Measurement of Transverse Wakefields Induced by a Misaligned Positron Bunch in a Hollow Channel Plasma Accelerator.

Hollow channel plasma wakefield acceleration is a proposed method to provide high acceleration gradients for electrons and positrons alike: a key to future lepton colliders. However, beams which are misaligned from the channel axis induce strong transverse wakefields, deflecting beams and reducing the collider luminosity. This undesirable consequence sets a tight constraint on the alignment accuracy of the beam propagating through the channel. Direct measurements of beam misalignment-induced transverse wakefields are therefore essential for designing mitigation strategies. We present the first quantitative measurements of transverse wakefields in a hollow plasma channel, induced by an off-axis 20 GeV positron bunch, and measured with another 20 GeV lower charge trailing positron probe bunch. The measurements are largely consistent with theory.

Low dystrophin variability between muscles and stable expression over time in Becker muscular dystrophy using capillary Western immunoassay.

Becker muscular dystrophy (BMD) is the milder allelic variant of Duchenne muscular dystrophy, with higher dystrophin levels. To anticipate on results of interventions targeting dystrophin expression it is important to know the natural variation of dystrophin expression between different muscles and over time. Dystrophin was quantified using capillary Western immunoassay (Wes) in the anterior tibial (TA) muscle of 37 BMD patients. Variability was studied using two samples from the same TA biopsy site in nine patients, assessing nine longitudinal TA biopsies, and eight simultaneously obtained vastus lateralis (VL) muscle biopsies. Measurements were performed in duplicate with two primary antibodies. Baseline dystrophin levels were correlated to longitudinal muscle strength and functional outcomes. Results showed low technical variability and high precision for both antibodies. Dystrophin TA levels ranged from 4.8 to 97.7%, remained stable over a 3-5 year period, and did not correlate with changes in longitudinal muscle function. Dystrophin levels were comparable between TA and VL muscles. Intra-muscle biopsy variability was low (5.2% and 11.4% of the total variability of the two antibodies). These observations are relevant for the design of clinical trials targeting dystrophin production, and may urge the need for other biomarkers or surrogate endpoints.

Exosome secretion, including the DNA damage-induced p53-dependent secretory pathway, is severely compromised in TSAP6/Steap3-null mice.

TSAP6 (tumor suppressor-activated pathway 6), also known as Steap3, is a direct p53 transcriptional target gene. It regulates protein secretion, for example translationally controlled tumor protein (TCTP), which is implicated in tumor reversion. In keeping with the latter, we show herein that TSAP6 is a glycosylated protein present in the trans-Golgi network, endosomal-vesicular compartment and cytoplasmic membrane. To further investigate the physiological function of TSAP6, we have generated TSAP6-deficient mice. These mice exhibit microcytic anemia with abnormal reticulocyte maturation and deficient transferrin receptor downregulation, a process known to be dependent on exosomal secretion. Moreover, we provide direct evidence that exosome production is severely compromised in TSAP6-null cells. Finally, we show that the DNA damage-induced p53-dependent nonclassical exosomal secretory pathway is abrogated in TSAP6-null cells. Given the fact that exosomes are used as cell-free vaccines against cancer and that they could be involved in the biogenesis and spread of human immunodeficiency virus, it is important to understand their regulation. The results presented here provide the first genetic demonstration that exosome formation is a tightly controlled biological process dependent of TSAP6.

TCTP protects from apoptotic cell death by antagonizing bax function.

Translationally controlled tumor protein (TCTP) is a potential target for cancer therapy. It functions as a growth regulating protein implicated in the TSC1-TSC2 -mTOR pathway or a guanine nucleotide dissociation inhibitor for the elongation factors EF1A and EF1Bbeta. Accumulating evidence indicates that TCTP also functions as an antiapoptotic protein, through a hitherto unknown mechanism. In keeping with this, we show here that loss of tctp expression in mice leads to increased spontaneous apoptosis during embryogenesis and causes lethality between E6.5 and E9.5. To gain further mechanistic insights into this apoptotic function, we solved and refined the crystal structure of human TCTP at 2.0 A resolution. We found a structural similarity between the H2-H3 helices of TCTP and the H5-H6 helices of Bax, which have been previously implicated in regulating the mitochondrial membrane permeability during apoptosis. By site-directed mutagenesis we establish the relevance of the H2-H3 helices in TCTP's antiapoptotic function. Finally, we show that TCTP antagonizes apoptosis by inserting into the mitochondrial membrane and inhibiting Bax dimerization. Together, these data therefore further confirm the antiapoptotic role of TCTP in vivo and provide new mechanistic insights into this key function of TCTP.

