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This paper brings contemporary debate in analytic philosophy of religion regarding the notion of worship into conversation with Jewish sources and attempts to identify the most promising philosophical grounds for a Jewish account of the putative obligatoriness of worship. Some philosophers have recently debated the notion of worship, focusing in particular on the claim that human beings have an obligation to worship God and on whether and how such an obligation might be adequately grounded. I first canvass the major bases for worshipping God that have featured in this debate. I then turn to some relevant liturgical and philosophical sources of Jewish tradition, identifying grounds for the obligatoriness of (exclusively) worshipping God that have been advanced in those sources. I next consider which grounds of the putative obligatoriness of worship are the most promising for a Jewish account in terms of both philosophical cogency and rootedness in Jewish tradition. I argue that a version of a divine command grounding of prayer in a Soloveitchikian mode is both well-rooted in Judaism and also plausibly surmounts philosophical objections to divine command accounts. In the final section, I briefly raise the issue of whether the concept of worship is truly well-suited to a Jewish context, suggesting that the rich Hebrew notions of avodah and tefillah are perhaps more appropriate in articulating a fully adequate Jewish understanding of the pertinent issues. In particular, I argue that these notions fit well with the Soloveitchikian divine command grounding of the obligation to worship God.

Receptor downregulation is instrumental for many therapeutic interventions. Receptor knockout through gene-editing technologies is efficient but can introduce off-target mutations and chromothripsis. Regulation of gene expression at the protein level is a promising alternative. Here, we present results showing the targeted T cell antigen receptor (TCR) degradation using chimeric E3 fusion proteins that we call Receptor Targeting Chimeras (ReceptorTAC). We show that TCR degradation is dependent on enzymatically active, membrane-anchored E3 ligase variants. TCR specificity was achieved by direct fusion of an E3 domain to the CD3ζ transmembrane sequence. Jurkat and primary T cells stably expressing the ReceptorTAC constructs showed significantly reduced responses to TCR stimulation. We also used our ReceptorTAC technology to generate TCR-deficient, claudin18.2-specific CAR T cells, where the activity of the CAR was unaffected by the expression of the ReceptorTAC. These data indicate that our ReceptorTAC molecule can be used to generate allogeneic CAR T cells.

Cells are dynamic structures that must respond to complex physical and chemical signals from their surrounding environment. The cytoskeleton is a key mediator of a cell's response to the signals of both the extracellular matrix and other cells present in the local microenvironment and allows it to tune its own mechanical properties in response to these cues. A growing body of evidence suggests that altered cellular viscoelasticity is a strong indicator of disease state; including cancer, laminopathy (genetic disorders of the nuclear lamina), infection, and aging. Here, we review recent work on the characterization of cell mechanics in disease and discuss the implications of altered viscoelasticity in regulation of immune responses. Finally, we provide an overview of techniques for measuring the mechanical properties of cells deeply embedded within tissues.

T cells discriminate between healthy and infected cells with remarkable sensitivity when mounting an immune response, which is hypothesized to depend on T cells combining stimuli from multiple antigen‐presenting cell interactions into a more potent response. To quantify the capacity for T cells to accomplish this, we have developed an antigen receptor that is optically tunable within cell conjugates, providing control over the duration, and intensity of intracellular T‐cell signaling. We observe limited persistence within the T‐cell intracellular network on disruption of receptor input, with signals dissipating entirely in ~15 min, and directly show sustained proximal receptor signaling is required to maintain gene transcription. T cells thus primarily accumulate the outputs of gene expression rather than integrate discrete intracellular signals. Engineering optical control in a clinically relevant chimeric antigen receptor (CAR), we show that this limited signal persistence can be exploited to increase CAR‐T cell activation threefold using pulsatile stimulation. Our results are likely to apply more generally to the signaling dynamics of other cellular networks., An optically controllable chimeric antigen receptor is developed for modulating T cell signaling dynamics. Limited signal persistence is found at key nodes in the intracellular network, constraining the window over which T cells can integrate discrete activation signals.

SUMMARYT cells discriminate between healthy and infected cells with remarkable sensitivity when mounting an immune response. It has been hypothesized that this efficient detection requires combining signals from discrete antigen-presenting cell interactions into a more potent response, requiring T cells to maintain a ‘memory’ of previous encounters. To quantify the magnitude of this phenomenon, we have developed an antigen receptor that is both optically and chemically tunable, providing control over the initiation, duration, and intensity of intracellular T-cell signaling within physiological cell conjugates. We observe very limited persistence within the T cell intracellular network on disruption of receptor input, with signals dissipating entirely in ~15 minutes, and directly confirm that sustained proximal receptor signaling is required to maintain active gene transcription. Our data suggests that T cells are largely incapable of integrating discrete antigen receptor signals but instead simply accumulate the output of gene expression. By engineering optical control in a clinically relevant chimeric antigen receptor, we show that this limited signal persistence can be exploited to increase the activation of primary T cells by ~3-fold by using pulsatile stimulation. Our results are likely to apply more generally to the signaling dynamics of other cellular networks.

