cssi/SciSciGPT-SciSciNet huggingface dataset:
Newly Characterized Region of CP190 Associates with Microtubules and Mediates Proper Spindle Morphology in Drosophila Stem Cells.

CP190 is a large, multi-domain protein, first identified as a centrosome protein with oscillatory localization over the course of the cell cycle. During interphase it has a well-established role within the nucleus as a chromatin insulator. Upon nuclear envelope breakdown, there is a striking redistribution of CP190 to centrosomes and the mitotic spindle, in addition to the population at chromosomes. Here, we investigate CP190 in detail by performing domain analysis in cultured Drosophila S2 cells combined with protein structure determination by X-ray crystallography, in vitro biochemical characterization, and in vivo fixed and live imaging of cp190 mutant flies. Our analysis of CP190 identifies a novel N-terminal centrosome and microtubule (MT) targeting region, sufficient for spindle localization. This region consists of a highly conserved BTB domain and a linker region that serves as the MT binding domain. We present the 2.5 A resolution structure of the CP190 N-terminal 126 amino acids, which adopts a canonical BTB domain fold and exists as a stable dimer in solution. The ability of the linker region to robustly localize to MTs requires BTB domain-mediated dimerization. Deletion of the linker region using CRISPR significantly alters spindle morphology and leads to DNA segregation errors in the developing Drosophila brain neuroblasts. Collectively, we highlight a multivalent MT-binding architecture in CP190, which confers distinct subcellular cytoskeletal localization and function during mitosis.
Abstract 61: Limited Eligibility for Trials of Endovascular Therapy for Acute Ischemic Stroke in the US: A Population-Based Assessment

BACKGROUND: Definitive evidence of the effectiveness of mechanical embolectomy for acute ischemic strokes (AIS) is lacking. In light of the recently futile Interventional Management of Stroke (IMS)...
Adaptive Partial-Current Discrete Ordinates Radiation Transport with Distribution Iteration: An Alternative to Source Iteration

Our partial-current-transport (PCT) approach uses the partial currents through the faces of cells in a spatial grid as the unknowns in a linear algebra problem. Emission and externally incident currents are the knowns. The coefficient matrix is determined by boundary conditions and transport within cells. Adaptive PCT models include within-cell flux-distribution parameters that are found by distribution iteration (DI). Upon convergence, scalar fluxes are computed. We develop the approach in general and derive (in slab geometry) afixed-coefficient PCT diffusion method and an adaptive PCT discrete ordinates method. A parallelized direct solver is used for the large but very sparse linear algebra problem that couples all the cells. Matrix inversion is used for the dense but small within-cell problems. These direct solvers eliminate scattering source iteration (SI). Though requiring more storage, much or most of the computational effort is pleasingly parallel, making the method attractive for large parallel machines with large memories. In comparing our slab geometry implementation with PARTISN, we observed that DI used as many or fewer iterations than SI and succeeded where SI failed, whether alone or with diffusion synthetic acceleration or transport synthetic acceleration. We conclude that DI for adaptive PCT holds great promise as an alternative to SI and its accelerators.
27-OR: AGGRESSIVE ACUTE ANTIBODY-MEDIATED REJECTION OF NEGATIVE FLOW CROSSMATCH 3rd KIDNEY TRANSPLANT WITH EXCLUSIVE DISPARITY AT HLA-DP

Aim To perform a retrospective analysis of the 3rd kidney transplant rejection with exclusive disparity at HLA-DP. Methods The 1st transplant, nearly completely mismatched, functioned well for 7 years but was rejected due to chronic allograft nephropathy. The 2nd transplant, completely matched except at DRB3 and DPB1, failed after 1 year with acute and chronic rejection. A 3rd kidney was completely matched except at DPA1*02:01 and DPB1*01:01. Although single antigen bead (SAB) analysis showed donor-specific alloantibodies (DSA) directed to DPA1*02:01 (3496-4024 MFI), both B and T flow crossmatches (FXM) were negative. Within 10 days the re-transplant underwent aggressive C4d+ acute antibody-mediated rejection (AMR; Banff 2a). Despite thymoglobulin therapy and 4 cycles of plasmapheresis, kidney failed within 6 months. At 30 days post-transplant, SAB assay revealed that DSA (directed to donor DPA1*02:01 and DPB1*01:01 bead) was IgG (9511 MFI) of IgG1 subclass (8664 MFI) with C1q binding function (22800 MFI). Results Epitope analysis showed that the 1st transplant shared DPA1*02:01 with the 3rd transplant while the 1st transplant DPB1*11:01 shared two epitopes (35YA, 84DEAV) with the 3rd donor DPB1*01:01. DSA response directed to just one epitope (111R) on DPA1*02:01 spread to other epitopes (83A, 51RA, 127P)(Fig. 1). Conclusions (1) DPA1 and DPB1 alleles may induce an aggressive acute AMR resulting in graft failure; (2) DSA directed to donor DPA1 allele may be undetected by FXM; (3) DPA1 and DPB1 alleles should be identified in donors of re-transplanted patients with DPA1/DPB1-directed Abs; and 4) epitope spreading and epitope sharing enhance FXM-undetectable DSA during acute AMR [Fig. 1].
Technology and Wage Differential: A Case Study Using the Indian Manufacturing Sector

