Development of a Functional Skin Matrix Requires Deposition of Collagen V Heterotrimers

ABSTRACT Collagen V is a minor component of the heterotypic I/III/V collagen fibrils and the defective product in most cases of classical Ehlers Danlos syndrome (EDS). The present study was undertaken to elucidate the impact of collagen V mutations on skin development, the most severely affected EDS tissues, using mice harboring a targeted deletion of the α2(V) collagen gene (Col5a2). Contrary to the original report, our studies indicate that the Col5a2 deletion (a.k.a. the pN allele) represents a functionally null mutation that affects matrix assembly through a complex sequence of events. First the mutation impairs assembly and/or secretion of the α1(V)2α2(V) heterotrimer with the result that the α1(V) homotrimer is the predominant species deposited into the matrix. Second, the α1(V) homotrimer is excluded from incorporation into the heterotypic collagen fibrils and this in turn severely impairs matrix organization. Third, the mutant matrix stimulates a compensatory loop by the α1(V) collagen gene that leads to additional deposition of α1(V) homotrimers. These data therefore underscore the importance of the collagen V heterotrimer in dermal fibrillogenesis. Furthermore, reduced thickness of the basement membranes underlying the epidermis and increased apoptosis of the stromal fibroblasts in pN/pN skin strongly indicate additional roles of collagen V in the development of a functional skin matrix.

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Mutations of the alpha2(V) chain of type V collagen impair matrix assembly and produce ehlers-danlos syndrome type I

Human Molecular Genetics ◽

10.1093/hmg/7.2.249 ◽

1998 ◽

Vol 7 (2) ◽

pp. 249-255 ◽

Cited By ~ 86

Author(s):

K Michalickova

Keyword(s):

Type I ◽

Syndrome Type ◽

Matrix Assembly ◽

Ehlers Danlos Syndrome ◽

Type V Collagen ◽

Type V ◽

Danlos Syndrome

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Endothelial k-RasV12 Expression Induces Capillary Deficiency Attributable to Marked Tube Network Expansion Coupled to Reduced Pericytes and Basement Membranes

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.121.316798 ◽

2021 ◽

Author(s):

Zheying Sun ◽

Scott S. Kemp ◽

Prisca K. Lin ◽

Kalia N. Aguera ◽

George E. Davis

Keyword(s):

Protein Kinase ◽

Basement Membrane ◽

Arteriovenous Malformations ◽

Network Formation ◽

Tube Formation ◽

Small Gtpase ◽

Basement Membranes ◽

Formation Mechanisms ◽

Lumen Formation ◽

The Impact

Objective: We sought to determine how endothelial cell (EC) expression of the activating k-Ras mutation, k-RasV12, affects their ability to form lumens and tubes and interact with pericytes during capillary assembly Approach and Results: Using defined bioassays where human ECs undergo observable tubulogenesis, sprouting behavior, pericyte recruitment to EC-lined tubes, and pericyte-induced EC basement membrane deposition, we assessed the impact of EC k-RasV12 expression on these critical processes that are necessary for proper capillary network formation. This mutation, which is frequently seen in human ECs within brain arteriovenous malformations, was found to markedly accentuate EC lumen formation mechanisms, with strongly accelerated intracellular vacuole formation, vacuole fusion, and lumen expansion and with reduced sprouting behavior, leading to excessively widened tube networks compared with control ECs. These abnormal tubes demonstrate strong reductions in pericyte recruitment and pericyte-induced EC basement membranes compared with controls, with deficiencies in fibronectin, collagen type IV, and perlecan deposition. Analyses of signaling during tube formation from these k-RasV12 ECs reveals strong enhancement of Src, Pak2 (P21 [RAC1 (Rac family small GTPase 1)] activated kinase 2), b-Raf (v-raf murine sarcoma viral oncogene homolog B1), Erk (extracellular signal–related kinase), and Akt activation and increased expression of PKCε (protein kinase C epsilon), MT1-MMP (membrane-type 1 matrix metalloproteinase), acetylated tubulin and CDCP1 (CUB domain-containing protein 1; most are known EC lumen regulators). Pharmacological blockade of MT1-MMP, Src, Pak, Raf, Mek (mitogen-activated protein kinase) kinases, Cdc42 (cell division cycle 42)/Rac1, and Notch markedly interferes with lumen and tube formation from these ECs. Conclusions: Overall, this novel work demonstrates that EC expression of k-RasV12 disrupts capillary assembly due to markedly excessive lumen formation coupled with strongly reduced pericyte recruitment and basement membrane deposition, which are critical pathogenic features predisposing the vasculature to develop arteriovenous malformations.

