Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics

An instrument to measure job satisfaction of nursing home administrators

BACKGROUND: The psychometric properties of the nursing home administrator job satisfaction questionnaire (NHA-JSQ) are presented, and the steps used to develop this instrument. METHODS: The NHA-JSQ subscales were developed from pilot survey activities with 93 administrators, content analysis, and a research panel. The resulting survey was sent to 1,000 nursing home administrators. Factor analyses were used to determine the psychometric properties of the instrument. RESULTS: Of the 1,000 surveys mailed, 721 usable surveys were returned (72 percent response rate). The factor analyses show that the items were representative of six underlying factors (i.e., coworkers, work demands, work content, work load, work skills, and rewards). CONCLUSION: The NHA-JSQ represents a short, psychometrically sound job satisfaction instrument for use in nursing homes

Increased Expression of PcG Protein YY1 Negatively Regulates B Cell Development while Allowing Accumulation of Myeloid Cells and LT-HSC Cells

Ying Yang 1 (YY1) is a multifunctional Polycomb Group (PcG) transcription factor that binds to multiple enhancer binding sites in the immunoglobulin (Ig) loci and plays vital roles in early B cell development. PcG proteins have important functions in hematopoietic stem cell renewal and YY1 is the only mammalian PcG protein with DNA binding specificity. Conditional knock-out of YY1 in the mouse B cell lineage results in arrest at the pro-B cell stage, and dosage effects have been observed at various YY1 expression levels. To investigate the impact of elevated YY1 expression on hematopoetic development, we utilized a mouse in vivo bone marrow reconstitution system. We found that mouse bone marrow cells expressing elevated levels of YY1 exhibited a selective disadvantage as they progressed from hematopoietic stem/progenitor cells to pro-B, pre-B, immature B and re-circulating B cell stages, but no disadvantage of YY1 over-expression was observed in myeloid lineage cells. Furthermore, mouse bone marrow cells expressing elevated levels of YY1 displayed enrichment for cells with surface markers characteristic of long-term hematopoietic stem cells (HSC). YY1 expression induced apoptosis in mouse B cell lines in vitro, and resulted in down-regulated expression of anti-apoptotic genes Bcl-xl and NFκB2, while no impact was observed in a mouse myeloid line. B cell apoptosis and LT-HSC enrichment induced by YY1 suggest that novel strategies to induce YY1 expression could have beneficial effects in the treatment of B lineage malignancies while preserving normal HSCs

Male-Specific Transfer and Fine Scale Spatial Differences of Newly Identified Cuticular Hydrocarbons and Triacylglycerides in a Drosophila Species Pair

We analyzed epicuticular hydrocarbon variation in geographically isolated populations of D. mojavensis cultured on different rearing substrates and a sibling species, D. arizonae, with ultraviolet laser desorption/ionization mass spectrometry (UV-LDI MS). Different body parts, i.e. legs, proboscis, and abdomens, of both species showed qualitatively similar hydrocarbon profiles consisting mainly of long-chain monoenes, dienes, trienes, and tetraenes. However, D. arizonae had higher amounts of most hydrocarbons than D. mojavensis and females of both species exhibited greater hydrocarbon amounts than males. Hydrocarbon profiles of D. mojavensis populations were significantly influenced by sex and rearing substrates, and differed between body parts. Lab food–reared flies had lower amounts of most hydrocarbons than flies reared on fermenting cactus substrates. We discovered 48 male- and species-specific hydrocarbons ranging in size from C22 to C50 in the male anogenital region of both species, most not described before. These included several oxygen-containing hydrocarbons in addition to high intensity signals corresponding to putative triacylglycerides, amounts of which were influenced by larval rearing substrates. Some of these compounds were transferred to female cuticles in high amounts during copulation. This is the first study showing that triacylglycerides may be a separate class of courtship-related signaling molecules in drosophilids. This study also extends the kind and number of epicuticular hydrocarbons in these species and emphasizes the role of larval ecology in influencing amounts of these compounds, many of which mediate courtship success within and between species

Presence of celiac disease epitopes in modern and old hexaploid wheat varieties: wheat breeding may have contributed to increased prevalence of celiac disease

Gluten proteins from wheat can induce celiac disease (CD) in genetically susceptible individuals. Specific gluten peptides can be presented by antigen presenting cells to gluten-sensitive T-cell lymphocytes leading to CD. During the last decades, a significant increase has been observed in the prevalence of CD. This may partly be attributed to an increase in awareness and to improved diagnostic techniques, but increased wheat and gluten consumption is also considered a major cause. To analyze whether wheat breeding contributed to the increase of the prevalence of CD, we have compared the genetic diversity of gluten proteins for the presence of two CD epitopes (Glia-α9 and Glia-α20) in 36 modern European wheat varieties and in 50 landraces representing the wheat varieties grown up to around a century ago. Glia-α9 is a major (immunodominant) epitope that is recognized by the majority of CD patients. The minor Glia-α20 was included as a technical reference. Overall, the presence of the Glia-α9 epitope was higher in the modern varieties, whereas the presence of the Glia-α20 epitope was lower, as compared to the landraces. This suggests that modern wheat breeding practices may have led to an increased exposure to CD epitopes. On the other hand, some modern varieties and landraces have been identified that have relatively low contents of both epitopes. Such selected lines may serve as a start to breed wheat for the introduction of ‘low CD toxic’ as a new breeding trait. Large-scale culture and consumption of such varieties would considerably aid in decreasing the prevalence of CD