In many recent studies, modern computer-oriented technological progress has been cited as one of the main reasons behind the diverging wage differential between workers with and without a college degree. This paper explores the relationship between change in wage differential and technological growth from a developing country's perspective. An individual-level dataset collected and published by the National Sample Survey Organisation (NSSO), Government of India, has been used for the study. Variables indicating Industry-specific technology change (from the Annual Survey of Industries data) are added to this primary dataset. Limitation of data does not allow us to look beyond salaried workers employed in the manufacturing industries. A three-stage sequential selection-correction mechanism, a-la Heckman, is used to take care of this sample selection problem. Moreover, this dataset is plagued with missing information on the earnings variable. A multiple imputation technique is employed to alleviate this problem. In the manufacturing sector, a converging wage differential is observed during the period 1983-1994. My main finding is that the technological change helped to raise the wages of workers at the lowest quartile of the wage distribution, whereas the effect of technological change is insignificant for workers at the topmost quartile of the wage distribution. Moreover I do not find any significant evidence of shift in labor demand towards workers employed in non-production jobs (traditionally, white-collar jobs), caused by technological change.
Resistance in Bermudagrass to the Fall Armyworm

Clones (441) of Bermuda grass, Cynodon dactylon (L.) Pers., were screened for resistance to 1st-instar fall armyworms, Spodoptera frugiperda (J. E. Smith). Among the 11 lines were rated resistant or intennediate in resistance to larval attack. Analysis of plant extracts for 6-methoxybenzoxazolinone and benzoxazolinone content show these compounds not to be indicators of fall armyworm resistance in Bermudagrass.
Numerical simulation of reacting fuel-rich flow field laden with boron particle in the ramjet combustor

Boron particle combustion model and turbulent no-premixed combustion model were established by using King theory and probability density function in order to study the reacting fuel-rich flow field laden with boron particle in the ramjet combustor. Some obtained numerical results were tested by examination. The results show that dump combustor can produce the large eddy of gas; the ring uniform distribution for fuel injectors can improve the efficiency of reaction and mixing between fuel-rich flow and air.
Phase Assemblages in the Melt State in Ag-Sheathed Bi-2212 Tape in 1% and 7.5% O2

Ag-sheathed Bi-2212 (Bi2Sr2CaCu2Ox) tape has been melt processed in 1% and 7.5% O2 remainder N2 atmospheres. In 7.5% O2 the melt from which 2212 forms on cooling contained liquid, (Sr,Ca)CuO2 (1:1), and (Sr,Ca)2Cu3 (2:1), and in 1% O2 it contained these same phases plus a Cu-free phase tentatively identified as Bi2(Sr,Ca)3Ox. The 2:1 phase appears to be advantageous for developing a homogeneous, well-aligned microstructure using melt processing, but the large grain size of 1:1 and the Cu-free phase cause severe problems with developing this desirable microstructure. It is concluded that processing in reduced pO2 (1% and 7.5% O2) is not advantageous for developing a homogeneous, highly-aligned microstructure by melt processing.
Velocity Maps in the Canine Aorta

Velocity distributions (maps) have been recorded at six locations along the aorta in awake and anesthetized beagle dogs using implanted flow cuffs and a pulsed Doppler. The recordings of the velocity maps have been made in 60° intervals around the circumference of the aorta in order to document the influence of individual arterial outflow tracts and curvatures upon the local velocity characteristics.
Plasma and ion beam process-induced damage in semiconductors: review and retrospective

The widespread adoption of plasma and ion beam techniques since the 1980s has led to critical evaluation of the resulting process-induced damage along with developing suitable techniques to passivate or remove the defects. Alternately in some cases the defects are strategically incorporated in device processing to achieve certain ends. Due to the relatively low energies of plasma processes, these defects are mostly confined to the near-surface region of the semiconductor and often have profound influence on the electrical interface with metals as well as insulators. A principal, near-universal phenomenon that is observed under generic ion bombardment in a wide range of commonly used semiconductors - elemental as well as compound - is generation of donor-like defects that reduce surface band bending in n-type material and increase the band bending in p-type. This paper provides a summary overview of the plasma and ion-beam induced defect phenomena, the nature of the defects, their control or removal, the influence of plasma species and thermal history, and their implications in device processing. It also includes a brief historical retrospective on this particular form of defect engineering in the evolution of semiconductor device processing. The focus is mostly on silicon and gallium arsenide, with passing reference to other crystalline semiconductors.
Superficial temporal artery haemorrhage caused by neurophysiological monitoring: a unique MRI finding

A woman aged 66 years with a history of diplopia, headaches and left Cranial Nerve 3 palsy was found to have a 2 cm left paraclinoid internal carotid artery aneurysm. She was started on aspirin and clopidogrel and underwent flow diversion treatment with Pipeline (Covidien Neurovascular, Irvine, California, USA) embolisation of the aneurysm. Intraoperative neurophysiological monitoring via EEG and somatosensory evoked potentials was performed. After the procedure, she was found to have a large right scalp haematoma extending to the right orbit anteriorly and the back of the head posteriorly. Despite manual compression, …
When Is the State? Topology, Temporality, and the Navigation of Everyday State Space in Delhi

