitivity for Neutrinoless Double-Beta Decay Using Single-Molecule Fluorescence Imaging.

A new method to tag the barium daughter in the double-beta decay of ^{136}Xe is reported. Using the technique of single molecule fluorescent imaging (SMFI), individual barium dication (Ba^{++}) resolution at a transparent scanning surface is demonstrated. A single-step photobleach confirms the single ion interpretation. Individual ions are localized with superresolution (∼2 nm), and detected with a statistical significance of 12.9σ over backgrounds. This lays the foundation for a new and potentially background-free neutrinoless double-beta decay technology, based on SMFI coupled to high pressure xenon gas time projection chambers.

E7 (1057ΔTA) mutation of the acidic α-glucosidase gene causes Pompe's disease in Droughtmaster cattle.

OBJECTIVE: To determine whether known loss-of-function alleles of the acidic α-glucosidase gene (GAA) are present in the Droughtmaster breed and, if so, whether the clinical signs and pathology of generalised glycogenosis (Pompe's disease) previously reported in other affected cattle are also seen in homozygous Droughtmasters. DESIGN: Existing genomic and other diagnostic tests developed for generalised glycogenosis in cattle were used to test for the presence of the three known loss-of-function alleles of GAA in a herd of Droughtmaster cattle. Two calves with clinical signs of generalised glycogenosis were submitted for necropsy. RESULTS: One loss-of-function GAA mutation (1057ΔTA or E7 allele) was identified using SNP chip technology and confirmed using conventional diagnostic DNA tests. Further testing demonstrated that the mutation was common within this herd and that two ill-thrift calves were homozygous for the E7 allele. Parentage analysis confirmed both sire and dam as heterozygous carriers. Pathology consistent with generalised glycogenosis was found in the skeletal and cardiac muscle and spinal cord of both of the affected calves. The 1783C>T (E13) or 2454ΔCA (E18) mutations associated with generalised glycogenosis in the Brahman and Shorthorn breeds, respectively, were not detected. CONCLUSION: The lethal mutation 1057ΔTA of GAA is present in the Droughtmaster breed, with pathology identical to that reported in pure Brahman animals. Droughtmaster breeders should take action to prevent any increase in the prevalence of this lethal allele in the breed as it could cause both welfare issues and production losses if ignored.

Lower-extremity muscle atrophy and fat infiltration after chronic spinal cord injury.

BACKGROUND: Atrophy and fatty-infiltration of lower-extremity muscle after spinal cord injury (SCI) predisposes individuals to metabolic disease and related mortality. OBJECTIVES: To determine the magnitude of atrophy and fatty-infiltration of lower-extremity muscles and related factors in a group of individuals with chronic SCI and diverse impairment. METHODS: Muscle cross-sectional area and density were calculated from peripheral quantitative computed tomography scans of the 66% site of the calf of 70 participants with chronic SCI [50 male, mean age 49 (standard deviation 12) years, C2-T12, AIS A-D] and matched controls. Regression models for muscle area and density were formed using 16 potential correlates selected a priori. RESULTS: Participants with motor-complete SCI had ≈ 32% lower muscle area, and ≈ 43% lower muscle density values relative to controls. Participants with motor-incomplete SCI had muscle area and density values that were both ≈ 14% lower than controls. Body mass (+), tetraplegia (+), motor function (+), spasticity (+), vigorous physical activity (+), wheelchair use (-), age (-), and waist circumference (-) were associated with muscle size and/or density in best-fit regression models. CONCLUSIONS: There are modifiable factors related to muscle size, body composition, and activity level that may offer therapeutic targets for preserving metabolic health after chronic SCI.

Boson sampling from a Gaussian state.

We pose a randomized boson-sampling problem. Strong evidence exists that such a problem becomes intractable on a classical computer as a function of the number of bosons. We describe a quantum optical processor that can solve this problem efficiently based on a Gaussian input state, a linear optical network, and nonadaptive photon counting measurements. All the elements required to build such a processor currently exist. The demonstration of such a device would provide empirical evidence that quantum computers can, indeed, outperform classical computers and could lead to applications.

