Final Phenotype Research Articles

Does the etiology of cardiac amyloidosis determine the myocardial uptake of [18F]-NaF PET/CT?

Cardiac amyloidosis (CA) leads to variable degrees of myocardial infiltration with a final echocardiographic phenotype of “hypertrophy.” Although many non-invasive imaging techniques (MRI, CT, scintigraphy, PET) are useful, the definitive diagnosis is still based on myocardial histology. We explored the possible role of [18F]-NaF PET/CT in the diagnosis of this disease in two cases with wild-type (ATTRwt) or mutant (ATTRm) Ile68Leu transthyretin (TTR)-related CA.

High Levels of Soluble Endoglin Induce a Proinflammatory and Oxidative-Stress Phenotype Associated with Preserved NO-Dependent Vasodilatation in Aortas from Mice Fed a High-Fat Diet

Aims: A soluble form of endoglin (sEng) was proposed to participate in the induction of endothelial dysfunction in small blood vessels. Here, we tested the hypothesis that high levels of sEng combined with a high-fat diet induce endothelial dysfunction in an atherosclerosis-prone aorta. Methods and Results: Six-month-old female and male transgenic mice overexpressing human sEng (Sol-Eng⁺) with low (Sol-Eng⁺low) or high (Sol-Eng⁺high) levels of plasma sEng were fed a high-fat rodent diet containing 1.25% cholesterol and 40% fat for 3 months. The plasma cholesterol and mouse sEng levels did not differ in the Sol-Eng⁺high and Sol-Eng⁺low mice. The expression of proinflammatory (P-selectin, ICAM-1, pNFκB and COX-2) and oxidative-stress-related markers (HO-1, NOX-1 and NOX-2) in the aortas of Sol-Eng⁺high female mice was significantly higher than in Sol-Eng⁺low female mice. Endothelium-dependent vasodilatation induced by acetylcholine was preserved better in the Sol-Eng⁺high female mice than in the Sol-Eng⁺low female mice. Conclusion: These results suggest that high concentrations of sEng in plasma in combination with a high-fat diet induce the simultaneous activation of proinflammatory, pro-oxidative and vasoprotective mechanisms in mice aorta and the balance of these biological processes determines whether the final endothelial phenotype is adaptive or maladaptive.

Expression of FBN1 during adipogenesis: Relevance to the lipodystrophy phenotype in Marfan syndrome and related conditions.

Fibrillin-1 is a large glycoprotein encoded by the FBN1 gene in humans. It provides strength and elasticity to connective tissues and is involved in regulating the bioavailability of the growth factor TGFβ. Mutations in FBN1 may be associated with depleted or abnormal adipose tissue, seen in some patients with Marfan syndrome and lipodystrophies. As this lack of adipose tissue does not result in high morbidity or mortality, it is generally under-appreciated, but is a cause of psychosocial problems particularly to young patients. We examined the role of fibrillin-1 in adipogenesis. In inbred mouse strains we found significant variation in the level of expression in the Fbn1 gene that correlated with variation in several measures of body fat, suggesting that mouse fibrillin-1 is associated with the level of fat tissue. Furthermore, we found that FBN1 mRNA was up-regulated in the adipose tissue of obese women compared to non-obese, and associated with an increase in adipocyte size. We used human mesenchymal stem cells differentiated in culture to adipocytes to show that fibrillin-1 declines after the initiation of differentiation. Gene expression results from a similar experiment (available through the FANTOM5 project) revealed that the decline in fibrillin-1 protein was paralleled by a decline in FBN1 mRNA. Examination of the FBN1 gene showed that the region commonly affected in FBN1-associated lipodystrophy is highly conserved both across the three human fibrillin genes and across genes encoding fibrillin-1 in vertebrates. These results suggest that fibrillin-1 is involved as the undifferentiated mesenchymal stem cells transition to adipogenesis but then declines as the developing adipocytes take on their final phenotype. Since the C-terminal peptide of fibrillin-1 is a glucogenic hormone, individuals with low fibrillin-1 (for example with FBN1 mutations associated with lipodystrophy) may fail to differentiate adipocytes and/or to accumulate adipocyte lipids, although this still needs to be shown experimentally.

