Striking Distinction Research Articles

The Gate of Ki Ranggo Wirosentiko's Grave: Traces of Non-Islamic Cultural Acculturation in the Material Culture Heritage of the Palembang Sultanate

Palembang is known as one of the centers of the Palembang Sultanate. One of the most important cultural relics in Palembang is the Palembang Sultan Cemetery complex. Each of these cemetery complexes has a different architectural shape of the tomb, one of which is the tomb complex of Ki Ranggo Wirosntiko. A Striking distinction in this tomb is the shape of the tomb gate complex building that depicts influences in non-Islam culture. This article will explain the differences in shape in the building of the gate and the influence of non-Islamic culture on the shape of the tomb gate of Ki Ranggo Wirosentiko. The method used is the archeological method using a stylistic analysis of the observation of the ornaments found in the gates of this complex. The results of this study show that the building of the tomb gate of Ki Ranggo Wirosentiko shows acculturation with non-Islamic culture. The profile of the outer gate depicting Hindu influence is marked by the similarity with the stylistic elements in the Bentar temple and Paduraksa Temple, East Java. The resemblance is also visible on the profile of the foot and the mould of the gate resembling the profile found in the Paduraksa Temple. On the profile of the third gate, there is an inscription of the year 1142 H or 1730 M using Arabic letters. The local influence appears on the third gate's appearance, indicating the presence of mustak. Based on the profile of the building of the tomb gate Ki Ranggo Wirosentiko shows the influence of Hindu, Buddhist, Arab, and local cultures on the decorative range of the construction of the grave of the temple.

Testing the Limits of Endogenous Thymic Regeneration after HCT Conditioning

T cell reconstitution following allogeneic hematopoietic cell transplantation (allo-HCT), recently emerging as a major predictor of clinical outcomes, is critically dependent upon thymic function. Previous clinical studies have implicated a link between thymic function pre-transplant to patient outcomes post-bone marrow transplantation. Thymic function is primarily driven by two functionally distinct groups of thymic epithelial cells (TECs) located in the cortex (cTECs) and the medulla (mTECs). These two stromal compartments contribute to the various stages of T cell development, culminating in the generation of a broad repertoire of self-tolerant T cells leaving the thymus and emigrating into the periphery. However, despite the thymus' crucial role in generating a broad array of T cells, the organ is highly sensitive to damage. Condition regiments required for successful HCT, such as ionizing radiation, have a profound damaging effect on the thymus. Although the thymus is sensitive to damaging agents, it also has a remarkable self-repair capacity through mechanisms that are still incompletely understood; and the organ's regenerative capacity also declines with age. Moreover, the specific thymic epithelial subpopulation that contributes to thymus regeneration remains undefined. Therefore, understanding endogenous cellular mechanisms of thymus regeneration, and limitations to its repair, will be crucial for creating therapies to boost thymic function. Although thymic function was restored to pre-conditioning levels after one round of total body irradiation (TBI), and multiple rounds of corticosteroid (Dexamethasone) damage saw no decline in its restorative ability, thymic regeneration was severely reduced upon subsequent rounds of ionizing radiation damage (Fig. 1A). A phenomenon that one may expect to see in the small subset of patients that need to undergo a second HCT. Using single cell RNA sequencing of highly purified TECs at multiple consecutive days after TBI, we identified that shortly after damage the TEC compartment contracts into distinct TEC subpopulations, including a previously reported CD104 expressing mTEC1 subpopulation implicated to provide pre-cursor support to the thymic medulla (Borstein 2018 Nature). To further understand the fundamental differences in regeneration from these different damage modalities, we compared the regeneration of thymic epithelial cells after either dexamethasone (Dex) or TBI damage. Consistent with its progenitor role, we found a significant decrease in the mTEC1 subpopulation in mice damaged with TBI compared to those damaged with Dex. The striking distinction in the mTEC1 compartments between the damage models can potentially explain a key functional difference in how these two damage modalities differ in their regenerative kinetics (Fig 1B). Overall, the results of these studies implicate a potential contribution of a specific mTEC subset (mTEC1s) to modulating thymic regeneration kinetics, and that the thymus cannot withstand multiple rounds of irradiation. The identification of mTEC1s as crucial mediators of thymic regeneration can inform future work in designing thymic boosting therapies that induce this stromal population to accelerate thymus regeneration after HCT.

