Restricted Basis Research Articles

THE NATURE OF LEGAL RESTRICTIONS IN ENVIRONMENTAL LAW

Purpose. The article is aimed at analyzing the general theoretical principles and the essential characteristics of legal restrictions in environmental law; defining category of “environmental legal restrictions”, their content, system and the status of the respective legislation. Methodology. The methodology consists in carrying out a comprehensive analysis of the provisions of environmental legislation and formulating relevant conclusions on this basis. During the research, the following methods of scientific research were used: terminological, systemic and structural, comparative legal, structural and functional. Results. The objectively determined necessity of unconditional adherence to the legally established environmental requirements, prohibitions and restrictions as well as their potential scientifically substantiated enhancement in order to achieve environmentally significant goals oriented towards the priorities of sustainable development is substantiated. Restrictive mechanisms are scattered across statutory and regulatory acts of different legal force and even different branches of law, therefore, the need for their systematization and unification as well as generalization of the experience of their practical implementation in order to establish a comprehensive system of environmental restrictions is discussed. In our opinion, the conceptual basis and general essential characteristics of public environmental requirements and restrictions should be reflected in the future Environmental Code of Ukraine. Scientific novelty. In the course of the research, the author defines restrictions in environmental law as a specific sectoral imperative mechanism for regulating relations in the field of environmental safety, which consists in systematically introducing legislation on imperative provisions of environmental law as well as establishing specific legal regimes and mechanisms for their application and implementation. Practical significance. The main conclusions can be used in law-making and law-enforcing activities, as well as in further theoretical and legal research and in the educational process.

ПЕРСПЕКТИВИ РОЗВИТКУ ЗЕЛЕНОЇ ЕКОНОМІКИ В УКРАЇНІ

The article is devoted to the development of certain areas of the green economy in Ukraine. In the general case, a “green” economy is understood as a direction in economic science, within the framework of which it is believed that the economy is a dependent component of the natural environment within which it exists and is a part of it. The green economy is aimed at maintaining the well-being of society through the efficient use of natural resources, as well as the return of end-use products to the production cycle. Choosing the European development path, Ukraine has updated all the issues of greening the domestic economy. The article discusses the objective prerequisites for the development of the most attractive sectors of the green economy in Ukraine: agriculture, energy supply and waste management. It is noted that, taking into account the development of local self-government, Ukrainian megacities can take us to a certain part of the tasks of "greening" the domestic economy. Moreover, foreign practice is replete with vivid examples of the development of green cities. It is emphasized that the development of a "green" economy is not possible without the activation of state management instruments, namely: support in the form of subsidies and reduced tax rates, tax holidays for new "green" enterprises; material support of priority sectors in the form of equity participation in the authorized capital; control over the activities of green enterprises at all stages of production; emissions trading; replacement of morally and physically worn out equipment; creating programs for recycling and waste; allocating more state educational grants in the field of environmentally friendly technologies. In conclusion, it is noted that in the conditions of transition to a market economy, an economic mechanism for environmental protection management should be provided on the basis of strict environmental restrictions for territories and ecosystems, the creation of a system of payments for nature management, taking environmental factors into account in taxation, streamlining of financing sources for conservation, reproduction and conservation of natural resources.

Verifying commuting quantum computations via fidelity estimation of weighted graph states

The instantaneous quantum polynomial time (IQP) model is one of promising models to demonstrate a quantum computational advantage over classical computers. If the IQP model can be efficiently simulated by a classical computer, an unlikely consequence in computer science can be obtained (under some unproven conjectures). In order to experimentally demonstrate the advantage using medium or large-scale IQP circuits, it is inevitable to efficiently verify whether the constructed IQP circuits faithfully work. There exist two types of IQP models, each of which is the sampling on hypergraph states or weighted graph states. For the first-type IQP model, polynomial-time verification protocols have already been proposed. In this paper, we propose verification protocols for the second-type IQP model. To this end, we propose polynomial-time fidelity estimation protocols of weighted graph states for each of the following four situations where a verifier can (i) choose any measurement basis and perform adaptive measurements, (ii) only choose restricted measurement bases and perform adaptive measurements, (iii) choose any measurement basis and only perform non-adaptive measurements, and (iv) only choose restricted measurement bases and only perform non-adaptive measurements. In all of our verification protocols, the verifier’s quantum operations are only single-qubit measurements. Since we assume no independent and identically distributed property on quantum states, our protocols work in any situation.

Linear-scaling ab initio simulations of spin diffusion in rotating solids.