Transgenerational effects enhance specific immune response in a wild passerine.

Vertebrate mothers transfer diverse compounds to developing embryos that can affect their development and final phenotype (i.e., maternal effects). However, the way such effects modulate offspring phenotype, in particular their immunity, remains unclear. To test the impact of maternal effects on offspring development, we treated wild breeding house sparrows (Passer domesticus) in Sevilla, SE Spain with Newcastle disease virus (NDV) vaccine. Female parents were vaccinated when caring for first broods, eliciting a specific immune response to NDV. The immune response to the same vaccine, and to the PHA inflammatory test were measured in 11-day-old chicks from their following brood. Vaccinated chicks from vaccinated mothers developed a stronger specific response that was related to maternal NDV antibody concentration while rearing their chicks. The chicks’ carotenoid concentration and total antioxidant capacity in blood were negatively related to NDV antibody concentration, whereas no relation with PHA response was found. Specific NDV antibodies could not be detected in 11-day-old control chicks from vaccinated mothers, implying that maternally transmitted antibodies are not directly involved but may promote offspring specific immunity through a priming effect, while other immunity components remain unaffected. Maternally transmitted antibodies in the house sparrow are short-lived, depend on maternal circulation levels and enhance pre-fledging chick specific immunity when exposed to the same pathogens as the mothers.

Clinical manifestations and long-term outcome of anti-Jo1 antisynthetase patients in a large cohort of Spanish patients from the GEAS-IIM group.

To evaluate the clinical manifestations, long-term clinical outcome and longitudinal pulmonary function in a large cohort of Spanish patients with anti-Jo1 antibodies. We retrospectively analyzed the clinical data and lung function parameters of 148 anti-Jo1 patients recruited from a multicentre registry including 18 Spanish hospitals. A composite endpoint was defined, comprising death due to respiratory failure directly related to antisynthetase syndrome (ASS), the need for long-term oxygen therapy or lung transplantation. Median follow-up was 78.3 months. Clinical presentation patterns at onset are as follows: isolated interstitial lung disease (ILD) (32.4%), isolated myositis (26.9%), concomitant myositis and ILD (22.8%), and isolated polyarthritis (17.9%). Myositis with ILD was the most frequent final clinical phenotype (67.6%). In most ASS patients, ILD was a non-progressive disease, tending to stabilize with therapy. The endpoint was reached in a significantly larger number of ILD patients with dyspnea at onset than those with paucisymptomatic or asymptomatic forms (p = 0.01). A steady FVC decrease was the hallmark of patients with end-stage lung disease. Estimated survival rates were 87.7% and 75.4% at 5 and 10 years, respectively. Cancer (p = 0.02) and advanced age at ASS diagnosis (p < 0.0001) were related to poorer survival. Mortality was significantly higher than in the general Spanish population, with a standardised mortality ratio (95% CI) of 4.03 (2.79-5.64). Anti-Jo1 ASS is a heterogeneous syndrome. ILD in ASS under immunosuppressive therapy is mainly a non-progressive disease. Dyspnea at ILD onset and a steady FVC decrease over time were related to a poorer respiratory prognosis.

Transcriptome profile of the early stages of breast cancer tumoral spheroids.

