cssi/SciSciGPT-SciSciNet huggingface dataset:
Anti-VEGFR therapy as a partner for immune-based therapy approaches in HCC

In hepatocellular carcinoma (HCC), chronic inflammation and vascular abnormalities often promote an environment characterized by hypoxia, immunosuppressive cell infiltration (M2-activated macrophages, T regulatory cells and myeloid-derived suppressor cells) and upregulation of immune checkpoints. These immunosuppressive cues lead to impaired effector CD8+ T lymphocyte infiltration and function, and ultimately to immune evasion. Reactivation of the immune response is critical to overcoming treatment resistance in HCC. Large clinical trials of anti-PD-1 blockade therapy are ongoing, and interim analyses showed promising responses in a subset of patients. The current challenge is to rationally combine anti-PD-1 antibodies with the existing drugs to substantially increase survival more broadly in HCC patients. Antiangiogenic multikinase inhibitors (sorafenib, regorafenib, lenvatinib) have shown efficacy in HCC. These drugs work in part by VEGF pathway inhibition in tumor endothelial cells, which can delay tumor growth. If the antivascular effects are too pronounced, treatment leads to increased hypoxia, inflammation, and fibrosis in the tumor tissues. These effects may affect anti-tumor immune response, which are critical for achieving durable treatment responses. Thus, successful implementation of combination therapies will require synergy between these interventions to reduce angiogenesis, modify vascular function, reverse the immunosuppressive environment and activate anti-tumor immunity in HCC.
Model adaptivity for goal-oriented inference using adjoints

Abstract An inverse problem seeks to infer unknown model parameters using observed data. We consider a goal-oriented inverse problem, where the goal of inferring parameters is to use them in predicting a quantity of interest (QoI). Recognizing that multiple models of varying fidelity and computational cost may be available to describe the physical system, we formulate a goal-oriented model adaptivity approach that leverages multiple models while controlling the error in the QoI prediction. In particular, we adaptively form a mixed-fidelity model by using models of different levels of fidelity in different subregions of the domain. Taking the solution of the inverse problem with the highest-fidelity model as our reference QoI prediction, we derive an adjoint-based third-order estimate for the QoI error from using a lower-fidelity model. Localization of this error then guides the formation of mixed-fidelity models. We demonstrate the method for example problems described by convection–diffusion–reaction models. For these examples, our mixed-fidelity models use the high-fidelity model over only a small portion of the domain, but result in QoI estimates with small relative errors. We also demonstrate that the mixed-fidelity inverse problems can be cheaper to solve and less sensitive to the initial guess than the high-fidelity inverse problems.
On on-line task assignment in spatial crowdsourcing

A new platform, termed spatial crowdsourcing (SC), is emerging that enables a requester to commission workers to physically travel to some specified locations to perform a set of spatial tasks (i.e., tasks related to a geographical location and time). For spatial crowdsourcing to scale to millions of workers and tasks, it should be able to efficiently assign tasks to workers, which in turn consists of both matching tasks to workers and computing a schedule for each worker. The current approaches for task assignment in spatial crowdsourcing cannot scale as either task matching or task scheduling will become a bottleneck. Instead, we propose an on-line assignment approach utilizing an auction-based framework where workers bid on every arriving task and the server determines the highest bidder, resulting in splitting the assignment responsibility between workers (for scheduling) and the server (for matching) and thus eliminating all bottlenecks. Through several experiments on both real-world and synthetic datasets, we compare the accuracy and efficiency of our real-time algorithm with state of the art algorithms proposed for similar problems. We show how other algorithms cannot generate as good of an assignment because they fail to manage the dynamism and/or take advantage of the spatiotemporal characteristics of SC.
Facilitating the Operation of Lithium-ion Cells with High-nickel Layered Oxide Cathodes with a Small Dose of Aluminum

Layered oxide cathodes with a high Ni content of >0.6 are promising for high-energy-density lithium-ion batteries. However, parasitic electrolyte oxidation of the charged cathode and mechanical degradation arising from phase transitions significantly deteriorate the cell performance and cycle life as the Ni content increases. We demonstrate here a significantly prolonged cycle life with superior cell performance by substituting a small-dose of Al (2 mol %) for Ni in LiNi0.92Co0.06Al0.02O2; the capacity retention after operating a full cell fabricated with graphite anode for 1000 cycles increases from 47% to 83% on going from the Al-free LiNi0.94Co0.06O2 to the Al-doped LiNi0.92Co0.06Al0.02O2 cathode. Through in situ X-ray diffraction, we provide the operando evidence that the Al-doping tunes the H2–H3 phase transition process from a two-phase reaction to a quasi-monophase reaction, minimizing the mechanical degradation. Furthermore, secondary-ion mass spectrometry reveals considerably suppressed transitio...
Evolution of the Second Amendment: 1939-2008

