Targeting GD2 after allogeneic SCT: effector cell composition defines the optimal use of ch14.18 and the bispecific antibody construct NG-CU (GD2-CD3).

We investigated whether T cell-recruiting bispecific anti-CD3/GD2 antibody NG-CU might be an alternative to therapeutic anti-GD2 monoclonal antibody (mAb) ch14.18, mediating complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) through natural killer (NK) cells for immunotherapy in high-risk/relapsed neuroblastoma after autologous/allogeneic stem cell transplantation (auto/alloSCT). Different antibody concentrations and effector-to-target ratios (E:T) were evaluated using xCELLigence RTCA system, peripheral blood mononuclear cells (PBMCs) (healthy donors and patients after alloSCT), and neuroblastoma cell lines (LS/LAN-1). Mean specific lysis of LS cells utilizing PBMCs from healthy donors and ch14.18 (1 µg/ml) was 40/66/75% after 12/24/48 h compared to 66/93/100% in the presence of NG-CU (100 ng/ml). NG-CU showed enhanced cytotoxicity compared to ch14.18, even at lower concentrations and E:T ratios, and completely eradicated LS cells after 72 h. To decipher the influence of effector cell subsets on lysis, different ratios of T and NK cells were tested. At a ratio of 1:1, ch14.18 was more effective than NG-CU. Using patient PBMCs taken at different time points posttransplant, significant lysis with both constructs was detectable depending on percentages and total numbers of T and NK cells; in the early posttransplant phase, NK cells were predominant and ch14.18 was superior, whereas later on, T cells represented the majority of immune cells and NG-CU was more effective. Our study highlights the importance of analyzing effector cell subsets in patients before initiating antibody-based therapy. Consequently, we propose an adjusted administration of both antibody constructs, considering the state of posttransplant immune recovery, to optimize anti-tumor activity.

Low Incidence of Advanced Neoplasia in Serrated Polyposis Syndrome After (Sub)total Colectomy: Results of a 5-Year International Prospective Cohort Study.

INTRODUCTION: Serrated polyposis syndrome (SPS) is accompanied by a substantially increased colorectal cancer (CRC) risk. To prevent or treat CRC in patients with a very high polyp burden, (sub)total colectomy with ileorectal or ileosigmoidal anastomosis is regularly performed. The CRC risk after (sub)total colectomy might be decreased, but evidence is lacking. We aimed to assess the yield of endoscopic surveillance in patients with SPS who underwent (sub)total colectomy. METHODS: For this post hoc analysis, we used prospectively collected data from a large international prospective cohort study. We included patients diagnosed with SPS (World Health Organization type I and/or III) who underwent (sub)total colectomy. Primary endpoint was the cumulative 5-year incidence of CRC and advanced neoplasia (AN). RESULTS: Forty-eight patients (mean age 61 [±7.8]; 52% men) were included and followed up for a median of 4.7 years (interquartile range 4.7-5.1). None of the patients developed CRC during follow-up. Five patients developed AN, corresponding to a cumulative 5-year AN incidence of 13% (95% confidence interval 1.2-23). In 4 patients, AN was diagnosed at the first surveillance endoscopy after study inclusion, and in 1 patient, AN was detected during subsequent rounds of surveillance. The risk of AN was similar for patients with ileorectal and ileosigmoidal anastomosis (logrank P = 0.83). DISCUSSION: (Sub)total colectomy mitigates much of the excess risk of CRC in patients with SPS. Advanced neoplasms are mainly detected at the first endoscopy after (sub)total colectomy. Based on these results, after the first surveillance, intervals might be extended beyond the currently recommended 1-2 years.

Conductivity fluctuations in proton-implanted ZnO microwires.

Electric noise can be an important limitation for applications of conducting elements in the nanometer size range. The intrinsic electrical noise of prospective materials for opto-spintronics applications like ZnO has not yet been characterized. In this study, we have investigated the conductivity fluctuations in 10 nm thick current paths produced by proton implantation of ZnO microwires at room temperature. The voltage noise under a constant dc current bias in undoped, as well as in Li-doped microwires, is characterized by [Formula: see text] power spectra with [Formula: see text]. The noise intensity scales with the square of the bias current pointing to bias-independent resistivity fluctuations as a source of the observed noise. The normalized power spectral density appears inversely proportional to the number of carriers in the probed sample volume, in agreement with the phenomenological Hooge law. For the proton-implanted ZnO microwire and at 1 Hz we obtain a normalized power spectral density as low as [Formula: see text] Hz(-1).