Oxygen or nutrient deprivation of early stage tumoral spheroids can be used to reliably mimic the initial growth of primary and metastatic cancer cells. However, cancer cell growth during the initial stages has not been fully explored using a genome-wide approach. Thus, in the present study, we investigated the transcriptome of breast cancer cells during the initial stages of tumoral growth using RNAseq in a model of Multicellular Tumor Spheroids (MTS). Network analyses showed that a metastatic signature was enriched as several adhesion molecules were deregulated, including EPCAM, E-cadherin, integrins and syndecans, which were further supported by an increase in cell migration. Interestingly, we also found that the cancer cells at this stage of growth exhibited a paradoxical hyperactivation of oxidative mitochondrial metabolism. In addition, we found a large number of regulated (long non coding RNA) lncRNAs, several of which were co-regulated with neighboring genes. The regulatory role of some of these lncRNAs on mRNA expression was demonstrated with gain of function assays. This is the first report of an early-stage MTS transcriptome, which not only reveals a complex expression landscape, but points toward an important contribution of long non-coding RNAs in the final phenotype of three-dimensional cellular models.

Foetal bovine serum-derived exosomes affect yield and phenotype of human cardiac progenitor cell culture.

Introduction: Cardiac progenitor cells (CPCs) represent a powerful tool in cardiac regenerative medicine. Pre-clinical studies suggest that most of the beneficial effects promoted by the injected cells are due to their paracrine activity exerted on endogenous cells and tissue. Exosomes are candidate mediators of this paracrine effects. According to their potential, many researchers have focused on characterizing exosomes derived from specific cell types, but, up until now, only few studies have analyzed the possible in vitro effects of bovine serum-derived exosomes on cell proliferation or differentiation. Methods: The aim of this study was to analyse, from a qualitative and quantitative point of view, the in vitro effects of bovine serum exosomes on human CPCs cultured either as cardiospheres or as monolayers of cardiosphere-forming cells. Results: Effects on proliferation, yield and molecular patterning were detected. We show, for the first time, that exogenous bovine exosomes support the proliferation and migration of human cardiosphere-forming cells, and that their depletion affects cardiospheres formation, in terms of size, yield and extra-cellular matrix production. Conclusion: These results stress the importance of considering differential biological effects of exogenous cell culture supplements on the final phenotype of primary human cell cultures.

Zinc in Early Life: A Key Element in the Fetus and Preterm Neonate.

Zinc is a key element for growth and development. In this narrative review, we focus on the role of dietary zinc in early life (including embryo, fetus and preterm neonate), analyzing consequences of zinc deficiency and adequacy of current recommendations on dietary zinc. We performed a systematic search of articles on the role of zinc in early life. We selected and analyzed 81 studies. Results of this analysis showed that preservation of zinc balance is of critical importance for the avoidance of possible consequences of low zinc levels on pre- and post-natal life. Insufficient quantities of zinc during embryogenesis may influence the final phenotype of all organs. Maternal zinc restriction during pregnancy influences fetal growth, while adequate zinc supplementation during pregnancy may result in a reduction of the risk of preterm birth. Preterm neonates are at particular risk to develop zinc deficiency due to a combination of different factors: (i) low body stores due to reduced time for placental transfer of zinc; (ii) increased endogenous losses; and (iii) marginal intake. Early diagnosis of zinc deficiency, through the measurement of serum zinc concentrations, may be essential to avoid severe prenatal and postnatal consequences in these patients. Typical clinical manifestations of zinc deficiency are growth impairment and dermatitis. Increasing data suggest that moderate zinc deficiency may have significant subclinical effects, increasing the risk of several complications typical of preterm neonates (i.e., necrotizing enterocolitis, chronic lung disease, and retinopathy), and that current recommended intakes should be revised to meet zinc requirements of extremely preterm neonates. Future studies evaluating the adequacy of current recommendations are advocated.

Biological Networks Underlying Abiotic Stress Tolerance in Temperate Crops--A Proteomic Perspective.