The Second Amendment has been regarded as a controversial political issue. Accordingly, legislators have often skirted the constitutionality of firearm legislation, often explaining the Amendment as referring to the National Guard as the modern militia. With the Supreme Court mostly avoiding cases directly involving the Second Amendment, legislators have been allowed to interpret the meaning of the Amendment. In fact, before District of Columbia et al. v. Heller (2008), the only case heard before the Court directly examining the Second Amendment was U.S. v. Miller (1939). While many have argued that the recent ruling in Heller (2008) is a vast departure from previous assumptions about the Second Amendment, I argue that the new ruling is merely a deeper explanation of the limits described of the Second Amendment that the Court in Miller (1939) alluded to and that Heller (2008) really does not present any new rights or even open the flood gates to groundbreaking challenges to gun control legislation beyond what was addressed in this case. Due to the approach taken by the opposing parties, the Heller (2008) ruling focused primarily on the issue of the Second Amendment being either a collective right or an individual right. I contend that the ruling of the most recent court case is not only consistent with the Miller (1939) decision, but also that it provides the first explanation of the protections afforded to citizens under the Second Amendment. Despite the historical backing provided by the Court in their ruling, there is still concern that Heller (2008) brought about a great deal of social change in favor of gun owners. I argue that the assumed disconnect between historical and constitutional findings on the Second Amendment and popular pro-gun control perspectives of recent times originates from a misunderstood reading of the history of the Second Amendment as well as the Miller (1939) ruling along with a logically inconsistent expectation of the Second Amendment to remain dead (in that the Amendment is outdated with the advent of a standing, state sponsored military) while other rights in the Bill of Rights are living and breathing (allowed to evolve over the years and encompass technological advancements in society). In order to examine these issues, this paper will first identify the context in which the Miller (1939) case was heard, including a discussion on the associated law under scrutiny, The National Firearms Act. It will also discuss the implications of the ruling. Next, the Heller (2008) ruling will be dissected. Finally, the manner in which the Heller (2008) ruling handles the previous Miller (1939) ruling will be discussed along with the implications that are presented by that treatment of Miller (2008).
Accelerated orthogonal least-squares for large-scale sparse reconstruction

Abstract We study the problem of inferring a sparse vector from random linear combinations of its components. We propose the Accelerated Orthogonal Least-Squares (AOLS) algorithm that improves performance of the well-known Orthogonal Least-Squares (OLS) algorithm while requiring significantly lower computational costs. While OLS greedily selects columns of the coefficient matrix that correspond to non-zero components of the sparse vector, AOLS employs a novel computationally efficient procedure that speeds up the search by anticipating future selections via choosing L columns in each step, where L is an adjustable hyper-parameter. We analyze the performance of AOLS and establish lower bounds on the probability of exact recovery for both noiseless and noisy random linear measurements. In the noiseless scenario, it is shown that when the coefficients are samples from a Gaussian distribution, AOLS with high probability recovers a k-sparse m-dimensional sparse vector using O ( k log ⁡ m k + L − 1 ) measurements. Similar result is established for the bounded-noise scenario where an additional condition on the smallest nonzero element of the unknown vector is required. The asymptotic sampling complexity of AOLS is lower than the asymptotic sampling complexity of the existing sparse reconstruction algorithms. In simulations, AOLS is compared to state-of-the-art sparse recovery techniques and shown to provide better performance in terms of accuracy, running time, or both. Finally, we consider an application of AOLS to clustering high-dimensional data lying on the union of low-dimensional subspaces and demonstrate its superiority over existing methods.
Elastic-plastic deformation of molybdenum single crystals shocked to 12.5 GPa: Crystal anisotropy effects

To understand crystal anisotropy effects on shock-induced elastic-plastic deformation of molybdenum (Mo), results from high-purity single crystals shocked along [110] and [111] orientations to an elastic impact stress of 12.5 GPa were obtained and compared with the [100] results previously reported [A. Mandal and Y. M Gupta, J. Appl. Phys. 121, 045903 (2017)]. Measured wave profiles showed a time-dependent response, and strong anisotropy was observed in the elastic wave attenuation with the propagation distance, elastic limits, shock speeds, and overall structure of the wave profiles. Resolved shear stresses on {110}〈111〉 and {112}〈111〉 slip systems provided insight into the observed anisotropy in elastic wave attenuation and elastic limits and showed that shear stresses, and not longitudinal stresses, are a better measure of strength in shocked single crystals. Under shock compression, resolved shear stresses at elastic limits were comparable to the Peierls stress of screw dislocations in Mo. Elastic wave attenuation was rapid when shear stresses were larger than the Peierls stress. Large differences in the elastic limits under shock and quasi-static loading are likely a consequence of the large Peierls stress value for Mo. Numerically simulated wave profiles, obtained using the dislocation-based plasticity model described in the [100] work, showed good agreement with all measured wave profiles but could not differentiate between the {110}〈111〉 and {112}〈111〉 slip systems. Overall, experimental results and corresponding numerical simulations for the three crystal orientations have provided a comprehensive insight into shock-induced elastic-plastic deformation of Mo single crystals, including the development of a continuum material model.
New Anatomical Evidence from the Male Asian Citrus Psyllid (Hemiptera: Liviidae) Invokes Controversy Over the Accepted Function of Some Male Reproductive Organs in Psylloidea