We investigated the utility of locally restricting the basis sets involved in low-order correlations in Liouville space (LCL) calculations of spin diffusion. Using well-known classical models of spin diffusion, we describe a rationale for selecting the optimal basis set for such calculations. We then show that the use of these locally restricted basis sets provides the same computational accuracy as the full LCL set while reducing the computational time by several orders of magnitude. Speeding up the calculations also enables us to use higher maximum spin orders and increase the computational accuracy. Furthermore, unlike exact and full LCL calculations, locally restricted LCL calculations scale linearly with the system size and should thus enable the ab initio study of spin diffusion in spin systems containing several thousand spins.

Restriction of Cellular Plasticity of Differentiated Cells Mediated by Chromatin Modifiers, Transcription Factors and Protein Kinases.

Ectopic expression of master regulatory transcription factors can reprogram the identity of specific cell types. The effectiveness of such induced cellular reprogramming is generally greatly reduced if the cellular substrates are fully differentiated cells. For example, in the nematode C. elegans, the ectopic expression of a neuronal identity-inducing transcription factor, CHE-1, can effectively induce CHE-1 target genes in immature cells but not in fully mature non-neuronal cells. To understand the molecular basis of this progressive restriction of cellular plasticity, we screened for C. elegans mutants in which ectopically expressed CHE-1 is able to induce neuronal effector genes in epidermal cells. We identified a ubiquitin hydrolase, usp-48, that restricts cellular plasticity with a notable cellular specificity. Even though we find usp-48 to be very broadly expressed in all tissue types, usp-48 null mutants specifically make epidermal cells susceptible to CHE-1-mediated activation of neuronal target genes. We screened for additional genes that allow epidermal cells to be at least partially reprogrammed by ectopic che-1 expression and identified many additional proteins that restrict cellular plasticity of epidermal cells, including a chromatin-related factor (H3K79 methyltransferase, DOT-1.1), a transcription factor (nuclear hormone receptor NHR-48), two MAPK-type protein kinases (SEK-1 and PMK-1), a nuclear localized O-GlcNAc transferase (OGT-1) and a member of large family of nuclear proteins related to the Rb-associated LIN-8 chromatin factor. These findings provide novel insights into the control of cellular plasticity.

SPI-1 is a missing host-range factor required for replication of the attenuated modified vaccinia Ankara (MVA) vaccine vector in human cells

Modified vaccinia virus Ankara (MVA) is the leading poxvirus vector for development of vaccines against diverse infectious diseases. This distinction is based on high expression of proteins and good immunogenicity despite an inability to assemble infectious progeny in human cells, which together promote efficacy and safety. Nevertheless, the basis for the host-range restriction is unknown despite past systematic attempts to identify the relevant missing viral gene(s). The search for host-range factors is exacerbated by the large number of deletions, truncations and mutations that occurred during the long passage history of MVA in chicken embryo fibroblasts. By whole genome sequencing of a panel of recombinant host-range extended (HRE) MVAs generated by marker rescue with 40 kbp segments of vaccinia virus DNA, we identified serine protease inhibitor 1 (SPI-1) as one of several candidate host-range factors present in those viruses that gained the ability to replicate in human cells. Electron microscopy revealed that the interruption of morphogenesis in human cells infected with MVA occurred at a similar stage as that of a vaccinia virus strain WR SPI-1 deletion mutant. Moreover, the introduction of the SPI-1 gene into the MVA genome led to more than a 2-log enhancement of virus spread in human diploid MRC-5 cells, whereas deletion of the gene diminished the spread of HRE viruses by similar extents. Furthermore, MRC-5 cells stably expressing SPI-1 also enhanced replication of MVA. A role for additional host range genes was suggested by the restoration of MVA replication to a lower level relative to HRE viruses, particularly in other human cell lines. Although multiple sequence alignments revealed genetic changes in addition to SPI-1 common to the HRE MVAs, no evidence for their host-range function was found by analysis thus far. Our finding that SPI-1 is host range factor for MVA should simplify use of high throughput RNAi or CRISPR/Cas single gene methods to identify additional viral and human restriction elements.

Restricted basis set coupled-channel calculations on atom-molecule collisions in magnetic fields.