Abiotic stress factors, especially low temperatures, drought, and salinity, represent the major constraints limiting agricultural production in temperate climate. Under the conditions of global climate change, the risk of damaging effects of abiotic stresses on crop production increases. Plant stress response represents an active process aimed at an establishment of novel homeostasis under altered environmental conditions. Proteins play a crucial role in plant stress response since they are directly involved in shaping the final phenotype. In the review, results of proteomic studies focused on stress response of major crops grown in temperate climate including cereals: common wheat (Triticum aestivum), durum wheat (Triticum durum), barley (Hordeum vulgare), maize (Zea mays); leguminous plants: alfalfa (Medicago sativa), soybean (Glycine max), common bean (Phaseolus vulgaris), pea (Pisum sativum); oilseed rape (Brassica napus); potato (Solanum tuberosum); tobacco (Nicotiana tabaccum); tomato (Lycopersicon esculentum); and others, to a wide range of abiotic stresses (cold, drought, salinity, heat, imbalances in mineral nutrition and heavy metals) are summarized. The dynamics of changes in various protein functional groups including signaling and regulatory proteins, transcription factors, proteins involved in protein metabolism, amino acid metabolism, metabolism of several stress-related compounds, proteins with chaperone and protective functions as well as structural proteins (cell wall components, cytoskeleton) are briefly overviewed. Attention is paid to the differences found between differentially tolerant genotypes. In addition, proteomic studies aimed at proteomic investigation of multiple stress factors are discussed. In conclusion, contribution of proteomic studies to understanding the complexity of crop response to abiotic stresses as well as possibilities to identify and utilize protein markers in crop breeding processes are discussed.

ASSOCIATION OF POLYMORPHISM CMA 1/B (G1903A) WITH THE INDEX OXYGEN TRANSPORT SYSTEM OF THE BODY IN YOUNG MEN WITH DIFFERENT LEVELS OF MOTOR ACTIVITY

In the study, we investigated the association of polymorphic locus CMA 1/B (G1903A) with indicators of oxygen transport system of the body. To determine the nucleotide substitutions in the gene CMA1/B, we used RFLP- analysis, PCR products were digested with the restriction enzyme BstXI. Analysis of the distribution of frequencies of alleles and genotypes CMA1/B showed statistically significant differences in the frequency of polymorphic variants of genotypes between athletes and controls. Athletes have predominant genotype A/A (0,52), and G/G (0,4), whereas in the control group, the most common genotype A/G (0,58). Using factor analysis, we revealed differences in the structure of the association between indicators of oxygen transport system depending on the genotype of the gene CMA. It was revealed the association of polymorphic gene variants with red blood parameters, hemodynamic and respiratory systems, as well as with physical endurance and tolerance to the muscular load. The closest connection between the studied traits detected at polymorphic variants CMA A/A. At this genotype physical endurance largely depends on the state of the circulatory system and the respiratory system functional reserves. It was also shown the correlation between adaptive capabilities of cardiovascular system and efficiency of the heart functioning with the level of motor activity. The interaction complex of the features that characterize the activities of the cardiorespiratory system, system, causes the formation of the final phenotype, which obviously explains the detected frequency distribution of different genotypes in athletes.

Phenotypic variability of CMT4C in a French-Canadian kindred.

Charcot-Marie-Tooth type 4C (CMT4C) is an autosomal recessive dysmyelinating neuropathy characterized by precocious and rapidly progressive scoliosis. Patients in a French-Canadian kindred were evaluated with clinical examination, electrophysiologic study, and genomic DNA extraction. Six of 10 siblings were clinically symptomatic with supportive electrophysiologic features. The proband presented with regional side-to-side sensorimotor asymmetry, typical pes cavus without obvious scoliosis, and unremarkable plain films of the spine. Affected siblings all share symptoms of foot deformity but have variable onset of neuropathic symptoms, degree of extremity weakness, progression of symptoms, and, most notably, evidence of scoliosis. DNA sequence analysis revealed a novel combination of 2 known recessive mutations, p.R904X and p.R954X, in the SH3TC2 gene. A broad spectrum of phenotypes should be considered in the possible diagnosis of CMT4C. The absence of scoliosis or late-onset symptoms should not exclude SH3TC2 from the list of candidate genes under consideration. Age of onset and clinical features were variable and suggest that polygenic factors contribute to the final phenotype.

