Pharmacokinetic Models for FcRn-Mediated IgG Disposition

The objectives were to review available PK models for saturable FcRn-mediated IgG disposition, and to explore an alternative semimechanistic model. Most available empirical and mechanistic PK models assumed equal IgG concentrations in plasma and endosome in addition to other model-specific assumptions. These might have led to inappropriate parameter estimates and model interpretations. Some physiologically based PK (PBPK) models included FcRn-mediated IgG recycling. The nature of PBPK models requires borrowing parameter values from literature, and subtle differences in the assumptions may render dramatic changes in parameter estimates related to the IgG recycling kinetics. These models might have been unnecessarily complicated to address FcRn saturation and nonlinear IgG PK especially in the IVIG setting. A simple semimechanistic PK model (cutoff model) was developed that assumed a constant endogenous IgG production rate and a saturable FcRn-binding capacity. The FcRn-binding capacity was defined as MAX, and IgG concentrations exceeding MAX in endosome resulted in lysosomal degradation. The model parameters were estimated using simulated data from previously published models. The cutoff model adequately described the rat and mouse IgG PK data simulated from published models and allowed reasonable estimation of endogenous IgG turnover rates

CO₂ gasification of bio-char derived from conventional and microwave pyrolysis

Thermal-chemical processing of biomass is expected to provide renewable and clean energy and fuels in the future. Due to the nature of endothermic reactions, microwave and conventional heating have been applied to this technology. However, more studies need to be carried out to clarify the difference between these two heating technologies. In this work, we investigated two bio-char samples produced from conventional pyrolysis of wood biomass (yield of bio-char: 38.48 and 59.70 wt.%, respectively) and one bio-char produced from microwave pyrolysis with a yield of 45.16 wt.% from the same biomass sample at different process conditions. Various methodologies have been used to characterise the bio-chars. CO₂ gasification of bio-char has also been studied using a thermogravimetric analyser (TGA) and a fixed-bed reaction system. The results show that volatile and carbon contents of the bio-char derived from microwave pyrolysis were between the two conventional bio-chars. However, the microwave bio-char is more reactive for CO₂ gasification, as more CO was released during TGA experiments, and the CO release peak was narrower compared with the CO₂ gasification of the conventional bio-chars. It is suggested that the conventional bio-char is less reactive due to the presence of more secondary chars which are produced from secondary reactions of volatiles during the conventional biomass pyrolysis. While the microwave pyrolysis generates more uniform bio-chars with less secondary char, and therefore, has advantages of producing bio-char for downstream char gasification

Evasion of cytotoxic T lymphocyte (CTL) responses by nef-dependent induction of Fas ligand (CD95L) expression on simian immunodeficiency virus-infected cells.

Published versio

Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice.

To gain insight into how mutant huntingtin (mHtt) CAG repeat length modifies Huntington's disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat lengths. We found repeat length-dependent transcriptional signatures to be prominent in the striatum, less so in cortex, and minimal in the liver. Coexpression network analyses revealed 13 striatal and 5 cortical modules that correlated highly with CAG length and age, and that were preserved in HD models and sometimes in patients. Top striatal modules implicated mHtt CAG length and age in graded impairment in the expression of identity genes for striatal medium spiny neurons and in dysregulation of cyclic AMP signaling, cell death and protocadherin genes. We used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at the protein level, and validated 22 striatal module genes as modifiers of mHtt toxicities in vivo

The Structural Basis for Promoter −35 Element Recognition by the Group IV σ Factors

The control of bacterial transcription initiation depends on a primary σ factor for housekeeping functions, as well as alternative σ factors that control regulons in response to environmental stresses. The largest and most diverse subgroup of alternative σ factors, the group IV extracytoplasmic function σ factors, directs the transcription of genes that regulate a wide variety of responses, including envelope stress and pathogenesis. We determined the 2.3-Å resolution crystal structure of the −35 element recognition domain of a group IV σ factor, Escherichia coli σ(E) (4), bound to its consensus −35 element, GGAACTT. Despite similar function and secondary structure, the primary and group IV σ factors recognize their −35 elements using distinct mechanisms. Conserved sequence elements of the σ(E) −35 element induce a DNA geometry characteristic of AA/TT-tract DNA, including a rigid, straight double-helical axis and a narrow minor groove. For this reason, the highly conserved AA in the middle of the GGAACTT motif is essential for −35 element recognition by σ(E) (4), despite the absence of direct protein–DNA interactions with these DNA bases. These principles of σ(E) (4)/−35 element recognition can be applied to a wide range of other group IV σ factors

Nerve Growth Factor Stimulates Interaction of Cayman Ataxia Protein BNIP-H/Caytaxin with Peptidyl-Prolyl Isomerase Pin1 in Differentiating Neurons