Mixed-use megaprojects on state-owned land have been increasingly occurring around the world over the past few decades. This article reviews the body of literature that has emerged on these projects during this period and investigates a number of projects more deeply by reviewing original planning documents and undertaking interviews with government officials, consultants, and other insiders. Project motives, delivery methods, and built outcomes have been examined in order to contextualize their emergence and proliferation, leading to a typological understanding, defined in this article as competitive precinct projects. A content analysis of 30 reviews covering 42 mixed-use megaprojects in 20 countries reveals remarkable global consistency in thematic criticisms. Framed in this article as the “five consistent criticisms of ‘global’ mixed-use megaprojects,” they pose a significant barrier to addressing increasingly complex urban challenges as well as to their successful management from inception to delivery. While the consistent criticisms represent patterns that have endured within a globally active urban development type for over three decades, this research shows that rather than being a neoliberal hegemony, there are mixed political and ideological aims and outcomes across projects and sometimes within the same project. A typological understanding allows patterns to be examined and understood, variances and hybridity to be evaluated, and more sophisticated future directions to be mapped out in the pursuit of broader based and city-scale project outcomes.

Spacecraft are subjected to a variety of extreme loads during the course of a mission. One period during which these demanding loads are observed occurs during the parachute deployment stage of reentry. The deployment process utilizes a mortar in order to deploy the parachute and the corresponding reaction forces from deployment generate large impulsive loads on the spacecraft and cause vibrations throughout the spacecraft. Accurate prediction of the forces exerted on the spacecraft during deployment is paramount to the design and safety of the spacecraft. Typically the time history of the reaction forces exerted during parachute deployment are measured experimentally using a tripod-mounted mortar assembly. This approach introduces coupling between the force generated by the mortar and the dynamics of the tripod legs, and does not account for the structural compliance of the actual spacecraft system. This will lead to erroneous results if compared to the true reaction forces observed during the in-service deployment of the parachute during reentry.

An investigation considering the efficiency gains of electrical pulse-shaping for a two-stage reluctance accelerator system has been undertaken. An optimum gross efficiency of (1.36 ± 0.02)% was achieved, amounting to an increase of (290 ± 20)% relative to the performance of an equivalent single-stage accelerator. The performance increase due to pulse-shaping for a two-stage setup was found to surpass that achieved for this single-stage setup in terms of both efficiency and velocity. This investigation highlights the potential of pulse-shaping methods to increase the feasibility and flexibility of electrical acceleration for a variety of practical applications. The intention of this paper was to exhibit the potential of reluctance acceleration technology in multi-stage, initially by using a two-stage system. Possible avenues for further investigation are proposed, to build upon the results of this study.

Introduction: Both physical therapy (PT) and surgery appear to have some efficacy in treating femoroacetabular impingement (FAI). Only recently have high-level evidence studies compared these two options, though results of these randomized controlled trials (RCTs) are contradictory. The purpose of this study was to perform a systematic review and meta-analysis of RCTs comparing PT and surgery in patients with FAI. Methods: A systematic review was performed to identify randomized trials comparing FAI and PT. Data was extracted for demographics, study design, patient reported outcomes (PROs), and study quality/bias. In total, 819 abstracts were reviewed, with three RCTs identified (Griffin 2018, Mansell 2018, and Palmer 2019). All three RCTs reported iHOT-33, while two studies reported HOS ADL and Sport (Mansell 2019 and Palmer 2019). In a random effects meta-analysis, between-group differences in post-intervention scores were assessed using intention-to-treat analysis in each study. Results: All 3 RCTs reported PROs improvement from baseline to follow-up for both PT and surgery. The meta-analysis demonstrated greater improved iHOT-33 outcomes with surgery compared to PT with a mean relative difference of 11.3 (95% CI 1.86-20.73, p=0.014). The meta-analysis for HOS ADL and Sports (two RCTs) similarly demonstrated higher scores with surgery with a mean difference of 3.9 (95% CI -9.6-17.3, p=0.571) and 6.2 (95% CI -6.8-19.2, p=0.347), respectively, though without statistical significance. The quality of two RCTs was assessed as good with minimal bias (Griffin and Palmer). In the third RCT, an extremely high crossover rate may affect its validity (Mansell 2018, 70% crossover from PT to surgery). For instance, HOS ADL outcome based on treatment received, adjusting for Mansell’s crossover rate, favored surgery with a larger mean difference of 12.0 (95% CI 7.5-16.5, pDiscussion: In patients with FAI, combined results of three RCTs demonstrate superior outcomes of surgery compared to PT. However, PT can result in improvements in some patients and does not appear to compromise surgical outcomes. Provided that the studies adjusted for certain patient characteristics, further research needs to identify patient characteristics that predict success of non-operative and operative treatment of FAI in specific patient subgroups. [Figure: see text]

The key driver for effective immunotherapies is the overall strength binding of the immune cell and the target cell(e.g. tumor cells). The overall strength is known as ‘avidity’, a parameter reflec...