Spatiotemporal analyses of neural lineages after embryonic and postnatal progenitor targeting combining different reporters.

Genetic lineage tracing with electroporation is one of the most powerful techniques to target neural progenitor cells and their progeny. However, the spatiotemporal relationship between neural progenitors and their final phenotype remain poorly understood. One critical factor to analyze the cell fate of progeny is reporter integration into the genome of transfected cells. To address this issue, we performed postnatal and in utero co-electroporations of different fluorescent reporters to label, in both cerebral cortex and olfactory bulb, the progeny of subventricular zone neural progenitors. By comparing fluorescent reporter expression in the adult cell progeny, we show a differential expression pattern within the same cell lineage, depending on electroporation stage and cell identity. Further, while neuronal lineages arise from many progenitors in proliferative zones after few divisions, glial lineages come from fewer progenitors that accomplish many cell divisions. Together, these data provide a useful guide to select a strategy to track the cell fate of a specific cell population and to address whether a different proliferative origin might be correlated with functional heterogeneity.

Integrated omics for the identification of key functionalities in biological wastewater treatment microbial communities.

Biological wastewater treatment plants harbour diverse and complex microbial communities which prominently serve as models for microbial ecology and mixed culture biotechnological processes. Integrated omic analyses (combined metagenomics, metatranscriptomics, metaproteomics and metabolomics) are currently gaining momentum towards providing enhanced understanding of community structure, function and dynamics in situ as well as offering the potential to discover novel biological functionalities within the framework of Eco-Systems Biology. The integration of information from genome to metabolome allows the establishment of associations between genetic potential and final phenotype, a feature not realizable by only considering single ‘omes’. Therefore, in our opinion, integrated omics will become the future standard for large-scale characterization of microbial consortia including those underpinning biological wastewater treatment processes. Systematically obtained time and space-resolved omic datasets will allow deconvolution of structure–function relationships by identifying key members and functions. Such knowledge will form the foundation for discovering novel genes on a much larger scale compared with previous efforts. In general, these insights will allow us to optimize microbial biotechnological processes either through better control of mixed culture processes or by use of more efficient enzymes in bioengineering applications.

Association of TNF-α Gene Variants With Clinical Manifestation of Cystic Fibrosis Patients of Iranian Azeri Turkish Ethnicity.

Background:Cystic fibrosis (CF), a life-limiting autosomal recessive disorder, is considered a monogenic disease that is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. According to several studies, mutation analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene alone is insufficient to predict the phenotypic manifestations observed in cystic fibrosis (CF) patients. In addition, some patients with a milder CF phenotype do not carry any pathogenic mutation. Tumor Necrosis Factor-alpha (TNF-α) contributes to the pathophysiology of CF by causing cachexia. There is a reverse association between TNF-α concentration in patient's sputum and their pulmonary function.Objectives:To assess the effect of non-CFTR genes on the clinical phenotype of CF, two polymorphic sites (-1031T/C and -308G/A) of the TNF-α gene, as a modifier, were studied.Patients and Methods:Focusing on the lung and gastrointestinal involvement as well as the poor growth, we first investigated the role of TNF-α gene in the clinical manifestation of CF. Furthermore, based on the hypothesis that the cumulative effect of specific alleles of multiple CF modifier genes, such as TNF-α, may create the final phenotype, we also investigated the potential role of TNF-α in non-classic CF patients without a known pathogenic mutation. In all, 80 CF patients and 157 healthy control subjects of Azeri Turkish ethnicity were studied by the PCR–RFLP method. The chi-square test with Yates' correction and Fisher's exact test were used for statistical analysis.Results:The allele and genotype distribution of the investigated polymorphisms, and their associated haplotypes were similar in all groups.Conclusions:There was no evidence that supported the association of TNF-α gene polymorphisms with non-classic CF disease or the clinical presentation of classic CF.