Reference-frame-independent quantum-key-distribution server with a telecom tether for an on-chip client.

We demonstrate a client-server quantum key distribution (QKD) scheme. Large resources such as laser and detectors are situated at the server side, which is accessible via telecom fiber to a client requiring only an on-chip polarization rotator, which may be integrated into a handheld device. The detrimental effects of unstable fiber birefringence are overcome by employing the reference-frame-independent QKD protocol for polarization qubits in polarization maintaining fiber, where standard QKD protocols fail, as we show for comparison. This opens the way for quantum enhanced secure communications between companies and members of the general public equipped with handheld mobile devices, via telecom-fiber tethering.

Clinical grade manufacturing of human alloantigen-reactive regulatory T cells for use in transplantation.

Regulatory T cell (Treg) therapy has the potential to induce transplantation tolerance so that immunosuppression and associated morbidity can be minimized. Alloantigen-reactive Tregs (arTregs) are more effective at preventing graft rejection than polyclonally expanded Tregs (PolyTregs) in murine models. We have developed a manufacturing process to expand human arTregs in short-term cultures using good manufacturing practice-compliant reagents. This process uses CD40L-activated allogeneic B cells to selectively expand arTregs followed by polyclonal restimulation to increase yield. Tregs expanded 100- to 1600-fold were highly alloantigen reactive and expressed the phenotype of stable Tregs. The alloantigen-expanded Tregs had a diverse TCR repertoire. They were more potent than PolyTregs in vitro and more effective at controlling allograft injuries in vivo in a humanized mouse model.

Prevalence and specificity of red-blood-cell antibodies in a multiethnic South and East Asian patient population and influence of using novel MUT+Mur+ kodecytes on its detection.

BACKGROUND AND OBJECTIVES: Appropriate screening for irregular red-cell antibodies is essential for ensuring transfusion compatibility and for antenatal management of mothers at risk of haemolytic disease of the foetus and newborn. Screening for all relevant antibodies is, however, limited by screening cells that do not express antigens present in the patient and donor population. Technology to artificially incorporate antigens into red cells is currently available and may be an option for customizing screening cells. MATERIALS AND METHODS: We sought to identify retrospectively the changing patterns of alloantibody prevalence in our multiethnic population on change of screening cells. Antibody screening records of 143 501 patients tested from 2004 to 2010 were retrieved and divided into two groups: period-1 (2004-2008) and period-2 (2009-2010). During period-1, standard screening cells were used while in period-2, MUT+Mur+ KODE(™) transformed red cells (kodecytes) were used. RESULTS: Four per cent of samples tested during period-2 were positive on antibody screening compared to 3·2% in period-1. Specific antibodies, excluding anti-D, were identified in 1·66% and 1·52% of patients in period-2 and -1, respectively. When confined to antibodies of clinical significance only, period-2 showed higher alloantibody prevalence of 1·16% as compared to 0·66% in period-1. Antibodies to glycophorin variants of MNS (vMNS) were more commonly detected while antibodies to Lewis antigens declined during period-2. CONCLUSION: Antibodies to vMNS antigens are common in South and East Asian populations and are often missed when using standard screening cells. Use of specifically engineered screening cells to express red-cell antigens artificially is beneficial in detecting the diverse alloantibodies present in our population.

Hip protectors: recommendations for conducting clinical trials--an international consensus statement (part II).

INTRODUCTION: While hip protectors are effective in some clinical trials, many, including all in community settings, have been unable to demonstrate effectiveness. This is due partly to differences in the design and analysis. The aim of this report is to develop recommendations for subsequent clinical research. METHODS: In November of 2007, the International Hip Protector Research Group met to address barriers to the clinical effectiveness of hip protectors. This paper represents a consensus statement from the group on recommended methods for conducting future clinical trials of hip protectors. RESULTS AND CONCLUSIONS: Consensus recommendations include the following: the use of a hip protector that has undergone adequate biomechanical testing, the use of sham hip protectors, the conduct of clinical trials in populations with annual hip fracture incidence of at least 3%, a run-in period with demonstration of adequate adherence, surveillance of falls and adherence, and the inclusion of economic analyses. Larger and more costly clinical trials are required to definitively investigate effectiveness of hip protectors.