This article seeks to insert questions of temporality into the core of geographical analysis of the state. It does so by drawing on extended fieldwork in slums and so-called unauthorized colonies in Delhi, India, to describe how those who live on the margins of the state employ a topological sensibility in accessing, influencing, and “timing” the state. By attending to the temporal rhythms of these residents' everyday efforts to secure water, electricity, and building permission, the article proposes two topological figures that move beyond narrower spatial metaphors that read that state either as a fixed, hierarchically scaled entity or as a flat, wholly malleable assemblage without consequential spatial order or historicity. These are the topological state and the state outside itself. The analysis of the topological state centers on how real-time connections are forged between residents and key nodes in the bureaucracy, producing momentary reconfigurations of state form that allow low-level state actor...
Comparison of continuous and discontinuous finite element methods for parabolic differential equations employing implicit time integration

ABSTRACTThis article compares the computational cost, stability, and accuracy of continuous and discontinuous Galerkin Finite Element Methods (GFEM) for various parabolic differential equations including the advection–diffusion equation, viscous Burgers’ equation, and Turing pattern formation equation system. The results show that, for implicit time integration, the continuous GFEM is typically 5–20 times less computationally expensive than the discontinuous GFEM using the same finite element mesh and element order. However, the discontinuous GFEM is significantly more stable than the continuous GFEM for advection dominated problems and is able to obtain accurate approximate solutions for cases where the classic, un-stabilized continuous GFEM fails.
Course of Action Analysis within an Effects-Based Operational Context

This article summarizes information related to the automated course of action (COA) development effort. The information contained in this document puts the COA effort into an operational perspective that addresses command and control theory, as well as touching on the military planning concept known as effects-based operations. The sections relating to the COA effort detail the rationale behind the functional models developed and identify technologies that could support the process functions. The functional models include a section related to adversarial modeling, which adds a dynamic to the COA process that is missing in current combat simulations. The information contained in this article lays the foundation for building a unique analytic capability.
Catastrophic Consequences: The Link Between Rural Opioid Use and HIV/AIDS

This chapter compares the rural–urban prevalence of HIV and opioid use, treatment, and harm reduction, and highlights efforts to control HIV and opioid use in rural states and communities. Rural persons who use opioids appear to have lower perceived risks of contracting HIV and lower perceived consequences associated with heroin use. Close social networks in rural communities and high-risk sex and injection drug use practices may facilitate exposure and transmission of HIV. Rural persons who use opioids may experience numerous potential barriers to HIV and substance abuse treatment and harm reduction activities. Given the challenges of studying a small population of opioid users and dealing with confidential information like HIV status and drug use, studies comparing rural and urban persons within the same state or nationwide will be important going forward.
The role of stem cell factor (c-kit ligand) and inflammatory cytokines in pulmonary mast cell activation

Mast cells play a critical role in allergic airway responses via IgE- specific activation and release of potent inflammatory mediators. In the present study, we have isolated and characterized primary mast cell lines derived from the upper airways of normal mice. The primary mast cell lines were grown and maintained by incubation with interleukin-3 (IL-3) and stem cell factor (SCF) and shown to be c-kit (SCF receptor) positive by flow cytometry. Subsequently, we examined the proliferation of both airway and bone marrow derived mast cell lines in response to inflammatory and hematopoietic cytokines, including SCF, IL-1, IL-3, interferon-gamma, IL-4, and IL-10. The results from the pulmonary mast cell lines were compared with those from bone marrow derived mast cells. Pulmonary mast cell lines were capable of proliferating in response to IL-3, IL-4, IL-10, and SCF, whereas the combination of SCF with the other cytokines did not increase the response over SCF alone. In contrast, the bone marrow-derived mast cells proliferated strongest to SCF or IL-3, but only modestly to IL-4 and IL-10. Furthermore, the combination of SCF with IL-3, but not the other cytokines, exhibited an increase in bone marrow-derived mast cell proliferation. Cytokine- specific stimulation of histamine release in the airway-derived and bone marrow-derived mast cells showed parallel results. SCF was the only cytokine shown to induce substantial histamine release. However, when certain nonhistamine releasing cytokines were combined with SCF, a synergistic increase in histamine release was induced in upper airway, but not bone marrow-derived mast cells. The results of these studies suggest that cytokines differentially modulate induction of proliferation and degranulation of bone marrow and upper airway-derived mast cells and may further indicate a cytokine activational cascade in tissue mast cells.
Minimal Important Difference in Voice Handicap Index-10.