Males of many Psylloidea are known to possess a characteristic structure at the functional hub of their reproductive apparatus, between afferent and efferent passage of seminal fluid. The structure is a squat, cylindrical endoskeleton consisting of two sections. Classical authors named them as 'sperm pump' and 'ejaculatory duct', based on superficial resemblance to a spring-loaded, thimble-shaped cylinder, encircled by smooth, vertical columns interpreted to be muscles which, when contracted, compress the cylinder and affect seminal fluid discharge. The discovery of numerous spherules of unknown composition and function in and around the columns of the Asian citrus psyllid male genitalia invoked rigorous scrutiny of the classical literature for evidence to support its claims, and determined that the grounds for vetting the structure as a sperm pump were fully teleological. This paper raises several objections to modern acceptance of this classical interpretation, presenting them as problematic, thought-provoking, and sometimes controversial anatomical features. The two sections are herein called 'drum' and 'spout'. As an endoskeleton, the sections are an invagination of the exoskeleton and therefore cannot receive seminal fluid into their hollow. A phallus is identified inside an aedeagal tube, indicating that it is the ejaculatory duct-the tube, drum, and spout are considered its housing. A sheath envelopes the drum and is directly continuous with the spout hypodermis, another problematical feature raising the question of whether it is detached from adherence to the drum cuticles. Also, there are four afferent tubes but only two openings in the drum to receive their seminal fluids.
Mechanical Behavior Evolution of SAC305 Lead Free Solder Joints under Thermal Cycling

Solder joints in electronic packages are frequently exposed to thermal cycling environment. Such exposures can occur in real life application as well as in accelerated thermal cycling tests used for the fatigue behavior characterization. Because of temperature variations and CTE mismatches of the assembly materials, cyclic temperature leads to damage accumulation and material property evolution in the solder joints. This eventually results in crack initiation, and subsequent crack growth and failure. In this study, the nanoindentation technique was used to understand the evolution of mechanical properties (modulus, hardness and creep behavior) of SAC305 BGA solder joints subjected to thermal cycling loading for various durations. In addition, microstructural changes in those joints that occur during thermal cycling were observed using both SEM and optical microscopy. BGA solder joint strip specimens were first prepared by cross sectioning BGA assemblies followed by surface polishing to facilitate SEM imaging and nanoindentation testing. The strip specimens were chosen to contain several single grain solder joints. This enabled large regions of solder material with equivalent mechanical behavior, which could then be indented several times after various durations of cycling. After preparation, the solder joint strip samples were thermally cycled from $\mathrm{T}=-40$ to 125°C in an environmental chamber. At various points in the cycling (e.g. after 0, 50, 100, and 250 cycles), the package was taken out from the chamber, and nanoindentation was performed on each single grain joint to obtain the modulus, hardness, and creep behavior at 25°C. This allowed the evolution of the mechanical properties with the duration of thermal cycling to be determined. Moreover, microstructural changes were also observed after various durations of cycling using optical microscopy. From the nanoindentation test results, it was found that the modulus and hardness of the SAC305 solder joints dropped significantly with thermal cycling. Moreover, the nanoindentation creep test results showed significant increases in the creep deformation and creep rate when joints were subjected to thermal cycling up to 250 cycles.
Dynamic Structures of Host-Guest Systems

As illustrated elsewhere in this volume, calixarenes have proven to be a remarkably versatile class of materials. Numerous schemes have been devised that employ the simple calixarenes, modified molecules, surface-bound species or larger assemblies for a variety of functions. With the large amount of information now available, it is quite appropriate to assess our state of knowledge, as ultimately the rational design of the next generation of materials depends on our level of understanding of structural and dynamic details of the currently known species. In this work we summarise studies that have contributed to our understanding of calixarenes. In previous reviews we have noted the difficulty that structural studies of even the simplest calixarenes has caused [1,2]: in general, the compounds are disordered, often with involvement of both guest and host sub-lattices and there is evidence for dynamic coupling between them. We have also advanced the use of synoptic approaches, where we use complementary techniques to develop improved structural models. Without a doubt, the combination of crystallography and solid-state nuclear magnetic resonance (NMR) spectroscopy has proven to be remarkably effective in solving a number of complex problems, and continuing progress in technique development will advance these capabilities further. During the course of our work on calixarenes we have stayed with the simple ptert-butylcalix[4]arenes (tBC), starting with the very first tBC structure reported, that with toluene as guest. This compound has been under study in our laboratory for nearly ten years, and it has shown some very unusual effects, such as superlattice diffraction peaks that fade with time and a wavelength-dependent structure. Also, a good structural model was found that refined very well but turned out to have the wrong symmetry as shown by NMR spectroscopy. At the start of this work, only a few guest species were known for the simple tBCs, presumably because of the low solubility in many solvents. Many commonly held views on calixarenes derive from a very limited database and are easily shown to be vast oversimplifications, e.g., the suitability of specific guest types for the tBCs, general structural features of the host-guest complexes and the contributing factors to compound stability. With some less conventional approaches we were able to prepare compounds Chapter 16
Educational programs to teach shared decision making to medical trainees: A systematic review.