Wavelet Analysis of Doppler Flow Velocity Waveforms from the Ocular Circulation Detects Abnormalities in Micro-vascular Function in Heart Failure

Aims: Many pathological processes may result in Heart Failure (HF), however, the final clinical phenotype appears to be common to all aetiologies. Microvascular abnormalities in HF have been demonstrated in a variety of vascular beds however the effect of HF on the retrobulbar circulation is not known. We employed a novel method of analysing blood flow velocity waveforms in order to quantify changes in the Doppler signal obtained from the retrobulbar arteries between HF patients and controls. FMD was also assessed. Methods and Results: 32 patients with systolic HF on maximal medical therapy and 10 age and sex-matched controls were studied. Doppler waveforms were obtained from the ophthalmic, central retinal and brachial artery in all subjects. Waveforms were analysed using a wavelet technique which expressed each waveform in constituent frequency bands, allowing direct comparisons to be made. Significant differences were found in ophthalmic and central retinal waveforms but not brachial waveforms between patients and controls. Flow mediated dilatation was also found to be abnormal in patients. Conclusion: This study suggests that abnormalities in microvascular function in the retrobulbar circulation are present in HF and that these changes can be detected by a novel wavelet analysis technique.

Frequency of COL4A3/COL4A4 mutations amongst families segregating glomerular microscopic hematuria and evidence for activation of the unfolded protein response. Focal and segmental glomerulosclerosis is a frequent development during ageing.

Familial glomerular hematuria(s) comprise a genetically heterogeneous group of conditions which include Alport Syndrome (AS) and thin basement membrane nephropathy (TBMN). Here we investigated 57 Greek-Cypriot families presenting glomerular microscopic hematuria (GMH), with or without proteinuria or chronic kidney function decline, but excluded classical AS. We specifically searched the COL4A3/A4 genes and identified 8 heterozygous mutations in 16 families (28,1%). Eight non-related families featured the founder mutation COL4A3-p.(G1334E). Renal biopsies from 8 patients showed TBMN and focal segmental glomerulosclerosis (FSGS). Ten patients (11.5%) reached end-stage kidney disease (ESKD) at ages ranging from 37-69-yo (mean 50,1-yo). Next generation sequencing of the patients who progressed to ESKD failed to reveal a second mutation in any of the COL4A3/A4/A5 genes, supporting that true heterozygosity for COL4A3/A4 mutations predisposes to CRF/ESKD. Although this could be viewed as a milder and late-onset form of autosomal dominant AS, we had no evidence of ultrastructural features or extrarenal manifestations that would justify this diagnosis. Functional studies in cultured podocytes transfected with wild type or mutant COL4A3 chains showed retention of mutant collagens and differential activation of the unfolded protein response (UPR) cascade. This signifies the potential role of the UPR cascade in modulating the final phenotype in patients with collagen IV nephropathies.

Genetic aspects of lone atrial fibrillation: what do we know?

Atrial fibrillation (AF) is the most common cardiac arrhythmia. A subgroup of patients presents with AF without traditional risk factors and is diagnosed before the age of 60 years. Such patients are commonly referred as having "lone AF" and comprise 10-20% of all cases. A number of studies have demonstrated that AF, and in particular lone AF, have a substantial genetic component. Genome-wide association studies (GWAS) have indicated that common single-nucleotide polymorphisms (SNPs) have a role in the development of AF. Furthermore, rare variants in genes encoding cardiac gap junction proteins, signalling molecules, ion channels, and accessory subunits have been associated with lone AF in several recent genetic reports. Most of these reports show gain-of-function or loss-of-function mutations, leading to increased risk of lone AF. To date, the pathophysiological mechanisms responsible for AF are not fully understood, and it is likely that this arrhythmia represents a final common phenotype of multiple. This review focuses on the genetic basis of lone AF and the role of both common and rare variants in the susceptibility of developing lone AF. Furthermore, three conceptual pathogenetic models of lone AF are discussed.