Importance The minimal important difference (MID) on patient-reported outcome measures can indicate how much of a change on that scale is meaningful. Objective To use an anchor-based approach to estimate MID in the Voice Handicap Index–10 (VHI-10) total score. Design, Setting, and Participants In this cohort study, a volunteer sample of adult patients visiting the voice clinic at the University of Minnesota from April 7, 2013, through July 3, 2016, completed the VHI-10 (range, 0-40, with higher scores indicating greater voice-related handicap) at baseline and 2 weeks later in conjunction with a global rating of change. An anchor-based approach was used to identify an MID. The association between the global change score and change in VHI-10 score was analyzed using Pearson rank correlation. A distribution-based method was used to corroborate the findings. Main Outcome and Measures Global rating of change on the VHI-10. Results Of the 273 participants, 183 (67.0%) were women and 90 (33.0%) were men (mean [SD] age, 54.3 [15.6] years); 259 (94.9%) were white. Participants had a variety of voice disorders, most commonly muscle tension dysphonia, irritable larynx, benign vocal fold lesions, and motion abnormalities. Among patients reporting no change on the global change score, the mean (SD) change in VHI-10 score was 1 (5). Among those reporting a small change, the mean (SD) change in VHI-10 was also 1 (5). Among those reporting a moderate change in voice symptoms, the mean (SD) change in VHI-10 score was 6 (8). Among those with a large change, the mean (SD) change in VHI-10 score was 9 (13). The correlation between the global change score and the change in VHI-10 score was 0.32 (95% CI, 0.12-0.49). Distribution-based analyses identified effect sizes comparable to those of the anchor-based categories. Conclusions and Relevance These findings suggest that a difference of 6 on the VHI-10 may represent an MID. This difference was associated with a moderate change on the global rating scale, and the small-change and no-change categories were indistinguishable. Given the lack of differentiation between small and no change and the modest correlation between the global change score and change in the VHI-10 score, additional studies are needed.
Multivariate normal maximum likelihood with both ordinal and continuous variables, and data missing at random

A novel method for the maximum likelihood estimation of structural equation models (SEM) with both ordinal and continuous indicators is introduced using a flexible multivariate probit model for the ordinal indicators. A full information approach ensures unbiased estimates for data missing at random. Exceeding the capability of prior methods, up to 13 ordinal variables can be included before integration time increases beyond 1 s per row. The method relies on the axiom of conditional probability to split apart the distribution of continuous and ordinal variables. Due to the symmetry of the axiom, two similar methods are available. A simulation study provides evidence that the two similar approaches offer equal accuracy. A further simulation is used to develop a heuristic to automatically select the most computationally efficient approach. Joint ordinal continuous SEM is implemented in OpenMx, free and open-source software.
State space representation of the open-loop dynamics of the space shuttle main engine

A parameter and structure estimation technique for multivariable systems is used to obtain state space representation of open loop dynamics of the Space Shuttle Main Engine (SSME). The parameterization being used is both minimal and unique. The simplified linear models may be used for fault detection studies and control system design and development.
Mental health apps in a college setting: openness, usage, and attitudes.

Background: The ubiquity of smartphones and the development of mental health apps (MHAs) calls for evaluation of consumers’ attitudes towards and usage of MHAs. Due to the increasing demand for mental health services on college campuses, research is especially needed to evaluate MHAs as a potentially viable treatment modality in that setting. Methods: The study team developed survey questions related to MHAs, added these to the Healthy Minds Study, and used Qualtrics as the platform. The participants were 741 students, age 18 and older, from a large Midwest public university. Students could answer a varying number of multiple choice questions based on embedded display logic, and the survey required 20–25 minutes for most participants to complete. Based on embedded display logic in the survey and how questions were answered, students could receive anywhere from 1–20 questions. Questions were primarily categorical (e.g., “Yes”, “Maybe”, “No”), with the remaining questions in free response format. The survey was fielded in April, 2016. Results: 26.1% of respondents were open to using an MHA yet only 7.3% had used an MHA. 9.0% of respondents preferred to use an MHA versus seeing a mental health professional. 13.2% of respondents felt that MHAs do have an evidence base. 23.8% of users felt that MHAs helped with their mental health. Those who reported receiving mental health services within the past 12 months were significantly more open to using MHAs than those who had not received services. Convenience, immediate availability, and confidentiality were common reasons for interest in MHAs. Conclusions: There is interest in, but limited usage, of MHAs among university students, providing evidence of MHAs as a potentially untapped treatment modality for this population. Further research could help assess how best to integrate this technology into the university and college mental health system.
DISPOSITION OF HEXACHLOROBENZENE IN DOMESTIC ANIMALS

ABSTRACT Hexachlorobenzene (HCB) is readily accumulated from dietary sources into all body tissues. Highly perfused tissues initially accept the greater proportion of the administered dose, but redistribution eventually results in residues proportional to the fat content of the tissue. Excretion is primarily by the fecal route, but biliary, intestinal and urinary excretion are also involved and species differences are apparent. In order to accurately define the various phases of the disposition of HCB in animals, sampling must be continued until post-distributive equilibrium is attained. Examination of the model suggests manipulations by which the body burden of HCB may be reduced.
Theory, Praxis, and American Politics in the Age of Post-truths