Mutations in ATCAY that encodes the brain-specific protein BNIP-H (or Caytaxin) lead to Cayman cerebellar ataxia. BNIP-H binds to glutaminase, a neurotransmitter-producing enzyme, and affects its activity and intracellular localization. Here we describe the identification and characterization of the binding between BNIP-H and Pin1, a peptidyl-prolyl cis/trans isomerase. BNIP-H interacted with Pin1 after nerve growth factor-stimulation and they co-localized in the neurites and cytosol of differentiating pheochromocytoma PC12 cells and the embryonic carcinoma P19 cells. Deletional mutagenesis revealed two cryptic binding sites within the C-terminus of BNIP-H such that single point mutants affecting the WW domain of Pin1 completely abolished their binding. Although these two sites do not contain any of the canonical Pin1-binding motifs they showed differential binding profiles to Pin1 WW domain mutants S16E, S16A and W34A, and the catalytically inert C113A of its isomerase domain. Furthermore, their direct interaction would occur only upon disrupting the ability of BNIP-H to form an intramolecular interaction by two similar regions. Furthermore, expression of Pin1 disrupted the BNIP-H/glutaminase complex formation in PC12 cells under nerve growth factor-stimulation. These results indicate that nerve growth factor may stimulate the interaction of BNIP-H with Pin1 by releasing its intramolecular inhibition. Such a mechanism could provide a post-translational regulation on the cellular activity of BNIP-H during neuronal differentiation. (213 words

Assessing batch effects of genotype calling algorithm BRLMM for the Affymetrix GeneChip Human Mapping 500 K array set using 270 HapMap samples

<p>Abstract</p> <p>Background</p> <p>Genome-wide association studies (GWAS) aim to identify genetic variants (usually single nucleotide polymorphisms [SNPs]) across the entire human genome that are associated with phenotypic traits such as disease status and drug response. Highly accurate and reproducible genotype calling are paramount since errors introduced by calling algorithms can lead to inflation of false associations between genotype and phenotype. Most genotype calling algorithms currently used for GWAS are based on multiple arrays. Because hundreds of gigabytes (GB) of raw data are generated from a GWAS, the samples are typically partitioned into batches containing subsets of the entire dataset for genotype calling. High call rates and accuracies have been achieved. However, the effects of batch size (i.e., number of chips analyzed together) and of batch composition (i.e., the choice of chips in a batch) on call rate and accuracy as well as the propagation of the effects into significantly associated SNPs identified have not been investigated. In this paper, we analyzed both the batch size and batch composition for effects on the genotype calling algorithm BRLMM using raw data of 270 HapMap samples analyzed with the Affymetrix Human Mapping 500 K array set.</p> <p>Results</p> <p>Using data from 270 HapMap samples interrogated with the Affymetrix Human Mapping 500 K array set, three different batch sizes and three different batch compositions were used for genotyping using the BRLMM algorithm. Comparative analysis of the calling results and the corresponding lists of significant SNPs identified through association analysis revealed that both batch size and composition affected genotype calling results and significantly associated SNPs. Batch size and batch composition effects were more severe on samples and SNPs with lower call rates than ones with higher call rates, and on heterozygous genotype calls compared to homozygous genotype calls.</p> <p>Conclusion</p> <p>Batch size and composition affect the genotype calling results in GWAS using BRLMM. The larger the differences in batch sizes, the larger the effect. The more homogenous the samples in the batches, the more consistent the genotype calls. The inconsistency propagates to the lists of significantly associated SNPs identified in downstream association analysis. Thus, uniform and large batch sizes should be used to make genotype calls for GWAS. In addition, samples of high homogeneity should be placed into the same batch.</p

White matter disturbances in major depressive disorder : a coordinated analysis across 20 international cohorts in the ENIGMA MDD working group