Acceleration of a trailing positron bunch in a plasma wakefield accelerator.

High gradients of energy gain and high energy efficiency are necessary parameters for compact, cost-efficient and high-energy particle colliders. Plasma Wakefield Accelerators (PWFA) offer both, making them attractive candidates for next-generation colliders. In these devices, a charge-density plasma wave is excited by an ultra-relativistic bunch of charged particles (the drive bunch). The energy in the wave can be extracted by a second bunch (the trailing bunch), as this bunch propagates in the wake of the drive bunch. While a trailing electron bunch was accelerated in a plasma with more than a gigaelectronvolt of energy gain, accelerating a trailing positron bunch in a plasma is much more challenging as the plasma response can be asymmetric for positrons and electrons. We report the demonstration of the energy gain by a distinct trailing positron bunch in a plasma wakefield accelerator, spanning nonlinear to quasi-linear regimes, and unveil the beam loading process underlying the accelerator energy efficiency. A positron bunch is used to drive the plasma wake in the experiment, though the quasi-linear wake structure could as easily be formed by an electron bunch or a laser driver. The results thus mark the first acceleration of a distinct positron bunch in plasma-based particle accelerators.

Big Data Analytics for Scanning Transmission Electron Microscopy Ptychography.

Electron microscopy is undergoing a transition; from the model of producing only a few micrographs, through the current state where many images and spectra can be digitally recorded, to a new mode where very large volumes of data (movies, ptychographic and multi-dimensional series) can be rapidly obtained. Here, we discuss the application of so-called "big-data" methods to high dimensional microscopy data, using unsupervised multivariate statistical techniques, in order to explore salient image features in a specific example of BiFeO3 domains. Remarkably, k-means clustering reveals domain differentiation despite the fact that the algorithm is purely statistical in nature and does not require any prior information regarding the material, any coexisting phases, or any differentiating structures. While this is a somewhat trivial case, this example signifies the extraction of useful physical and structural information without any prior bias regarding the sample or the instrumental modality. Further interpretation of these types of results may still require human intervention. However, the open nature of this algorithm and its wide availability, enable broad collaborations and exploratory work necessary to enable efficient data analysis in electron microscopy.

Prosthetic use in elderly patients with dysvascular above-knee and through-knee amputations.

Fifty-five patients with vascular insufficiency resulting in above-knee (AK) and through-knee (TK) amputations were studied to determine factors related to prosthetic candidacy and functional outcome. Chart review showed that the only difference between patients who were fitted with prostheses and those who were not fitted with prostheses was their respective number of medical complications. Twenty-three of 31 patients with prostheses were evaluated 7 to 35 months after receiving the prostheses. Ten (44%) of these patients wore their prostheses all day every day and used wheelchairs minimally or not at all. Over half of the patients evaluated used their wheelchairs most of the time. Two (9%) of the 23 patients had stopped wearing their prostheses. Patients who demonstrated increased walking distances and velocities at follow-up used their prostheses more and their wheelchairs less than did the other patients. Neither gait factors nor hip range of motion at discharge was predictive of continued prosthetic use. Functional outcome and prosthetic use were limited in this group of elderly patients with dysvascular AK and TK amputations. The results of this study may serve as a basis for clinical determination of prosthetic candidacy and functional goals.

Ambulation, activity level, and pain. Outcomes of a program for spinal pain.

The purpose of this study was to investigate changes in ambulation distance, activity level, medical care sought, and perceived pain in 49 patients with chronic spinal pain who completed an inpatient rehabilitation program. Therapy included patient education, reduction in pain medications, increased quotas for activity and ambulation, and reinforcement of nonpain behaviors. Change was measured by a 12-minute walk, an activity check list, and pain and activity self-ratings. Tests were administered at admission and discharge and at one, three, and six months after discharge. Patients improved significantly in walking distance, frequency of both exercises and physical conditioning activities performed, and pain self-rating. Medical care sought decreased. Activity self-rating on a 10-point scale was unchanged. This program had a positive effect on a number of factors and warrants consideration for patients with chronic spinal pain.

Energy cost of propulsion in standard and ultralight wheelchairs in people with spinal cord injuries.