Abstract Objective Shared decision-making (SDM) is a process of collaboration between patients and clinicians. An increasing number of educational programs to teach SDM have been developed. We aimed to summarize and evaluate the body of evidence assessing the outcomes of these programs. Methods We conducted a systematic review of studies that aimed to teach SDM to medical trainees. Reviewers worked independently and in duplicate to select studies, extract data and evaluate the risk of bias. Results Eighteen studies were included. Most studies focused on residents/fellows (61 %) and combined a didactic component with a practical experience (50 % used a standardized patient). Overall, participants reported satisfaction with the courses. The effects on knowledge, attitudes/confidence and comfort with SDM were small; no clear improvement on SDM skills was noted. Evaluation of clinical behavior and outcomes was limited (3/18 studies). Studies had moderate risk of bias. Conclusion Very low quality evidence suggests that educational programs for teaching SDM to medical trainees are viewed as satisfactory and have a small impact on knowledge and comfort with SDM. Their impact on clinical skills, behaviors and patient outcomes is less clear. Practical implications Integration of formal and systematic outcomes evaluation (effects on behavior/clinical practice) should be part of future programs.
Inferior vena cava occlusion in retroperitoneal fibrosis and exogenous testosterone administration.

Abstract Retroperitoneal fibrosis (RPF) causing large vessel stenosis and thrombosis is rare but well-described. We describe a 50-year-old man with rapid progression of central venous thrombosis in the presence of RPF and exogenous testosterone use. Therapeutic anticoagulation was initiated and catheter directed thrombolysis was performed after placement of an inferior vena cava (IVC) filter. Repeat venogram revealed severe focal retrohepatic IVC stenosis, which was treated with serial venoplasty and stenting. Clinical improvement was significant 48 hours after intervention. This case represents a rare presentation of IVC occlusion in the setting of RPF and exogenous testosterone administration successfully treated with endovascular interventions.
11 Psychological Assessment in Child Mental Health Settings

The unique characteristics of children and adolescents and the processes through which they come to the attention of mental health professionals make the considerable accumulated knowledge regarding the clinical evaluation of adults of little use when conducting the comparable evaluation of youth. This chapter suggests, following a considerable review of child assessment issues as well as the study of child psychopathology phenomena, that a core assessment procedure consisting of multidimensional inventories completed by multiple informants is a strategy that is sensitive to many of the unique characteristics and challenges of child mental health evaluation. These youth are not self-referred and therefore are not optimally motivated to participate in their evaluation. Children also vary in their capacity to contribute meaningfully to the assessment process because of their developmental status. Children are often referred by adults who observe them systematically at home or at school; these adults are therefore necessary contributors to the assessment process. In addition, because youth are primarily referred by adults, it is more likely that they often present with multiple dimensions of problem adjustment that generate adult concern. We describe in some detail four different published assessment systems that consist of multidimensional questionnaires completed by parent, teacher, and student. In addition, other useful single-informant measures for youth or their families with either broad or more focused application are described. Keywords: child problem behaviors; differential diagnosis; informant assessment; inventory evaluation
Sparse subsurface radar reflectors in Hellas Planitia, Mars

Abstract Geomorphological features potentially related to subsurface ice, such as scalloped depressions, expanded craters, pedestal craters, and banded terrain, are present in and around Hellas Planitia, Mars. We present a radar survey of the region using the Shallow Radar (SHARAD) instrument on board the Mars Reconnaissance Orbiter (MRO) to identify candidate subsurface reflectors that may be due to the presence of potentially ice-rich deposits. We found that the majority of radar returns are likely from off-nadir surface topography (“clutter”), arising from the rough topography of the region. There is no widespread radar return from any subsurface interfaces. However, we identify a group of six reflectors adjacent to each other on a plateau in Malea Patera in which we have higher confidence. Landforms associated with a likely ice-rich mantle are associated with the plateau, but the thickness of this mantle does not correspond to the expected depth of the reflectors. However, layers beneath the mantle and marginal pitting at the edge of the plateau are similar to those associated with pedestal craters, which may be ice rich and are a similar thickness to the expected depth of the reflectors. Malea Patera has been interpreted to be a volcanic caldera, so the reflectors may be associated with a volcanic deposit within the plateau, although the evidence for this is inconclusive. Because this radar detection is localized and its origin ambiguous, we cannot use it to make conclusions about the thickness of subsurface deposits in the Hellas region as a whole. The lack of widespread radar reflectors in this region, as compared to the northern mid-latitudes where extensive radar reflections have been mapped, may be due in part to higher surface roughness, which creates radar clutter that may obscure subsurface reflectors. However on the southern rim of the basin and south of the basin, the lack of reflectors may indicate that the possible ice-rich deposits observed geomorphologically in this region are too thin to be resolved by SHARAD, are dielectrically similar to the underlying unit, or have a gradual vertical transition in ice content that is not reflective for the radar. This would imply that recent climate processes may have favored widespread, thick ice deposition or preservation in the northern hemisphere as compared to the southern hemisphere.
CFD-DEM and PR-DNS studies of low-temperature densely packed beds