2-amino-N-(2,6-dichloropyridin-3-yl)acetamide derivatives as a novel class of HBV capsid assembly inhibitor.

Capsid structure is crucial for the maturation and maintenance of the stable hepatitis B virion. Therefore, chemicals that inhibit capsid assembly might potentially act as potent antiviral compounds. However, only a few chemicals are known to block the capsid assembly process and further viral proliferation. In this study, we present a novel family of capsid assembly inhibitors that act against hepatitis B virus (HBV). Based on X-ray crystallographic data of the HBV core protein (Cp), we built dimer and hexamer structural models to be used in library searches. Several chemicals in the 2-amino-N-(2,6-dichloropyridin-3-yl)acetamide family were predicted to have high affinity for the groove structure in Cp. Using in vitro assembly and the HepG2.2.15 cell culture test, we verified that these chemicals demonstrated inhibitory effects on capsid assembly. Furthermore, we investigated the combinatorial effects of these assembly inhibitor chemicals with lamivudine and revealed that, in combination, they have synergistic inhibitory effects on decreasing viral concentration. We propose that these inhibitors could be utilized as an effective combination treatment against HBV infection.

Risk of second primary malignancies following a diagnosis of cutaneous malignant melanoma or nonmelanoma skin cancer in Alberta, Canada from 1979 to 2009.

BACKGROUND: Recent studies have revealed geographical variations with respect to the risk of second primary malignancies (SPMs) following cutaneous malignant melanoma (CMM) and nonmelanoma skin cancer (NMSC). OBJECTIVES: To provide the largest analysis of the risk of SPM following skin cancers in Canada and to detect associations that may shed light on common pathogeneses between linked malignancies. METHODS: Relative risks for development of SPMs following a diagnosis of CMM or NMSC were calculated via a retrospective analysis of data retrieved from the Alberta Cancer Registry (ACR) from 1979 to 2009. RESULTS: From 1979 to 2009, 85,967 NMSC and 6884 CMM incident cases were recorded in the ACR. In total 19,869 SPMs were identified following a primary NMSC (7709 cutaneous and 12,160 noncutaneous), while 1437 SPMs (908 cutaneous and 529 noncutaneous) followed CMM. Patients with a previous history of skin cancer had a 60% increased risk of developing an SPM compared with those without [observed/expected ratio (O/E) 1.6, 95% confidence interval (CI) 1.6-1.7; P < 0.001]. Thirty and 10 different SPMs were significantly identified to follow a diagnosis of NMSC and CMM, respectively. Patients under the age of 40 years with a prior history of CMM had a marked increased expectancy for SPM [O/E 5.6, 95% CI 4.5-7.0; P < 0.001). CONCLUSIONS: Further studies are warranted to identify environmental and molecular connections among linked cutaneous and noncutaneous malignancies, which may lead to earlier detection of related neoplasms via expanded screening protocols and development of shared treatment regimens. Heightened surveillance for the development of SPMs in patients with CMM under the age of 40 years should be considered.

[Pelvic vein thrombosis : Current treatment options and importance of recanalization procedures]. / Beckenvenenthrombose : Aktuelle Therapieoptionen und Stellenwert rekanalisierender Verfahren.

Venous thrombosis is a frequent disorder. A distinction is made between an acute phase of the disease and a chronic manifestation, the postthrombotic syndrome. In particular, proximal venous thrombosis/pelvic vein thrombosis can cause a life-threatening pulmonary embolism during the acute phase of the disease. The postthrombotic syndrome is characterized by the remodeling of the affected venous section, which is often caused by inflammation. Locally, the typical clinical finding is caused by scarred stricture of the vein with restricted drainage and peripheral venous hypertension. Acute thrombosis should be primarily treated by therapeutic anticoagulation and compression therapy of the affected extremity. The duration of these measures depends on clinical presentation, cause (provoked, unprovoked) and risk factors for venous thrombosis/recurrent thrombosis. Venous revascularization procedures are important both in the acute phase of the disease and in the treatment of postthrombotic syndrome. The recanalization treatment is mostly carried out as an endovascular or hybrid intervention and venous bypass procedures are reserved for special situations.

