Genetic Processes Commons^™

The Effects Of Emerging Technology On Healthcare And The Difficulties Of Integration, Skyler J. Pavlish-Carpenter

Honors Undergraduate Theses

Background: Disruptive technology describes technology that is significantly more advanced than previous iterations, such as: 3D printing, genetic manipulation, stem cell research, innovative surgical procedures, and computer-based charting software. These technologies often require extensive overhauls to implement into older systems and must overcome many difficult financial and societal complications before they can be widely used. In a field like healthcare that makes frequent advancements, these difficulties can mean that the technology will not be utilized to its full potential or implemented at all.

Objective: To determine the inhibiting factors that prevent disruptive technology from being implemented in conventional healthcare.

Methods: …

An Overview Of Technical Considerations When Using Quantitative Real-Time Pcr Analysis Of Gene Expression In Human Exercise Research, Jujiao Kuang, Xu Yan, Amanda Genders, Cesare Granata, David J. Bishop

Research outputs 2014 to 2021

Gene expression analysis by quantitative PCR in skeletal muscle is routine in exercise studies. The reproducibility and reliability of the data fundamentally depend on how the experiments are performed and interpreted. Despite the popularity of the assay, there is a considerable variation in experimental protocols and data analyses from different laboratories, and there is a lack of consistency of proper quality control steps throughout the assay. In this study, we present a number of experiments on various steps of quantitative PCR workflow, and demonstrate how to perform a quantitative PCR experiment with human skeletal muscle samples in an exercise study. …

Rare Single Gene Disorders: Estimating Baseline Prevalence And Outcomes Worldwide, Hannah Blencowe, Sowmiya Moorthie, Mary Petrou, Hanan Hamamy, Alan Bittles, Stephen Gibbons, Matthew Darlison, Bernadette Modell, Congenital Disorders Expert Group .

Research outputs 2014 to 2021

As child mortality rates overall are decreasing, non-communicable conditions, such as genetic disorders, constitute an increasing proportion of child mortality, morbidity and disability. To date, policy and public health programmes have focused on common genetic disorders. Rare single gene disorders are an important source of morbidity and premature mortality for affected families. When considered collectively, they account for an important public health burden, which is frequently under-recognised. To document the collective frequency and health burden of rare single gene disorders, it is necessary to aggregate them into large manageable groupings and take account of their family implications, effective interventions and …

Inactivation Of Endoplasmic Reticulum Stress And The Prevention Of Neurodegenerative Diseases, Ian James Martins

Research outputs 2014 to 2021

Biotherapeutics and nutritional therapy are essential for the treatment of endoplasmic reticulum (ER) stress in diabetes and neurodegenerative diseases. Oxidative stress and nutrient excess may induce ER stress associated with activation of the unfolded protein response and connected to cell death. The heat shock gene Sirtuin 1 (Sirt 1) is important to the heat shock response with amyloid beta aggregation associated with the induction of mitophagy and ER stress in neuron cells. Genomic medicine that activates nuclear Sirt 1 is essential for the prevention of mitochondrial apoptosis and ER stress. Inhibitors such as drugs, alcohol, excess caffeine and palmitic acid …

Spiritual Care In Cancer Genetic Counseling: Patient Perceptions Of Methods, Christopher Michael Spencer

Theses and Dissertations

The integration of spirituality into medical care is a growing area of debate among professionals, involving a delicate balance between serving patients who may benefit from this without alienating those who would not. To date, little research has targeted spirituality in cancer genetic counseling, particularly concerning the various methods a genetic counselor can use to address spirituality with their patients. A paper questionnaire was created and distributed to patients following their cancer genetic counseling appointments to gain insight on their perception of these methods. Fifty-two participants completed this questionnaire. The eight different spiritual integration methods presented each showed positive responses …

Snf1 Dependent Destruction Of Med13 Is Required For Programmed Cell Death Following Oxidative Stress In Yeast, Stephen D Willis, David C Stieg, R. Shah, Randy Strich, Katrina F Cooper