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Cytokine Overproduction and Immune System Dysregulation in alloHSCT and COVID-19 Patients

Frontiers in Immunology ◽

10.3389/fimmu.2021.658896 ◽

2021 ◽

Vol 12 ◽

Author(s):

Andrzej Lange ◽

Janusz Lange ◽

Emilia Jaskuła

Keyword(s):

Immune System ◽

Adaptive Immunity ◽

Inflammatory Cytokines ◽

Cytokine Production ◽

Conditioning Regimen ◽

Laboratory Data ◽

Hematopoietic Stem ◽

Post Transplant ◽

Sequence Of Events ◽

The Impact

The COVID-19 pathomechanism depends on (i) the pathogenicity of the virus, (ii) ability of the immune system to respond to the cytopathic effect of the virus infection, (iii) co-morbidities. Inflammatory cytokine production constitutes a hallmark of COVID-19 that is facilitated by inability of adaptive immunity to control virus invasion. The effect of cytokine release syndrome is deleterious, but the severity of it depends on other confounding factors: age and comorbidities. In this study, we analyze the literature data on the post-transplant course of allogeneic hematopoietic stem cell transplanted (alloHSCT) patients, which is affected by generated inflammatory cytokines. The sequence of events boosting cytokine production was analyzed in relation to clinical and laboratory data highlighting the impact of cytokine generation on the post-transplant course. The collected data were compared to those from studies on COVID-19 patients. The similarities are: (i) the damage/pathogen-associated molecular pattern (DAMP/PAMP) stage is similar except for the initiation hit being sterile in alloHSCT (toxic damage of conditioning regimen) and viral in COVID-19; (ii) genetic host-derived factors play a role; (iii) adaptive immunity fails, DAMP signal(s) increases, over-production of cytokines occurs; (iv) monocytes lacking HLADR expression emerge, being suppressor cells hampering adaptive immunity; (v) immune system homeostasis is broken, the patient’s status deteriorates to bed dependency, leading to hypo-oxygenation and malnutrition, which in turn stimulates the intracellular alert pathways with vigorous transcription of cytokine genes. All starts with the interaction between DAMPs with appropriate receptors, which leads to the production of pro-inflammatory cytokines, the inflammatory process spreads, tissue is damaged, DAMPs are released and a vicious cycle occurs. Attempts to modify intracellular signaling pathways in patients with post-alloHSCT graft vs host disease have already been undertaken. The similarities documented in this study show that this approach may also be used in COVID-19 patients for tuning signal transduction processes to interrupt the cycle that powers the cytokine overproduction.

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Timely Communication Through Telehealth: Added Value for a Caregiver During COVID-19

Frontiers in Public Health ◽

10.3389/fpubh.2021.755391 ◽

2021 ◽

Vol 9 ◽

Author(s):

Lauren Hajjar ◽

Ben Kragen

Keyword(s):