Breaking Down Silos Between Medical Education and Health Systems: Creating an Integrated Multilevel Data Model to Advance the Systems-Based Practice Competency.

ABSTRACT: The complexity of improving health in the United States and the rising call for outcomes-based physician training present unique challenges and opportunities for both graduate medical education (GME) and health systems. GME programs have been particularly challenged to implement systems-based practice (SBP) as a core physician competency and educational outcome. Disparate definitions and educational approaches to SBP, as well as limited understanding of the complex interactions between GME trainees, programs, and their health system settings, contribute to current suboptimal educational outcomes elated to SBP. To advance SBP competence at individual, program, and institutional levels, the authors present the rationale for an integrated multilevel systems approach to assess and evaluate SBP, propose a conceptual multilevel data model that integrates health system and educational SBP performance, and explore the opportunities and challenges of using multilevel data to promote an empirically driven approach to residency education. The development, study, and adoption of multilevel analytic approaches to GME are imperative to the successful operationalization of SBP and thereby imperative to GME's social accountability in meeting societal needs for improved health. The authors call for the continued collaboration of national leaders toward producing integrated and multilevel datasets that link health systems and their GME-sponsoring institutions to evolve SBP.

How a Team Effectiveness Approach to Health Systems Science Can Illuminate Undergraduate Medical Education Outcomes.

ABSTRACT: Health care delivery requires physicians to operate in teams to successfully navigate complexity in caring for patients and communities. The importance of training physicians early in core concepts of working in teams (i.e., "teaming") has long been established. Over the past decade, however, little evidence of team effectiveness training for medical students has been available. The recent introduction of health systems science as a third pillar of medical education provides an opportunity to teach and prepare students to work in teams and achieve related core competencies across the medical education continuum and health care delivery settings. Although educators and health care system leaders have emphasized the teaching and learning of team-based care, conceptual models and evidence that inform effective teaming within all aspects of undergraduate medical education (including classroom, clinical, and community settings) are needed to advance the science regarding learning and working in teams. Anchoring teaming through the core foundational theory of team effectiveness and its operational components could catalyze the empirical study of medical student teams, uncover modifiable factors that lead to the evidence for improved student learning, and improve the link among competency-based assessments between undergraduate medical education and graduate medical education. In this article, authors articulate several implications for medical schools through 5 conceptual areas: admissions, the design and teaching of team effectiveness in health systems science curricula, the related competency-based assessments, and course and program evaluations. The authors then discuss the relevance of the measurable components and intended outcomes to team effectiveness in undergraduate medical education as critical to successfully prepare students for teaming in clerkships and eventually residency and clinical practice.

Evaluation of GPT-4 ability to identify and generate patient instructions for actionable incidental radiology findings.

OBJECTIVES: To evaluate the proficiency of a HIPAA-compliant version of GPT-4 in identifying actionable, incidental findings from unstructured radiology reports of Emergency Department patients. To assess appropriateness of artificial intelligence (AI)-generated, patient-facing summaries of these findings. MATERIALS AND METHODS: Radiology reports extracted from the electronic health record of a large academic medical center were manually reviewed to identify non-emergent, incidental findings with high likelihood of requiring follow-up, further sub-stratified as "definitely actionable" (DA) or "possibly actionable-clinical correlation" (PA-CC). Instruction prompts to GPT-4 were developed and iteratively optimized using a validation set of 50 reports. The optimized prompt was then applied to a test set of 430 unseen reports. GPT-4 performance was primarily graded on accuracy identifying either DA or PA-CC findings, then secondarily for DA findings alone. Outputs were reviewed for hallucinations. AI-generated patient-facing summaries were assessed for appropriateness via Likert scale. RESULTS: For the primary outcome (DA or PA-CC), GPT-4 achieved 99.3% recall, 73.6% precision, and 84.5% F-1. For the secondary outcome (DA only), GPT-4 demonstrated 95.2% recall, 77.3% precision, and 85.3% F-1. No findings were "hallucinated" outright. However, 2.8% of cases included generated text about recommendations that were inferred without specific reference. The majority of True Positive AI-generated summaries required no or minor revision. CONCLUSION: GPT-4 demonstrates proficiency in detecting actionable, incidental findings after refined instruction prompting. AI-generated patient instructions were most often appropriate, but rarely included inferred recommendations. While this technology shows promise to augment diagnostics, active clinician oversight via "human-in-the-loop" workflows remains critical for clinical implementation.