Rowan-Virtua School of Osteopathic Medicine Departmental Research

All eukaryotic cells, when faced with unfavorable environmental conditions, have to decide whether to mount a survival or cell death response. The conserved cyclin C and its kinase partner Cdk8 play a key role in this decision. Both are members of the Cdk8 kinase module that, along with Med12 and Med13, associate with the core mediator complex of RNA polymerase II. In S. cerevisiae, oxidative stress triggers Med13 destruction¹, which thereafter releases cyclin Ci nto the cytoplasm. Cytoplasmic cyclin C associates with mitochondria where it induces hyper-fragmentation and programmed cell death². This suggests a model in …

Translocation Of Cyclin C During Oxidative Stress Is Regulated By Interactions With Multiple Trafficking Proteins, Daniel G J Smethurst, Katrina F Cooper, Randy Strich

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Eukaryotic cells take cues from their environment and interpret them to enact a response. External stresses can produce a decision between adjusting to behaviors which promote surviving the stress, or enacting a cell death program. The decision to undergo programmed cell death (PCD) is controlled by a complex interaction between nuclear and mitochondrial signals. The mitochondria are highly dynamic organelles that constantly undergo fission and fusion. However, a dramatic shift in mitochondrial morphology toward fission occurs early in the PCD process. We have identified the transcription factor cyclin C as the biochemical trigger for stress‐induced mitochondrial hyper‐fragmentation in yeast (Cooper …

Analysis Of Diagnostic, Preventive, And Disease-Modifying Therapeutic Measures Of Alzheimer’S Disease, Ghazal Habib Havoutis

HCNSO Student Capstones

Alzheimer’s disease (AD) is the most common late-onset neurodegenerative disorder and cause of dementia, characterized by the formation of neurofibrillary tangles and senile plaque deposits. The heterogeneous nature of the disease (both genetically and environmentally) makes it difficult to prevent or cure. Without prevention, the prevalence of AD is expected to triple by 2050. However, because the diagnosis of AD is usually preceded by years of cognitive impairment, early detection may aid in reducing prevalence. Thus, there is a need for validated diagnostic measures for early and improved diagnosis and prevention. In this review, current and ongoing classifiers of early …

Impact Of Kras/Nras Mutational Heterogeneity On Clinical Outcomes In Colorectal Cancer, Jonathan M. Loree

Dissertations and Theses (Open Access)

Introduction: Mutations in KRAS/NRAS (RAS) predict a lack of benefit from anti-EGFR agents in metastatic colorectal cancer (mCRC). As next generation sequencing (NGS) has advanced, we are discovering atypical and low allele frequency mutations. We aimed to evaluate how NGS can optimally define RAS mutant CRC and the role of relative mutant allele frequency (rMAF) as a biomarker.

Methods: Using institutional and public cohorts of mCRC patients with NGS results, we described the prevalence and clinical impact of atypical (not in current guidelines) and low rMAF RAS mutations (RAS MAF by the MAF of the mutated gene with …

Mechanism Of Transcription Anti-Termination In Human Mitochondria., Hauke S Hillen, Andrey V Parshin, Karen Agaronyan, Yaroslav I Morozov, James J Graber, Aleksandar Chernev, Kathrin Schwinghammer, Henning Urlaub, Michael Anikin, Patrick Cramer, Dmitry Temiakov

Rowan-Virtua School of Osteopathic Medicine Departmental Research

In human mitochondria, transcription termination events at a G-quadruplex region near the replication origin are thought to drive replication of mtDNA by generation of an RNA primer. This process is suppressed by a key regulator of mtDNA-the transcription factor TEFM. We determined the structure of an anti-termination complex in which TEFM is bound to transcribing mtRNAP. The structure reveals interactions of the dimeric pseudonuclease core of TEFM with mobile structural elements in mtRNAP and the nucleic acid components of the elongation complex (EC). Binding of TEFM to the DNA forms a downstream "sliding clamp," providing high processivity to the EC. …

Endonucleolytic Cleavage In The Expansion Segment 7 Of 25s Rrna Is An Early Marker Of Low-Level Oxidative Stress In Yeast, Daniel Shedlovskiy, Jessica A Zinskie, Ethan Gardner, Dimitri G Pestov, Natalia Shcherbik