Abstract Over the past few decades, granular media is gaining attention as a viable option for heat transfer fluids (HTFs). Several research efforts are studying the use of particle-based heat transfer fluids in a wide variety of applications. With this motivation, the current work focusses on analyzing the different heat transfer mechanisms in low-temperature mono-sized densely packed granular media. To study the heat transfer behavior of granular media at different scales, the current work employs a two-way coupled computational strategy. The motion of particles is solved using the Discrete Element Method (DEM) and the interstitial air is solved using a Finite-Volume (CFD) approach. The Open-Source library CFDEM Coupling® is used in the current study to join the Finite Volume PISO solver of OpenFOAM® and the DEM solver of LIGGGHTS®. Typically, particle-particle contact conduction and particle-air convection are the most popular closure models. But recent research identified a different heat transfer phenomenon in packed beds that cannot be identified by conduction or convection models. Though closure models were developed to implement this on a CFD-DEM framework, they did not capture the effect of intra-particulate thermal gradients on this phenomenon. Hence the current work also employs Particle-Resolved Direct Numerical Simulations (PR-DNS) to gain valuable insights allowing for the modification of existing models. A new closure model is then proposed here and is implemented in the CFD-DEM framework. This model provides key insights into the different heat transfer mechanism of packed beds.
Ethics of information‐gathering interventions in innovative practice

Innovative practice involves medical interventions that deviate from standard practice in significant ways. For many patients, innovative practice offers the best chance of successful treatment. Because little is known about most innovative treatments, clinicians who engage in innovative practice might consider including extra procedures, such as scans or blood draws, to gather information about the innovation. Such information-gathering interventions can yield valuable information for modifying the innovation to benefit future patients and for designing scientific studies of the innovation. However, existing guidelines do not say when or whether it is appropriate to add potentially risky information-gathering interventions for these purposes. As a result, clinicians may assume that information-gathering interventions are ethically inappropriate and should not be used in innovative practice. This assumption can lead to seriously negative consequences, such as increasing the likelihood that harmful or ineffective innovations will be adopted and creating new barriers to the development of genuinely beneficial treatments. We argue that health care institutions need to promote the responsible use of information-gathering interventions as an adjunct to innovative practice, and that these interventions are not clinical research and should not be subject to research oversight.
Rapid Screening of Physiological Changes Associated With COVID-19 Using Soft-Wearables and Structured Activities: A Pilot Study

Objective: Controlling the spread of the COVID-19 pandemic largely depends on scaling up the testing infrastructure for identifying infected individuals. Consumer-grade wearables may present a solution to detect the presence of infections in the population, but the current paradigm requires collecting physiological data continuously and for long periods of time on each individual, which poses limitations in the context of rapid screening. Technology: Here, we propose a novel paradigm based on recording the physiological responses elicited by a short (~2 minutes) sequence of activities (i.e. “snapshot”), to detect symptoms associated with COVID-19. We employed a novel body-conforming soft wearable sensor placed on the suprasternal notch to capture data on physical activity, cardio-respiratory function, and cough sounds. Results: We performed a pilot study in a cohort of individuals (n=14) who tested positive for COVID-19 and detected altered heart rate, respiration rate and heart rate variability, relative to a group of healthy individuals (n=14) with no known exposure. Logistic regression classifiers were trained on individual and combined sets of physiological features (heartbeat and respiration dynamics, walking cadence, and cough frequency spectrum) at discriminating COVID-positive participants from the healthy group. Combining features yielded an AUC of 0.94 (95% CI=[0.92, 0.96]) using a leave-one-subject-out cross validation scheme. Conclusions and Clinical Impact: These results, although preliminary, suggest that a sensor-based snapshot paradigm may be a promising approach for non-invasive and repeatable testing to alert individuals that need further screening.
Recombinant Erythroid Kruppel-Like Factor Fused to GATA1 up-Regulates δ-Globin Expression In Erythroid Cells.