Rigorous coupled-channel quantum scattering calculations on molecular collisions in external fields are computationally demanding due to the need to account for a large number of coupled channels and multiple total angular momenta J of the collision complex. We show that by restricting the total angular momentum basis to include only the states with helicities K ≤ Kmax, it is possible to obtain accurate elastic and inelastic cross sections for low-temperature He + CaH, Li + CaH, and Li + SrOH collisions in the presence of an external magnetic field at a small fraction of the computational cost of the full coupled-channel calculations (where K is the projection of the molecular rotational angular momentum on the atom-diatom axis). The optimal size of the truncated helicity basis set depends on the mechanism of the inelastic process and on the magnitude of the external magnetic field, with the minimal basis set (Kmax = 0) producing quantitatively accurate results for, e.g., ultracold Li + CaH and Li + SrOH scattering at low magnetic fields, leading to nearly 90-fold gain in computational efficiency. Larger basis sets are required to accurately describe the resonance structure in the magnetic field dependence of Li + CaH and Li + SrOH inelastic cross sections in the few partial wave-regime as well as indirect spin relaxation in He + CaH collisions. Our calculations indicate that the resonance structure is due to an interplay of the spin-rotation and Coriolis couplings between the basis states of different K and the couplings between the rotational states of the same K induced by the anisotropy of the interaction potential.

Adoptive Therapy with EBV-Specific T Cells for Treatment of CNS EBV Post-Transplant Lymphoproliferative Disease Arising after Hematopoietic Stem Cell Transplant or Solid Organ Transplant

Adoptive immunotherapy with EBV-specific T-cells (EBV-CTLs) derived from primary hematopoietic transplant donors is effective in the treatment of EBV disease complicating allogeneic hematopoietic stem cell transplant (HCT). In addition, third party donor-derived EBV-CTLs (tabelecleucel) have demonstrated efficacy in the treatment of EBV post-transplant lymphoproliferative in the setting of both HCT and solid organ transplant (SOT). While the introduction of first line therapy with rituximab has reduced the mortality associated with EBV-PTLD, EBV PTLD involving the central nervous system (CNS) remains a particularly ominous event as the efficacy of rituximab for CNS disease is limited by poor CNS bioavailability.Between 1996 and 2016 we treated nineteen patients for EBV-PTLD involving the CNS arising after HCT (12) or SOT (7). These patients received EBV-CTLs from their primary transplant donor (7), tabelecleucel from a third-party donor (11) or from both types of donor (1). Patients were treated for either isolated CNS disease (10) or CNS and systemic disease (9). Patients developing EBV-PTLD after HCT were recipients of T Cell Depleted (N=6), cord blood (N=3) and conventional (N=3) transplant. Those developing EBV-PTLD after SOT had undergone renal (N=4) heart (1) liver (1) and heart/liver (1) transplants.All of these patients had received prior therapy including rituximab (N=17), radiation therapy (N=6), and chemotherapy (N=9).Primary donor EBV-CTLs were generated from EBV seropositive hematopoietic transplant donors at the time of or after the patient underwent transplant. Third party tabelecleucel were selected from a bank of 330 lines generated under GMP conditions from normal HCT donors who specifically consented to use of their T cells in patients other than their designated transplant recipient. Selection of third party tabelecleucel lines was made on the basis of HLA restriction by at least one HLA allele shared by the patient's tumor and the HCT donor, and matching for ≥ 2/10 recipient alleles. Patients received 3 weekly infusions of approximately 1-2x106 T cells/kg/infusion. Patients were sequentially evaluated for clinical and radiographic response, and quantifications of EBV DNA by PCR. Patients not achieving a complete response to an initial cycle of EBV directed cellular therapy were eligible to receive subsequent cycles of cells from either the same or a different donor. Responses were assessed 21-35 days after the first of each cycle of EBV-CTLs. Responses were evaluated based on Lugano criteria with CNS disease being assessed by MRI, CSF or thalium scan. Two patients treated for CNS and systemic disease had simultaneous therapy of their CNS disease and achieved responses of both CNS and systemic disease but the CNS specific response could not be attributed to cell therapy alone.Of the 19 patients, 7 achieved complete responses and 5 durable partial responses for an overall response rate of 63%. The one-year overall survival (OS) for this cohort of 19 patients was 60% with responding patients experiencing one year OS of 91.7% and non-responding patients one year OS of just 14.3%. Eight of the 10 patients treated for isolated CNS disease responded to adoptive EBV directed T cell therapy. One-year overall survival for patients treated for isolated CNS disease is 70% and with CNS and systemic disease is 55.6%. Toxicities associated with infusions in this cohort are limited with 8 patients experiencing adverse events of ≥ grade 3 severity with one patient experiencing a possibly related grade 3 eventThis study demonstrates a high response rate among patients with otherwise refractory EBV PTLD affecting the CNS. Adoptive therapy with EBV directed cellular therapy (primary donor or third party derived) can effectively treat this otherwise frequently lethal complication. The availability of 3rd party tabelecleucel enables treatment early in the course of disease and may thereby improve response rates while minimizing toxicity from chemotherapy.Atara Biotherapeutics holds the IND and has a license to develop and commercialize the EBV and CMV cell therapy programs at Memorial Sloan Kettering. MSKCC and several MSK investigators hold a financial interest in Atara Biotherapeutics. DisclosuresProckop:Atara Biotherapeutics: Research Funding; Mesoblast: Research Funding. Doubrovina:Atara Biotherapeutics: Consultancy, Patents & Royalties, Research Funding. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. O'Reilly:Atara Biotherapeutics: Consultancy, Patents & Royalties, Research Funding.