Rowan-Virtua School of Osteopathic Medicine Departmental Research

The ability to detect and respond to oxidative stress is crucial to the survival of living organisms. In cells, sensing of increased levels of reactive oxygen species (ROS) activates many defensive mechanisms that limit or repair damage to cell components. The ROS-signaling responses necessary for cell survival under oxidative stress conditions remain incompletely understood, especially for the translational machinery. Here, we found that drug treatments or a genetic deficiency in the thioredoxin system that increase levels of endogenous hydrogen peroxide in the yeast Saccharomyces cerevisiae promote site-specific endonucleolytic cleavage in 25S ribosomal RNA (rRNA) adjacent to the c loop of …

Inhibition Of Post-Transcriptional Steps In Ribosome Biogenesis Confers Cytoprotection Against Chemotherapeutic Agents In A P53-Dependent Manner, Russell T Sapio, Anastasiya N Nezdyur, Matthew Krevetski, Leonid Anikin, Vincent J Manna, Natalie Minkovsky, Dimitri G Pestov

Rowan-Virtua School of Osteopathic Medicine Departmental Research

The p53-mediated nucleolar stress response associated with inhibition of ribosomal RNA transcription was previously shown to potentiate killing of tumor cells. Here, we asked whether targeting of ribosome biogenesis can be used as the basis for selective p53-dependent cytoprotection of nonmalignant cells. Temporary functional inactivation of the 60S ribosome assembly factor Bop1 in a 3T3 cell model markedly increased cell recovery after exposure to camptothecin or methotrexate. This was due, at least in part, to reversible pausing of the cell cycle preventing S phase associated DNA damage. Similar cytoprotective effects were observed after transient shRNA-mediated silencing of Rps19, but not …

Dnmt3a Haploinsufficiency Provokes Hematologic Malignancy Of B-Lymphoid, T-Lymphoid, And Myeloid Lineage In Mice, Garland Michael Upchurch

Theses & Dissertations

DNA methyltransferase 3A (DNMT3A) is a master epigenetic regulator of benign and malignant hematopoiesis. To dissect the biological consequences of homozygous and heterozygous Dnmt3a inactivation in malignant hematopoiesis, we generated Dnmt3a homozygous null (Dnmt3a^Δ/Δ) and Dnmt3a heterozygous (Dnmt3a^+/–) mice and compared the presentations of hematologic malignancies between cohorts. Bi-allelic inactivation of Dnmt3a results in the presentation of mature lymphoid neoplasms resembling chronic lymphocytic leukemia (CLL; B220⁺CD19⁺CD5⁺; 88% penetrance (37/42)) and CD8+ peripheral T-cell lymphoma (PTCL; TCRβ⁺CD3⁺CD8⁺CD4^—; 40% penetrance (17/42)). …

Germ-Line Gene Editing And Congressional Reaction In Context: Learning From Almost 50 Years Of Congressional Reactions To Biomedical Breakthroughs, Russell A. Spivak, J.D., I. Glenn Cohen, J.D., Eli Y. Adashi, M.D., M.S.

Journal of Law and Health

On December 18, 2015, President Obama signed into law a policy rider forestalling the therapeutic modification of the human germ line. The rider, motivated by the science’s potential unethical ends, is only the most recent instance in which the legislature cut short the ongoing national conversation on the acceptability of a developing science. This essay offers historical perspective on what bills were proposed and passed surrounding four other then-developing scientific breakthroughs—Recombinant DNA, in vitro fertilization, Cloning, Stem Cells—to better analyze how Congress is, and should, regulate this exciting and promising science.

Pas Signaling Mechanisms In Aer And Aer2, Darysbel Garcia

Loma Linda University Electronic Theses, Dissertations & Projects

PAS domains are widespread signal sensors that share a conserved three-dimensional αβ fold that consists of a central β-sheet flanked by several α- helices. The aerotaxis receptor Aer from Escherichia coli and the Aer2 chemoreceptor from Pseudomonas aeruginosa both contain PAS domains. Aer senses oxygen (O2) indirectly via an FAD cofactor bound to its PAS domain, while Aer2 directly binds O2 to its PAS b-type heme cofactor. The Aer and Aer2 PAS domains both interact with a signal transduction domain known as a HAMP domain. The PAS-HAMP arrangement differs between Aer and Aer2, with Aer- PAS residing adjacent to its …

Investigating The Role Of Dispatched In Hedgehog Ligand Transport And Delivery, William Bodeen