Spacecraft are subjected to a variety of extreme loads during the course of a mission. One such demanding period during reentry is parachute deployment when a mortar on the spacecraft is used to deploy the parachute. Firing the mortar to expel the parachute imparts an impulsive force on the spacecraft and results in vibration throughout the spacecraft. Successful deployment of the parachute is critical to the success of the mission, and accurate prediction of the impulsive forces exerted on the spacecraft during deployment is paramount to the design and safety of the spacecraft. Typically the time history of the reaction force of the mortar is measured experimentally using a rigid mounting system. This approach neglects the structural compliance of the spacecraft and thus neglects the dynamic interaction between the mortar and spacecraft. This may lead to differences between the force profile observed during laboratory testing and those observed during the mission of the spacecraft.

In the field of structural dynamics, real-time hybrid simulation (RTHS) continues to receive increased interest from researchers conducting component testing incorporating system-level behaviour. Increased digital computing power has allowed advances in RTHS. However, limitations in RTHS will persist due to the effects of discrete errors caused by quantisation and corresponding numerical integration time step limitations, which can limit the bandwidth and nonlinearities of the system studied. In this paper, an analogue electronic computer is constructed to conduct RTHS of a modelled base-isolated structure with a physically tested viscous damping device. The analogue computer models a two-degree-of-freedom (2DOF) structure and solves the equations of motion required in RTHS testing. Results of the RTHS tests using the analogue computer are compared to RTHS tests implemented with a digital computer in order to validate the proposed analogue RTHS method. Further applications of RTHS testing with analogue computing including high-frequency dynamic testing are discussed.

The following paper illustrates a mathematical framework for identifying discrete convolution filters and applies that framework to a time varying dynamic problem. Convolution matrices, formulated using Kronecker products, allow for least means squares solution of arbitrarily structured discrete convolution models. The framework exposes the convolution structure and the filter coefficients independently in order to solve for the time varying weights of a known model, or an unknown time varying filter. Transforms are shown to apply standard discrete spectral processing methods to this architecture. The identification methods were successfully applied to identify the stiffness-like and damping-like operating regimes of a typical viscous damper in a dynamic system subjected to periodic motion. The results show that discrete time varying system identification successfully predicts measured test data and provides intuitive results showing stiffness-like behavior at low force inputs and damping-like behavior for higher force inputs.

The bacterial chemoreceptor complex governs signal detection and the upstream elements of chemotactic behavior, but the detailed molecular mechanism is still unclear. We have assembled nativelike functional arrays of an aspartate receptor cytoplasmic fragment (CF) with its two cytoplasmic protein partners (CheA and CheW) for solid-state nuclear magnetic resonance (NMR) studies of structural changes involved in signaling. In this initial study of the uniformly (13)C- and (15)N-enriched CF in these13.8 MDa size arrays, residue-type assignments are made for amino acids that together make up 90% of the protein. We demonstrate that homo- and heteronuclear two-dimensional spectra are consistent with structure-based chemical shift predictions: a number of major assignable correlations are consistent with the predominantly α-helical secondary structure, and minor correlations are consistent with the disordered C-terminal tail. Sub-parts per million line widths and spectral changes upon freezing of samples suggest these arrays are structurally homogeneous and sufficiently immobilized for efficient solid-state NMR.

Summary Drilling and completion fluids based on cesium formate brines were selected by Statoil for use in the development of the high-pressure/high-temperature (HP/HT) Kvitebjørn field. CsFo brine was selected primarily to minimize well-control problems and maximize well productivity. These important benefits had been recognized by Statoil in previous HP/HT drilling and completion operations over the past 5 years. The use of the same fluid system for both drilling and completion gives the additional benefits of simplified operations, reduced waste, and elimination of fluid-incompatibility problems. The challenge on the Kvitebjørn field was to drill long, deviated well paths through significant sequences of shales into reservoirs with pressures as great as 81 MPa (11,700 psi) and temperatures up to 155°C (311°F). So far, the CsFo brine has enabled the successful drilling and completion of seven high-angle, HP/HT production wells on Kvitebjørn, two completed with a cemented/perforated liner and five with sand screens. Additionally, an extended-reach exploration well was drilled from the Kvitebjørn platform to the Valemon structure. The 705-m (2,313-ft) -long reservoir section of this 7380-m (24,213-ft) -long well with an inclination of 69° was drilled successfully with the same CsFo fluid system. In all these wells, the CsFo-brine system once again demonstrated clear performance benefits such as very low equivalent circulating densities (ECDs), moderate-to-high rates of penetration (ROPs), good hole cleaning, and excellent wellbore stability while logging. Quick, trouble-free, safe, and robust completion operations were also accomplished, and the wells that have been put on production show high production rates with low skin. Full openhole formation evaluation of the Kvitebjørn reservoir has been carried out successfully with logging-while-drilling (LWD) tools. The evaluation has been aided by the development of a novel logging-interpretation solution for a LWD density tool, in which the extremely high photoelectric effect of cesium-rich filtrate plays a vital role. CsFo brine has helped Statoil to achieve a record of zero well-control incidents in all 15 HP/HT-drilling operations and 20 HP/ HT-completion operations in the Kvitebjørn, Kristin, and Huldra fields over a period of 5 years.

