Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is a rare genetic blood disorder that leads to abnormal bleeding due to absent capillaries and multiple abnormal blood vessels known as arteriovenous malformations. A feature of HHT is high-output heart failure due to multiple arteriovenous malformations. High-output heart failure can lead to recurrent epistaxis Kiesselbach area syndrome (REKAS), further exacerbating heart failure through increased blood loss and resultant anemia. We report a patient with HHT who presented with high-output heart failure contributing to REKAS. In patients with REKAS, we propose if anemia is present, REKAS can be avoided by correcting the anemia by increasing the hemoglobin level to greater than 9 to 10 g/dL. This decreases hyperdynamic circulation and reduces pressure in the blood vessels of the nose.

We recently showed that the Wiskott-Aldrich syndrome protein (WASP) family member,WASH, localizes to endosomal subdomains and regulates endocytic vesicle scission in an Arp2/3-dependent manner. Mechanisms regulating WASH activity are unknown. Here we show that WASH functions in cells within a 500 kDa core complex containing Strumpellin, FAM21, KIAA1033 (SWIP), and CCDC53. Although recombinant WASH is constitutively active toward the Arp2/3 complex, the reconstituted core assembly is inhibited, suggesting that it functions in cells to regulate actin dynamics through WASH. FAM21 interacts directly with CAPZ and inhibits its actin-capping activity. Four of the five core components show distant (approximately 15% amino acid sequence identify) but significant structural homology to components of a complex that negatively regulates the WASP family member, WAVE. Moreover, biochemical and electron microscopic analyses show that the WASH and WAVE complexes are structurally similar. Thus, these two distantly related WASP family members are controlled by analogous structurally related mechanisms. Strumpellin is mutated in the human disease hereditary spastic paraplegia, and its link to WASH suggests that misregulation of actin dynamics on endosomes may play a role in this disorder.

Neonatal Abstinence Syndrome (NAS) remains an ever-growing public health issue and a continued avenue for future research. The research question for this retrospective study was whether polysubstance exposure is related to the dose of medication the infant received or to the number of opioid-medications required to treat the infants’ withdrawal symptoms? The hypothesis for the retrospective study was there will be a significant relationship between polysubstance exposure and the dose of medication the infant received as well as the number of opioid-medications required to treat the infants’ withdrawal symptoms. A bivariate correlational indicated that there was not a significant association between the number of substances exposed to prenatally and the total number of drugs infants were treated with (n = 294, r = 0.093, p = .113). Additionally, within the largest group of pharmacologically treated infants (i.e., morphine), the highest dosage of morphine was not related to the number of drugs infants were exposed to prenatally, n = 195, r = -0.098, p = .172.

High-density lipoproteins and their major protein, apolipoprotein A-I (apoA-I), remove excess cellular cholesterol and protect against atherosclerosis. However, in acquired amyloidosis, non-variant full-length apoA-I deposits as fibrils in arteries contributing to atherosclerosis. In hereditary amyloidosis (AApoAI), a potentially fatal disease, N-terminal fragments of variant apoA-I deposit in vital organs and damage them. There is no cure for apoA-I amyloidosis and its structural basis is unknown. Previously, AApoAI mutations were mapped on the crystal structure of the human C-terminally truncated Δ(185-243)apoA-I. The results suggested that the mutation-induced destabilization of the lipid-free protein initiates β-aggregation. Our biophysical studies showed that amyloidogenic mutations G26R, W50R, F71Y and L170P did not necessarily destabilize the native structure, prompting us to search for additional triggers of apoA-I misfolding. We mapped residue segments predicted to promote β-aggregation (termed amyloid hot spots) on the atomic structure of ∆(185-243)apoA-I. The results suggested that perturbed packing of these hot spots, particularly residues 14-22, triggers amyloidosis. This enabled us to propose the first molecular mechanism of apoA-I misfolding. To explore a potential mechanism, we combined structural, stability, dynamics and functional studies of several amyloidogenic mutants and a non-amyloidogenic control, L159R. All mutants reduced structural protection of the segment 14-22, supporting our hypothesis that increased dynamics of this segment triggers AApoAI. The non-amyloidogenic mutant showed helical unfolding near the mutation site indicating susceptibility to proteolysis. We propose that the major factors that make apoA-I amyloidogenic are reduced protection of the major amyloidogenic segments combined with the structural integrity of the four-helix bundle to facilitate protein aggregation. Together, our results suggest that the fate of apoA-I in vivo depends on the balance between its misfolding, proteolysis, and protective protein-lipid interactions. Our structural and bioinformatics analysis of other members of the apolipoprotein family (A-II, A-IV, A-V, B, C-I, C-II, C-III, E, SAA) showed that apolipoproteins’ propensity to form amyloid is rooted in the proteins’ hydrophobicity, which is key to the lipid binding ability. The overlap of functional and pathologic interfaces suggests competition between normal protein function and misfolding. Therefore, increasing apolipoprotein retention on the lipid surface provides a potential therapeutic strategy against amyloidosis.

