Mechanical loading impacts intramuscular drug transport : impact on local drug delivery

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008.Includes bibliographical references (leaves 152-166).Controlled-release drug-delivery systems enable efficient and defined administration of therapeutic agents to target tissues. However, ultimate drug distribution and pharmacologic effect are determined by target tissue pharmacokinetics. In muscular tissues, complex architecture that is further augmented by dynamic motion and contraction can alter the pharmacokinetics and deposition of locally delivered macromolecules. We developed a system and applied a quantitative schema to investigate the impact of controlled mechanical loads applied to skeletal and cardiac muscle tissue on intramuscular transport of locally delivered drug. In a series of studies, we examined how the interaction between architectural configuration and functional mechanics alters the transport of drugs across both physicochemical and binding properties. We correlated these pharmacokinetic effects with characteristic parameters in the physiologic range of the tissue to derive mechanistic insight into the fundamental structural and dynamic elements that underlie these effects. While previous studies have revealed the unilateral scaling of substrate uptake with mechanical influences, we elucidated an architecturally defined pharmacokinetic setpoint whereby maximal drug penetration corresponds with optimal muscle function. Our findings elucidate basic biologic design in muscle that optimizes the interface between tissue and its physical environment. The unique insights from our investigations have broad impact on current understanding of the pharmacokinetic influences of biologic form and function, and elucidate new clinical strategies for controlled release and local delivery of a wide range of therapeutic compounds to mechanically active tissues.by Peter I-Kung Wu.Ph.D

Skeletal muscle biomechanics drives intramuscular transport of locally delivered drugs

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2007.Includes bibliographical references (leaves 70-74).Introduction: Effective local drug delivery to contractile tissues such as skeletal muscle requires a thorough understanding of the impact of mechanical loads on intramuscular pharmacokinetics. Current preparations for studying skeletal muscle biomechanics typically use: mounting techniques that lead to mechanical disruption of the tissue, which can create drug transport artifacts. In order to accurately study mechanical influences on drug transport, experimental techniques and setups need to meet the particular design requirements of both biomechanical testing setups and local drug delivery preparations. Studies of intramuscular pharmacokinetics require anatomically physiologic and functionally viable conditions for accurate drug transport. In this study, we invent a method for the surgical isolation and mounting of whole skeletal muscles of small rodents that maintains the physiologic configuration of the tissue. We also invent a mounting assembly and dynamic loading system designed appropriately for in vitro drug transport studies. We present an effective protocol for tissue processing and visually quantifying intramuscular distribution of drug. With the primary objective of investigating muscle pharmacokinetics, we use these techniques in a study to elucidate the influence of mechanical loading on the intramuscular transport and distribution of locally delivered drug. Methods and Results: The dynamic loading system was characterized and used to investigate intramuscular transport of aqueous macromolecular drug. The loading system was designed to achieve a maximal force, velocity, and acceleration of up to 72N, 0.45m/s, and 8.5m/s2, respectively, for imposing cyclic strain on soleus muscle samples. Total compliance of the series assembly from the motor to muscle mounting blocks was less then 0.0057 ± 0.002mm/N.(cont.) Under proportional-integral-derivative (PID) control with a positional resolution of 20gpm, the loading system achieved a positional precision of +60gm or better for sinusoidal reference curves required in our studies. Tissue architectural and functional integrity as well as a technique for quantifying intramuscular fluorescent dextran were validated using the loading system. Histologic studies of rat soleus showed that interstitial porosity was consistent in tissues subjected to mechanical loading for 70 minutes, and changes in porosity were independent of the nature of imposed static (0-15% fixed strain) and cyclic (3Hz sinusoidal strain with amplitude of 2.5% oscillating about mean strains of 5-15%) loads. Permanent changes in architectural integrity depended only on the duration of time spent in vitro after isolation, in which porosity increased at the tissue edge from 11.1 + 3.3% to 21.0 + 6.1% over the course of a 70-minute incubation. The source solution used for local delivery of drug (dextran) preserved tissue functional viability, allowing muscle samples to maintain isometric twitch contractile activity at a rate of 3Hz for at least 1 hour. The active twitch force- length characteristic of soleus samples showed 0.24 + 0.06N at 0% strain, a maximum of 0.35 + 0.06N at 10% strain, and a decrease to 0.19 + 0.06N at 20% strain. Isometric twitch contractile force was at least 0.19N when measured every 15 minutes over a 2 hour period. Fractional volume of distribution for dextran was 84% of the bulk source concentration over the range of 0.1 M-lmM bulk concentrations, and demonstrated the non-binding properties of dextran. Fluorescence intensity of FITC-dextran equilibrated in soleus tissue exhibited a linear dependence on dextran concentration.(cont.) Dextran penetration and distribution in soleus muscles under either cyclic (3Hz, 0-20% peak-to- peak) or static (fixed at 0%) tensile strain for 80 minutes was quantified by fluorescent imaging. Penetration depth of 1mM 20kDa FITC-dextran at the planar surfaces of the soleus increased significantly from 0.52 + 0.09mm under static strain to 0.81 + 0.09mm under cyclic strain. Penetration at the curved margins of the soleus was significantly greater than at planar surfaces by a factor of 1.57 and 2.52 under static and cyclic strain, respectively. Penetration at curved surfaces increased to a greater extent, by a factor of 1.6, than at planar surfaces under cyclic strain. Discussion: This investigation demonstrated that dynamic, or cyclic, tensile strain impacts the penetration and distribution of aqueous drug in skeletal muscle. In the course of this study, we established an effective and robust experimental system and protocol for studying mechanical influences on intramuscular pharmacokinetics. The innovation of our surgical isolation and mounting technique allowed for the investigation of an isolated soleus muscle without disrupting the muscle, tendons, or physiologic bone attachments. The mounting device enabled muscles to be secured in a physiologic in situ configuration, to undergo more physiologically distributed tensile stresses and strains, and to be mechanically loaded while incubated in vitro in drug. Thus, the method and device eliminated the artificial tissue stresses typically introduced by current tissue handling techniques that could result in drug transport artifacts.(cont.) While effective as a standalone biomechanical testing preparation, characterization and validation of the dynamic loading system with a protocol for tissue processing and quantitative assessment of intramuscular fluorescent drug distribution demonstrated that it is a novel and robust preparation for investigating both tissue biomechanics and pharmacokinetics. With the finding from the present study that dynamic loading influences intramuscular drug transport in an architecturally dependent manner, we intend to investigate the isolated effects of different mechanical loading regimens on drug transport to establish a broader understanding of muscle pharmacokinetics. It is hoped that the insights from this work will guide the design and application of future local drug delivery strategies to mechanically active tissues.by Peter I-Kung Wu.S.M