Wood Storks (Mycteria americana) were first recorded nesting in Georgia in 1965 at Blackbeard Island National Wildlife Refuge (Harris 1995). In 1992, biologists initiated annual aerial surveys of known wading bird rookery sites to document Wood Stork distribution and estimate the number of nesting pairs in Georgia. Additionally, personnel from the U.S Fish and Wildlife Service and Savannah River Ecology Laboratory have contributed annual ground-count data for several colonies. Since surveys began, stork nesting has been documented at least once in 43 locations across the Coastal Plain of the state, with an average of 14 active sites per year. The documented nesting effort for storks has increased from four pairs in one wading bird colony in 1965 to a high count of 1,817 pairs in 19 colonies in 2005. A regression of log-transformed nest totals for the 14-year time-series (1992-2005) showed no significant overall trend in nesting pair numbers (P = 0.84) for that period. However, it is possible that...

Much ink has been spilt over the question of “Nietzsche and the Jews” ever since the distortion of Nietzsche's manuscripts by his sister, Elizabeth Förster-Nietzsche, forged the links with Nazism that would be further developed by the likes of Alfred Bäumler into a “carefully orchestrated cult.” Though it is a portrait long dismissed in the academic world, a combination of Nazi propaganda and some subsequent scholarship has ensured that the picture of Nietzsche as a virulent anti-Semite who provided Nazism with its conceptual underpinnings lingers in the popular mind. Most scholars, however, now accept at worst a more ambivalent picture. Others go beyond ambivalence, with Weaver Santaniello turning the accusation of anti-Semitism on its head by arguing that Nietzsche's contempt for anti-Semitism was one of the driving forces behind his critique of liberal Christianity, which in its use of “conservative theological concepts . . . perpetuate[s] anti-Semitism.” Even Crane Brinton, arguably one of those scholars most responsible for perpetuating the misrepresentation of Nietzsche as an anti-Semite, insisted that he had never maintained “that Nietzsche was a ‘proto-Nazi’.” But whilst Nietzsche is almost universally exonerated from the charge of personal anti-Semitism, Brinton's claim that “occasionally [Nietzsche] comes very close indeed to the Nazi program,” though based on poor use of Nietzsche's writings and rightly dismissed by Walter Kaufmann, continues to find echoes even amongst more careful Nietzsche scholars, who claim that he “did have some responsibility for Nazi crimes.”

We investigated the impact of nerve sparing technique on erectile function, urinary continence and health related quality of life after radical perineal prostatectomy using a validated self-assessment questionnaire.The Expanded Prostate Cancer Index Composite questionnaire was administered preoperatively and at defined intervals after surgery to 265 patients who underwent radical perineal prostatectomy at 2 institutions between January 2001 and December 2004. Of these patients 153 (57.7%) and 112 (42.3%) underwent nonnerve sparing and nerve sparing approaches, respectively. Kaplan-Meier analysis was used to determine time to recovery of erectile function (erections firm enough for intercourse) and urinary continence (0 pads per day).Median patient age was 60.6 years. Median followup was 15 months. In multivariate analysis preoperative erectile function (p = 0.005) and preservation of the neurovascular bundle (p = 0.018) were independent predictors of earlier recovery of erectile function, with hazard ratios of 2.3 (95% CI 1.2-4.6) and 4.0 (95% CI 1.5-10.3), respectively. Median time to recovery of urinary continence was 4.8 months in the nerve sparing group and 6.1 months in the nonnerve sparing group (p = 0.001). In multivariate analysis nerve sparing technique (p = 0.001, HR 1.4, 95% CI 1.1-1.9) and age (p = 0.012, HR 1.7, 95% CI 1.3-2.2) were independent predictors of recovery of continence.This analysis suggests that nerve sparing radical perineal prostatectomy is associated with improved recovery of urinary continence and favorable health related quality of life scores and, therefore, should be considered a viable alternative to other nerve sparing approaches.