Comparison of the tuberculin skin test and interferon-γ release assay for the diagnosis of latent tuberculosis infection before kidney transplantation.

PURPOSE: The evaluation of latent tuberculosis infection (LTBI) is recommended before kidney transplantation. The interferon-γ release assay has been reported to be more specific than the tuberculin skin test (TST) for detecting LTBI. We compared the TST and QuantiFERON-TB Gold In-Tube test (QFT-GIT) for the screening for LTBI and determined the agreement between the two tests in renal transplant recipients before transplantation. METHODS: Adult patients who were evaluated for renal transplantation between May 2010 and February 2012 at Severance Hospital in South Korea were prospectively enrolled. We performed TST and QFT-GIT. RESULTS: Of the 126 patients, 23 (19.3 %) had positive TST results and 53 (42.1 %) had positive QFT-GIT results. Agreement between the TST and QFT-GIT was fair (κ = 0.26, P < 0.001). The induration size of TST was significantly correlated with a positive rate of QFT-GIT (P = 0.015). Age (odds ratio [OR] 1.08, 95 % confidence interval [CI] 1.03-1.13, P = 0.003), male sex (OR 2.73, 95 % CI 1.17-6.38, P = 0.021), and risk for LTBI (OR 4.62, 95 % CI 1.15-18.64, P = 0.031) were significantly associated with positive QFT-GIT results. For positive TST results, only male sex was associated (OR 4.29, 95 % CI 1.40-13.20, P = 0.011). CONCLUSION: The positivity for QFT-GIT was higher than the positivity for TST, and QFT-GIT more accurately reflected the risk for LTBI. However, a further longitudinal study is needed in order to confirm that the QFT-GIT test can truly predict the development of TB after renal transplantation.

Inactivation of hnRNP K by expanded intronic AUUCU repeat induces apoptosis via translocation of PKCdelta to mitochondria in spinocerebellar ataxia 10.

We have identified a large expansion of an ATTCT repeat within intron 9 of ATXN10 on chromosome 22q13.31 as the genetic mutation of spinocerebellar ataxia type 10 (SCA10). Our subsequent studies indicated that neither a gain nor a loss of function of ataxin 10 is likely the major pathogenic mechanism of SCA10. Here, using SCA10 cells, and transfected cells and transgenic mouse brain expressing expanded intronic AUUCU repeats as disease models, we show evidence for a key pathogenic molecular mechanism of SCA10. First, we studied the fate of the mutant repeat RNA by in situ hybridization. A Cy3-(AGAAU)(10) riboprobe detected expanded AUUCU repeats aggregated in foci in SCA10 cells. Pull-down and co-immunoprecipitation data suggested that expanded AUUCU repeats within the spliced intronic sequence strongly bind to hnRNP K. Co-localization of hnRNP K and the AUUCU repeat aggregates in the transgenic mouse brain and transfected cells confirmed this interaction. To examine the impact of this interaction on hnRNP K function, we performed RT-PCR analysis of a splicing-regulatory target of hnRNP K, and found diminished hnRNP K activity in SCA10 cells. Cells expressing expanded AUUCU repeats underwent apoptosis, which accompanied massive translocation of PKCdelta to mitochondria and activation of caspase 3. Importantly, siRNA-mediated hnRNP K deficiency also caused the same apoptotic event in otherwise normal cells, and over-expression of hnRNP K rescued cells expressing expanded AUUCU repeats from apoptosis, suggesting that the loss of function of hnRNP K plays a key role in cell death of SCA10. These results suggest that the expanded AUUCU-repeat in the intronic RNA undergoes normal transcription and splicing, but causes apoptosis via an activation cascade involving a loss of hnRNP K activities, massive translocation of PKCdelta to mitochondria, and caspase 3 activation.