Impaired receptor editing and heterozygous RAG2 mutation in a patient with systemic lupus erythematosus and erosive arthritis

Impaired receptor editing and heterozygous RAG2 mutation in a patient with systemic lupus erythematosus and erosive arthritis

Epstein-Barr virus-encoded latent membrane protein 2A promotes the epithelial-mesenchymal transition in nasopharyngeal carcinoma via metastatic tumor antigen 1 and mechanistic target of rapamycin signaling induction.

Epstein-Barr virus-encoded latent membrane protein 2A (LMP2A) promotes the epithelial-mesenchymal transition (EMT) of nasopharyngeal carcinoma (NPC), thereby increasing tumor invasion. Recently, the dysregulation of metastatic tumor antigen 1 (MTA1) was found to enhance tumor metastasis in a variety of cancers. A molecular connection between these two proteins has been proposed but not firmly established. In this study, we reported the overexpression of MTA1 in 29/60 (48.3%) NPC patients, and the overexpression of MTA1 significantly correlated with tumor metastasis. The overexpression of MTA1 promoted EMT via the Wnt1 pathway and β-catenin activation. We demonstrated that LMP2A reinforces the expression of MTA1 via the mechanistic target of rapamycin (mTOR) pathway to promote EMT in NPC. Furthermore, by knocking down 4EBP1 in combination with the new mTOR inhibitor INK-128 treatment, we discovered that LMP2A expression activates the 4EBP1-eIF4E axis and increases the expression of MTA1 at the translational level partially independent of c-myc. These findings provided novel insights into the correlation between the LMP2A and MTA1 proteins and reveal a novel function of the 4EBP1-eIF4E axis in EMT of nasopharyngeal carcinoma. Importance: Prevention of the recurrence and metastasis of NPC is critical to achieving a successful NPC treatment. As we all know, EMT has a vital role in metastasis of malignancies. LMP2A, an oncoprotein of Epstein-Barr virus, a well-known NPC activator, induces EMT and has been proved to exert a promoting effect in tumor metastasis. Our study demonstrated that LMP2A could induce EMT by activating MTA1 at the translational level via activating mTOR signaling and the 4EBP1-eIF4E axis. Taken together, our findings bridge the gap between the NPC-specific cell surface molecule and the final phenotype of the NPC cells. Additionally, our findings indicate that LMP2A and mTOR will serve as targets for NPC therapy in the future.

Interrelationships Between Bones, Muscles, and Performance: Biting in the Lizard Tupinambis merianae

The origins of and potential constraints on the evolution of phenotypic diversity remain one of the central questions in evolutionary biology. The vertebrate skeleton is governed by historical, developmental, architectural, and functional constraints that all play a role in establishing its final form. Whereas the factors underlying shape variation in single bones are fairly well understood, this is less so the case for complex assemblages of bones as observed in the cranium or mandible. It is often suggested that the final phenotype must reflect the mechanical constraints imposed by the loading of the skeleton as bones remodel to withstand loading. Yet, in the cranium, in contrast to the mandible, the final phenotype is likely constrained by demands other than loading including the protection of sensory systems and the brain. Architectural design constraints may further limit the final form of complex units like the vertebrate cranium. Here we use geometric morphometric approaches to quantify the shape of the cranium and mandible in a lizard and test whether the observed shape co-varies with both the muscles attaching to these structures as well as functional traits such as bite force. Our results show that co-variation between the cranium and mandible is significant and likely driven by the muscles that link the two systems. Moreover, our results show that the patterns of co-variation are stronger between the mandible and ventral side of the cranium. Muscular cross sectional areas, bite force, and the ventral side of the cranium, also co-vary more than the dorsal side of the cranium does with muscle properties and function. Finally, our results show sex-specific patterns of co-variation with males showing a stronger degree of integration between the cranium, mandible, muscles and bite force suggesting that constraints on bite force drive the evolution of cranial shape to a greater extent in males compared to females.