Chronic Disease ◽

Pediatric Patient ◽

Care Coordination ◽

Informal Caregiver ◽

Relational Coordination ◽

Coordination Of Care ◽

Ehlers Danlos Syndrome ◽

Coordination Theory ◽

Provider Payment ◽

The Impact

Objective: This caregiver case study applies the lens of relational coordination theory (RC) to examine the value of telehealth as a medium of care coordination for a pediatric patient with hypermobile Ehlers-Danlos Syndrome (hEDS) during the COVID-19 pandemic.Background: The COVID-19 pandemic has placed an unprecedented burden on the delivery of healthcare around the globe and has increased the reliance on telehealth services. Delivering telehealth requires a high level of communication and coordination within and across providers as well as between providers, patients and their families. However, it is less clear how telehealth impacts the coordination of care. In this paper, we provide insight into the quality of care coordination between providers and an informal caregiver following policy changes to the provider payment structure in Massachusetts.Methods: This paper employs a single-case, autoethnographic study design where one of the authors uses their experiential insights, as mother of the patient, to inform a wider cultural and political understanding of the shift to remote caregiving for a pediatric patient with hEDS. Data was collected using reflective journaling, interactive interviews, and participant observation and analyzed using content analysis.Results: Findings revealed four interrelating roles of the caregiver including, logistics support, boundary spanner, home health aide, and cultural translator. The adoption of telehealth was associated with improved timeliness and frequency of communication between the caregiver and providers. Findings about the impact of telehealth adoption on accuracy of communication were mixed. Mutual respect between the caregiver and providers remained unchanged during the study period.Conclusions: This paper highlights areas where payer policy may be modified to incentivize timely communication and improve coordination of care through telehealth services. Additional insight from the perspective of an informal caregiver of a patient with a rare chronic disease provides an understudied vantage to the care coordination process. We contribute to relational coordination theory by observing the ways that caregivers function as boundary spanners, and how this process was facilitated by the adoption of telehealth. Insights from this research will inform the development of telehealth workflows to engage caregivers in a way that adds value and strengthens relational coordination in the management of chronic disease.

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Introduction: Understanding the Partisan-Chetnik Conflict

Genocide and Resistance in Hitler’s Bosnia ◽

10.5871/bacad/9780197263808.003.0001 ◽

2006 ◽

Author(s):

Marko Attila Hoare

Keyword(s):

Sequence Of Events ◽

History Of ◽

The Impact

This introductory chapter sets out the purpose of the book, which is to present a history of the birth and rise of the Partisans in Bosnia-Hercegovina, as a Communist-led movement of resistance to the German and Italian occupiers and their domestic collaborators; of the emergence of a Chetnik movement as a conservative, Serb-nationalist rival to the Partisans; and of the conflict between the two. It analyses the impact that the conflict with the Chetniks had on Partisan policy and organization, and the evolution of the Partisan movement under the influence of this conflict. Finally, it examines the sequence of events that enabled the Partisans to emerge effectively as the victors in the contest with the Chetniks in Bosnia-Hercegovina by the autumn of 1943, and the reasons for the Partisan success. An overview of the subsequent chapters is also presented.

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Spray-Dried Amorphous Solid Dispersions of Griseofulvin in HPC/Soluplus/SDS: Elucidating the Multifaceted Impact of SDS as a Minor Component

Pharmaceutics ◽

10.3390/pharmaceutics12030197 ◽

2020 ◽

Vol 12 (3) ◽

pp. 197 ◽

Cited By ~ 6

Author(s):

Mahbubur Rahman ◽

Stephanie Ahmad ◽

James Tarabokija ◽

Nathaniel Parker ◽

Ecevit Bilgili

Keyword(s):