This chapter provides readers with an overview of some of the theory and praxis that is involved with the study of one of President Donald Trump’s most famous tweets, the one that involved the alleged “fable” of General John J. Pershing’s shooting of 49 Moro with bullets dipped in pig blood. What began as a simple “fact-checking” issue quickly morphed into debates about Trump’s rhetorical habits, the “post-truth” ideas of his followers, General Pershing’s deterrence strategies during the American-Moro “rebellion,” and today’s use of counterinsurgency techniques. This chapter also explains to readers why public and scholarly interest in “post-truth” studies surfaced in 2016, and how Trump may have stumbled across “tough” guy histories of these conflicts.
The human cytomegalovirus lytic cycle is induced by 1,25-dihydroxyvitamin D3 in peripheral blood monocytes and in the THP-1 monocytic cell line

Human cytomegalovirus (HCMV) resides in a latent form in hematopoietic progenitors and undifferentiated cells within the myeloid lineage. Maturation and differentiation along the myeloid lineage triggers lytic replication. Here, we used peripheral blood monocytes and the monocytic cell line THP-1 to investigate the effects of 1,25-dihydroxyvitamin D3 on HCMV replication. Interestingly, 1,25-dihydroxyvitamin D3 induces lytic replication marked by upregulation of HCMV gene expression and production of infectious virus. Moreover, we demonstrate that the effects of 1,25-dihydroxyvitamin D3 correlate with maturation/differentiation of the monocytes and not by directly stimulating the MIEP. These results are somewhat surprising as 1,25-dihydroxyvitamin D3 typically boosts immunity to bacteria and viruses rather than driving the infectious life cycle as it does for HCMV. Defining the signaling pathways kindled by 1,25-dihydroxyvitamin D3 will lead to a better understanding of the underlying molecular mechanisms that determine the fate of HCMV once it infects cells in the myeloid lineage.
Primary Care Practices' Ability to Report Electronic Clinical Quality Measures in the EvidenceNOW Southwest Initiative to Improve Heart Health.

Importance The capability and capacity of primary care practices to report electronic clinical quality measures (eCQMs) are questionable. Objective To determine how quickly primary care practices can report eCQMs and the practice characteristics associated with faster reporting. Design, Setting, and Participants This quality improvement study examined an initiative (EvidenceNOW Southwest) to enhance primary care practices’ ability to adopt evidence-based cardiovascular care approaches: aspirin prescribing, blood pressure control, cholesterol management, and smoking cessation (ABCS). A total of 211 primary care practices in Colorado and New Mexico participating in EvidenceNOW Southwest between February 2015 and December 2017 were included. Interventions Practices were instructed on eCQM specifications that could be produced by an electronic health record, a registry, or a third-party platform. Practices received 9 months of support from a practice facilitator, a clinical health information technology advisor, and the research team. Practices were instructed to report their baseline ABCS eCQMs as soon as possible. Main Outcomes and Measures The main outcome was time to report the ABCS eCQMs. Cox proportional hazards models were used to examine practice characteristics associated with time to reporting. Results Practices were predominantly clinician owned (48%) and in urban or suburban areas (71%). Practices required a median (interquartile range) of 8.2 (4.6-11.9) months to report any ABCS eCQM. Time to report differed by eCQM: practices reported blood pressure management the fastest (median [interquartile range], 7.8 [3.5-10.4] months) and cholesterol management the slowest (median [interquartile range], 10.5 [6.6 to >12] months) (log-rankP Conclusions and Relevance In this study, time to report eCQMs varied by measure and practice type, with very few practices reporting quickly. Practices took longer to report a new cholesterol measure than other measures. Programs that require eCQM reporting should consider the time and effort practices must exert to produce reports. Practices may benefit from additional support to succeed in new programs that require eCQM reporting.
Like Skillful Looms: Marvell, Cromwell, and the Politics of Weeping

Recent work has illuminated the spiritual, eschatological, and gender dynamics of Marvell’s poetry of tears, but the politics of Marvellian weeping have yet to be tackled. Contextualizing the Cromwell encomia (‘The First Anniversary of the Government under His Highness the Lord Protector’ and ‘A Poem upon the Death of his Late Highness the Lord Protector’) amidst the man’s proclivity for weeping, this essay argues that Marvell poetically employs tears not just to embrace the vulnerability of the Lord Protector at the center of England’s new political settlement; he also attempts to bind moderate yet impassioned allies around a bourgeois Protestantism. The essay begins with a reading of ‘Eyes and Tears’ to establish the religious, economic, and ornamental dimensions of Marvellian weeping. ‘The First Anniversary’ echoes the aspect of luxurious display central to Marvell’s bourgeois Protestantism in ‘Eyes and Tears’, but it adds an emphasis on domestic productivity to suggest that private weeping can be publically beneficial. In this way, Marvell can speak to Cromwell as a well-known practitioner of weeping while also speaking to, and as, an audience of bourgeois Protestants, for whom religious devotion and economic productivity are mutually reinforcing endeavors. The essay concludes with a theoretical reflection on Marvellian weeping as affective politics, in which the externalization of internal emotion attempts to forge community. Ultimately, the affective politics of Marvellian weeping consists in publicizing private piety without forfeiting the sanctity of private life altogether.
The AKT isoforms 1 and 2 drive B cell fate decisions during the germinal center response.