Objective Radical prostatectomy is the most effective treatment for localized prostate cancer. With increasing use of minimally invasive treatment methods, clinical outcomes are becoming important assessment tools to compare one option to another. Perineal prostatectomy is modified to incorporate contemporary surgical ideas, including preservation of cavernosal nerve bundles, sphincteric urethra at the prostatic apex, and the bladder neck. Methods Objective parameters and physician-reported clinical outcomes are collected prospectively on 704 consecutive patients undergoing radical perineal prostatectomy (RPP) by one surgeon. The technique described herein is the current state of evolution of RPP. The enclosed digital video is edited from two recent nerve-sparing RPPs. Results Freedom from prostate-specific antigen (PSA) detectability by stage is 94.5%, 80.0%, and 81.5% for organ-confined, specimen-confined, and margin-positive disease with actual 5-yr follow-up. Margins are positive in 18% of cases. By 1, 3, 6 mo and 1 yr, 52%, 71%, 85%, and 94% of the men are free from using pads. Although >97% of nerve-spared patients have spontaneous erections, >80% can penetrate to complete intercourse. Conclusions This method of prostatectomy is able to achieve complete cancer resection while preserving urinary and sexual function in the majority of men presenting with clinically localized prostate cancer. The simplicity and minimally invasive nature of this procedure contribute to a short recovery and low overall cost of therapy. The anatomic RPP is a cost-efficient, outcome-effective minimally invasive method of treating men with localized prostate cancer.

We present a measurement of the sky distribution of positronium (Ps) annihilation continuum emission obtained with the SPI spectrometer on board ESA's INTEGRAL observatory. The only sky region from which significant Ps continuum emission is detected is the Galactic bulge. The Ps continuum emission is circularly symmetric about the Galactic centre, with an extension of about 8 deg FWHM. Within measurement uncertainties, the sky distribution of the Ps continuum emission is consistent with that found by us for the 511 keV electron-positron annihilation line using SPI. Assuming that 511 keV line and Ps continuum emission follow the same spatial distribution, we derive a Ps fraction of 0.92 +/- 0.09. These results strengthen our conclusions regarding the origin of positrons in our Galaxy based on observations of the 511 keV line. In particular, they suggest that the main source of Galactic positrons is associated with an old stellar population, such as Type Ia supernovae, classical novae, or low-mass X-ray binaries. Light dark matter is a possible alternative source of positrons., accepted for publication by A&A

The 2- to 5-year results of the APR-II total hip arthroplasty system (APR-II, Zimmer, Warsaw, Ind) were previously reported for 107 consecutive total hip arthroplasties performed between January 1994 and January 1995. The purpose of this study was to report the 10-year survival data in this same cohort of patients. Seventy-two (73%) of the 99 hips originally studied met the inclusion criteria for this report. None of the femoral or acetabular components had radiographic or clinical loosening. Three hips had had revision surgery for the acetabulum with 2 for recurrent dislocation and 1 for liner disassociation. All femoral components were retained. The 10-year Kaplan-Meier survivorship analysis, with failure defined as mechanical loosening, was 100% for both the cup and stem. These hip replacements have not shown any postoperative deterioration of clinical result, fixation, or wear up to 10 years.

Objectives To compare the early recovery of erectile function and urinary continence in patients undergoing nerve-sparing and non-nerve-sparing radical perineal prostatectomy (RPP) using a validated patient self-assessment instrument. Methods Eighty-eight patients who underwent RPP by a single surgeon between January 2002 and July 2003 were given a validated patient self-assessment questionnaire, the Expanded Prostate Cancer Index Composite, preoperatively and subsequently at 3- to 6-month intervals. Of the 88 patients, 40 underwent non-nerve-sparing and 48 nerve-sparing RPP. The time to recover erectile function and urinary continence, as well as sexual and urinary health-related quality of life was analyzed using the Kaplan-Meier method and a multivariate Cox proportional hazards model. Results Nerve-sparing RPP was a predictor of the time to recover erections sufficient for intercourse ( P = 0.013). In a multivariate regression model adjusting for baseline erectile function, age, and prostate size, preservation of the neurovascular bundle ( P = 0.007) was an independent predictor of the time to recover erectile function sufficient for intercourse (hazard ratio 5.3; 95% confidence interval 1.2 to 23.1). The median time to recover urinary continence, defined as no pad use, was 4.7 months in the nerve-sparing group compared with 5.6 months in the non-nerve-sparing group ( P = 0.021). In multivariate analysis, nerve-sparing status was an independent predictor ( P = 0.003) of an earlier recovery of continence (hazard ratio 2.2; 95% confidence interval 1.3 to 3.6). Conclusions Patient self-assessed outcomes support a benefit of nerve-sparing RPP for the postoperative recovery of erectile function and urinary continence. Future studies with larger patient numbers and longer follow-up are necessary to validate these findings.