BACKGROUND AND PURPOSE: Wheelchair- and subject-related factors influence the efficiency of wheelchair propulsion. The purpose of this study was to compare wheelchair propulsion in ultralight and standard wheelchairs in people with different levels of spinal cord injury. SUBJECTS: Seventy-four subjects (mean age=26.2 years, SD=7.14, range=17-50) with spinal cord injury resulting in motor loss (30 with tetraplegia and 44 with paraplegia) were studied. METHOD: Each subject propelled standard and ultralight wheelchairs around an outdoor track at self-selected speeds, while data were collected at 4 predetermined intervals. Speed, distance traveled, and oxygen cost (VO2 mL/kg/m) were compared by wheelchair, group, and over time, using a Bonferroni correction. RESULTS: In the ultralight wheelchair, speed and distance traveled were greater for both subjects with paraplegia and subjects with tetraplegia, whereas VO2 was less only for subjects with paraplegia. Subjects with paraplegia propelled faster and farther than did subjects with tetraplegia. CONCLUSION AND DISCUSSION: The ultralight wheelchair improved the efficiency of propulsion in the tested subjects. Subjects with tetraplegia, especially at the C6 level, are limited in their ability to propel a wheelchair.

The effect of an exercise program on change in curve in adolescents with minimal idiopathic scoliosis. A preliminary study.

Forty-two adolescents with minimal idiopathic scoliosis, who had been on an exercise program for 9 to 15 months, were evaluated to determine the influence of exercise on change in their curvatures. A difference of 4 degrees or greater between initial and final curve measurements was considered to be a change. Five percent of the curves increased, 74% remained the same, and 21% decreased. Change in curvature for these patients was also compared with that of a matched retrospective group of adolescents with scoliosis who had not had the exercise program. No significant difference in change in curve between the two groups was found. For patients who had been on the exercise program, there was no significant relationship between change in curve and extent of physical activity or between change in curve and exercise recall, correct performance, or frequency. Limitations in the study design and possible explanations for the results are discussed.

Phase transitions, phase coexistence, and piezoelectric switching behavior in highly strained BiFeO(3) films.

Highly strained BiFeO3 films transition into a true tetragonal state at 430 °C but remain polar to much higher temperatures (∼800 °C). Piezoelectric switching is only possible up to 300 °C, i.e., at temperatures for which strain stabilizes the stripe-like coexistence of multiple polymorphs.

Suppression of Myc oncogenic activity by nucleostemin haploinsufficiency.

Nucleostemin (NS), a nucleolar GTPase, is highly expressed in stem/progenitor cells and in most cancer cells. However, little is known about the regulation of its expression. Here, we identify the NS gene as a novel direct transcriptional target of the c-Myc oncoprotein. We show that Myc overexpression enhances NS transcription in cultured cells and in pre-neoplastic B cells from Eµ-myc transgenic mice. Consistent with NS being downstream of Myc, NS expression parallels that of Myc in a large panel of human cancer cell lines. Using chromatin immunoprecipitation we show that c-Myc binds to a well-conserved E-box in the NS promoter. Critically, we show NS haploinsufficiency profoundly delays Myc-induced cancer formation in vivo. NS+/-Eµ-myc transgenic mice have much slower rates of B-cell lymphoma development, with life spans twice that of their wild-type littermates. Moreover, we demonstrate that NS is essential for the proliferation of Myc-overexpressing cells in cultured cells and in vivo: impaired lymphoma development was associated with a drastic decrease of c-Myc-induced proliferation of pre-tumoural B cells. Finally, we provide evidence that in cell culture NS controls cell proliferation independently of p53 and that NS haploinsufficiency significantly delays lymphomagenesis in p53-deficient mice. Together these data indicate that NS functions downstream of Myc as a rate-limiting regulator of cell proliferation and transformation, independently from its putative role within the p53 pathway. Targeting NS is therefore expected to compromise early tumour development irrespectively of the p53 status.

Context specificity in stability of hyperactivity-impulsivity.

This paper exemplifies a secondary data analysis of context-specific differences in children's hyperactivity-impulsivity while controlling for informant-specific effects. Participants were boys and girls from the NICHD Study of Early Child Care and Youth Development who were measured in 1(st), 3(rd), and 5(th) grades. Latent factor models were structured using multi-informant reports including mothers, fathers, teachers, and observers. Temporal stability within a context was stronger than cross-context consistency, and the magnitude of longitudinal stability was higher in the home context compared to the school context. Controlling for informant-specific effects resulted in a significantly improved model fit and increased within-context stability. Our findings highlight the importance of considering both context and informant effects when studying longitudinal stability and change in personality development.