The β-hemoglobinopathies sickle cell disease and β-thalassemia are among the most common human genetic disorders worldwide. Hemoglobin A2 (HbA2, α2δ2) and fetal hemoglobin (HbF, α2γ2) both inhibit the polymerization of hemoglobin S that results in erythrocyte sickling. Expression of erythroid Kruppel-like factor (EKLF) and GATA1 is critical for transitioning hemoglobin from HbF to hemoglobin A (HbA, α2β2) and HbA2. The lower levels of δ-globin expression compared with β-globin expression seen in adulthood are likely due to the absence of an EKLF-binding motif in the δ-globin proximal promoter. In an effort to upregulate δ-globin to increase HbA2 expression, we created a series of EKLF-GATAl fusion constructs composed of the transactivation domain of EKLF and the DNA-binding domain of GATAl and then tested their effects on hemoglobin expression. EKLF-GATAl fusion proteins activated δ-, γ-, and β-globin promoters in K562 cells, and significantly upregulated δ- and γ-globin RNA transcript and protein expression in K562 and/or CD34+ cells. The binding of EKLF-GATA1 fusion proteins at the GATA1 consensus site in the δ-globin promoter was confirmed by chromatin immunoprecipitation assay. Our studies demonstrate that EKLF-GATA1 fusion proteins can enhance δ-globin expression through interaction with the δ-globin promoter, and may represent a new genetic therapeutic approach to β-hemoglobinopathies.
Summing Up: International Symposium on Recent Trends in the Immunological Diagnosis of Leukemias and Lymphomas

Professor Stefan Thierfelder asked if I would give a personal view of the symposium. Needless to say, I was reluctant to do so, because I realize full well that personal views reflect personal prejudices and not more than that. It is, of course, presumptuous for me to try to analyze the many excellent presentations that have been given over the past days. Thus, I must begin by making an apology for the exciting presentations that I cannot discuss. The symposium, in my opinion, has been excellent and fully met all my expectations.
“Natural” and “induced” regulatory T cells — purpose and problems associated with an emerging distinction

is grounded in a fundamental insightinto the nature of the vertebrate immune system that is about as old as the scienceof modern immunology: immune responses, which are characterized by dynamicalterations of the physiological steady state, have to be balanced, curtailed, regulat-ed or suppressed in order to preserve organismal homeostasis [1, 2]. This processinvolves an array of immune cell subtypes, effector molecules and tissue environ-ments that control in concert the extent of protective immune responses, autoim-munity and transplantation immunity. Thus, immune regulation is not merely theproperty of isolated and committed “regulatory cells” but an integral part of theactivity and functionality of the immune system. Nevertheless, the particularities ofdefined model systems have allowed the identification of several parameters that arepreferentially associated with ability of immune regulation. In light of these consid-erations, we prefer the notion that regulatory cells are best defined as cells capableof suppressing other immune responses
Bioeffect modeling of nonuniform dose distributions for paired organs

Evaluating treatment plans on the basis of risk/benefit to the patient depends on accurate characterization of dose-response distributions from clinical data. Typically, response data is defined as a binary complication variable according to a pre-determined threshold value. This binning of the data into two groups can mask gradual dose-response changes, and may make the dose-response model overly sensitive to the choice of complication threshold. Here, the authors explore two new fitting functions, the Generalized Mills Ratio (GMR) and the log-normal integral (LNI), with the goal of modeling the bioeffect indicator without the use of binning. These new fitting functions give the modeling a wide range of response curves of the type the authors are working with. These functions are applied to dose-response data for parotid glands treated with 3D treatment planning techniques, primarily intensity modulated radiation therapy (IMRT). Stimulated saliva flow 6 months after treatment is used as the bioeffect indicator. Preliminary analysis indicates that for the parotid glands, the lesser of the two mean doses may be an important indicator. In other words, the response may be correlated, and new methods of data analysis are important to analyze the correlation. An example of the computation of confidence intervals is given using bootstrap resampling techniques.
Building Party Systems in Developing Democracies

1. Introduction 2. A theory of aggregation incentives 3. Testing the theory 4. Aggregation, nationalization, and the number of parties in Thailand 5. Explaining aggregation in Thailand 6. Term limits, aggregation incentives, and the number of parties in the Philippines 7. Conclusion.
Relationship between airport congestion and at-gate delay

The relationship between airport congestion and passenger delays at an airport is determined by many factors. Among these factors are scheduled and actual flight times, flight itineraries, airport capacity, and turn around time between flights. From the existing recorded data, it is possible to present a general profile of both airport congestion and passenger delays, measured with respect to the published schedule, at major airports within the US. This paper illustrates the discrepancy between the two measurements. Airport congestion may be masked by flight schedules which account for routine arrival delays and/or with slack time provided for turn around at an airport. It is possible for an airport to be heavily utilized, with little or unnoticeable at-gate delays (measured with respect to scheduled arrival time). On the other hand, at-gate delays can occur at under-utilized airports. Arrival and departure queuing delays are better indicators of airport congestion than passenger delays. Average flight at-gate delays are derived from performance data and compared with simulation results for 30 of the busiest airports in USA for a good weather day. The effects of variations in schedule flight time and slack time are studied parametrically in the simulation and calibrated to match the recorded baseline national airspace system (NAS) delay profiles. This paper illustrates a technique for estimating NAS-wide impact of propagated flight delays, based upon a method for calibration a system-level simulation against real world delays as well as delays derived from other simulations.
Vaccines against Respiratory Viral Pathogens for Use in Neonates: Opportunities and Challenges