It is believed that core-collapse supernovae (CCSN), occurring at a rate about once per century, have seeded the interstellar medium with long-lived radioisotopes such as 60Fe (half-life 1.5 Myr), which can be detected by the gamma rays emitted when they beta-decay. Here we report the detection of the 60Fe decay lines at 1173 keV and 1333 keV with fluxes 3.7 +/- 1.1 x 10(-5) ph cm(-2) s(-1) per line, in spectra taken by the SPI spectrometer on board INTEGRAL during its first year. The same analysis applied to the 1809 keV line of 26Al yielded a line flux ratio 60Fe/26Al = 0.11 +/- 0.03. This supports the hypothesis that there is an extra source of 26Al in addition to CCSN.

Objective: Localized prostate cancer is a common disease for which minimally invasive treatment methods are being explored. Perineal prostatectomy, as a historical open procedure, is modified to incorporate contemporary surgical ideas. There is relatively little in the literature regarding modern adaptations of perineal prostatectomy. This method of anatomic radical perineal prostatectomy has been developed to accomplish a minimally invasive method of achieving goals of disease control and preservation of genito-urinary functions. Methods: Prospective outcome data is accumulated on 508 consecutive radical perineal prostatectomies by a single surgeon. Pathologic stage and PSA detectability are measures of cancer control. Pad use and ability to complete intercourse measure urinary and sexual function. General complications and other outcome measures are evaluated. Results: Freedom from PSA detectability by pathologic stage is 96.3%, 79.4%, and 69.4% for organ confined, specimen confined and margin positive in the absence of seminal vesical invasion with an average 4 years follow up (3–114 months). Margins are positive in 18% of cases. The average cancer size is 9.4g and 36% of cases have extracapsular invasion. By the first, third, sixth months and one year, 38%, 65%, 88% and 96% are free of pad use and report being dry. While over 80% of nerve-spared patients enjoy the return of spontaneous erectile function, the men with bilateral nerve preservation note earlier and more complete return of function. There are no cardiopulmonary complications or deaths. Transfusions occurred in 1%, none in the past 400 cases. Average total hospital charges are USD$4889.00 in 1999 and 2000. Anterior urethral strictures, anastomotic strictures and fecal urgency/stress flatus occur 2%, 2% and 2–4%, respectively. Conclusions: This method of prostatectomy is able to achieve complete cancer resection while preserving urinary and sexual function as well as laparoscopic or retropubic prostatectomy. The simplicity and minimally invasive nature of this procedure contribute to a short recovery and low overall cost of therapy. The anatomic radical perineal prostatectomy is a cost-efficient, outcome effective minimally invasive method of treating men with localized prostate cancer.

The sculpting of blood vessels to meet the changing requirements of the tissues they supply is essential for life. Many researchers believe that endothelial cell apoptosis plays an important role in this process. This belief is bolstered by the detection of endothelial apoptosis within remodeling vessels in vivo, the dramatic vascular phenotypes of mice in which regulators of endothelial apoptosis have been inactivated and the apparent dependence of angiogenesis on endothelial apoptosis in vitro. However, when examined carefully, the evidence for or against endothelial cell apoptosis playing an important role in vascular biology is largely indirect and is far from clear-cut. In this review, we will discuss the idiosyncratic process of endothelial cell apoptosis. We will then examine its complex regulation and weigh the in vitro and in vivo evidence that it plays a significant role in mammalian vascular biology.

This article describes three studies in prosody and their potential application to the field of forensic linguistics. It begins with a brief introduction to prosody. It then proceeds to describe Miglio, Gries, & Harris (2014), a comparison of prosodic coding of new information by bilingual Spanish-English speakers and monolingual Spanish speakers. A description of Harris & Gries (2011) follows. This study compares the vowel duration variability of bilingual Spanish-English speakers and monolingual Spanish speakers, and touches upon corpus-based frequency effects and differences in linguistic aptitude between the two speaker groups. Finally, a portion of anongoing study is described (Harris in preparation). This section describes the use of prosodic variables and ensemble methods (or methods that use multiple learning algorithms) to classify languages, even in the case of impoverished data. All three experiments have implications and applications to the field of forensic linguistics, which are touched upon in each respective section and discussed in a more in-depth manner in the final section of this article. Furthermore, the applications of these methods to forensic linguistics are discussed in light of best practices for forensic linguistics, as outlined in Chaski (2013).