Genetic and mechanistic basis for APOBEC3H alternative splicing, retrovirus restriction, and counteraction by HIV-1 protease

Human APOBEC3H (A3H) is a single-stranded DNA cytosine deaminase that inhibits HIV-1. Seven haplotypes (I–VII) and four splice variants (SV154/182/183/200) with differing antiviral activities and geographic distributions have been described, but the genetic and mechanistic basis for variant expression and function remains unclear. Using a combined bioinformatic/experimental analysis, we find that SV200 expression is specific to haplotype II, which is primarily found in sub-Saharan Africa. The underlying genetic mechanism for differential mRNA splicing is an ancient intronic deletion [del(ctc)] within A3H haplotype II sequence. We show that SV200 is at least fourfold more HIV-1 restrictive than other A3H splice variants. To counteract this elevated antiviral activity, HIV-1 protease cleaves SV200 into a shorter, less restrictive isoform. Our analyses indicate that, in addition to Vif-mediated degradation, HIV-1 may use protease as a counter-defense mechanism against A3H in >80% of sub-Saharan African populations.

The Interferon-Induced Exonuclease ISG20 Exerts Antiviral Activity through Upregulation of Type I Interferon Response Proteins.

Type I interferon (IFN)-stimulated genes (ISGs) have critical roles in inhibiting virus replication and dissemination. Despite advances in understanding the molecular basis of ISG restriction, the antiviral mechanisms of many remain unclear. The 20-kDa ISG ISG20 is a nuclear 3'-5' exonuclease with preference for single-stranded RNA (ssRNA) and has been implicated in the IFN-mediated restriction of several RNA viruses. Although the exonuclease activity of ISG20 has been shown to degrade viral RNA in vitro, evidence has yet to be presented that virus inhibition in cells requires this activity. Here, we utilized a combination of an inducible, ectopic expression system and newly generated Isg20-/- mice to investigate mechanisms and consequences of ISG20-mediated restriction. Ectopically expressed ISG20 localized primarily to Cajal bodies in the nucleus and restricted replication of chikungunya and Venezuelan equine encephalitis viruses. Although restriction by ISG20 was associated with inhibition of translation of infecting genomic RNA, degradation of viral RNAs was not observed. Instead, translation inhibition of viral RNA was associated with ISG20-induced upregulation of over 100 other genes, many of which encode known antiviral effectors. ISG20 modulated the production of IFIT1, an ISG that suppresses translation of alphavirus RNAs. Consistent with this observation, the pathogenicity of IFIT1-sensitive alphaviruses was increased in Isg20-/- mice compared to that of wild-type viruses but not in cells ectopically expressing ISG20. Our findings establish an indirect role for ISG20 in the early restriction of RNA virus replication by regulating expression of other ISGs that inhibit translation and possibly other activities in the replication cycle.IMPORTANCE The host immune responses to infection lead to the production of type I interferon (IFN), and the upregulation of interferon-stimulated genes (ISGs) reduces virus replication and virus dissemination within a host. Ectopic expression of the interferon-induced 20-kDa exonuclease ISG20 suppressed replication of chikungunya virus and Venezuelan equine encephalitis virus, two mosquito-vectored RNA alphaviruses. Since the replication of alphavirus genomes occurs exclusively in the cytoplasm, the mechanism of nucleus-localized ISG20 inhibition of replication is unclear. In this study, we determined that ISG20 acts as a master regulator of over 100 genes, many of which are ISGs. Specifically, ISG20 upregulated IFIT1 genes and inhibited translation of the alphavirus genome. Furthermore, IFIT1-sensitive alphavirus replication was increased in Isg20-/- mice compared to the replication of wild-type viruses but not in cells ectopically expressing ISG20. We propose that ISG20 acts as an indirect regulator of RNA virus replication in the cytoplasm through the upregulation of many other ISGs.