Myo-Inositol and D-Chiro-Inositol as Modulators of Ovary Steroidogenesis: A Narrative Review.

Myo-inositol is a natural polyol, the most abundant among the nine possible structural isomers available in living organisms. Inositol confers some distinctive traits that allow for a striking distinction between prokaryotes and eukaryotes, the basic clusters into which organisms are partitioned. Inositol cooperates in numerous biological functions where the polyol participates or by furnishing the fundamental backbone of several related derived metabolites, mostly obtained through the sequential addition of phosphate groups (inositol phosphates, phosphoinositides, and pyrophosphates). Overall myo-inositol and its phosphate metabolites display an entangled network, which is involved in the core of the biochemical processes governing critical transitions inside cells. Noticeably, experimental data have shown that myo-inositol and its most relevant epimer D-chiro-inositol are both necessary to permit a faithful transduction of insulin and of other molecular factors. This improves the complete breakdown of glucose through the citric acid cycle, especially in glucose-greedy tissues, such as the ovary. In particular, while D-chiro-inositol promotes androgen synthesis in the theca layer and down-regulates aromatase and estrogen expression in granulosa cells, myo-inositol strengthens aromatase and FSH receptor expression. Inositol effects on glucose metabolism and steroid hormone synthesis represent an intriguing area of investigation, as recent results have demonstrated that inositol-related metabolites dramatically modulate the expression of several genes. Conversely, treatments including myo-inositol and its isomers have proven to be effective in the management and symptomatic relief of a number of diseases associated with the endocrine function of the ovary, namely polycystic ovarian syndrome.

Bloom syndrome: an oral potentially malignant disorders aiding in malignancy vigour.

Bloom syndrome: an oral potentially malignant disorders aiding in malignancy vigour.

Targeting CNS Lymphoma with Intravenous Axicabtagene Ciloleucel: Evidence for Transcriptional Evolution Towards a Prominent Interferon Signature in CAR-T Cells Trafficking to the Tumor Site