Most motile bacteria sense and respond to their environment through a transmembrane chemoreceptor array whose structure and function have been well-studied, but many species also contain an additional cluster of chemoreceptors in their cytoplasm. Although the cytoplasmic cluster is essential for normal chemotaxis in some organisms, its structure and function remain unknown. Here we use electron cryotomography to image the cytoplasmic chemoreceptor cluster in Rhodobacter sphaeroides and Vibrio cholerae. We show that just like transmembrane arrays, cytoplasmic clusters contain trimers-of-receptor-dimers organized in 12-nm hexagonal arrays. In contrast to transmembrane arrays, however, cytoplasmic clusters comprise two CheA/CheW baseplates sandwiching two opposed receptor arrays. We further show that cytoplasmic fragments of normally transmembrane E. coli chemoreceptors form similar sandwiched structures in the presence of molecular crowding agents. Together these results suggest that the 12-nm hexagonal architecture is fundamentally important and that sandwiching and crowding can replace the stabilizing effect of the membrane. DOI: http://dx.doi.org/10.7554/eLife.02151.001, eLife digest Many bacteria swim through water by rotating tiny hair-like structures called flagella. In E. coli, if all the flagella on the surface of a bacterium rotate in a counterclockwise fashion, then it will swim in a particular direction, but if the flagella all rotate in an clockwise fashion, then the bacterium will stop swimming and start to tumble. Bacteria use a combination of swimming and tumbling in order to move towards or away from certain chemicals. For example, a bacterium is able to move towards a source of nutrients because it is constantly evaluating its environment and will swim forward for longer periods of time when it recognizes the concentration of the nutrient is increasing. And if it senses that the nutrient concentration is decreasing, it will tumble in an effort to move in a different direction. Many bacteria, such as E. coli, rely on proteins in their cell membrane called chemoreceptors to sense specific chemicals and then send signals that tell the flagella how to rotate. These transmembrane receptors and their role in chemotaxis—that is, movement towards or away from specific chemicals in the environment—have been widely studied. However, other bacteria also have chemoreceptors in the cytoplasm inside the bacterial cell, and much less is known about these. Now, Briegel et al. have examined the cytoplasmic chemoreceptors of two unrelated bacteria, R. sphaeroides and V. cholera, and found that the cytoplasmic chemoreceptors arrange themselves in hexagonal arrays, similar to the way that transmembrane chemoreceptors are arranged. However, the cytoplasmic chemoreceptors arrange themselves in a two-layer sandwich-like structure, whereas the transmembrane chemoreceptors are arranged in just one layer. The next step is to understand how chemical binding causes these arrays to send their signals to the motor. A complete understanding of this signaling system may ultimately allow scientists to re-engineer it to draw bacteria to targets of medical or environmental interest, such as cancer cells or contaminated soils. DOI: http://dx.doi.org/10.7554/eLife.02151.002

The breeding population of Wood Storks (Mycteria americana) in the southeastern United States has declined since the 1930s, resulting in the listing of all United States populations of the species as endangered in 1984. We assessed genetic structure within and among nine colonies of Wood Storks from Georgia and Florida. Levels of band sharing based on multilocus oligonucleotide DNA fingerprinting of individuals from seven colonies ranged from 58% among nests within the same tree to approximately 55% within the same colony. Levels of band sharing were similar to those reported for other populations of birds that have experienced drastic reductions in population size. A more thorough analysis of four polymorphic microsatellite loci for 136 individuals from nine colonies indicated low levels of allelic diversity and low genetic divergence among colonies. Genetic differentiation (F ST = 0.015) was similar to levels detected from allozymes for 15 colonies of Wood Storks in Florida (F ST = 0.019). These data, together with demographic studies of these populations, indicated high levels of gene flow among colonies (N m = 16.4). In agreement with previous studies, we recommend that all colonies of Wood Storks in the southeastern United States be managed on a regional basis as a single interbreeding population. Similar genetic surveys of the disjunct breeding populations of Wood Storks in South America and Central America would be beneficial in understanding the total genetic differentiation in the species.

We have obtained spectra of the Galactic center at energies 400-600 keV from high-resolution data acquired by the TGRS Ge spectrometer on board the WIND mission during 1995-1997. The data were obtained using an on-board occulter, and are relatively free from systematics and backgrounds. Analysis of the spectra reveals a well-resolved electron-positron annihilation line at 511 keV and the associated continuum due to annihilation via positronium formation. Measurements of the line width and the line-to-continuum ratio allow some constraints to be placed on the interstellar sites where annihilation occurs.

We have searched over 9 yr of data from the Solar Maximum Mission (SMM) Gamma Ray Spectrometer for gamma-ray bursts (GRBs) with abnormally hard spectra that may have been missed in previous searches in the 0.35-0.8 MeV energy band. For this purpose, we searched the higher 0.8-10 MeV band. We have found only two new GRBs in this search, compared to 177 GRBs found in the 0.35-0.8 MeV band. We have made a careful examination of the threshold conditions for identifying the 0.8-10 MeV events, which confirms that there is no undiscovered population of hard-spectrum GRBs that have escaped detection by SMM, BATSE, and other instruments triggered by low-energy γ-ray emission. This conclusion does not apply to GRBs with duration less than 2 s, nor to those that are much fainter than the general population. Our results constrain models of GRBs that require or allow the peak in energy emission to be above 1 MeV.