Intradiscal treatment of the cartilage endplate for improving solute transport and disc nutrition

Poor nutrient transport through the cartilage endplate (CEP) is a key factor in the etiology of intervertebral disc degeneration and may hinder the efficacy of biologic strategies for disc regeneration. Yet, there are currently no treatments for improving nutrient transport through the CEP. In this study we tested whether intradiscal delivery of a matrix-modifying enzyme to the CEP improves solute transport into whole human and bovine discs. Ten human lumbar motion segments harvested from five fresh cadaveric spines (38–66 years old) and nine bovine coccygeal motion segments harvested from three adult steers were treated intradiscally either with collagenase enzyme or control buffer that was loaded in alginate carrier. Motion segments were then incubated for 18 h at 37 °C, the bony endplates removed, and the isolated discs were compressed under static (0.2 MPa) and cyclic (0.4–0.8 MPa, 0.2 Hz) loads while submerged in fluorescein tracer solution (376 Da; 0.1 mg/ml). Fluorescein concentrations from site-matched nucleus pulposus (NP) samples were compared between discs. CEP samples from each disc were digested and assayed for sulfated glycosaminoglycan (sGAG) and collagen contents. Results showed that enzymatic treatment of the CEP dramatically enhanced small solute transport into the disc. Discs with enzyme-treated CEPs had up to 10.8-fold (human) and 14.0-fold (bovine) higher fluorescein concentration in the NP compared to site-matched locations in discs with buffer-treated CEPs (p < 0.0001). Increases in solute transport were consistent with the effects of enzymatic treatment on CEP composition, which included reductions in sGAG content of 33.5% (human) and 40% (bovine). Whole disc biomechanical behavior—namely, creep strain and disc modulus—was similar between discs with enzyme- and buffer-treated CEPs. Taken together, these findings demonstrate the potential for matrix modification of the CEP to improve the transport of small solutes into whole intact discs

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Author Correction: Elucidating causative gene variants in hereditary Parkinson’s disease in the Global Parkinson’s Genetics Program (GP2)

Correction to: s41531-023-00526-9 npj Parkinson’s Disease, published online 27 June 2023 In this article the Global Parkinson’s Genetics Program (GP2) members names and affiliations were missing in the main author list of the Original article which are listed in the below

To which world regions does the valence–dominance model of social perception apply?