Solid Dispersions ◽

Sodium Dodecyl ◽

Minor Component ◽

Amorphous Solid ◽

Amorphous Solid Dispersions ◽

Acetone Water ◽

Poorly Soluble ◽

A Minor ◽

The Impact ◽

Spray Dried

This study aimed to elucidate the impact of a common anionic surfactant, sodium dodecyl sulfate (SDS), along with hydroxypropyl cellulose (HPC) and Soluplus (Sol) on the release of griseofulvin (GF), a poorly soluble drug, from amorphous solid dispersions (ASDs). Solutions of 2.5% GF and 2.5%–12.5% HPC/Sol with 0.125% SDS/without SDS were prepared in acetone–water and spray-dried. The solid-state characterization of the ASDs suggests that GF–Sol had better miscibility and stronger interactions than GF–HPC and formed XRPD-amorphous GF, whereas HPC-based ASDs, especially the ones with a lower HPC loading, had crystalline GF. The dissolution tests show that without SDS, ASDs provided limited GF supersaturation (max. 250%) due to poor wettability of Sol-based ASDs and extensive GF recrystallization in HPC-based ASDs (max. 50%). Sol-based ASDs with SDS exhibited a dramatic increase in supersaturation (max. 570%), especially at a higher Sol loading, whereas HPC-based ASDs with SDS did not. SDS did not interfere with Sol’s ability to inhibit GF recrystallization, as confirmed by the precipitation from the supersaturated state and PLM imaging. The favorable use of SDS in a ternary ASD was attributed to both the wettability enhancement and its inability to promote GF recrystallization when used as a minor component along with Sol.

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The effect of performing versus preparing a task on the subsequent switch cost

Psychological Research ◽

10.1007/s00426-019-01254-7 ◽

2019 ◽

Cited By ~ 1

Author(s):

Rachel Swainson ◽

Laura Prosser ◽

Kostadin Karavasilev ◽

Aleksandra Romanczuk

Keyword(s):

Task Switching ◽

Relative Size ◽

Limited Extent ◽

Two Stage ◽

Subsequent Performance ◽

Sequence Of Events ◽

Switch Costs ◽

Task Preparation ◽

Switching Models ◽

The Impact

Abstract Behaviour occurs not as isolated incidents, but within an ongoing sequence of events. The task-switching paradigm provides a useful way to investigate the impact of different events upon subsequent performance. An implication of two-stage task-switching models is that preparing a task without performing it might affect task readiness only to a limited extent. However, recent research has surprisingly shown larger switch costs following preparation (“cue-only” trials) than following performance (“completed” trials). We set out to conduct a rigorous comparison of the size of switch costs following cue-only versus completed trials. In Experiments 1 and 2, we controlled the timing between critical trial events. This had the effect of roughly equating, but not reversing, the relative size of switch costs. In Experiment 3, we restructured the paradigm to equate the predictability of cue and target events. Switch costs following cue-only trials were now smaller than those following completed trials. These studies confirm that task preparation alone is sufficient to drive subsequent switch costs. They also indicate that task performance might increase the size of these costs, consistent with two-stage task-switching models. Switch costs appear to be affected by both the timing and predictability of trial events.

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Purges and Production: Soviet Economic Growth, 1928–1940

The Journal of Economic History ◽

10.1017/s0022050700075641 ◽

1975 ◽

Vol 35 (3) ◽

pp. 567-590 ◽

Cited By ~ 7

Author(s):

Barbaba G. Katz

Keyword(s):

Growth Rate ◽

Industrial Production ◽

Alternative Hypothesis ◽

Second World War ◽

Constant Elasticity ◽

Constant Elasticity Of Substitution ◽

Sequence Of Events ◽

Massive Scale ◽

The Impact ◽

Second World

Did preparations for the Second World War account for the precipitous drop in the growth rate of Soviet industrial production from 10–12 percent per annum in the period 1928–1937 to only 2–3 percent per annum in the period 1937–1940? According to some who study the Soviet economy the answer is “yes.” This view has been succinctly expressed by Stanley Cohn: “After 1937, the rising spectre of Hitler forced the Soviet leadership to shift resources into armaments on a massive scale. As a result, the growth rate fell drastically to 3.6 percent per year between 1937 and 1940.” Such a sequence of events, however, has never been empirically demonstrated. The purpose of this paper is to investigate formally the validity of this explanation, via aggregate production functions, particularly of the CES (constant elasticity of substitution) variety, as well as to explore an alternative hypothesis, espoused, among others, by Naum Jasny, Alec Nove and Warren Nutter. This hypothesis stresses a domestic factor as the major contributor to the disruption in industrial production: namely, the impact of Stalin's terror in the form of chaos-producing political purges.

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