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Equine hyperelastosis cutis (HC or HERDA), a connective tissue disorder in American Quarter Horses, results in hyperelastic skin with poor wound healing. Similar conditions are found in many species and all forms display decreased skin tensile strength. Fibroblasts produce collagen and elastin fibers, forming networks, providing the dermis with strength, and elasticity. This study aims to carry out a 3-part evaluation between horse skin fibroblast (cells from horses affected with HERDA, cells from horses that are carriers of HERDA (recessive HERDA gene), and cells from horses that are normal (neither affected or carriers of HERDA); Studies include: 1. Cell proliferation assay 2. Apoptosis analysis of fibroblasts 3. Mechanobiology of stretched fibroblast. Studies have shown cellular deformation to have an overall effect on mechanical properties of healthy and unhealthy tissues. This investigation provides a micromechanical evaluation of HC/HERDA in an effort to quantify the cellular level differences between each condition.

Hereditary Equine Regional Derma Asthenia (HERDA) is a painful disfiguring autosomal recessive skin disorder of Quarter Horse lineages. Affected horses cannot be ridden and most are humanely destroyed. Five years following homozygosity mapping of a putative causal mutation responsible for HERDA, it remains unclear how this mutation causes the HERDA syndrome. HERDA horses have a missense mutation in peptidyl-prolyl cis-trans isomerase B (PPIB) which encodes cyclophilin B (CYPB) and alters folding and post-translational modifications of fibrillar collagen. Loss of function mutations in CYPB recognized in other species classically present as the debilitating bone disease, severe to lethal osteogenesis imperfect (OI). Objectives of this study were to develop a novel method for cryogenic clamping of tendons and ligaments of high tensile strength and validate its performance by ultimate tensile strength testing of normal equine deep digital flexor tendon. This validated method was then used to compare tendon and ligament of HERDA vs. control horses along with great vessels and skin. We hypothesized that all tissues of high fibrillar collagen content would have altered tensile properties due to the CYPB mutation affecting fibrous connective tissue globally within HERDA horses. Based on previous studies in our laboratory identifying reduced hydroxylysine content and altered collagen crosslink ratios in the skin of HERDA affected animals that implicate lysyl hydroxylase-1 (LH1) dysfunction, we hypothesized that the HERDA PPIB mutation modified an interaction between CYPB and LH1, interfering with hydroxylysine synthesis and its availability for collagen crosslink formation. In addition, we hypothesized that mutant CYPB may also lead to modifications of other known CYPB protein complexes, such as the CYPB, prolyl-3 hydroxylase-1 (P3H1) and cartilage associated protein (CRTAP) triplex. Goals of this study were to investigate the tensile properties of tissues with high fibrillar collagen content from HERDA homozygotes, to elucidate the mechanistic relationship of the HERDA CYPB mutation to the clinical disease, and to provide evidence to substantiate a heterozygote phenotype in HERDA which could be useful to explaining the correlation between lineages that carry the HERDA allele and performance outcomes in the discipline of western cutting competition.

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