The PI3K pathway is integral for the germinal center (GC) response. However, the contribution of protein kinase B (AKT) as a PI3K effector in GC B cells remains unknown. Here, we show that mice lacking the AKT1 and AKT2 isoforms in B cells failed to form GCs, which undermined affinity maturation and antibody production in response to immunization. Upon B-cell receptor stimulation, AKT1/2–deficient B cells showed poor survival, reduced proliferation, and impaired mitochondrial and metabolic fitness, which collectively halted GC development. By comparison, Foxo1T24A mutant, which cannot be inactivated by AKT1/2 phosphorylation and is sequestered in the nucleus, significantly enhanced antibody class switch recombination via induction of activation-induced cytidine deaminase (AID) expression. By contrast, repression of FOXO1 activity by AKT1/2 promoted IRF4-driven plasma cell differentiation. Last, we show that T-cell help via CD40, but not enforced expression of Bcl2, rescued the defective GC response in AKT1/2–deficient animals by restoring proliferative expansion and energy production. Overall, our study provides mechanistic insights into the key role of AKT and downstream pathways on B cell fate decisions during the GC response.
Chapter 14 – The Second-Best Theory of Taxation with General Production Technologies and Many Consumers

Chapter 14 extends the analysis of distorting taxes in two directions to make it more responsive to real-world economies. The first is to incorporate general production technologies, with increasing cost production-possibilities frontiers. An important result is that the optimal commodity tax rule is unchanged; it does not include production terms. A second extension is to consider the case of many consumers with different tastes and different marginal social welfare weights. The social welfare maximizing pattern of tax rates is derived under both linear and general technologies. Other topics include the effects on social welfare of any given change in taxes and an analysis of whether U.S. commodity taxes are close to optimal.
Benton-Cohen, Katherine: "Inventing the Immigration Problem: The Dillingham Commission and Its Legacy". Cambridge, Harvard University Press, 2018. 352 pp

Benton-Cohen, Katherine: "Inventing the Immigration Problem: The Dillingham Commission and Its Legacy". Cambridge, Harvard University Press, 2018. 352 pp
Pathology of Brain Metastases

In this chapter, we consider the diagnostic approach to brain metastases in a routine clinical setting. Here we review standard assessment of tissue from intraoperative frozen section analysis to conventional histological and immunohistochemical assays. Clinicopathological differential diagnoses particular to the central nervous system (CNS) axis are discussed as well as commonly used panels of antibodies. Finally, we consider the molecular testing that is currently employed at our own institution, and remark on how the trajectory of molecular pathology is likely to impact the evaluation of brain metastases in the near future.
Development of a physiologically-based pharmacokinetic model for ocular disposition of monoclonal antibodies in rabbits

Development of protein therapeutics for ocular disorders, particularly age-related macular degeneration (AMD), is a highly competitive and expanding therapeutic area. However, the application of a predictive and translatable ocular PK model to better understand ocular disposition of protein therapeutics, such as a physiologically-based pharmacokinetic (PBPK) model, is missing from the literature. Here, we present an expansion of an antibody platform PBPK model towards rabbit and incorporate a novel anatomical and physiologically relevant ocular component. Parameters describing all tissues, flows, and binding events were obtained from existing literature and fixed a priori. First, translation of the platform PBPK model to rabbit was confirmed by evaluating the model's ability to predict plasma PK of a systemically administered exogenous antibody. Then, the PBPK model with the new ocular component was validated by estimation of serum and ocular (i.e. aqueous humor, retina, and vitreous humor) PK of two intravitreally administered monoclonal antibodies. We show that the proposed PBPK model is capable of accurately (i.e. within twofold) predicting ocular exposure of antibody-based drugs. The proposed PBPK model can be used for preclinical-to-clinical translation of antibodies developed for ocular disorders, and assessment of ocular toxicity for systemically administered antibody-based therapeutics.
The Pocket Guide to the DSM-5 Diagnostic Exam

PrefaceSECTION I:Chapter 1. Introduction to the Diagnostic InterviewChapter 2. Alliance Building During a Diagnostic InterviewChapter 3. The 30-Minute Diagnostic InterviewChapter 4. Adventures in DimensionsChapter 5. Key Changes in DSM-5SECTION II:Chapter 6. The DSM-5 Diagnostic InterviewSECTION III:Chapter 7. A Brief Version of DSM-5Chapter 8. A Stepwise Approach to Differential DiagnosisChapter 9. The Mental Status Examination: A Psychiatric GlossaryChapter 10. The American Board of Psychiatry and Neurology Clinical Skills EvaluationChapter 11. Selected DSM-5 Assessment MeasuresChapter 12. Dimensional Diagnosis of Personality DisordersChapter 13. Alternative Diagnostic Systems and Rating ScalesReferencesIndex
Informal Hierarchy Strength Changes and Their Effect on Performance

Despite qualitative evidence suggesting that changes in informal hierarchy strength likely impact performance, informal hierarchy strength changes have received little theoretical or empirical atte...
Omega-3 and omega-6 fatty acids have distinct effects on endothelial fatty acid content and nitric oxide bioavailability.