Bacterial chemoreceptors cluster in highly ordered, cooperative, extended arrays with a conserved architecture, but the principles that govern array assembly remain unclear. Here we show images of cellular arrays as well as selected chemoreceptor complexes reconstituted in vitro that reveal new principles of array structure and assembly. First, in every case, receptors clustered in a trimers-of-dimers configuration, suggesting this is a highly favored fundamental building block. Second, these trimers-of-receptor dimers exhibited great versatility in the kinds of contacts they formed with each other and with other components of the signaling pathway, although only one architectural type occurred in native arrays. Third, the membrane, while it likely accelerates the formation of arrays, was neither necessary nor sufficient for lattice formation. Molecular crowding substituted for the stabilizing effect of the membrane and allowed cytoplasmic receptor fragments to form sandwiched lattices that strongly resemble the cytoplasmic chemoreceptor arrays found in some bacterial species. Finally, the effective determinant of array structure seemed to be CheA and CheW, which formed a “superlattice” of alternating CheA-filled and CheA-empty rings that linked receptor trimers-of-dimer units into their native hexagonal lattice. While concomitant overexpression of receptors, CheA, and CheW yielded arrays with native spacing, the CheA occupancy was lower and less ordered, suggesting that temporal and spatial coordination of gene expression driven by a single transcription factor may be vital for full order, or that array overgrowth may trigger a disassembly process. The results described here provide new insights into the assembly intermediates and assembly mechanism of this massive macromolecular complex.

Biological solid-state NMR has shown impressive progress over the past 15 years, from the resonance assignment of small soluble proteins to the structure determination of a ∼35 kDa integral membrane protein in a lipid bilayer. This chapter highlights advances in methodology that are enabling the study of ever larger and more complex systems. These include novel probe designs and sample types that make it possible to apply NMR to more physiological samples, as well as methods for sensitivity enhancement that will make it possible to extend NMR to large proteins and multi-protein complexes in which the concentration of the protein or interface of interest may be quite low. Finally, studies of three membrane protein complexes illustrate the promise of approaches ranging from complete structure determination to targeted measurements for understanding structure and mechanism in such systems. Solid-state NMR is poised to make key contributions to understanding how proteins function in the large complexes they form in cells, which is critical to understanding fundamental biological processes and providing insights of medical importance.

Bispecific antibodies that retarget cytotoxic T cell activity to kill cancer cells are currently under clinical evaluation. However, the molecular mechanism for how CD3-bispecific antibodies 'trigger' intracellular T cell signaling is not known. We demonstrate that bispecific antibodies invoke an equivalent biophysical mechanism of TCR triggering as that observed for the TCR/pMHC interaction, including target clustering and exclusion of CD45 phosphatase from the synapse. The dimensions of the target molecule play a key role in the efficiency of the synapse formation. However, we demonstrate that rational epitope selection can overcome the spatial inhibition caused by target molecules with a large extracellular domain and result in efficient synapse formation and highly potent T cell triggering. With this insight, we developed a novel T-cell dependent bispecific (TDB) antibody, anti-FcRH5/CD3 TDB, targeting the B cell lineage marker FcRH5 for multiple myeloma. Anti-FcRH5/CD3 TDB demonstrated cytotoxicity against human plasma cells and patient derived myeloma tumor cells at picomolar doses. Very low target expression level is sufficient to induce anti-FcRH5/CD3 TDB mediated killing, indicating broad activity in multiple myeloma where the prevalence of FcRH5 expression is 100%. In primates, anti-FcRH5/CD3 treatment resulted in complete depletion of tissue B cells and bone marrow plasma cells. Anti-FcRH5/CD3 TDB induces immunosuppressive feedback signaling, including PD1 up-regulation, which can be overcome by PD-L1 antibodies. These data demonstrate the potential for the anti-FcRH5/CD3 TDB, alone or in combination with inhibition of PD1/PDL1 signaling in the treatment of multiple myeloma and other B-cell malignancies. Disclosures Li: Genentech: Employment. Stagg:Genentech: Employment. Johnston:Genentech: Employment. DiCara:Genentech: Employment. Clark:Genentech: Employment. Cook:Genentech: Employment. Slaga:Genentech: Employment. Nakamura:Genentech: Employment. Luke:Genentech: Employment. Sukumaran:Genentech: Employment. Luis:Genentech: Employment. Ye:Genentech: Employment. Sumiyoshi:Genentech: Employment. Danilenko:Genentech: Employment. Lee:Genentech: Employment. Totpal:Genentech: Employment. Ellerman:Genentech: Employment. Hötzel:Genentech: Employment. Junttila:Genentech: Employment.