Localization and function of the renal calcium-sensing receptor

The ability to monitor changes in the ionic composition of the extracellular environment is a crucial feature that has evolved in all living organisms. The cloning and characterization of the extracellular calcium-sensing receptor (CaSR) from the mammalian parathyroid gland in the early 1990s provided the first description of a cellular, ion-sensing mechanism. This finding demonstrated how cells can detect small, physiological variations in free ionized calcium (Ca 2+) in the extracellular fluid and subsequently evoke an appropriate biological response by altering the secretion of parathyroid hormone (PTH) that acts on PTH receptors expressed in target tissues, including the kidney, intestine, and bone. Aberrant Ca 2+ sensing by the parathyroid glands, as a result of altered CaSR expression or function, is associated with impaired divalent cation homeostasis. CaSR activators that mimic the effects of Ca 2+ (calcimimetics) have been designed to treat hyperparathyroidism, and CaSR antagonists (calcilytics) are in development for the treatment of hypercalciuric disorders. The kidney expresses a CaSR that might directly contribute to the regulation of many aspects of renal function in a PTH-independent manner. This Review discusses the roles of the renal CaSR and the potential impact of pharmacological modulation of the CaSR on renal function

Measurement of H Λ 4 and He Λ 4 binding energy in Au+Au collisions at s NN = 3 GeV

Measurements of mass and Λ binding energy of Λ4H and Λ4He in Au+Au collisions at sNN=3 GeV are presented, with an aim to address the charge symmetry breaking (CSB) problem in hypernuclei systems with atomic number A = 4. The Λ binding energies are measured to be 2.22±0.06(stat.)±0.14(syst.) MeV and 2.38±0.13(stat.)±0.12(syst.) MeV for Λ4H and Λ4He, respectively. The measured Λ binding-energy difference is 0.16±0.14(stat.)±0.10(syst.) MeV for ground states. Combined with the γ-ray transition energies, the binding-energy difference for excited states is −0.16±0.14(stat.)±0.10(syst.) MeV, which is negative and comparable to the value of the ground states within uncertainties. These new measurements on the Λ binding-energy difference in A = 4 hypernuclei systems are consistent with the theoretical calculations that result in ΔBΛ4(1exc+)≈−ΔBΛ4(0g.s.+)<0 and present a new method for the study of CSB effect using relativistic heavy-ion collisions

Electric-charge-dependent directed flow splitting of produced quarks in Au+Au collisions

We report directed flow (v1) of multistrange baryons (Ξ and Ω) and improved v1 data for K−, p¯, Λ¯ and ϕ in Au+Au collisions at sNN=27 and 200 GeV from the STAR experiment at the Relativistic Heavy Ion Collider (RHIC). We focus on particles whose constituent quarks are not transported from the incoming nuclei but instead are produced in the collisions. At intermediate impact parameters, we examine quark coalescence behavior for particle combinations with identical quark content, and search for any departure from this behavior (“splitting”) for combinations having non-identical quark content. Under the assumption of quark coalescence for produced quarks, the splitting strength appears to increase with the electric charge difference of the constituent quarks in the combinations, consistent with electromagnetic effect expectations

Measurements of charged-particle multiplicity dependence of higher-order net-proton cumulants in p + p collisions at s = 200 GeV from STAR at RHIC

We report on the charged-particle multiplicity dependence of net-proton cumulant ratios up to sixth order from s=200 GeV p+p collisions at the Relativistic Heavy Ion Collider (RHIC). The measured ratios C4/C2, C5/C1, and C6/C2 decrease with increased charged-particle multiplicity and rapidity acceptance. Neither the Skellam baselines nor PYTHIA8 calculations account for the observed multiplicity dependence. In addition, the ratios C5/C1 and C6/C2 approach negative values in the highest-multiplicity events, which implies that thermalized QCD matter may be formed in p+p collisions

Light nuclei femtoscopy and baryon interactions in 3 GeV Au+Au collisions at RHIC

We report the measurements of proton-deuteron (p-d) and deuteron-deuteron (d-d) correlation functions in Au+Au collisions at sNN = 3 GeV using fixed-target mode with the STAR experiment at the Relativistic Heavy-Ion Collider (RHIC). For the first time, the source size (RG), scattering length (f0), and effective range (d0) are extracted from the measured correlation functions with a simultaneous fit. The spin-averaged f0 for p-d and d-d interactions are determined to be -5.28 ± 0.11(stat.) ± 0.82(syst.) fm and -2.62 ± 0.02(stat.) ± 0.24(syst.) fm, respectively. The measured p-d interaction is consistent with theoretical calculations and low-energy scattering experiment results, demonstrating the feasibility of extracting interaction parameters using the femtoscopy technique. The reasonable agreement between the experimental data and the calculations from the transport model indicates that deuteron production in these collisions is primarily governed by nucleon coalescence