Caveolae are specialized, invaginated plasma membrane domains that are defined morphologically and by the expression of signature proteins called, caveolins. Caveolae and caveolins are abundant in a ...variety of cell types including vascular endothelium, glia, and fibroblasts where they play critical roles in transcellular transport, endocytosis, mechanotransduction, cell proliferation, membrane lipid homeostasis, and signal transduction. Given these critical cellular functions, it is surprising that ablation of the caveolae organelle does not result in lethality suggesting instead that caveolae and caveolins play modulatory roles in cellular homeostasis. Caveolar components are also expressed in ocular cell types including retinal vascular cells, Müller glia, retinal pigment epithelium (RPE), conventional aqueous humor outflow cells, the corneal epithelium and endothelium, and the lens epithelium. In the eye, studies of caveolae and other membrane microdomains (i.e., “lipid rafts”) have lagged behind what is a substantial body of literature outside vision science. However, interest in caveolae and their molecular components has increased with accumulating evidence of important roles in vision-related functions such as blood-retinal barrier homeostasis, ocular inflammatory signaling, pathogen entry at the ocular surface, and aqueous humor drainage. The recent association of CAV1/2 gene loci with primary open angle glaucoma and intraocular pressure has further enhanced the need to better understand caveolar functions in the context of ocular physiology and disease. Herein, we provide the first comprehensive review of literature on caveolae, caveolins, and other membrane domains in the context of visual system function. This review highlights the importance of caveolae domains and their components in ocular physiology and pathophysiology and emphasizes the need to better understand these important modulators of cellular function.
This paper has two objectives. The first is to explore the form and action of raising and lowering operators expressed in geometric algebra (GA). The second is to show how increasing the number of ...dimensions of Euclidean space from three to four opens a new avenue for understanding the chiral asymmetry of electroweak interactions. These explorations are guided by isomorphisms among groups represented in complex Clifford algebra, matrix algebra, and GA. With these isomorphisms, expressions for raising and lowering operators for electron and neutrino states in complex Clifford algebra are translated into GA and elaborated to include positrons and antineutrinos. This paper addresses such operators in the context of the electroweak sector of the SM utilizing (1) the GA
G
3
for the Hestenes–Dirac equation in a Euclidean lab frame, (2)
G
4
to introduce chiral asymmetry, and (3)
G
4
,
1
to express the electroweak fermion states of the first generation of the SM and demonstrate their
SU
(2) relationships.
The E12-14-012 experiment, performed in Jefferson Lab Hall A, has measured the $(e, e'p)$ cross section in parallel kinematics using a natural argon target. Here, we report the full results of the ...analysis of the data set corresponding to beam energy 2.222 GeV, and spanning the missing momentum and missing energy range $15 \lesssim p_m \lesssim 300$ MeV/c and $12 \lesssim E_m \lesssim 80$ MeV. The reduced cross section, determined as a function of $p_m$ and $E_m$ with $\approx$4\% accuracy, has been fitted using the results of Monte Carlo simulations involving a model spectral function and including the effects of final state interactions. The overall agreement between data and simulations turns out to be quite satisfactory ($\chi^2$/n.d.o.f.=1.9). Furthermore, the resulting spectral function will provide valuable new information, needed for the interpretation of neutrino interactions in liquid argon detectors.
Polymorphisms in the CAV1/2 genes that encode signature proteins of caveolae are associated with glaucoma, the second leading cause of blindness worldwide, and with its major risk factor, intraocular ...pressure (IOP). We hypothesized that caveolin-1 (Cav-1) participates in IOP maintenance via modulation of aqueous humor drainage from the eye. We localize caveolae proteins to human and murine conventional drainage tissues and show that caveolae respond to mechanical stimulation. We show that Cav-1-deficient (Cav-1
) mice display ocular hypertension explained by reduced pressure-dependent drainage of aqueous humor. Cav-1 deficiency results in loss of caveolae in the Schlemm's canal (SC) and trabecular meshwork. However, their absence did not appear to impact development nor adult form of the conventional outflow tissues according to rigorous quantitative ultrastructural analyses, but did affect cell and tissue behavior. Thus, when IOP is experimentally elevated, cells of the Cav-1
outflow tissues are more susceptible to plasma membrane rupture indicating that caveolae play a role in mechanoprotection. Additionally, aqueous drainage from Cav-1
eyes was more sensitive to nitric oxide (NO) synthase inhibition than controls, suggesting that excess NO partially compensates for outflow pathway dysfunction. These results provide a functional link between a glaucoma risk gene and glaucoma-relevant pathophysiology.
Development of Biosimilars AL-Sabbagh, Ahmad, MD; Olech, Ewa, MD; McClellan, Joseph E., PhD, MBA ...