Altres ajuts: The ENIGMA-Major Depressive Disorder working group gratefully acknowledges support from the NIH Big Data to Knowledge (BD2K) award (U54 EB020403 to PMT) and NIH grant R01 MH116147 (PMT). LS is supported by an NHMRC MRFF Career Development Fellowship (APP1140764). We wish to acknowledge the patients and control subjects that have particiaped int the study. We thank Rosa Schirmer, Elke Schreiter, Reinhold Borschke and Ines Eidner for image acquisition and data preparation, and Anna Oliynyk for quality checks. We thank Dorothee P. Auer and F. Holsboer for initiation of the RUD study. We wish to acknowledge the patients and control subjects that have particiaped int the study. We thank Rosa Schirmer, Elke Schreiter, Reinhold Borschke and Ines Eidner for image acquisition and data preparation, and Anna Oliynyk for quality checks. We thank Dorothee P. Auer and F. Holsboer for initiation of the RUD study. NESDA: The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, grant number 10-000-1002) and is supported by participating universities (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen) and mental health care organizations, see www.nesda.nl. M-JvT was supported by a VENI grant (NWO grant number 016.156.077). UCSF: This work was supported by the Brain and Behavior Research Foundation (formerly NARSAD) to TTY; the National Institute of Mental Health (R01MH085734 to TTY; K01MH117442 to TCH) and by the American Foundation for Suicide Prevention (PDF-1-064-13) to TCH. Stanford: This work was supported by NIMH Grants R01MH59259 and R37101495 to IHG. MS is partially supported by an award funded by the Phyllis and Jerome Lyle Rappaport Foundation. Muenster: This work was funded by the German Research Foundation (SFB-TRR58, Projects C09 and Z02 to UD) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD). Marburg: This work was funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 to UD; KI 588/ 14-1, KI 588/14-2 to TK; KR 3822/7-1, KR 3822/7-2 to AK; JA 1890/ 7-1, JA 1890/7-2 to AJ). IMH-MDD: This work was supported by the National Healthcare Group Research Grant (SIG/15012) awarded to KS. Barcelona: This study was funded by two grants of the Fondo de Investigación Sanitaria from the Instituto de Salud Carlos III, by the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM). The author is funded through 'Miguel Servet' research contract (CP16-0020), co-financed by the European Regional Development Fund (ERDF) (2016-2019). QTIM: We thank the twins and singleton siblings who gave generously of their time to participate in the QTIM study. We also thank the many research assistants, radiographers, and IT support staff for data acquisition and DNA sample preparation. This study was funded by White matter disturbances in major depressive disorder: a coordinated analysis across 20 international. . . 1521 the National Institute of Child Health & Human Development (RO1 HD050735); National Institute of Biomedical Imaging and Bioengineering (Award 1U54EB020403-01, Subaward 56929223); National Health and Medical Research Council, Australia (Project Grants 496682, 1009064). NIH ENIGMA-BD2K U54 EB020403 (Thompson); R01 MH117601 (Jahanshad/Schmaal). Magdeburg: M.L. and M.W. are funded by SFB 779. Bipolar Family Study: This study has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013). This paper reflects only the author's views and the European Union is not liable for any use that may be made of the information contained therein. This work was also supported by a Wellcome Trust Strategic Award (104036/Z/14/Z). Minnesota Adolescent Depression Study: The study was funded by the National Institute of Mental Health (K23MH090421), the National Alliance for Research on Schizophrenia and Depression, the University of Minnesota Graduate School, the Minnesota Medical Foundation, and the Biotechnology Research Center (P41 RR008079 to the Center for Magnetic Resonance Research), University of Minnesota, and the Deborah E. Powell Center for Women's Health Seed Grant, University of Minnesota. Dublin: This study was supported by Science Foundation Ireland through a Stokes Professorhip grant to TF. MPIP: The MPIP Sample comprises patients included in the Recurrent Unipolar Depression (RUD) Case-Control study at the clinic of the Max Planck Institute of Psychiatry, Munich, German. The RUD study was supported by GlaxoSmithKline.Alterations in white matter (WM) microstructure have been implicated in the pathophysiology of major depressive disorder (MDD). However, previous findings have been inconsistent, partially due to low statistical power and the heterogeneity of depression. In the largest multi-site study to date, we examined WM anisotropy and diffusivity in 1305 MDD patients and 1602 healthy controls (age range 12-88 years) from 20 samples worldwide, which included both adults and adolescents, within the MDD Working Group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium. Processing of diffusion tensor imaging (DTI) data and statistical analyses were harmonized across sites and effects were meta-analyzed across studies. We observed subtle, but widespread, lower fractional anisotropy (FA) in adult MDD patients compared with controls in 16 out of 25 WM tracts of interest (Cohen's d between 0.12 and 0.26). The largest differences were observed in the corpus callosum and corona radiata. Widespread higher radial diffusivity (RD) was also observed (all Cohen's d between 0.12 and 0.18). Findings appeared to be driven by patients with recurrent MDD and an adult age of onset of depression. White matter microstructural differences in a smaller sample of adolescent MDD patients and controls did not survive correction for multiple testing. In this coordinated and harmonized multisite DTI study, we showed subtle, but widespread differences in WM microstructure in adult MDD, which may suggest structural disconnectivity in MDD

The domestic garden: its contribution to urban green infrastructure

Domestic gardens provide a significant component of urban green infrastructure but their relative contribution to eco-system service provision remains largely un-quantified. ‘Green infrastructure’ itself is often ill-defined, posing problems for planners to ascertain what types of green infrastructure provide greatest benefit and under what circumstances. Within this context the relative merits of gardens are unclear; however, at a time of greater urbanization where private gardens are increasingly seen as a ‘luxury’, it is important to define their role precisely. Hence, the nature of this review is to interpret existing information pertaining to gardens /gardening per se, identify where they may have a unique role to play and to highlight where further research is warranted. The review suggests that there are significant differences in both form and management of domestic gardens which radically influence the benefits. Nevertheless, gardens can play a strong role in improving the environmental impact of the domestic curtilage, e.g. by insulating houses against temperature extremes they can reduce domestic energy use. Gardens also improve localized air cooling, help mitigate flooding and provide a haven for wildlife. Less favourable aspects include contributions of gardens and gardening to greenhouse gas emissions, misuse of fertilizers and pesticides, and introduction of alien plant species. Due to the close proximity to the home and hence accessibility for many, possibly the greatest benefit of the domestic garden is on human health and well-being, but further work is required to define this clearly within the wider context of green infrastructure