Spin Polarization through Floquet Resonances in a Driven Central Spin Model

Adiabatically varying the driving frequency of a periodically driven many-body quantum system can induce controlled transitions between resonant eigenstates of the time-averaged Hamiltonian, corresponding to adiabatic transitions in the Floquet spectrum and presenting a general tool in quantum many-body control. Using the central spin model as an application, we show how such controlled driving processes can lead to a polarization-based decoupling of the central spin from its decoherence-inducing environment at resonance. While it is generally impossible to obtain the exact Floquet Hamiltonian in driven interacting systems, we exploit the integrability of the central spin model to show how techniques from quantum quenches can be used to explicitly construct the Floquet Hamiltonian in a restricted many-body basis and model Floquet resonances.

Коллективные действия: подходы к пониманию и особенности организации (библиографический обзор зарубежной литературы)

<p>Статья посвящена анализу подходов в зарубежной науке к пониманию значимого социально-политического феномена — коллективных действий граждан, трактовка которых разная. Выделяется два подхода к пониманию коллективных действий: как отклоняющегося поведения (И. Друри, С. Скот) и как рационального поведения, направленного на защиту своих прав и интересов (К. Д. Опп, С. М. Бичлер).</p><p>Ключевое значение для формирования коллективных общностей людей, осуществления ими целенаправленных действий имеет, по мнению исследователей, чувство общности, идентичности. При этом есть расхождения во мнениях, что первично: идентичность, которая стимулирует к коллективным действиям, или коллективные действия, которые позволяют формироваться идентичности коллективно действующих людей. Чем сильнее индивидуумы идентифицируют себя с группой, тем более вероятно, что они будут участвовать в акциях поддержки данной группы, иных формах коллективного действия.</p><p>Современные исследователи акцентируют внимание на особой значимости сетевых структур информационно-коммуникационных технологий (Интернета, социальных сетей), позволяющих приобретать коллективным действиям большую эффективность. В этих условиях между индивидуумами постепенно формируются устойчивые взаимоотношения, укрепляющие саму организацию коллективных действий.</p><p>Автор соглашается с рядом исследователей в том, что коллективные действия не всегда заранее подготовлены. Они изначально могут быть спонтанными, и только впоследствии может формироваться координирующий механизм. Законодательное регулирование коллективных действий снижает возможности спонтанного их проявления. В то же время отсутствие иерархической организации, неопределенность (двусмысленность) ситуации и событий, эмоциональная основа и опыт предыдущих действий, пространственные контексты и ограничения, наоборот, способствуют спонтанности коллективных действий.</p>

Simplified box orbitals for molecules containing atoms beyond Ar

ABSTRACTSimplified Box Orbitals (SBOs) are a kind of spatially restricted basis functions with a similar use to Slater functions, but fulfilling an exact version of the zero-differential overlap approximation. These functions also allow for a drastic reduction in the number of bielectronic integrals when dealing with huge systems, and can be adapted to study confined systems such as molecules in solution. In previous studies, the necessary SBOs parameters to be used for different elements were defined. However, the accuracy of those basis functions decreases with the atomic number of the atoms under study, and therefore their use was discouraged beyond the Ar atom. In the present study, we verify that slightly increasing the terms of SBOs for a better definition, is enough to correctly handling atoms beyond Ar. This, together with other improvements exposed in this work, allowed obtaining accurate SBOs for K–Kr atoms. To make possible the use of SBOs in standard quantum chemistry calculation software, Gaussian expansions to the proposed basis functions–were achieved. Then, simple formulas for directly obtaining those expansions were deduced. Finally, the results of an SZ basis set of the proposed SBOs are analysed and compared with a similar STO basis set.

A unique major histocompatibility complex Class II-binding register correlates with HLA-DR11-associated immunogenicity of the major K blood group antigen.