Background: Chemorefractory primary and secondary central nervous system lymphomas (CNSL) have a dismal prognosis, and represent a major unmet need in oncology. To address this, we conducted a pilot trial of axi-cel in patients with relapsed/refractory CNSL. All patients had Ommaya reservoirs, such that after CAR-T infusion, paired CSF and blood could be collected and analyzed daily, allowing the interrogation of single-cell CAR-T transcriptional profiles at an unprecedented level of detail. This analysis enabled us to address key mechanistic questions relevant to CAR-T therapy for CNS lymphoma, including determining the impact of tumor site (brain vs lymphoid tissue) on CAR-T efficacy and toxicity, and discovering the drivers of CAR-T cell transcriptional evolution as these cells move between their sites of action. Methods: Adult patients with either primary or secondary relapsed/refractory CNSL were enrolled on the 'Axi-cel In CNS Lymphoma' Trial (Clinicaltrials.gov# NCT04608487). Patients received fludarabine/cyclophosphamide lymphodepletion followed by axi-cel infusion. Blood and CSF were sampled daily between D0-14 after infusion, with data from CAR-T maximum expansion (Days 5-9) reported here. 5' 10x Single-cell RNA-Seq (scRNA-Seq) and TCR-Seq were performed on peripheral blood mononuclear cells (PBMC), enriched T cells, and CSF-derived cells. scRNA-Seq data was analyzed with the Python packages 'scanpy' and 'scVI' to identify and characterize high-quality CD4+ and CD8+ T cells, and to conduct differential expression tests. Gene set enrichment analysis (GSEA) was used to compare CSF and blood CD4+ and CD8+ CAR-T cells using the 'clusterProfiler' package in R. Results: Detailed clinical results from this trial are reported in an accompanying abstract. In brief, data from the first 7 patients on-study demonstrated no treatment-limiting toxicities and an ORR of 86%, with 6 of 6 responding patients achieving a CR by 3 months. 2 of the responding patients have progressed, 1 at 6 months and 1 at 15 months. To interrogate the mechanisms driving axi-cel efficacy in inducing CNS responses, we analyzed 129,088 CAR+ and non-CAR T cells from the peripheral blood (64,337 cells), the CSF (37,070 cells), and the axi-cel product (27,681 cells) from 5 enrolled patients, with blood/CSF collected around the time of maximum CAR-T expansion (Days 5-9 post-infusion). Enumeration of CAR-T cells in the blood vs CSF revealed a mean 13% CAR-Ts of total blood T cells (range 7-24%), and a mean 18% (range 13-28%) in the CSF. CD4+ CAR-T cells predominated in the infused product (mean 79% CAR-T cells were CD4+, range 68-95%), with the CD4:CD8 balance maintained at peak expansion (with 77% (range 60-83%) CAR-T cells in the blood being CD4+, and 95% (range 91-97%) CAR-T cells in the CSF being CD4+). Sc-TCR sequencing enabled an evaluation of the T cell repertoire, revealing a similarly broad CAR-T repertoire in both the blood (mean 1,375 clones (range 313-2,563) and CSF (mean 1,090 clones, range 268-1,965). scRNA-Seq gene expression and clustering analysis revealed a striking distinction between blood and CSF CAR-Ts: While blood CAR-Ts exhibited a prominent proliferation gene expression signature (analyzed by single cell GSEA), CSF CAR-Ts, obtained on the same days as those from the blood, exhibited strong enrichment for interferon-pathway associated genes (Panel 1). Although the majority of CAR-T clones identified were unique to either the blood or CSF, we were able to identify 54 shared clones between these compartments. Analysis of these clones further substantiated the transcriptional evolution of CAR-Ts between the blood and CSF. Thus, individual shared clones tracked in blood and CSF from multiple patients exhibited an evolution from a more diverse proliferation/IFN pathway profile in the blood, to predominantly IFN pathways enriched in CSF CAR-Ts (Panel 2). Conclusions: Daily examination of the blood and CSF by scRNA-Seq and scTCR-Seq has identified a major distinction between blood and CSF CAR-Ts at the level of individual CAR-T clones, revealing the evolution of a prominent interferon pathway transcriptomic signature of CAR-Ts in the CSF. These results suggest that IFN pathway enrichment may play a major role in CAR-T efficacy for the eradication of CNS disease in patients with CNSL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Telomere-to-Telomere Genome Sequences across a Single Genus Reveal Highly Variable Chromosome Rearrangement Rates but Absolute Stasis of Chromosome Number.

Genome rearrangements in filamentous fungi are prevalent but little is known about the modalities of their evolution, in part because few complete genomes are available within a single genus. To address this, we have generated and compared 15 complete telomere-to-telomere genomes across the phylogeny of a single genus of filamentous fungi, Epichloë. We find that the striking distinction between gene-rich and repeat-rich regions previously reported for isolated species is ubiquitous across the Epichloë genus. We built a species phylogeny from single-copy gene orthologs to provide a comparative framing to study chromosome composition and structural change through evolutionary time. All Epichloë genomes have exactly seven nuclear chromosomes, but despite this conserved ploidy, analyses reveal low synteny and substantial rearrangement of gene content across the genus. These rearrangements are highly lineage-dependent, with most occurring over short evolutionary distances, with long periods of structural stasis. Quantification of chromosomal rearrangements shows they are uncorrelated with numbers of substitutions and evolutionary distances, suggesting that different modes of evolution are acting to create nucleotide and chromosome-scale changes.