Hip protectors: recommendations for biomechanical testing--an international consensus statement (part I).

INTRODUCTION: Hip protectors represent a promising strategy for preventing fall-related hip fractures. However, clinical trials have yielded conflicting results due, in part, to lack of agreement on techniques for measuring and optimizing the biomechanical performance of hip protectors as a prerequisite to clinical trials. METHODS: In November 2007, the International Hip Protector Research Group met in Copenhagen to address barriers to the clinical effectiveness of hip protectors. This paper represents an evidence-based consensus statement from the group on recommended methods for evaluating the biomechanical performance of hip protectors. RESULTS AND CONCLUSIONS: The primary outcome of testing should be the percent reduction (compared with the unpadded condition) in peak value of the axial compressive force applied to the femoral neck during a simulated fall on the greater trochanter. To provide reasonable results, the test system should accurately simulate the pelvic anatomy, and the impact velocity (3.4 m/s), pelvic stiffness (acceptable range: 39-55 kN/m), and effective mass of the body (acceptable range: 22-33 kg) during impact. Given the current lack of clear evidence regarding the clinical efficacy of specific hip protectors, the primary value of biomechanical testing at present is to compare the protective value of different products, as opposed to rejecting or accepting specific devices for market use.

Effect of soft shell hip protectors on pressure distribution to the hip during sideways falls.

INTRODUCTION: While hip protectors represent a promising strategy for preventing hip fractures, clinical efficacy has been limited by poor user compliance. Soft shell protectors may be more acceptable to users than traditional hard shell designs. However, before embarking on clinical trials to assess efficacy, laboratory experiments are required to determine how soft shell protectors affect the force applied during impact to the hip. This was the goal of the current study. METHODS: Fifteen women participated in "pelvis release experiments," which safely simulate the impact stage of a sideways fall. During the trials, we measured total impact force and mean pressure over the greater trochanter with the participant unpadded, and while wearing two commercially available soft shell protectors. RESULTS: Mean pressure over the greater trochanter was reduced by 76% by a 14-mm thick horseshoe-shaped protector and by 73% by a 16-mm thick continuous protector. Total force was reduced by 9% by the horseshoe and by 19% by the continuous protector. CONCLUSIONS: Soft shell hip protectors substantially reduce the pressure over the greater trochanter, while only modestly reducing total impact force during simulated sideways falls. These data support the need for clinical trials to determine whether soft shell protectors reduce hip fracture risk in vulnerable populations.

An anatomical study of the gracilis muscle and its application in groin wounds.

The management of groin wounds is a common and challenging problem encountered in surgical practice. The purpose of this study is to examine the anatomic basis of the gracilis muscle with relation to this problem. Twelve cadaveric lower limbs were studied to examine both the extramuscular and intramuscular vasculature of the gracilis muscle. These underwent dissection and in 3 cases radiologic examination. The mean entry point of the dominant arterial pedicle was 9.4 cm, with mean length and width of the muscle recorded as 38.4 cm and 6.2 cm, respectively. Each gracilis muscle was then mobilized between the adductor longus and adductor magnus muscles on its dominant pedicle and transposed into the femoral triangle. In each case, the gracilis muscle mobilized easily on its dominant pedicle to adequately cover the groin. The gracilis muscle is a reliable muscle flap with a consistent blood supply, which can be transposed easily into the groin, based on its dominant pedicle, and offers adequate coverage of the femoral vessels.

Effectiveness of a participatory ergonomics intervention in improving communication and psychosocial exposures.