Theses and Dissertations (ETD)

During the development of all metazoans, the Hedgehog (Hh) signaling pathway provides instructional cues influencing a variety of cellular processes. The pathway ligand, Hh, is dually lipidated by cholesterol and palmitate, which effectively anchors the molecule to the lipid bilayer of the signal producing cell. To complicate the Hh pathway induction process, the Hh ligand is often produced at a significant distance from the cells it influences. Only one known conserved molecule, Dispatched (Disp), can alleviate the membrane tethering imparted by Hh lipidation. Underscoring the importance of Disp protein during development, knockout animals succumb to lethality at E9.5, an exact …

Activity Of Distinct Growth Factor Receptor Network Components In Breast Tumors Uncovers Two Biologically Relevant Subtypes, Moom Roosan, Shelley M. Macneil, David F. Jenkins, Gajendra Shrestha, Sydney R. Wyatt, Jasmine A. Mcquerry, Stephen R. Piccolo, Laura M. Heiser, Joe W. Gray, W. Evan Johnson, Andrea H. Bild

Pharmacy Faculty Articles and Research

Background
The growth factor receptor network (GFRN) plays a significant role in driving key oncogenic processes. However, assessment of global GFRN activity is challenging due to complex crosstalk among GFRN components, or pathways, and the inability to study complex signaling networks in patient tumors. Here, pathway-specific genomic signatures were used to interrogate GFRN activity in breast tumors and the consequent phenotypic impact of GRFN activity patterns.

Methods
Novel pathway signatures were generated in human primary mammary epithelial cells by overexpressing key genes from GFRN pathways (HER2, IGF1R, AKT1, EGFR, KRAS (G12V), RAF1, BAD). The pathway analysis toolkit Adaptive Signature Selection …

El Acceso Y Uso De Las Pruebas Genéticas Para La Detección Precoz De Enfermedades Congénitas En Mujeres Embarazadas En La Ciudad Autónoma De Buenos Aires En El Año 2017 \ The Access And Use Of Genetic Tests For Early Detection Of Congenital Diseases In Pregnant Women In The Autonomous City Of Buenos Aires In The Year 2017, Anna Anna Bauer

Independent Study Project (ISP) Collection

Las pruebas genéticas son una herramienta útil para la prevención y el diagnóstico de defectos congénitos en las mujeres embarazadas. Esta investigación explora el acceso y uso de estas pruebas para mujeres que residen en la Ciudad Autónoma de Buenos Aires en el año 2017. Se trata de un tema amerita una investigación porque la tecnología para hacer estudios genéticos todavía es algo novedosa. Además, a través de las pruebas genéticas es posible detectar si el feto tiene un alto riesgo para desarrollar un defecto congénito, el cual es una de las causas más importantes de la mortalidad prenatal y …

Fast Genome-Wide Qtl Association Mapping On Pedigree And Population Data, Hua Zhou, John Blangero, Thomas D. Dyer, Kei-Hang K. Chan, Kenneth Lange, Eric M. Sobel

School of Medicine Publications

Since most analysis software for genome-wide association studies (GWAS) currently exploit only unrelated individuals, there is a need for efficient applications that can handle general pedigree data or mixtures of both population and pedigree data. Even datasets thought to consist of only unrelated individuals may include cryptic relationships that can lead to false positives if not discovered and controlled for. In addition, family designs possess compelling advantages. They are better equipped to detect rare variants, control for population stratification, and facilitate the study of parent-of-origin effects. Pedigrees selected for extreme trait values often segregate a single gene with strong effect. …

P33. Design And Evaluation Of An Escherichia Coli Biomarker For Indication Of Ph, Kevin X. Zhou, Luana Langlois, Ashmita Singh, John Prince

Western Research Forum

Measuring pH is one of the most commonly used techniques in both the laboratory as well as the field due to its importance in a multitude of biochemical processes. Traditional methods of measuring pH may be highly developed in accuracy and precision but often involve disruption of the environment. Biological markers offer an alternative that allows for long-term pH monitoring. This innovative approach allows for vast applications such as in the manufacturing, food processing and research industries. Under moderate acidic conditions, the asr (acid shock RNA) gene is highly inducible and has been demonstrated to be crucial for growth at …