Seminars in arthritis and rheumatism,
04/2016, Letnik:
45, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Objective To provide an overview of the underlying scientific principles and standards for developing a biosimilar product. Methods An Internet-based literature search through June 2015 was performed ...for information related to biosimilar manufacturing and development, including a review of regulatory guidelines and requirements. Results Biologics, both biosimilars and their corresponding reference products, are complex molecules produced by biotechnology in living systems. The development of biologics involves multiple levels of intricate, highly controlled manufacturing processes, combined with preclinical structural, functional, and biological assessments, as well as clinical efficacy and safety, including immunogenicity, analyses. In addition, to ensure a high degree of similarity, a biosimilar must undergo a comparability exercise at every step of its development, as outlined by regulatory agencies, to demonstrate that potential differences from the reference product are not clinically meaningful with regard to quality, safety, and efficacy (European Medicines Agency EMA) or safety, purity, and potency (US Food and Drug Administration FDA). At the foundation of the biosimilar development process lays the establishment of a high degree of structural similarity with its reference product. State-of-the-art technologies must be employed to demonstrate a high degree of structural and functional similarity. Finally, clinical pharmacokinetic and pharmacodynamic as well as clinical efficacy and safety similarity must be confirmed between biosimilar and originator. Regulators, including the FDA and the EMA consider the totality of the evidence from this comprehensive step-wise comparative similarity exercise in its determination of biosimilarity for licensing. Conclusions The rigorous and highly regulated processes required to develop a biosimilar have been designed as such to establish a high degree of biosimilarity with a reference product in terms of the structural, functional, biological, and clinical attributes.
The E12-14-012 experiment, performed in Jefferson Lab Hall A, has measured the (e, e'p) cross section in parallel kinematics using a natural titanium target. In this paper, we report the analysis of ...the dataset obtained in different kinematics for our solid natural titanium target. Data were obtained in a range of missing momentum and missing energy between 15 ≲ pm ≲ 250 MeV / c and 12 ≲ Em ≲ 80 MeV, respectively, and using an electron beam energy of 2.2 GeV. We measured the reduced cross section with ~7% accuracy as a function of both missing momentum and missing energy. Furthermore, our Monte Carlo simulation, including both a model spectral function and the effects of final-state interactions, satisfactorily reproduces the data.
The development of a biosimilar is based on comparative structural, physicochemical, functional and clinical assessments. The sum of these analyses encompasses the 'totality of evidence', which ...demonstrates no clinically meaningful differences between the biosimilar and the reference product (RP). Once biosimilarity has been established, provided there is suitable scientific justification, clinical data may be extrapolated to other indications of the RP. AVT02 has been developed as a biosimilar to high-concentration, low-volume Humira (adalimumab), an anti-tumour necrosis factor-alpha monoclonal antibody approved for various chronic inflammatory indications. The totality of evidence for AVT02 is described, supporting its approval as an adalimumab biosimilar for all approved indications globally. Analytical similarity assessments using mass spectrometry methods demonstrated identical amino acid sequences for AVT02 and the RP, with high similarity in terms of primary structure, post-translational modifications and higher-order structural attributes. The mechanism of action was assessed by various cell-based potency assays and binding assays, and the results demonstrated that AVT02 is highly similar to the RP. No clinically meaningful differences in terms of purity, potency and safety were observed, and minor differences in a few physiochemical attributes did not impact the
biologic activity and were not considered clinically relevant. Clinical similarity was demonstrated by comparing the pharmacokinetic, efficacy, safety and immunogenicity profiles of AVT02 with those of the RP. Clinical studies supported similar pharmacokinetic and comparable immunogenicity profiles between AVT02 and the RP in healthy participants and participants with moderate-to-severe chronic plaque psoriasis, with no new safety signals detected. The totality of evidence described demonstrates the biosimilarity of AVT02 to the RP, thereby fulfilling the scientific and regulatory requirements for AVT02 as a high-concentration biosimilar for the treatment of chronic plaque psoriasis and all approved indications of the RP.
A 30-year reform movement in higher education--assessment of student learning outcomes--has become "an unavoidable condition of doing business" (Ewell 2002, 22) for colleges and universities. The ...majority of undergraduate institutions have established common learning goals and processes for gathering evidence of students' academic achievement (Kuh et al. 2014). A "scholarship of assessment" and a community of assessment professionals, coordinators, and committees have materialized (Ewell 2002; Kinzie and Jankowski 2015). Despite its success in entering the higher education mainstream, outcomes assessment activity on most campuses is wrapped in a "culture of compliance" (Kuh et al. 2015, 5). Skepticism about the purposes and value of assessment pervades academia, especially the arts and sciences (Ewell, Paulson, and Kinzie 2011). In political science--which has accomplished as much as any non-accredited discipline to promote understanding and best practices of assessment (Deardorff, Hamann, and Ishiyama 2009)--the dominant stance of most programs is acquiescence to outside demands rather than commitment from faculty to improve curriculum and instruction (Young, Cartwright, and Rudy 2014). This article examines outcomes assessment in higher education as a case study of policy implementation, taking three separate approaches to analyze why the assessment movement has encountered difficulty in achieving campus involvement and acceptance. Moreover, it shows that despite obstacles to effective implementation, assessment activity and use have risen in the past decade. The result is that outcomes assessment is here to stay, presenting challenges and opportunities for political scientists and the discipline.
Neurocognitive functioning is an integral phenotype of 22q11.2 deletion syndrome relating to severity of psychopathology and outcomes. A neurocognitive battery that could be administered remotely to ...assess multiple cognitive domains would be especially beneficial to research on rare genetic variants, where in-person assessment can be unavailable or burdensome. The current study compares in-person and remote assessments of the Penn computerised neurocognitive battery (CNB).
Participants (mean age = 17.82, SD = 6.94 years; 48% female) completed the CNB either in-person at a laboratory (n = 222) or remotely (n = 162).
Results show that accuracy of CNB performance was equivalent across the two testing locations, while slight differences in speed were detected in 3 of the 11 tasks.
These findings suggest that the CNB can be used in remote settings to assess multiple neurocognitive domains.
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