Kell is a glycoprotein expressed on red blood cells (RBCs). Its K and k variants contain either Met (K antigen) or Thr (k antigen) at Position 193, respectively. Development of anti-K after K-mismatched antigen exposure via blood transfusions or pregnancy can destroy RBCs, leading to hemolytic transfusion reactions and hemolytic disease of the fetus and newborn. The immunogenicity of overlapping 15-mer Kell peptides with M193 or T193 at every possible position was investigated previously. Interestingly, Peptide W179 to M193, with the polymorphic M193T residue at the peptide's C-terminus, was the most effective at stimulating CD4 T cells from a series of K-immunized women. This study investigates the basis for HLA restriction of anti-K immune responses. Major histocompatibility complex Class II (MHCII)-binding prediction algorithms and quantitative peptide-MHCII-binding assays were employed to determine the binding registers; anchor residues; and affinities of wild-type, truncated, and sequence-modified K and k peptides. Predictions were generated using Immune Epitope Database and ProPred algorithms. Competitive peptide-MHCII-binding assays utilized 12 recombinant HLA-DR proteins, K and k peptides, and high-affinity MHCII-restricted reference peptides. The peptide-MHCII-binding assays identified a unique K peptide-binding register (W179-S187) restricted to HLA-DRB1*11:01, in addition to partially overlapping binding registers that included the K/k M193T polymorphic site and that bound promiscuously to multiple HLA-DR proteins. Three partially overlapping MHCII-binding motifs for HLA-DRB1*11:01 result in high-avidity K-peptide binding, which may contribute to HLA-DR11-restricted immunogenicity associated with the K allele.

A placenta clinic approach to the diagnosis and management of fetal growth restriction

Effective detection and management of fetal growth restriction is relevant to all obstetric care providers. Models of best practice to care for these patients and their families continue to evolve. Since much of the disease burden in fetal growth restriction originates in the placenta, the concept of a multidisciplinary placenta clinic program, managed primarily within a maternal-fetal medicine division, has gained popularity. In this context, fetal growth restriction is merely one of many placenta-related disorders that can benefit from an interdisciplinary approach, incorporating expertise from specialist perinatal ultrasound and magnetic resonance imaging, reproductive genetics, neonatal pediatrics, internal medicine subspecialties, perinatal pathology, and nursing. The accurate diagnosis and prognosis for women with fetal growth restriction is established by comprehensive clinical review and detailed sonographic evaluation of the fetus, combined with uterine artery Doppler and morphologic assessment of the placenta. Diagnostic accuracy for placenta-mediated fetal growth restriction may be enhanced by quantification of maternal serum biomarkers including placenta growth factor alone or combined with soluble fms-like tyrosine kinase-1. Uterine artery Doppler is typically abnormal in most instances of early-onset fetal growth restriction and is associated with coexistent preeclampsia and underlying maternal vascular malperfusion pathology of the placenta. By contrast, rare but potentially more serious underlying placental diagnoses, such as massive perivillous fibrinoid deposition, chronic histiocytic intervillositis, or fetal thrombotic vasculopathy, may be associated with normal uterine artery Doppler waveforms. Despite minor variations in placental size, shape, and cord insertion, placental function remains, largely normal in the general population. Consequently, morphologic assessment of the placenta is not currently incorporated into current screening programs for placental complications. However, placental ultrasound can be diagnostic in the context of fetal growth restriction, for example in Breus' mole and triploidy, which in turn may enhance diagnosis and management. Several examples are illustrated in our figures and supplementary videos. Recent advances in the ability of multiparameter screening and intervention programs to reduce the risk of severe preeclampsia will likely increase efforts to deliver similar improvements for women at risk of fetal growth restriction. Placental pathology is important because the underlying pathologies associated with fetal growth restriction have a wide range of recurrence risks. Rare conditions such as massive perivillous fibrinoid deposition or chronic histolytic intervillositis may recur in >50% of subsequent pregnancies. Postpartum care in a placenta-focused program can provide effective counseling for modifiable maternal risk factors, and can assist in planning future pregnancy care based on the pathologic basis of fetal growth restriction.

Adoptive T-Cell Therapy with 3rd Party CMV-pp65-Specific CTLs for CMV Viremia and Disease Arising after Allogeneic Hematopoietic Stem Cell Transplant