Intersectional Disparities in Emergency Medicine Residents' Performance Assessments by Race, Ethnicity, and Sex.

Importance: Previous studies have demonstrated sex-specific disparities in performance assessments among emergency medicine (EM) residents. However, less work has focused on intersectional disparities by ethnoracial identity and sex in resident performance assessments. Objective: To estimate intersectional sex-specific ethnoracial disparities in standardized EM resident assessments. Design, Setting, and Participants: This retrospective cohort study used data from the Association of American Medical Colleges and the Accreditation Council for Graduate Medical Education Milestones (Milestones) assessments to evaluate ratings for EM residents at 128 EM training programs in the US. Statistical analyses were conducted in June 2020 to January 2023. Exposure: Training and assessment environments in EM residency programs across comparison groups defined by ethnoracial identity (Asian, White, or groups underrepresented in medicine [URM], ie, African American/Black, American Indian/Alaska Native, Hispanic/Latine, and Native Hawaiian/Other Pacific Islander) and sex (female/male). Main Outcomes and Measures: Mean Milestone scores (scale, 0-9) across 6 core competency domains: interpersonal and communications skills, medical knowledge, patient care, practice-based learning and improvement, professionalism, and system-based practice. Overall assessment scores were calculated as the mean of the 6 competency scores. Results: The study sample comprised 128 ACGME-accredited programs and 16 634 assessments for 2708 EM residents of which 1913 (70.6%) were in 3-year and 795 (29.4%) in 4-year programs. Most of the residents were White (n = 2012; 74.3%), followed by Asian (n = 477; 17.6%), Hispanic or Latine (n = 213; 7.9%), African American or Black (n = 160; 5.9%), American Indian or Alaska Native (n = 24; 0.9%), and Native Hawaiian or Other Pacific Islander (n = 4; 0.1%). Approximately 14.3% (n = 386) and 34.6% (n = 936) were of URM groups and female, respectively. Compared with White male residents, URM female residents in 3-year programs were rated increasingly lower in the medical knowledge (URM female score, -0.47; 95% CI, -0.77 to -0.17), patient care (-0.18; 95% CI, -0.35 to -0.01), and practice-based learning and improvement (-0.37; 95% CI, -0.65 to -0.09) domains by postgraduate year 3 year-end assessment; URM female residents in 4-year programs were also rated lower in all 6 competencies over the assessment period. Conclusions and Relevance: This retrospective cohort study found that URM female residents were consistently rated lower than White male residents on Milestone assessments, findings that may reflect intersectional discrimination in physician competency evaluation. Eliminating sex-specific ethnoracial disparities in resident assessments may contribute to equitable health care by removing barriers to retention and promotion of underrepresented and minoritized trainees and facilitating diversity and representation among the emergency physician workforce.

Clinicopathological comparisons of index and second primary melanomas in paediatric and adult populations.

BACKGROUND: The high incidence of cutaneous melanoma globally has sparked interest in the features associated with second primary melanomas (SPMs). OBJECTIVES: To identify differences and similarities between index and second primary melanomas while comparing the absolute and relative risk of subsequent melanoma development in paediatric and adult patients. METHODS: A retrospective analysis of patients diagnosed with invasive malignant melanoma from 1973 to 2008 inclusive was completed with data obtained from the Surveillance, Epidemiology and End Results (SEER) database. RESULTS: In total, 208,289 patients were diagnosed with invasive melanoma in the SEER database from 1973 to 2008, with subsequent primary melanomas diagnosed in 6888 (3.3%). The incidence of SPMs increased with increasing age of diagnosis of the patient's first melanoma. However, the relative risk of developing a subsequent melanoma was nearly double for patients diagnosed with their first melanoma at the age of 19 years and younger compared with patients greater than the age of 19 years. Compared with a patient's initial invasive melanoma, 44% of the subjects had a different melanoma subtype with their subsequent melanoma. SPMs were located in a different anatomical site from the index malignancy in 55% of patients. Nodular melanomas were more common as index melanomas compared with SPMs. CONCLUSIONS: Although invasive cutaneous melanoma is primarily a malignancy of adulthood, the heightened relative risk of SPMs in the paediatric population calls for careful long-term scrutiny in this latter population following an index melanoma diagnosis.