Employing The Enzyme Cofactor Function Of Ascorbic Acid To Affect Oncogenic Pathways In Human Melanoma: Modulating Hypoxia Inducible Factor-1Α And Dna Demethylation To Reduce Malignant Potential, Adam Patrick Fischer

Theses, Dissertations and Capstones

Dioxygenase enzymes such as the HIF hydroxylases (PHD1-3, FIH) and the Ten-eleven translocation (TET1-3) enzymes regulate the activity of the hypoxia inducible factor-1_a (HIF1_a) transcription factor and the DNA methylation status of cells, respectively. Aberrant accumulation and activation of HIF-1_a can allow malignant cells to acquire attributes that promote progression, chemotherapy resistance, and survival, while aberrant hypermethylation of gene promoters can silence the expression of tumor suppressor genes essential to preventing tumorigenesis. Inadequate levels of intracellular ascorbic acid (AA), a necessary cofactor for optimal dioxygenase enzyme function, could potentiate these tumorigenic conditions. In fact, plasma levels …

Adoptees’ Experiences With Direct-To-Consumer Genetic Testing: Emotions, Satisfaction, And Motivating Factors, Anna Childers

Theses and Dissertations

Public awareness of the role of genetics in disease continues to expand along with the use of direct-to-consumer genetic testing (DTC-GT). One subset of customers taking advantage of the growing DTC-GT market is adoptees. Prior research has shown that adoptees appear to be more motivated than non-adoptees to learn about their genetic disease risk but have similar responses to health-related information acquired through DTC-GT. In this exploratory qualitative study, fourteen adoptees were asked about their motivations for pursuing DTC-GT; satisfaction with results; emotions throughout the process; and interest in meeting with a genetic counselor. Motivations for pursuing DTCGT fell into …

Assessment Of Patient Satisfaction With The Provision Of Fertility Information In Women With Lynch Syndrome, Rachel Elizabeth Hickey

Theses and Dissertations

Lynch Syndrome (LS), one of the most common hereditary cancer syndromes, is primarily known for its substantially increased risks for colorectal cancer. The incidence of gynecologic cancers (endometrial and ovarian cancers) equals or exceeds the incidence of colorectal cancers in female patients with LS. The prevention and treatment methods for these cancers can drastically affect fertility and reproduction. Previous studies with cancer patients have revealed challenges in acquiring information related to these topics; thus far, no research has assessed whether there is an informational gap regarding fertility information for women in the LS population. The purpose of this study was …

Sleep Disturbances And Depression: The Role Of Genes And Trauma, Mackenzie J. Lind

Theses and Dissertations

Sleep disturbances and insomnia are prevalent, with around 33% of adults indicating that they experience at least one main symptom of insomnia, and bidirectional relationships exist with common psychopathology, particularly major depressive disorder (MDD). However, genetic and environmental (e.g., traumatic event exposure) contributions to the etiology of these phenotypes are not yet well understood. A genetically informative sample of approximately 12,000 Han Chinese women aged 30-60 (50% with recurrent MDD) was used to address several gaps within the sleep literature. Sleep disturbances were assessed in all individuals using a general item addressing sleeplessness (GS). A sleep within depression sum score …

Multiethnic Genome-Wide Meta-Analysis Of Ectopic Fat Depots Identifies Loci Associated With Adipocyte Development And Differentiation, Audrey Y. Chu, Xuan Deng, Virginia A. Fisher, Alexander Drong, Yang Zhang, Mary F. Feitosa, Ching-Ti Liu, Olivia Weeks, Audrey C. Choh, Qing Duan, Thomas D. Dyer

School of Medicine Publications

Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men for six ectopic fat traits in European, African, Hispanic, and Chinese ancestry populations, with and without sex stratification. In total, 7 new loci were identified in association with ectopic fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; PATXN1 and UBE2E2 …

Integrative Genomic And Transcriptomic Analysis For Pinpointing Recurrent Alterations Of Plant Homeodomain Genes And Their Clinical Significance In Breast Cancer, Huimei Yu, Yuanyuan Jiang, Lanxin Liu, Wenqi Shan, Xiaofang Chu, Zhe Yang, Zeng-Quan Yang