Abstract 1983: Modulation of immune gene expression by intra-tumoral oncolytic adenovirus ONCOS-102 is associated with clinical response in anti-PD-1 refractory/resistant melanoma

Abstract Background: Defining molecular parameters of clinical response to immune modulators may lead to development of novel biomarkers, new therapeutic targets and drug combinations in cancer treatment. We recently completed phase I/II testing of ONCOS-102, a GM-CSF-encoding oncolytic adenovirus (Ad5/3-D24-GMCSF), for therapeutic efficacy and capacity to remodel tumor micro-environment (TME) in combination with pembrolizumab (pem) in patients (pts) with non-resectable, stage III-IV, anti-PD-1 resistant/refractory (R/R) melanoma (NCT03003676). Here we report comparative, longitudinal gene expression analysis of tumor samples from pts with complete/partial response (CR/PR), stable (SD) or progressive (PD) disease by RECIST1.0. Methods: In study part 1, n=9 pts received three intra-tumoral (i.t.) injections of ONCOS-102 every 3 days during the first week of treatment. Pem was administered i.v. at 10 mg/kg from day 22 every 3 weeks for 6 months. In study part 2, n=12 pts received additional injections of ONCOS-102 at day 15 and then every 3 weeks along with pem. On-treatment tumor biopsies were collected at baseline, day 22 and 64. Total RNA sequencing followed by differential gene expression analysis using DESeq1 was conducted on n=17 pts to disclose dynamic transcriptome changes associated with ONCOS-102 administration and clinical response. Results: Baseline biopsies of CR/PR pts showed 1,5-2 fold higher levels of expression of innate and adaptive immune response-related genes compared to PD pts. Treatment with ONCOS-102 upregulated immune related genes at day 22 across most tumors with no clear PR/PD differentiation. However, at day 64 a striking distinction between pts with CR/PR compared to PD emerged, showing 4-5 fold increase in expression levels for several immune-related gene categories including check-points, co-stimulatory and cellular cytotoxicity genes. TME remodeling in CR/PR pts was sustained at least until day 64. On individual genes,higher and more sustained upregulation of several co-stimulatory molecules (4-1BB, OX40, CD28) and checkpoints (LAG-3, TIGID, TIM-3) was seen in responders. Expression of adenovirus genes was more prevalent in CR/PR (2 of 3 pts) than PD (0 of 2 pts) on day 64, suggesting that tumor susceptibility to virus entry and replication drives clinical benefit of ONCOS-102. Our findings were supported by analysis of other gene subsets and comparison of different schedules of ONCOS-102 administration. Conclusions: ONCOS-102 drives pro-inflammatory modulation of the TME in PD-1 R/R melanoma tumors. Clinical response ONCOS-102 is associated with efficient viral gene expression and strong, sustained activation of immune-related genes, which may be targets for future combinations of ONCOS-102 and immune-modulators beyond PD-1/PD-L1 inhibitors. Citation Format: Erik Digman Wiklund, Lukasz Kuryk, Sandeep Kumar, Magnus Jaderberg, Victor levitsky, Thomas Birkballe Hansen, Anne-Sophie Moller, Alexander Shoushtari. Modulation of immune gene expression by intra-tumoral oncolytic adenovirus ONCOS-102 is associated with clinical response in anti-PD-1 refractory/resistant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1983.

Proteomic analysis distinguishes extracellular vesicles produced by cancerous versus healthy pancreatic organoids

Extracellular vesicles (EVs) are produced and released by both healthy and malignant cells and bear markers indicative of ongoing biological processes. In the present study we utilized high resolution flow cytometry to detect EVs in the plasma of patients with pancreatic ductal adenocarcinoma (PDAC) and in the supernatants of PDAC and healthy control (HC) pancreatic organoid cultures. Using ultrafiltration and size exclusion chromatography, PDAC and HC pancreatic organoid EVs were isolated for mass spectrometry analysis. Proteomic and functional protein network analysis showed a striking distinction in that EV proteins profiled in pancreatic cancer organoids were involved in vesicular transport and tumorigenesis while EV proteins in healthy organoids were involved in cellular homeostasis. Thus, the most abundant proteins identified in either case represented non-overlapping cellular programs. Tumor-promoting candidates LAMA5, SDCBP and TENA were consistently upregulated in PDAC EVs. Validation of specific markers for PDAC EVs versus healthy pancreatic EVs will provide the biomarkers and enhanced sensitivity necessary to monitor early disease or disease progression, with or without treatment. Moreover, disease-associated changes in EV protein profiles provide an opportunity to investigate alterations in cellular programming with disease progression.