The Reliability of Graduate Medical Education Quality of Care Clinical Performance Measures.

Background: Graduate medical education (GME) program leaders struggle to incorporate quality measures in the ambulatory care setting, leading to knowledge gaps on how to provide feedback to residents and programs. While nationally collected quality of care data are available, their reliability for individual resident learning and for GME program improvement is understudied. Objective: To examine the reliability of the Healthcare Effectiveness Data and Information Set (HEDIS) clinical performance measures in family medicine and internal medicine GME programs and to determine whether HEDIS measures can inform residents and their programs with their quality of care. Methods: From 2014 to 2017, we collected HEDIS measures from 566 residents in 8 family medicine and internal medicine programs under one sponsoring institution. Intraclass correlation was performed to establish patient sample sizes required for 0.70 and 0.80 reliability levels at the resident and program levels. Differences between the patient sample sizes required for reliable measurement and the actual patients cared for by residents were calculated. Results: The highest reliability levels for residents (0.88) and programs (0.98) were found for the most frequently available HEDIS measure, colorectal cancer screening. At the GME program level, 87.5% of HEDIS measures had sufficient sample sizes for reliable measurement at alpha 0.7 and 75.0% at alpha 0.8. Most resident level measurements were found to be less reliable. Conclusions: GME programs may reliably evaluate HEDIS performance pooled at the program level, but less so at the resident level due to patient volume.

Racial and Ethnic Differences in Internal Medicine Residency Assessments.

Importance: Previous studies have demonstrated racial and ethnic inequities in medical student assessments, awards, and faculty promotions at academic medical centers. Few data exist about similar racial and ethnic disparities at the level of graduate medical education. Objective: To examine the association between race and ethnicity and performance assessments among a national cohort of internal medicine residents. Design, Setting, and Participants: This retrospective cohort study evaluated assessments of performance for 9026 internal medicine residents from the graduating classes of 2016 and 2017 at Accreditation Council of Graduate Medical Education (ACGME)-accredited internal medicine residency programs in the US. Analyses were conducted between July 1, 2020, and June 31, 2022. Main Outcomes and Measures: The primary outcome was midyear and year-end total ACGME Milestone scores for underrepresented in medicine (URiM [Hispanic only; non-Hispanic American Indian, Alaska Native, or Native Hawaiian/Pacific Islander only; or non-Hispanic Black/African American]) and Asian residents compared with White residents as determined by their Clinical Competency Committees and residency program directors. Differences in scores between Asian and URiM residents compared with White residents were also compared for each of the 6 competency domains as supportive outcomes. Results: The study cohort included 9026 residents from 305 internal medicine residency programs. Of these residents, 3994 (44.2%) were female, 3258 (36.1%) were Asian, 1216 (13.5%) were URiM, and 4552 (50.4%) were White. In the fully adjusted model, no difference was found in the initial midyear total Milestone scores between URiM and White residents, but there was a difference between Asian and White residents, which favored White residents (mean [SD] difference in scores for Asian residents: -1.27 [0.38]; P < .001). In the second year of training, White residents received increasingly higher scores relative to URiM and Asian residents. These racial disparities peaked in postgraduate year (PGY) 2 (mean [SD] difference in scores for URiM residents, -2.54 [0.38]; P < .001; mean [SD] difference in scores for Asian residents, -1.9 [0.27]; P < .001). By the final year 3 assessment, the gap between White and Asian and URiM residents' scores narrowed, and no racial or ethnic differences were found. Trends in racial and ethnic differences among the 6 competency domains mirrored total Milestone scores, with differences peaking in PGY2 and then decreasing in PGY3 such that parity in assessment was reached in all competency domains by the end of training. Conclusions and Relevance: In this cohort study, URiM and Asian internal medicine residents received lower ratings on performance assessments than their White peers during the first and second years of training, which may reflect racial bias in assessment. This disparity in assessment may limit opportunities for physicians from minoritized racial and ethnic groups and hinder physician workforce diversity.

Humanized theta-defensins (retrocyclins) enhance macrophage performance and protect mice from experimental anthrax infections.