The first six months of life reflect a time of high susceptibility to severe disease following respiratory virus infection. Although this could be improved significantly by immunization, current vaccines are not approved for use in these very young individuals. This is the result of the combined effects of poor immune responsiveness and safety concerns regarding the use of live attenuated vaccines or potent adjuvants in this population. Vaccines to effectively combat respiratory viral infection ideally would result in robust CD4(+) and CD8(+) T cell responses, as well as high-affinity Ab. Inclusion of TLR agonists or single-cycle viruses is an attractive approach for provision of signals that can act as potent stimulators of dendritic cell maturation, as well as direct activators of T and/or B cells. In this article, I discuss the challenges associated with generation of a robust immune response in neonates and the potential for adjuvants to overcome these obstacles.
Pregnancy continuation and organizational religious activity following prenatal diagnosis of a lethal fetal defect are associated with improved psychological outcome

Objective The aim of the article is to examine the psychological impact, specifically symptoms of grief, post-traumatic stress and depression, in women and men who either terminated or continued a pregnancy following prenatal diagnosis of a lethal fetal defect.
Multiple dispersed loci produce small cytoplasmic Alu RNA

Alu repeats are short interspersed elements (SINEs) of dimeric structure whose transposition sometimes leads to heritable disorders in humans. Human cells contain a poly(A)- small cytoplasmic transcript of -120 nucleotides (nt) homologous to the left Alu monomer. Although its monomeric size indicates that small cytoplasmic Alu (scAlu) RNA is not an intermediary of human Alu transpositions, a less abundant poly(A)-containing Alu transcript of dimeric size and specificity expected of a transposition intermediary is also detectable in HeLa cells (A. G. Matera, U. Hellmann, M. F. Hintz, and C. W. Schmid, Mol. Cell. Biol. 10:5424-5432, 1990). Although its function is unknown, the accumulation of Alu RNA and its ability to interact with a conserved protein suggest a role in cell biology (D.-Y. Chang and R. J. Maraia, J. Biol. Chem. 268:6423-28, 1993). The relationship between the -120- and -300-nt Alu transcripts had not been determined. However, a B1 SINE produces scB1 RNA by posttranscriptional processing, suggesting a similar pathway for scAlu. An Alu SINE which recently transposed into the neurofibromatosis 1 locus was expressed in microinjected frog oocytes. This neurofibromatosis 1 Alu produced a primary transcript followed by the appearance of the scAlu species. 3' processing of a synthetic -300-nt Alu RNA by HeLa nuclear extract in vitro also produced scAlu RNA. Primer extension of scAlu RNA indicates synthesis by RNA polymerase III. HeLa-derived scAlu cDNAs were cloned so as to preserve their 5'-terminal sequences and were found to correspond to polymerase III transcripts of the left monomeric components of three previously identified Alu SINE subfamilies. Rodent x human somatic cell hybrids express Alu RNAs whose size, heterogeneous length, and chromosomal distribution indicate their derivation from SINEs. The coexpression of dimeric and monomeric Alu RNA in several hybrids suggests a precursor-product relationship.
High voltage breakdown analysis of nickle-zinc ferrite double-positive metamaterials

Metamaterials are currently under development to reduce the size of high power antennas. These materials may also have applications in other high power, dielectric-loaded components, including nonlinear transmission lines. A new procedure has been developed at the University of Missouri-Columbia that produces a double-positive metamaterial by combining nickel-zinc ferrite powders with a dielectric binder. The resulting composite is a machinable bulk material produced at significantly lower temperatures than sintered components. Previous measurements have shown this material to possess positive relative permeability and permittivity values in the range of 4 to 6 for frequencies between 200 MHz and 2 GHz. The dielectric strengths of five different types of ferrite-based composites were measured to evaluate the potential of these materials for high power applications. A pulser with a magnitude up to 100 kV and rise time on the order of tens of nanoseconds was used to determine the dielectric strength of disks with a diameter of 2.54 cm and a thickness of 2 mm. This work presents a statistical analysis of the dielectric strength data and projects the power handling capabilities of the composites.
Network‐based analysis reveals stronger local diffusion‐based connectivity and different correlations with oral language skills in brains of children with high functioning autism spectrum disorders