Common Treatment, Common Variant: Evolutionary Prediction of Functional Pharmacogenomic Variants.

Pharmacogenomics holds the promise of personalized drug efficacy optimization and drug toxicity minimization. Much of the research conducted to date, however, suffers from an ascertainment bias towards European participants. Here, we leverage publicly available, whole genome sequencing data collected from global populations, evolutionary characteristics, and annotated protein features to construct a new in silico machine learning pharmacogenetic identification method called XGB-PGX. When applied to pharmacogenetic data, XGB-PGX outperformed all existing prediction methods and identified over 2000 new pharmacogenetic variants. While there are modest pharmacogenetic allele frequency distribution differences across global population samples, the most striking distinction is between the relatively rare putatively neutral pharmacogene variants and the relatively common established and newly predicted functional pharamacogenetic variants. Our findings therefore support a focus on individual patient pharmacogenetic testing rather than on clinical presumptions about patient race, ethnicity, or ancestral geographic residence. We further encourage more attention be given to the impact of common variation on drug response and propose a new ‘common treatment, common variant’ perspective for pharmacogenetic prediction that is distinct from the types of variation that underlie complex and Mendelian disease. XGB-PGX has identified many new pharmacovariants that are present across all global communities; however, communities that have been underrepresented in genomic research are likely to benefit the most from XGB-PGX’s in silico predictions.

Gravitational lensing in rotating and twisting universes

Gravitational lensing caused by the gravitational field of massive objects has been studied and acknowledged for a long period of time. In this paper, however, we propose a different mechanism where the bending of light stems from the non-linear interaction of gravitational, electromagnetic and axion waves that creates the high curvature zone in the space-time fabric. The striking distinction in the present study is that in contrast to the convex lensing in the gravitational field of a massive object, hyperbolic nature of the high curvature zone of the background space-time may give rise to concave lensing. Expectedly detection of this kind of lensing becomes possible through satellite detectors.

Monopole Contribution to the Stark Width of Hydrogenlike Spectral Lines in Plasmas: Analytical Results

One of the most reliable and frequently used methods for diagnosing various laboratory and astrophysical plasmas is based on the Stark broadening of spectral lines. It allows for determining from the experimental line profiles important parameters, such as the electron density and temperature, the ion density, the magnetic field, and the field strength of various types of the electrostatic plasma turbulence. Since, in this method, radiating atoms or ions are used as the sensitive probes of the above parameters, these probes have to be properly calibrated. In other words, an accurate theory of the Stark broadening of spectral lines in plasmas is required. In the present paper, we study, analytically, the monopole contribution to the Stark width of hydrogen-like spectral lines in plasmas. For this purpose, we use the formalism from paper by Mejri, Nguyen, and Ben Lakhdar. We show that the monopole contribution to the width has a non-monotonic dependence on the velocity of perturbing electrons. Namely, at relatively small electron velocities, the width decreases as the velocity increases. Then it reaches a minimum and (at relatively large electron velocities), as the velocity further increases, the width increases. The non-monotonic dependence of the monopole contribution to the width on the electron velocity is a counter-intuitive result. The outcome that at relatively large electron velocities, the monopole contribution to the width increases with the increase in the electron velocity is in a striking distinction to the dipole contribution to the width, which decreases as the electron velocity increases. We show that, in the situation encountered in various areas of plasma research (such as in magnetically-controlled fusion), where there is a relativistic electron beam (REB) in a plasma, the monopole contribution to the width due to the REB exceeds the corresponding dipole contribution by four orders of magnitude and practically determines the entire Stark width of hydrogenic spectral lines due to the REB.

