Early Acid/Base and Electrolyte Changes in Permanent Middle Cerebral Artery Occlusion: Aged Male and Female Rats

BACKGROUND: Early changes in acid/base and electrolyte concentrations could provide insights into the development of neuropathology at the onset of stroke. We evaluated associations between acid/base and electrolyte concentrations, and outcomes in permanent middle cerebral artery occlusion (pMCAO) model. METHODS: 18-month-old male and female Sprague-Dawley rats underwent pMCAO. Pre-, post- (7 min after occlusion), and at 72 hr of pMCAO venous blood samples provided pH, carbon dioxide, oxygen, glucose, hematocrit, hemoglobin, and electrolyte values of ionized calcium, potassium, and sodium. Multiple linear regression determined predictors of infarct and edema volumes from these values, Kaplan-Meier curve analyzed morality between males and females at 72 hr, and a Cox regression model was used to determine predictors for mortality. RESULTS: Analysis indicated significant differences in acid/base balance and electrolyte levels in aged rats not dependent on sex between the three time points in the pMCAO model. Changes in pH (from pre- to post and post- to 72 hr) and changes in sodium and ionized calcium (from post- to 72 hr) were predictors of infarct volume and edema volume, respectively. Cox Regression revealed there is a 3.25 times increased risk for mortality based on changes in bicarbonate (pre- to post-MCAO). CONCLUSIONS: These early venous blood changes in acid/base balance and electrolytes can be used to predict stroke outcomes in our rat model of stroke. This study provides potential biomarkers to be examined in the human condition that could provide profound prognostic tools for stroke patients

Translational Evaluation of Acid/Base and Electrolyte Alterations in Rodent Model of Focal Ischemia

BACKGROUND AND PURPOSE: Acid/base and electrolytes could provide clinically valuable information about cerebral infarct core and penumbra. We evaluated associations between acid/base and electrolyte changes and outcomes in 2 rat models of stroke, permanent, and transient middle cerebral artery occlusion. METHODS: Three-month old Sprague-Dawley rats underwent permanent or transient middle cerebral artery occlusion. Pre- and post-middle cerebral artery occlusion venous samples for permanent and transient models provided pH, carbon dioxide, oxygen, glucose, and electrolyte values of ionized calcium, potassium, and sodium. Multiple regression determined predictors of infarct volume from these values, and Kaplan-Meier curve analyzed morality between permanent and transient middle cerebral artery occlusion models. RESULTS: Analysis indicated significant differences in the blood gas and electrolytes between pre- to post-middle cerebral artery occlusion. A decrease in pH and sodium with increases in carbon dioxide, potassium, ionized calcium, and glucose changes were found in both middle cerebral artery occlusion models; while hematocrit and hemoglobin were significant in the transient model. pH and ionized calcium were predictors of infarct volume in the permanent model, as changes in pH and ionized calcium decreased, infarct volume increased. CONCLUSIONS: There are acute changes in acid/base balance and electrolytes during stroke in transient and permanent rodent models. Additionally, we found pH and ionized calcium changes predicted stroke volume in the permanent middle cerebral artery occlusion model. These preliminary findings are novel, and warrant further exploration in human conditions

Vaccination with Venezuelan equine encephalitis replicons encoding cowpox virus structural proteins protects mice from intranasal cowpox virus challenge

An anti-poxvirus vaccine based on replicon particles of Venezuelan equine encephalitis virus (VRP) is being developed. The cowpox virus genes encoding structural proteins corresponding to vaccinia virus proteins A33, B5, and A27 were each expressed from VRP. High serum IgG titers against these proteins were generated in BALB/c mice vaccinated with each of these VRP. VRP induced both IgG1 and IgG2a with a strong predominance of IgG2a production. The response is long-lasting, as evidenced by the retention of high anti-B5 serum IgG titers through at least 50 weeks after priming immunization. Mice vaccinated with B5-, A33- or A27-VRP individually or together survived intranasal challenge with cowpox virus, with the multivalent vaccine formulation providing more effective protection from weight loss and clinical signs of illness than the monovalent vaccines. These results demonstrate that VRP may provide an effective alternative to vaccinia virus vaccines against poxvirus infection

The Rodin-Ohno hypothesis that two enzyme superfamilies descended from one ancestral gene: an unlikely scenario for the origins of translation that will not be dismissed

Abstract Background Because amino acid activation is rate-limiting for uncatalyzed protein synthesis, it is a key puzzle in understanding the origin of the genetic code. Two unrelated classes (I and II) of contemporary aminoacyl-tRNA synthetases (aaRS) now translate the code. Observing that codons for the most highly conserved, Class I catalytic peptides, when read in the reverse direction, are very nearly anticodons for Class II defining catalytic peptides, Rodin and Ohno proposed that the two superfamilies descended from opposite strands of the same ancestral gene. This unusual hypothesis languished for a decade, perhaps because it appeared to be unfalsifiable. Results The proposed sense/antisense alignment makes important predictions. Fragments that align in antiparallel orientations, and contain the respective active sites, should catalyze the same two reactions catalyzed by contemporary synthetases. Recent experiments confirmed that prediction. Invariant cores from both classes, called Urzymes after Ur = primitive, authentic, plus enzyme and representing ~20% of the contemporary structures, can be expressed and exhibit high, proportionate rate accelerations for both amino-acid activation and tRNA acylation. A major fraction (60%) of the catalytic rate acceleration by contemporary synthetases resides in segments that align sense/antisense. Bioinformatic evidence for sense/antisense ancestry extends to codons specifying the invariant secondary and tertiary structures outside the active sites of the two synthetase classes. Peptides from a designed, 46-residue gene constrained by Rosetta to encode Class I and II ATP binding sites with fully complementary sequences both accelerate amino acid activation by ATP ~400 fold. Conclusions Biochemical and bioinformatic results substantially enhance the posterior probability that ancestors of the two synthetase classes arose from opposite strands of the same ancestral gene. The remarkable acceleration by short peptides of the rate-limiting step in uncatalyzed protein synthesis, together with the synergy of synthetase Urzymes and their cognate tRNAs, introduce a new paradigm for the origin of protein catalysts, emphasize the potential relevance of an operational RNA code embedded in the tRNA acceptor stems, and challenge the RNA-World hypothesis. Reviewers This article was reviewed by Dr. Paul Schimmel (nominated by Laura Landweber), Dr. Eugene Koonin and Professor David Ardell