Treatment with high dose icosapent ethyl (IPE), an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA), significantly reduced ischemic events in patients with either cardiovascular disease (CV) or diabetes plus other risk factors (REDUCE-IT) but the mechanism is not well understood. We compared the effects of EPA, docosahexaenoic acid (DHA), and the omega-6 fatty acid arachidonic acid (AA) on bioavailability of nitric oxide (NO) and fatty acid composition. Human umbilical vein endothelial cells (HUVECs) were pretreated with EPA, DHA, or AA (10 µM). Cells were stimulated with calcium ionophore and NO and peroxynitrite (ONOO-) were measured using porphyrinic nanosensors. Levels of EPA, DHA, AA and other fatty acids were measured by gas chromatography (GC). EPA treatment caused the greatest NO release (18%, p < 0.001) and reduction in ONOO- (13%, p < 0.05) compared to control; the [NO]/[ ONOO-] ratio increased by 35% (p < 0.001). DHA treatment increased NO levels by 12% (p < 0.01) but had no effect on ONOO- release. AA did not affect either NO or ONOO- release. Fatty acid treatments increased their respective levels in endothelial cells. EPA levels increased 10-fold to 4.59 mg/g protein (p < 0.001) with EPA treatment and the EPA/AA ratio increased by 10-fold (p < 0.001) compared to vehicle. Only EPA increased docosapentaenoic acid (DPA, omega-3) levels by 2-fold (p < 0.001). AA alone decreased the EPA/AA ratio 4-fold (p<0.001). These findings support a preferential benefit of EPA on endothelial function and omega-3 fatty acid content.
Drug Resistant Epilepsy and the hypothesis of intrinsic severity: What about the High-Frequency Oscillations?

Drug-resistant epilepsy (DRE) affects approximately one-third of the patients with epilepsy. Based on experimental findings from animal models and brain tissue from patients with DRE, different hypotheses have been proposed to explain the cause(s) of drug resistance. One is the intrinsic severity hypothesis that posits that drug resistance is an inherent property of epilepsy related to disease severity. Seizure frequency is one measure of epilepsy severity, but frequency alone is an incomplete measure of severity and doesn't fully explain basic research and clinical studies on drug resistance; thus, other measures of epilepsy severity are needed. One such measure could be pathological high-frequency oscillations (HFOs), which are believed to reflect the neuronal disturbances responsible for the development of epilepsy and the generation of spontaneous seizures. In this manuscript, we will briefly review the intrinsic severity hypothesis, describe basic and clinical research on HFOs in the epileptic brain, and based on this evidence discuss whether HFOs could be a clinical measure of epilepsy severity. Understanding the mechanisms of DRE is critical for producing breakthroughs in the development and testing of novel strategies for treatment.
Radiocarbon Dating of the Western Initial Middle Missouri Variant: Some New Dates and a Critical Review of Old Dates

Recently obtained radiocarbon dates for the Plains Village tradition, Initial Middle Missouri variant components at the Antelope Dreamer (39LM146) and the Stony Point (39ST235) village sites indica...
Fast Decompilation of Compiled Prolog Clauses

Serious Prolog implementations in recent years have been primarily compiler-based, nearly all of which are founded on the abstract instruction set of Warren [1983]. The performance achieved by such implementations greatly outstrips that attainable in interpreter-based systems. Unfortunately, the sophistication of these compiler-based environments is often inferior to environments of interpreter-based systems to the extent that a “compatible” interpreter is often required for serious software development. Among the deficiencies of these environments, database operations such as assert, retract, and clause seem to be particularly afflicted. In addition, the ability to debug compiled code has been either non-existent or at best, very constrained.
What Should the Courts Do About Memories of Sexual Abuse? Toward a Balanced Approach

One of the most heated and troubling debates to enter the courts in recent years involves the reliability of delayed memories of sexual abuse. A topic once limited to discussion among psychologists and research scientists now occupies headlines and, on occasion, court dockets. Can people forget and then remember events from earlier in their lives - and, in particular, traumatic events such as sexual abuse? Are memories always accurate, or can they sometimes be mistaken?To the uninitiated, there might seem to be a relatively simple and obvious answer to these questions - that memories of all kinds of events, whether from yesterday or from many years ago, can be accurate or inaccurate (or, often, some combination of both). Indeed, existing research seems to support this common sense response. The courts have for many years grappled with the general issue of how to assess the reliability of memory in testimony; it is an issue that crops up literally every time someone testifies about any event that occurred prior to the moment of testifying. The legal response in general has been a measured one, avoiding the pitfalls of extremism on either side (all memories are accurate, or all memories are unreliable). As in so many other areas, judges and juries have taken the more difficult, fact-specific path of sorting out the likelihood of accuracy in each individual case, weighing all that is known about the particular situation before them in determining what to believe. And yet, in the area of remembered childhood sexual abuse, both the courts and the media seem to be in danger of swinging between extremes - first accepting perhaps too credulously claims of remembered sexual abuse, but more recently showing signs of barring any such claim without reasoned consideration.
Session 6 keynote address