From Mystical Asceticism to Heresy and Heterodoxy: Rewriting St Antony in Late Medieval Spain

This article examines the malleability of hagiographic identity, commenting on the representation of St Antony in the two most influential early sources of his life, the Vita Antonii and the Apophthegmata Patrum, drawing on sources that had for many years circulated in the oral tradition, together with their conflation in the context of Jacobus de Voragine’s Legenda aurea. It shows how Voragine’s text was subsequently reworked into Castilian in two different ways: the Gran flos sanctorum, which appears to have been designed for scholarly reception, and the Leyenda de los santos, which is characterized by a series of more popularizing features. A striking distinction between the two texts is that the Leyenda de los santos, as is the case with its treatment of other saints, fails to transmit episodes centred on descriptions of mystical ecstasy or the prophetic visions experienced by the saint, thus producing a very different Antony. It seems possible, therefore, that it was shaped by an awareness of the dangers of heresy and the possibility of unorthodox interpretation

Young Versus Old Age at Diagnosis Confers Distinct Genomic Profiles in Patients with Polycythemia Vera

Introduction: Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) characterized by overproduction of mature erythrocytes and a propensity for transformation to myelofibrosis (MF) and acute myeloid leukemia (AML). The defining genetic feature of PV is the JAK2 V617F mutation, present in 95-97% of patients, resulting in overactive JAK-STAT signaling. Secondary mutations have been identified which may modulate PV disease phenotype. Although typically diagnosed in older individuals, PV occurs in young patients (≤ 45 years old) as well. Compared with old patients (≥ 65 years old), a significant association with young PV and female gender, lower white blood cell count, lower JAK2 V617F allele burden, palpable splenomegaly, and splanchnic vein thrombosis has been reported. In the same study, the frequency of transformation to MF or AML was found to be similar, although the median time to transformation was shorter in old PV. The reasons for these age-related associations are not clearly understood. Since somatic mutations have been shown to accumulate with age, we hypothesized that the mutational profile of young PV patients may differ from that of old PV, which could contribute to the differences in clinical phenotypes observed.Methods: DNA from tumor (bulk peripheral blood mononuclear cells or granulocytes) and matched normal tissue (skin or sorted CD3+ T cells) was isolated from samples from 10 young (≤ 45 years old) and 11 old (≥ 65 years old) PV patients. Enhanced exome sequencing utilizing the standard IDT exome capture panel plus additional probes for genes known to be recurrently mutated in MPN and/or AML was performed. To determine order of mutation acquisition (and to rule out the possibility of biclonal disease) qPCR-based genotyping was performed on single cell-derived colonies from patients with ≥ 1 secondary mutation (in addition to JAK2 V617F). Plasma concentrations of 10 cytokines were assayed in 15 young and 23 old PV patient samples compared with age-matched healthy controls.Results: Comparative analysis of 7 young and 10 old patients (four samples were removed due to sample contamination/artifact issues) identified a total of 133 somatic mutations. A significantly higher overall mutational load was observed in the old group (mean 10.9 vs 3.4; p = 0.0025). A trend toward higher JAK2 V617F variant allele frequency (VAF) was observed in old versus young PV in the sequenced patients, and in a separate clinical cohort the JAK2 V617F VAF was significantly higher in old PV patients (p = 0.0067). Notably, putative secondary driver mutations were identified in 9/10 old PV patients (including ASXL1, TET2, and DNMT3A), whereas JAK2 appeared to be the only driver mutation present in each of the young PV patients. Secondary mutations were validated as being acquired before, after, or coincident with JAK2 V617F, with no specific predominant pattern observed. MPN-predisposing germline JAK2 46/1 haplotype occurrence did not differ with age, and additional germline mutations in MPN genes were not enriched in either cohort. Supranormal levels of multiple cytokines (e.g. IFNγ, IL-2Rα, IP-10, MIP-1α) were observed in both young and old PV, with a slight enhancement observed with increased age.Conclusions: These data indicate a striking age-based distinction in the near uniform absence (young) or presence (old) of secondary non-JAK2 mutations in PV patients. The finding that putative secondary driver mutations were acquired before JAK2 V617F in only a minority of old PV suggests that the overall increase of secondary mutations in this cohort may not merely be a function of aging, implying that these mutations do in fact contribute to PV development and/or progression. As transformation can be induced by accrual of disease-modifying mutations, the presence of secondary mutations in old PV patients is consistent with the reported shorter time to transformation in this age group, since young PV patients would likely need additional time to acquire secondary mutations. Abnormal inflammatory cytokine production was common to both young and old PV, suggesting this is not the predominant factor distinguishing these two cohorts. The contribution of additional non-genomic factors (e.g. epigenetic, hormonal) will be the subject of future study. DisclosuresOh:Janssen: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharma: Research Funding; Gilead: Research Funding; Takeda: Research Funding.