Cosmopolitan Sentiment: Politics, Charity, and Global Poverty

Duties to address global poverty face a motivation gap. We have good reasons for acting yet we do not, at least consistently. A ‘sentimental education’, featuring literature and journalism detailing the lives of distant others has been suggested as a promising means by which to close this gap (Nussbaum in Upheavals of Thought: The Intelligence of Emotions, CUP, Cambridge, 2001; Rorty in Truth and Progress: Philosophical Papers, vol. 3, CUP, Cambridge, 1998). Although sympathetic to this project, I argue that it is too heavily wed to a charitable model of our duties to address global poverty—understood as requiring we sacrifice a certain portion of our income. However, political action, aimed at altering institutions at both a global and a local level is likely to be necessary in order to provide effective long-term solutions to poverty globally. To rectify this, the article develops an alternative dialogical account of sentimental education, suitable for motivating support for political action to address global poverty

Functional Class I and II Amino Acid-activating Enzymes Can Be Coded by Opposite Strands of the Same Gene

Aminoacyl-tRNA synthetases (aaRS) catalyze both chemical steps that translate the universal genetic code. Rodin and Ohno offered an explanation for the existence of two aaRS classes, observing that codons for the most highly conserved Class I active-site residues are anticodons for corresponding Class II active-site residues. They proposed that the two classes arose simultaneously, by translation of opposite strands from the same gene. We have characterized wild-type 46-residue peptides containing ATP-binding sites of Class I and II synthetases and those coded by a gene designed by Rosetta to encode the corresponding peptides on opposite strands. Catalysis by WT and designed peptides is saturable, and the designed peptides are sensitive to active-site residue mutation. All have comparable apparent second-order rate constants 2.9–7.0E-3 m−1 s−1 or ∼750,000–1,300,000 times the uncatalyzed rate. The activities of the two complementary peptides demonstrate that the unique information in a gene can have two functional interpretations, one from each complementary strand. The peptides contain phylogenetic signatures of longer, more sophisticated catalysts we call Urzymes and are short enough to bridge the gap between them and simpler uncoded peptides. Thus, they directly substantiate the sense/antisense coding ancestry of Class I and II aaRS. Furthermore, designed 46-mers achieve similar catalytic proficiency to wild-type 46-mers by significant increases in both kcat and Km values, supporting suggestions that the earliest peptide catalysts activated ATP for biosynthetic purposes

Brexit and the work-family conflict:a Scottish perspective

This paper examines the Scottish Government’s desire to maintain ties with EU law post-Brexit in the context of employment and equality law, particularly those laws which impact on work-family conflict. The paper critically examines whether there is, or could be, a distinctly Scottish perspective in the context of work-family rights post-Brexit. The paper frames the analysis by considering the potentially gendered implications of Brexit in this context. In doing so, it examines this issue from the perspective of traditional heterosexual dual-partnered working family models. It is argued that rights for working fathers will be most vulnerable post-Brexit, with related consequences for working mothers. Consequently, the implications of Brexit in this context are primarily viewed through the lens of working fathers. The paper then critically examines the Scottish Government’s position on EU employment and equality law in the post-Brexit context

No father required? The welfare assessment in the Human Fertilisation and Embryology Act 2008

Of all the changes to the Human Fertilisation and Embryology Act 1990 that were introduced in 2008 by legislation of the same name, foremost to excite media attention and popular controversy was the amendment of the so-called welfare clause. This clause forms part of the licensing conditions which must be met by any clinic before offering those treatment services covered by the legislation. The 2008 Act deleted the statutory requirement that clinicians consider the need for a father of any potential child before offering a woman treatment, substituting for it a requirement that clinicians must henceforth consider the child’s need for “supportive parenting”. In this paper, we first briefly recall the history of the introduction of s 13(5) in the 1990 Act, before going on to track discussion of its amendment through the lengthy reform process that preceded the introduction of the 2008 Act. We then discuss the meaning of the phrase “supportive parenting” with reference to guidance regarding its interpretation offered by the Human Fertilisation and Embryology Authority. While the changes to s 13(5) have been represented as suggesting a major change in the law, we suggest that the reworded section does not represent a significant break from the previous law as it had been interpreted in practice. This raises the question of why it was that an amendment that is likely to make very little difference to clinical practice tended to excite such attention (and with such polarising force). To this end, we locate debates regarding s 13(5) within a broader context of popular anxieties regarding the use of reproductive technologies and, specifically, what they mean for the position of men within the family

Beyond the Bayley: Neurocognitive Assessments of Development During Infancy and Toddlerhood

The use of global, standardized instruments is conventional among clinicians and researchers interested in assessing neurocognitive development. Exclusively relying on these tests for evaluating effects may underestimate or miss specific effects on early cognition. The goal of this review is to identify alternative measures for possible inclusion in future clinical trials and interventions evaluating early neurocognitive development. The domains included for consideration are attention, memory, executive function, language and socio-emotional development. Although domain-based tests are limited, as psychometric properties have not yet been well-established, this review includes tasks and paradigms that have been reliably used across various developmental psychology laboratories