▪Adoptive immunotherapy with transplant donor-derived virus-specific T-cells is effective in the treatment of CMV viremia and disease complicating allogeneic hematopoietic stem cell transplant (HCT), but is not available if the donor is seronegative or unavailable to provide lymphocytes. In addition, CMV-specific T-cell lines (CMV-CTLs) from non-identical donors may be restricted by HLA alleles not shared by the patient, rendering them ineffective. This limitation has become more problematic with increased use of haploidentical HCT donors.We treated 50 transplant recipients with third party donor-derived CMVpp65-specific T-cells between 10/14/11 and 11/28/16, evaluable for response assessment as of 6/20/17. Patients had received an unmodified (n=11) or T-cell depleted HCT (n=33) or a cord blood (n=6), transplant. Fifteen were treated for overt CMV disease involving CNS (N=6) GI (N=10) and Lung (N=2) and 35 for CMV viremia persisting despite >2 weeks of induction therapy with 1-3 antiviral agents. Treatment with CMVpp65-CTLs was initiated at a median of 151 (29-4940) days post transplant and 128 (7-564) days after CMV reactivation. One patient was treated for CMV colitis developing more than 10 years after transplant due to immune suppression for chronic graft versus host disease. Patients had received a median of 3 (1-6) prior antiviral treatments.Third party CMVpp65-CTLs were selected from a bank of 186 lines generated under GMP conditions from normal HCT donors who specifically consented to use of their T cells in patients other than their designated transplant recipient. Selection was made on the basis of HLA restriction by at least one HLA allele shared by the patient and HCT donor, and matching for > 2/10 recipient alleles. If such a line was not available, a patient could be treated with a line matched at only one HLA allele as long as the restriction was through that matched allele. Patients received 3 weekly infusions of approximately 1x106 CMVpp65-CTL/kg/infusion. Patients were sequentially evaluated for clinical and radiographic changes, quantifications of CMV DNA by PCR and IFN+ CMVpp65-specific T-cells in the blood. Responses were assessed 28-42 days after the first of each cycle of CMVpp65-CTLs. Response in patients with CMV disease was considered complete (CR) if all sites were cleared of virus by biopsy and blood sampling and partial (PR) if symptoms resolved and viremia met criteria of PR. In patients treated for persistent viremia, responses were complete if CMV DNA was cleared in repeated testing, and partial if the level of CMV fell based on the testing method by >50% (N=2) or by 2log10 (N=12).Of the 50 patients 18 had a complete and 14 a partial response for an overall response rate of 64%. Response rates in patients with disease (5CR+4PR/15) were similar to those of patients with persistent viremia (13CR+10PR/35). In patients treated for viremia alone, survival at 6 months was 65.7% and in those with disease 60.0% (a). More extensively pretreated patients who received CMVpp65 CTLs > 100 days post CMV initial detection fared as well as those treated earlier (62.1% vs. 66.7% OS) (b). Patients who responded to CMVpp65-CTL therapy (CR or PR) had an improved survival with 6 month overall survival of 81.3% (b) and 12 month overall survival of 62.1% (c); only 1 of these 32 patients died of CMV. In contrast 7 of 18 non-responding patients died of CMV; overall survival in this cohort was 33.3% at 6 months. By 12 months, 8 non-responding patients had died of CMV and overall survival had decreased to 22.2%.Toxicities associated with CMVpp65-CTL infusions in this cohort are limited with 5 patients experiencing adverse events of > grade 3 severity deemed possibly related to CMVpp65-CTL therapy. Two of these patients died, one due to sepsis and one due to progression of CMV.This study demonstrates a high response rate among patients with otherwise refractory CMV viremia and disease. The bank of CMVpp65-CTLs can provide an immediate source of HLA partially-matched appropriately restricted T cells for adoptive immunotherapy to treat persistent CMV viremia and CMV disease, including disease isolated to the CNS. The availability of 3rd party CMVpp65-CTLs enables treatment early in the course of disease and may thereby improve response rates while minimizing toxicity from anti-viral therapy. [Display omitted] DisclosuresDoubrovina:Atara: Consultancy, Research Funding. Hasan:Atara Biotherapeutics: Consultancy, Other: During time of this study, Research Funding; Merck: Employment. Kernan:Gentium: Other: Received grants from Gentium during the conduct of the study and research was supported by The National Cancer Institute of the National Institutes of Health under award number P30 CA 008748, Research Funding. Koehne:Atara: Consultancy, Patents & Royalties. O'Reilly:Atara: Patents & Royalties, Research Funding.