A participatory ergonomics programme was implemented in an automotive parts manufacturing factory in which an ergonomics change team was formed, composed of members from management, the organized labour union and the research team. It was hypothesized that the participatory nature of this change process would result in enhanced worker perceptions of workplace communication dynamics, decision latitude and influence, which in conjunction with anticipated mechanical exposure reductions would lead to reduced worker pain severity. Utilizing a sister plant in the corporation as a referent group, a quasi-experimental design was employed with a longitudinal, repeat questionnaire approach to document pre-post intervention changes. Nine participatory activities (psychosocial interventions) were implemented as part of the process. Communication dynamics regarding ergonomics were significantly enhanced at the intervention plant compared to the referent plant. However, there were no significantly different changes in worker perceptions of decision latitude or influence between the two plants, nor did pain severity change. Possible explanations for these results include limited intervention intensity, context and co-intervention differences between the two plants, high plant turnover reducing the statistical power of the study and lack of sensitivity and specificity in the psychosocial measures used. Further research should include the development of psychosocial tools more specific to participatory ergonomic interventions and the assessment of the extent of change in psychosocial factors that might be associated with improvements in pain.

A systemic provascular response in bone marrow to musculoskeletal trauma in mice.

Post-natal vasculogenesis, the process by which vascular committed bone marrow stem cells or endothelial precursor cells migrate, differentiate and incorporate into the nacent endothelium and thereby contribute to physiological and pathological neurovascularisation, has stimulated much interest. Its contribution to neovascularisation of tumours, wound healing and revascularisation associated with ischaemia of skeletal and cardiac muscles is well established. We evaluated the responses of endothelial precursor cells in bone marrow to musculoskeletal trauma in mice. Bone marrow from six C57 Black 6 mice subjected to a standardised, closed fracture of the femur, was analysed for the combined expression of cell-surface markers stem cell antigen 1 (sca-1(+)) and stem cell factor receptor, CD117 (c-kit(+)) in order to identify the endothelial precursor cell population. Immunomagnetically-enriched sca-1(+) mononuclear cell (MNC(sca-1+)) populations were then cultured and examined for functional vascular endothelial differentiation. Bone marrow MNC(sca-1+,c-kit+) counts increased almost twofold within 48 hours of the event, compared with baseline levels, before decreasing by 72 hours. Sca-1(+) mononuclear cell populations in culture from samples of bone marrow at 48 hours bound together Ulex Europus-1, and incorporated fluorescent 1,1'-dioctadecyl- 3,3,3,'3'-tetramethylindocarbocyanine perchlorate-labelled acetylated low-density lipoprotein intracellularily, both characteristics of mature endothelium. Our findings suggest that a systemic provascular response of bone marrow is initiated by musculoskeletal trauma. Its therapeutic manipulation may have implications for the potential enhancement of neovascularisation and the healing of fractures.

Mobilization of endothelial precursor cells: systemic vascular response to musculoskeletal trauma.

Postnatal vasculogenesis, the process by which vascular committed bone marrow stem cells or endothelial precursor cells (EPC) migrate, differentiate, and incorporate into the nacent endothelium contributing to physiological and pathological neovascularization, has stimulated much interest. Its contribution to tumor nonvascularization, wound healing, and revascularization associated with skeletal and cardiac muscles ischaemia is established. We evaluated the mobilization of EPCs in response to musculoskeletal trauma. Blood from patients (n = 15) following AO type 42a1 closed diaphyseal tibial fractures was analyzed for CD34 and AC133 cell surface marker expression. Immunomagnetically enriched CD34+ mononuclear cell (MNC(CD34+)) populations were cultured and examined for phenotypic and functional vascular endothelial differentiation. Circulating MNC(CD34+) levels increased sevenfold by day 3 postinjury. Circulating MNC(AC133+) increased 2.5-fold. Enriched MNC(CD34+) populations from day 3 samples in culture exhibited cell cluster formation with sprouting spindles. These cells bound UEA-1 and incorporated fluorescent DiI-Ac-LDL intracellularily. Our findings suggest a systemic provascular response is initiated in response to musculoskeletal trauma. Its therapeutic manipulation may have implications for the potential enhancement of fracture healing.