Women at the Wheel [Book Reviews

This book looks at women and the automobile. The author draws a striking distinction between men and women’s attitudes towards driving. Whereas men have traditionally embraced the car as transforming of their lives, women on the other hand have not found that it offered them the same sense of independence. The book takes a gendered lens to automobile history. The author makes use of evidence to support her contentions by beginning the book with stereotypes of women as bad drivers or as backseat drivers, emphasizing women’s primary historical association with the car as a passenger or as a service driver in the role of wife or mother. The author contextualizes this history, underlining the role of the car as part and parcel of the country’s shift to the suburbs. With the emergence and eventual dominance of the automobile in the United States, women had to go out and get products and services once delivered to the home. And women used the car to drive men to work and children to school and to extracurricular activities. The more than thirty historical illustrations offer graphic evidence to the text. The book is filled with contradictions, starting with the cover design.

Extensive Transduction and Enhanced Spread of a Modified AAV2 Capsid in the Non-human Primate CNS.

The present study was designed to characterize transduction of non-human primate brain and spinal cord with a modified adeno-associated virus serotype 2, incapable of binding to theheparan sulfate proteoglycan receptor, referred to as AAV2-HBKO. AAV2-HBKO was infused into the thalamus, intracerebroventricularly or via a combination of both intracerebroventricular and thalamic delivery. Thalamic injection of this modified vector encoding GFP resulted in widespread CNS transduction that included neurons in deep cortical layers, deep cerebellar nuclei, several subcortical regions, and motor neuron transduction in the spinal cord indicative of robust bidirectional axonal transport. Intracerebroventricular delivery similarly resulted in widespread cortical transduction, with one striking distinction that oligodendrocytes within superficial layers of the cortex were the primary cell type transduced. Robust motor neuron transduction was also observed in all levels of the spinal cord. The combination of thalamic and intracerebroventricular delivery resulted in transduction of oligodendrocytes in superficial cortical layers and neurons in deeper cortical layers. Several subcortical regions were also transduced. Our data demonstrate that AAV2-HBKO is a powerful vector for the potential treatment of a wide number of neurological disorders, and highlight that delivery route can significantly impact cellular tropism and pattern of CNS transduction.

Absolute vs. Intensity-based Caps for Carbon Emissions Target Setting

AbstractLinking the European Union Emissions Trading System (EU ETS) to the Chinese national ETS promises considerable economic and political benefits. However, different policy choices regarding cap setting between the systems are likely to impede a potential linking. A striking distinction is that the EU ETS relies upon an absolute cap, while the Chinese national ETS appears to apply an ‘intensity-based cap’ during the early stages. The current linking literature focuses on mapping legal barriers in general and has not yet focused on EU and China, let alone the intricacies of policy design. This article seeks to fill this gap by concentrating on (static and dynamic) efficiency and environmental effectiveness implications of linking and cap design. From the analysis of the cap we derive policy implications for a hypothetical ETS linking between the EU and China. In response, comprehensive and predictable regulation is needed to ensure the attainment of ETS targets and thus facilitate better regulation.

A new species of Athripsodes from the southwest of the Iberian Peninsula (Trichoptera, Leptoceridae)

A new species of the genus Athripsodes from the Iberian Peninsula is described and illustrated: Athripsodes alentexanus sp. nov. Adults of the new species are close to those of A. taounate Dakki & Malicky, 1980 and A. ygramul Malicky & Lounaci, 1987, but the shape of their inferior appendages provides the most striking distinction between males of these three species.