Over the past 10 years, Oosterhof and Todorov’s valence–dominance model has emerged as the most prominent account of how people evaluate faces on social dimensions. In this model, two dimensions (valence and dominance) underpin social judgements of faces. Because this model has primarily been developed and tested in Western regions, it is unclear whether these findings apply to other regions. We addressed this question by replicating Oosterhof and Todorov’s methodology across 11 world regions, 41 countries and 11,570 participants. When we used Oosterhof and Todorov’s original analysis strategy, the valence–dominance model generalized across regions. When we used an alternative methodology to allow for correlated dimensions, we observed much less generalization. Collectively, these results suggest that, while the valence–dominance model generalizes very well across regions when dimensions are forced to be orthogonal, regional differences are revealed when we use different extraction methods and correlate and rotate the dimension reduction solution.C.L. was supported by the Vienna Science and Technology Fund (WWTF VRG13-007); L.M.D. was supported by ERC 647910 (KINSHIP); D.I.B. and N.I. received funding from CONICET, Argentina; L.K., F.K. and Á. Putz were supported by the European Social Fund (EFOP-3.6.1.-16-2016-00004; ‘Comprehensive Development for Implementing Smart Specialization Strategies at the University of Pécs’). K.U. and E. Vergauwe were supported by a grant from the Swiss National Science Foundation (PZ00P1_154911 to E. Vergauwe). T.G. is supported by the Social Sciences and Humanities Research Council of Canada (SSHRC). M.A.V. was supported by grants 2016-T1/SOC-1395 (Comunidad de Madrid) and PSI2017-85159-P (AEI/FEDER UE). K.B. was supported by a grant from the National Science Centre, Poland (number 2015/19/D/HS6/00641). J. Bonick and J.W.L. were supported by the Joep Lange Institute. G.B. was supported by the Slovak Research and Development Agency (APVV-17-0418). H.I.J. and E.S. were supported by a French National Research Agency ‘Investissements d’Avenir’ programme grant (ANR-15-IDEX-02). T.D.G. was supported by an Australian Government Research Training Program Scholarship. The Raipur Group is thankful to: (1) the University Grants Commission, New Delhi, India for the research grants received through its SAP-DRS (Phase-III) scheme sanctioned to the School of Studies in Life Science; and (2) the Center for Translational Chronobiology at the School of Studies in Life Science, PRSU, Raipur, India for providing logistical support. K. Ask was supported by a small grant from the Department of Psychology, University of Gothenburg. Y.Q. was supported by grants from the Beijing Natural Science Foundation (5184035) and CAS Key Laboratory of Behavioral Science, Institute of Psychology. N.A.C. was supported by the National Science Foundation Graduate Research Fellowship (R010138018). We acknowledge the following research assistants: J. Muriithi and J. Ngugi (United States International University Africa); E. Adamo, D. Cafaro, V. Ciambrone, F. Dolce and E. Tolomeo (Magna Græcia University of Catanzaro); E. De Stefano (University of Padova); S. A. Escobar Abadia (University of Lincoln); L. E. Grimstad (Norwegian School of Economics (NHH)); L. C. Zamora (Franklin and Marshall College); R. E. Liang and R. C. Lo (Universiti Tunku Abdul Rahman); A. Short and L. Allen (Massey University, New Zealand), A. Ateş, E. Güneş and S. Can Özdemir (Boğaziçi University); I. Pedersen and T. Roos (Åbo Akademi University); N. Paetz (Escuela de Comunicación Mónica Herrera); J. Green (University of Gothenburg); M. Krainz (University of Vienna, Austria); and B. Todorova (University of Vienna, Austria). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.https://www.nature.com/nathumbehav/am2023BiochemistryGeneticsMicrobiology and Plant Patholog

Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

publisher: Elsevier articletitle: Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes journaltitle: Cell articlelink: https://doi.org/10.1016/j.cell.2018.05.046 content_type: article copyright: © 2018 Elsevier Inc