Oncology Faculty Publications

A wide range of the epigenetic effectors that regulate chromatin modification, gene expression, genomic stability, and DNA repair contain structurally conserved domains called plant homeodomain (PHD) fingers. Alternations of several PHD finger-containing proteins (PHFs) due to genomic amplification, mutations, deletions, and translocations have been linked directly to various types of cancer. However, little is known about the genomic landscape and the clinical significance of PHFs in breast cancer. Hence, we performed a large-scale genomic and transcriptomic analysis of 98 PHF genes in breast cancer using TCGA and METABRIC datasets and correlated the recurrent alterations with clinicopathological features and survival of …

Multipoint Genome-Wide Linkage Scan For Nonword Repetition In A Multigenerational Family Further Supports Chromosome 13q As A Locus For Verbal Trait Disorders, D. T. Truong, L. D. Shriberg, S. D. Smith, K. L. Chapman, A. R. Scheer-Cohen, M. M.C. Demille, A. K. Adams, Alejandro Q. Nato Jr., E. M. Wijsman, J. D. Eicher, J. R. Gruen

Biochemistry and Microbiology

Verbal trait disorders encompass a wide range of conditions and are marked by deficits in five domains that impair a person’s ability to communicate: speech, language, reading, spelling, and writing. Nonword repetition is a robust endophenotype for verbal trait disorders that is sensitive to cognitive processes critical to verbal development, including auditory processing, phonological working memory, and motor planning and programming. In the present study, we present a six-generation extended pedigree with a history of verbal trait disorders. Using genome-wide multipoint variance component linkage analysis of nonword repetition, we identified a region spanning chromosome 13q14–q21 with LOD = 4.45 between …

Regulation Of Cancer Metastasis By Protein Kinase D1: A Global Regulatory Cascade, Aditya Ganju

Theses and Dissertations (ETD)

Protein Kinase D1 (PKD1) is a serine threonine kinase which is downregulated in Prostate, Breast and Colon Cancer. It functions as a tumor suppressor in different cancer cells. Downregulation of PKD1 is known to be associated with aggressiveness of the cancer. PKD1 is known to regulate many key oncogenic signaling pathways such as E-cadherin, β-catenin and Androgen Receptor signaling pathways. Aberrant expression of these oncogenic pathways leads to transformation of cells from normal to malignant phenotype, thereby leading to increased proliferation, growth and metastasis to distant organs of these cancer cells. Literature evidence also points to the fact that E-cadherin …

High-Throughput Allele-Specific Expression Across 250 Environmental Conditions, Gregory A. Moyerbrailean, Allison L. Richards, Daniel Kurtz, Cynthia A. Kalita, Gordon O. Davis, Chris T. Harvey, Adnan Alazizi, Donovan Watza, Yoram Sorokin, Nancy J. Hauff, Xiang Zhou, Xiaoquan Wen, Roger Pique-Regi, Francesca Luca

Center for Molecular Medicine and Genetics

Gene-by-environment (GxE) interactions determine common disease risk factors and biomedically relevant complex traits. However, quantifying how the environment modulates genetic effects on human quantitative phenotypes presents unique challenges. Environmental covariates are complex and difficult to measure and control at the organismal level, as found in GWAS and epidemiological studies. An alternative approach focuses on the cellular environment using in vitro treatments as a proxy for the organismal environment. These cellular environments simplify the organism-level environmental exposures to provide a tractable influence on subcellular phenotypes, such as gene expression. Expression quantitative trait loci (eQTL) mapping studies identified GxE interactions in response …

Replication-Transciption Switch In Human Mitochondria, Karen Agaronyan

Graduate School of Biomedical Sciences Theses and Dissertations

Coordinated replication and expression of mitochondrial genome is critical for metabolically active cells during various stages of development. However, it is not known whether replication and transcription can occur simultaneously without interfering with each other and whether mtDNA copy number can be regulated by the transcription machinery. Human mitochondrial RNA polymerase (mtRNAP) is a central enzyme involved in gene expression in mitochondria. It generates genome-size polycistronic transcripts and also makes replication primers at two origins of replication. MtRNAP is distantly related to phage T7 RNAP. While T7 RNAP is optimized to produce large amounts of transcripts to overcompete the bacterial …