The designer's ability to create new compact memory storage cells and dense layouts had served as a goal of the industry until recently, when new challenges began to appear. Today, the focus is on narrower market segments, where the profit margins can be significant, without requiring the lowest manufacturing costs. Up graded circuits in this new design era include those used in telecommunications, analog/digital interfaces and other application specific functions. Designer skills needed today are dramatically different today and will continue to change with changing technologies. The value of the chip is now in the implemented algorithms and architectures, and on the time to market. The answer to this need has been to use such techniques, as gate arrays and standard cell designs: two approaches that almost eliminate IC designers from the design process. The traditional designer's contribution must evolve into one that is primarily centered on determining new applications for ICs and new architectures that will make these applications possible. In circuits of 10's of thousands of transistors or larger, it is no longer rational to perform significant optimization at the transistor level, because architectural decisions can have considerably more impact. We have seen this in performance achieved by RISC microprocessors, and by recently developed image processing circuits performing hundreds of millions of operations/sec. The problem of enormous design complexity has frequently been attacked by the inefficient application of more manpower, rather than by use of efficient software tools. These tools should not replace the designer, rather they should relieve him of documentation and other mundane tasks. He can contribute and introduce innovations at the applications and architectural levels. However, the designer must be comfortable with software development, because only he will know what tools are required for unburdening him of the details, while leaving him in control of the design process. Enter - a new methodology- the reorganization of the traditional centralized CAD group and separate design groups into a more homogeneous mix of designers and tool developers. Relieving the designer of low-level tasks, permitting him to focus on identifying new applications, will require a greater systems level of orientation and the increasing use of diversified talent. The IC designer will become more of a facilitator between those who have applications and those who provide the circuit implementation. Also, the integration of analog circuit functions is becoming increasingly critical for many applications such as telecommunications. The design style used is now in the process of undergoing a major upheaval. The traditional techniques based on precision components are being replaced by techniques that are more compatible with the integration of systems on a chip. In summary, IC design of the future must be carefully reassessed.
Sympathy for the devil: Reconsidering Ernst Mach's empiricism

Aristotle claimed that the sign of an educated mind was the ability to entertain a thought without accepting it. Yet, as we all know, sometimes we encounter a position so foreign to our own ways of thinking that even entertaining it is impossible. John Blackmore, over his long career of writing about the life, work and influence of Ernst Mach, has never been able to see anything of value in Mach’s philosophical writings, and what is more, his historical coverage of Mach’s career is often punctuated with tirades against what Blackmore calls Mach’s ‘‘phenomenalism,’’ the belief in the reality of human sense experience and literally nothing else. Blackmore reiterates that view in Ernst Mach’s Philosophy Pro and Con, his first book devoted exclusively to Mach’s philosophy, along with a recent offering about Ernst Mach’s Prague. In previous work, Blackmore has identified as an historian and claimed to avoid taking sides in philosophical disputes, but this has never been entirely true. It seems he cannot resist promulgating an erroneous, though widely shared, reading of Mach’s philosophy that has damaged Mach’s reputation for more than one hundred years, and one that I have tried to set straight in my (2003) and will again in this essay. Before getting to that, I will say that Blackmore’s work purely as an historian has been exemplary and does certainly demonstrate his ability to serve as a neutral judge. He has done a great deal to get all of the evidence out there and even publishes documents by Mach himself and writings by others, which do not square with Blackmore’s reading of Mach’s philosophy. Since his 1972 biography of Mach, Blackmore published a selection from Mach’s Correspondence in 1985 (with Klaus Hentschel), an excellent collection of essays called Ernst Mach—A Deeper Look in 1992, and Ernst Mach’s Vienna in 2001. A fifth volume, called Ernst
Augmented lipopolysaccharide-induced TNF-α production by peritoneal macrophages in type 2 diabetic mice is dependent on elevated glucose and requires p38 MAPK

Dysregulated inflammation is a complication of type 2 diabetes (T2D). In this study, we show that augmented LPS-induced TNF-alpha production by resident peritoneal macrophages (PerMphi) in type 2 diabetic (db/db) mice is dependent on elevated glucose and requires p38 MAPK. Intraperitoneal LPS administered to db/db and nondiabetic (db/+) mice induced 3- and 4-fold more TNF-alpha in the peritoneum and serum, respectively, of db/db mice as compared with db/+ mice. Examination of the TLR-4/MD2 complex and CD14 expression showed no difference between db/db and db/+ PerMphi. Ex vivo stimulation of PerMphi with LPS produced a similar 3-fold increase in TNF-alpha production in db/db PerMphi when compared with db/+ PerMphi. PerMphi isolated from db/+ mice incubated in high glucose (4 g/L) medium for 12 h produced nearly 2-fold more TNF-alpha in response to LPS than PerMphi incubated in normal glucose medium (1 g/L). LPS-dependent stimulation of PI3K activity, ERK1/2 activation, and p38 kinase activity was greater in PerMphi from db/db mice as compared with db/+ mice. Only inhibition of p38 kinase blocked LPS-induced TNF-alpha production in PerMphi from db/db mice. Taken together, these data indicate that augmented TNF-alpha production induced by LPS in macrophages during diabetes is due to hyperglycemia and increased LPS-dependent activation of p38 kinase.