Retrocyclins are humanized versions of the -defensin peptides expressed by the leukocytes of several nonhuman primates. Previous studies, performed in serum-free media, determined that retrocyclins 1 (RC1) and RC2 could prevent successful germination of Bacillus anthracis spores, kill vegetative B. anthracis cells, and inactivate anthrax lethal factor. We now report that retrocyclins are extensively bound by components of native mouse, human, and fetal calf sera, that heat-inactivated sera show greatly enhanced retrocyclin binding, and that native and (especially) heat-inactivated sera greatly reduce the direct activities of retrocyclins against spores and vegetative cells of B. anthracis. Nevertheless, we also found that retrocyclins protected mice challenged in vivo by subcutaneous, intraperitoneal, or intranasal instillation of B. anthracis spores. Retrocyclin 1 bound extensively to B. anthracis spores and enhanced their phagocytosis and killing by murine RAW264.7 cells. Based on the assumption that spore-bound RC1 enters phagosomes by "piggyback phagocytosis," model calculations showed that the intraphagosomal concentration of RC1 would greatly exceed its extracellular concentration. Murine alveolar macrophages took up fluorescently labeled retrocyclin, suggesting that macrophages may also acquire extracellular RC1 directly. Overall, these data demonstrate that retrocyclins are effective in vivo against experimental murine anthrax infections and suggest that enhanced macrophage function contributes to this property.

Functions of unconventional myosins.

To date, fourteen classes of unconventional myosins have been identified. Recent reports have implicated a number of these myosins in organelle transport, and in the formation, maintenance and/or dynamics of actin-rich structures involved in a variety of cellular processes including endocytosis, cell migration, and sensory transduction. Characterizations of organelle dynamics in pigment cells and neurons have further defined the contributions made by unconventional myosins and microtubule motors to the transport and distribution of organelles. Several studies have provided evidence of complexes through which cooperative organelle transport may be coordinated. Finally, the myosin superfamily has been shown to contain at least one processive motor and one backwards motor.

Improvement of transmittance by fabricating broadband subwavelength anti-reflection structures for polycarbonate.

We report on how to increase transmittance of a 0.2 mm thick polycarbonate (PC) film by periodic subwavelength anti-reflection structures in the visible spectral range. Subwavelength anti-reflection structures like moth-eyes are fabricated into the polycarbonate substrate itself by thermal nano-imprinting lithography (TH-NIL), which uses silicon stamps that have periodic structures such as gratings (lines and spaces) and pillared dots, and are fabricated by laser interference lithography (LIL) and transformer coupled plasma etching. To increase transmittance of a polycarbonate film, we control the periods and shapes of patterns, the number of patterned surfaces, and the overlapping direction of patterns that are fabricated into its surfaces. As a result of this, we show that average transmittance improves as the pattern period gets shorter and as both surfaces of the film are patterned. We also show that the spectrum range gets larger as the pattern period gets shorter and is determined by the longer pattern period in the case of designing a film to have different pattern period on its surfaces. The maximum average transmittance of a polycarbonate film increases up to approximately 6% compared to a bare sample in the 470-800 nm spectral range.

Model reduction techniques for the computation of extended Markov parameterizations for generalized Langevin equations.

The generalized Langevin equation is a model for the motion of coarse-grained particles where dissipative forces are represented by a memory term. The numerical realization of such a model requires the implementation of a stochastic delay-differential equation and the estimation of a corresponding memory kernel. Here we develop a new approach for computing a data-driven Markov model for the motion of the particles, given equidistant samples of their velocity autocorrelation function. Our method bypasses the determination of the underlying memory kernel by representing it via up to about twenty auxiliary variables. The algorithm is based on a sophisticated variant of the Prony method for exponential interpolation and employs the positive real lemma from model reduction theory to extract the associated Markov model. We demonstrate the potential of this approach for the test case of anomalous diffusion, where data are given analytically, and then apply our method to velocity autocorrelation data of molecular dynamics simulations of a colloid in a Lennard-Jones fluid. In both cases, the velocity autocorrelation function and the memory kernel can be reproduced very accurately. Moreover, we show that the algorithm can also handle input data with large statistical noise. We anticipate that it will be a very useful tool in future studies that involve dynamic coarse-graining of complex soft matter systems.