Turbulent wake behind a curved circular cylinder

AbstractThis paper reports results from a direct numerical simulation of the flow past a circular cylinder with axial curvature. The main objective is to explore the effects of spanwise curvature on the stability of the shear layers and the turbulent wake at the subcritical Reynolds number of 3900. The bluff-body geometry is adapted from a previous study conducted at lower Reynolds numbers, in which a quarter segment of a ring represented the deformed cylinder. A convex configuration in which the free-stream direction is towards the outer face of the ring is adopted here. The present results show a striking distinction between the upper and lower wake regions. Despite the turbulent character of the wake, the upper wake region is more coherent due to the periodic vortex shedding of primary vortical structures, which are in close alignment with the axial curvature. A mild axial flow develops upwards along the lee face of the curved cylinder, displacing the vortex formation region further downstream from the location expected for a straight cylinder at the same Reynolds number. In the lower wake region the vortex shedding strength is drastically reduced due to larger local inclination, resulting in higher three-dimensionality and loss of coherence. A strong downdraft with a swirling pattern is the dominating feature in the lower base region. This is associated with a substantial decrease of the base suction, and the suppression of the characteristic recirculating backflow.

Archive Footage and the Image of Historical Documentary

This research aims to unveil the royal agenda issues on the documentary ‘Jungle Green Khaki Brown: Malaya's fight against terrorism’. ‘Jungle Green Khaki Brown: Malaya's fight against terrorism’ is a documentary that members devote to his struggle againstcommunist terrorists safety. Every aspect of the documentary is to be visualized representation of the struggle against bandit. A series rather than social factors, technological and cultural influence beyond the eroding attitude formation are still obscure Malaysian nation with a history of their own country. ‘Jungle Green Khaki Brown: Malaya's fight against terrorism’ has become a silent byproduct material injected historical value and value in the eyes of the Bangsa Malaysia (Malaysian Nation). This documentary has been a witness to the history that applies to every Bangsa Malaysia (Malaysian nation). The problem is there message this kingdom can achieve set goals? Overview over the audience documentary has run to get their views on the visual elements shown owing to documentary, is there they see it as something that actually describes the situation or just a symbolism? The model form in visual communication backing up two possibilities: the audience will be able to understand any visual elements that display as it is constituted by language (Barthes), or visual communication, such as sign language and has put imagery, and create something of meaning (Kress and Van Leeuwen), to make room for the audience to ‘read’ thoroughly about what to say, like what otherwise is a documentary that free offerings actually. This study rejects both those views. The image may communicate without language, but there is a very striking distinction between the images that make up the easy system and language imagery that form a complex system. The semiotic system imagery is easy to represent the real existent (Halliday) and every experience we went through. The existence of index alongside the linguistic discourse allows the audience to understand every visual offering by linking each index with the actual state of the world. The implication can add further unique offerings and appeal over the documentary.

Variables separated equations: Strikingly different roles for the Branch Cycle Lemma and the finite simple group classification

Davenport’s Problem asks: What can we expect of two polynomials, over Z, with the same ranges on almost all residue class fields? This stood out among many separated variable problems posed by Davenport, Lewis and Schinzel. By bounding the degrees, but expanding the maps and variables in Davenport’s Problem, Galois stratification enhanced the separated variable theme, solving an Ax and Kochen problem from their Artin Conjecture work. Denef and Loeser applied this to add Chow motive coefficients to previously introduced zeta functions on a diophantine statement. By restricting the variables, but leaving the degrees unbounded, we found the striking distinction between Davenport’s problem over Q, solved by applying the Branch Cycle Lemma, and its generalization over any number field, solved by using the simple group classification. This encouraged Thompson to formulate the genus 0 problem on rational function monodromy groups. Guralnick and Thompson led its solution in stages. We look at two developments since the solution of Davenport’s problem. We use these to consider: Going beyond the simple group classification to handle imprimitive groups, and what is the role of covers and correspondences in going from algebraic equations to zeta functions with Chow motive coefficients.