Neuroimaging has uncovered both long-range and short-range connectivity abnormalities in the brains of individuals with autism spectrum disorders (ASD). However, the precise connectivity abnormalities and the relationship between these abnormalities and cognition and ASD symptoms have been inconsistent across studies. Indeed, studies find both increases and decreases in connectivity, suggesting that connectivity changes in the ASD brain are not merely due to abnormalities in specific connections, but rather, due to changes in the structure of the network in which the brain areas interact (i.e., network topology). In this study, we examined the differences in the network topology between high-functioning ASD patients and age and gender matched typically developing (TD) controls. After quantitatively characterizing the whole-brain connectivity network using diffusion tensor imaging (DTI) data, we searched for brain regions with different connectivity between ASD and TD. A measure of oral language ability was then correlated with the connectivity changes to determine the functional significance of such changes. Whole-brain connectivity measures demonstrated greater local connectivity and shorter path length in ASD as compared to TD. Stronger local connectivity was found in ASD, especially in regions such as the left superior parietal lobule, the precuneus and angular gyrus, and the right supramarginal gyrus. The relationship between oral language ability and local connectivity within these regions was significantly different between ASD and TD. Stronger local connectivity was associated with better performance in ASD and poorer performance in TD. This study supports the notion that increased local connectivity is compensatory for supporting cognitive function in ASD.
Randomized phase II trial of docetaxel with or without PSA-TRICOM vaccine in patients with castrate-resistant metastatic prostate cancer: A trial of the ECOG-ACRIN cancer research group (E1809)

Anti-tumor vaccines have demonstrated efficacy in patients with castration-resistant metastatic prostate cancer. One vaccine, Prostvac-VF®, using a heterologous prime-boost strategy with vaccinia and fowlpox viral vectors encoding PSA, is currently being evaluated in a registration phase III multinational clinical trial. The current trial was planned to assess the clinical efficacy of this vaccine in patients with castration-resistant metastatic prostate cancer receiving subsequent docetaxel chemotherapy. 10 patients with metastatic castration-resistant prostate cancer, with a predicted survival of at least 18 months, were enrolled out of a planned 144 patients. Eight of 10 patients were treated and were randomized to receive docetaxel chemotherapy alone (Arm B, n = 2) versus treatment with Prostvac-VF (days 1, 15, 29, 43, 57) followed by docetaxel (Arm A, n = 6) chemotherapy beginning at month 3. The primary endpoint of the trial was overall survival, and secondary endpoints included time to radiographic...
Steps Toward Eight‐Meter Honeycomb Mirror Blanks: I. Rationale and Approach

The best form for 8-m telescope mirrors is discussed. It is concluded that honeycomb sandwich structure can meet the most exacting demand goals for subarcsecond image quality in optical and infrared astronomy. These structures are light, have good stiffness against gravitational and wind loading, and have low thermal inertia. The latter permits them to be operated at the ambient air temperature to avoid local seeing problems. Borosilicate and aluminosilicate glasses are adequate materials for ventilated honeycombs, which do not require low expansion materials.
HBeAg-negative chronic hepatitis B: why do I treat my patients with pegylated interferon-alfa?

HBeAg-negative chronic hepatitis B (CHB) is the most frequent and aggressive type of CHB. The current therapeutic options for CHB include pegylated-interferon-alfa (PEG-IFNα) and nucleos(t)ide analogues (NAs). NAs are well-tolerated and safe agents that effectively inhibit viral replication, but they should be given as long-term, probably lifelong therapy, in particular in HBeAg-negative CHB. Thus, the finite, usually 48-week, duration is the main advantage of PEG-IFNα, providing sustained virological responses (SVR) off-therapy in approximately one-fourth of patients with HBeAg-negative CHB and often leading to HBsAg loss. However, the limited efficacy is the main factor restricting the use of PEG-IFNα in CHB and therefore identifying the predictors of response is of great clinical importance. No reliable baseline predictors of response to PEG-IFNα have been identified to date, but certain studies have identified satisfactory predictors of post-PEG-IFNα response using on-treatment serological markers, mostly HBsAg levels. In particular, in HBeAg-negative CHB patients mostly with genotype D a lack of decline in HBsAg levels and a lack of decrease in HBV DNA levels ≥2 log10 copies/ml at week-12 has a nearly 100% negative predictive value for SVR off-treatment and is now recommended as a stopping rule for early discontinuation of ineffective PEG-IFNα. Prolonging PEG-IFNα therapy to 96 weeks seems to provide higher SVR rates but the application and efficacy of this approach requires further study. The combination of PEG-IFNα with NAs, mostly lamivudine, has not resulted in any therapeutic benefit so far, but newer combined approaches with PEG-IFNα and NA(s) are currently under study.
Running induces widespread structural alterations in the hippocampus and entorhinal cortex

Physical activity enhances hippocampal function but its effects on neuronal structure remain relatively unexplored outside of the dentate gyrus. Using Golgi impregnation and the lipophilic tracer DiI, we show that long-term voluntary running increases the density of dendritic spines in the entorhinal cortex and hippocampus of adult rats. Exercise was associated with increased dendritic spine density not only in granule neurons of the dentate gyrus, but also in CA1 pyramidal neurons, and in layer III pyramidal neurons of the entorhinal cortex. In the CA1 region, changes in dendritic spine density are accompanied by changes in dendritic arborization and alterations in the morphology of individual spines. These findings suggest that physical activity exerts pervasive effects on neuronal morphology in the hippocampus and one of its afferent populations. These structural changes may contribute to running-induced changes in cognitive function.