Principles of subsidiarity and proporcionality in tax law enforcement

Subject. The principles of subsidiarity proportionality, which serve as the basic principles fordetermining the competence of integration associations, are considered in the article.Aim. The aim of this paper is to analyse the place and the importance of Member States’ obligationsderiving from the EU legal order in order to address the relationships between EU lawand national tax law, as well as to analyse the practice of using of principles of subsidiarity andproportionality by the highest courts of the Russian Federation as a federal state.Methodology. The author uses methods of theoretical analysis, particularly the theory ofintegrative legal consciousness, as well as legal methods, including formal legal method andcomparative law.Results, scope. The exercise of power by the European Union in the areas of shared competencemust respect the principle of subsidiarity. The founding Treaties make clear thatsubsidiarity is a legal enforceable legal principle. However. the case law of the EuropeanCourt of Justice reveals that the enforcement of subsidiarity as a judicial principle has beenineffective.The article examines cross-border loss relief for group companies in the context of EuropeanUnion law and considers how this has affected Member States such as the UK. Thecase law of the Court of Justice is then analysed in an attempt to assess whether some ofthe principles set out in these legislative initiatives found their way to Member State lawsthrough the Court's jurisprudence. Following this, the judicial and legislative response tothe Marks & Spencer judgment in the UK are critically assessed.The practical suggestions are looking at developing EU compatible tax principles to be appliedto cross-border taxation within the EU.Having considered the principles of subsidiarity and proportionality in the context of interactionbetween integration and national tax law, the author suggests directions for improvingthe practice of integration tax law. The supranational judicial authority should dwell onthe position that only those differences that are directly based on the origin of the incomeor nationality of the taxpayer can be justified on the basis of restrictions on fundamentalfreedoms.Conclusions. The author comes to the conclusion that a co-ordinated approach to crossborder tax is essential. The effectiveness of integration tax law will largely depend on how the ratio of the norms of integration and national law in the tax jurisdiction of the Union and member states will be formed. However, historically direct tax has been viewed by Member States as central to national sovereignty.

A Model Hand Prosthesis Controlled by Foot and Toe Movements

An approach to controlling hand prostheses using foot and toe movements is proposed. Construction of a model hand prosthesis with independent finger movements is described. A wireless remote control system for the prosthesis by tactile insoles fitted into the shoes is presented. Transfer parameters are selected by a synthesis based on the required final foot positions in the input and output sides of the system. Pneumatic bellows parameters, bracing spring stiffness, and pressure in the pneumatic circuit are selected on the basis of size restrictions and forces on the fingers. The study was supported by the Russian Foundation for Basic Research (Grant No. 16-08-00305A).

Physicochemical and Nutritional Requirements for Axenic Replication Suggest Physiological Basis for Coxiella burnetii Niche Restriction.

Bacterial obligate intracellular parasites are clinically significant animal and human pathogens. Central to the biology of these organisms is their level of adaptation to intracellular replication niches associated with physicochemical and nutritional constraints. While most bacterial pathogens can adapt to a wide range of environments, severe niche restriction—an inability to thrive in diverse environments—is a hallmark of bacterial obligate intracellular parasites. Herein the physicochemical and nutritional factors underlying the physiological basis for niche restriction in the zoonotic bacterial obligate intracellular parasite and Q fever agent Coxiella burnetii are characterized. Additionally, these factors are reviewed in the context of C. burnetii evolution and continued (patho) adaptation. C. burnetii replication was strictly dependent on a combination of moderately acidic pH, reduced oxygen tension, and presence of carbon dioxide. Of macronutrients, amino acids alone support replication under physicochemically favorable conditions. In addition to utilizing gluconeogenic substrates for replication, C. burnetii can also utilize glucose to generate biomass. A mutant with a disruption in the gene pckA, encoding phosphoenolpyruvate carboxykinase (PEPCK), the first committed step in gluconeogenesis, could be complemented chemically by the addition of glucose. Disruption of pckA resulted in a moderate glucose-dependent growth defect during infection of cultured host cells. Although, C. burnetii has the theoretical capacity to synthesize essential core metabolites via glycolysis and gluconeogenesis, amino acid auxotrophy essentially restricts C. burnetii replication to a niche providing ample access to amino acids. Overall, the described combination of physiochemical and nutritional growth requirements are strong indicators for why C. burnetii favors an acidified phagolysosome-derived vacuole in respiring tissue for replication.

Competition and vested interests in taxis in Ireland: A tale of two statutory instruments

This paper addresses, for the taxi market in Ireland, whether judicial, legislative and regulatory processes promote taxi users’ welfare or taxi license holders’ welfare. It is argued that the 2000 decision to remove quantitative restrictions on taxi numbers favoured taxi users; the 2010 decision to re impose such restrictions, with the exception of wheelchair accessible taxis, had the effect of favouring taxi license holders, while doing little to meet its declared object to increase the number of wheelchair accessible taxis and the ready availability of such vehicles for wheelchair customers. Whether the late 2010s/early 2020s will be a rerun of the late 1990s, with increasing waiting times for taxi users, is a moot point. An applicant refused a taxi license might, as in 2000, successfully bring a High Court case contesting the legal basis for the present quantitative restrictions. The Competition and Consumer Protection Commission might spark debate on taxi regulatory policy, while the Minister for Transport, Tourism and Sport might issue a policy direction to the National Transport Authority, the taxi regulator, requiring it to clarify the objectives and benchmarks for success of its existing prohibition on taxi licenses and to consider how best to create incentives for those with wheelchair accessible taxis to use them to service wheelchair users.