Male and female mice show equal variability in food intake across 4-day spans that encompass estrous cycles.

The exclusion of female rodents from biomedical research is well documented and persists in large part due to perceptions that ovulatory cycles render female traits more variable than those of males, and females must be tested at each of four stages of the estrous cycle to generate reliable data. These beliefs are not empirically based. The magnitude of trait variance associated with the estrous cycle may be sufficiently low and of little impact, or trait variability of males tested on 4 consecutive days may be as great as that of females over the 4 days of the estrous cycle. Here, we analyzed food intake data from mice in 4-day blocks, corresponding to the females 4-day estrous cycle in several schedules of food procurement or reward. Variance was compared within and across individual mice. In no instance did the overall variance differ by sex under any of the food reward schedules. This extends earlier observations of trait variability in body temperature and locomotor activity of mice and supports the claim that there is no empirical basis for excluding female rodents from biomedical research

Portacaval Transposition in the Rat: A New Model for Investigation of Portal-Systemic Encephalopathy

The object of this work was to establish an experimental model in the rat to examine the relative roles of portal-systemic diversion and of impaired liver function in the pathogenesis of chronic portal-systemic encephalopathy (PSE). The problem with conventional end-to-side portacaval shunting, both clinically and in the experimental animal, is that in addition to producing total shunting of portal blood into the systemic circulation, the procedure itself leads to hepatocellular atrophy and impaired hepatic function. For this reason the new model of portacaval transposition (PCT) was developed in the rat. In this preparation total portal shunting takes place, but blood flow through the portal tracts of the liver is replaced by systemic blood from the inferior vena cava. Comparison of this model with the conventional portacaval shunt (PCS) should allow separation of the two phenomena of shunting and liver dysfunction. This is of some clinical importance, since it has been proposed that selection of patients or "tailoring" of portal diversion procedures on the basis of haemodynamic characteristics should lead to a lower incidence of chronic post-shunt encephalopathy, which remains the major clinical disadvantage of such operations. It was first established (Chapter III) that PCT is attended by retention of a normal body growth pattern, little reduction in relative liver weight, and maintenance of normal hepatic morphology. This contrasts with PCS, following which there is impaired body growth and specific atrophy of the liver with marked histological changes. Since PCS rats were shown to have reduced food intake, the specific nature of these findings was confirmed by using PCT and control animals which were pair-fed against PCS rats. It was also demonstrated that biochemical parameters of liver function were better conserved in the PCT preparation. It was further confirmed by use of radio-labelled Rose Bengal clearance that liver blood flow was in fact reduced in PCS rats and normal after PCT. Sections prepared from the rapidly perfused brains of these animals were examined microscopically (Chapter IV). In both groups (and in a small number of control animals) it was possible to identify changes in the astroglial cells similar to those described by Alzheimer and characteristic of the brain in PSE in man and in experimental animals. However, these changes were significantly greater in the PCS rats than in the PCT rats, and in one experiment the abnormal cell count in PCT rats did not differ from control values. These results were also validated in a small group of pair-fed animals. This finding confirms the importance of hepatic dysfunction in the pathogenesis of central nervous system damage in these models, and suggests that maintenance of total hepatic blood flow even in the absence of direct perfusion by portal blood might confer protection against the development of PSE. A characteristic pattern of plasma amino acids was seen following PCS, with reduction in the branched-chain amino acids valine, leucine and isoleucine, and elevation of the aromatic amino acids tyrosine and phenylalanine. This pattern, which characterizes chronic liver failure and PSE in man and experimental animals, was not seen after PCT (Chapter V). SUMMARY Similar results were found in the pair-feeding experiment. Plasma insulin and glucagon levels were elevated to a similar degree after PCS and PCT. These results suggest that the hormone elevation seen as a result of portal-systemic diversion cannot entirely explain the amino acid imbalance, which appears to depend largely upon hepatic dysfunction in the PCS rats. Changes in levels of glutamine, glutamate and tryptophan, substances known to be associated with central nervous system neurotransmission and possibly with glial function, were also examined (Chapter V). The differences observed did not achieve statistical significance, although the patterns seen amongst the groups were consistent with small but biologically important changes masked by metabolic compartmentation within the brain. We conclude that the PCT model has proved valuable in separating the effects of portal diversion from those of hepatic dysfunction. The results confirm the vital role of normal liver function in protecting the brain against damage resulting from portal-systemic diversion, and suggest that liver function may be maintained close to normal even in the absence of direct portal perfusion if total liver blood flow is maintained. These findings are in keeping with the observation in man that a substantial compensatory increase in arterial flow following total portal diversion results in a lesser degree of encephalopathy. The establishment of the PCS/PCT model permits a further degree of refinement in future studies of the fundamental biochemical and cellular mechanisms of hepatic coma

Sex differences in variability across timescales in BALB/c mice.

BackgroundFemales are markedly underinvestigated in the biological and behavioral sciences due to the presumption that cyclic hormonal changes across the ovulatory cycle introduce excess variability to measures of interest in comparison to males. However, recent analyses indicate that male and female mice and rats exhibit comparable variability across numerous physiological and behavioral measures, even when the stage of the estrous cycle is not considered. Hormonal changes across the ovulatory cycle likely contribute cyclic, intra-individual variability in females, but the source(s) of male variability has, to our knowledge, not been investigated. It is unclear whether male variability, like that of females, is temporally structured and, therefore, quantifiable and predictable. Finally, whether males and females exhibit variability on similar time scales has not been explored.MethodsThese questions were addressed by collecting chronic, high temporal resolution locomotor activity (LA) and core body temperature (CBT) data from male and female BALB/c mice.ResultsContrary to expectation, males are more variable than females over the course of the day (diel variability) and exhibit higher intra-individual daily range than females in both LA and CBT. Between mice of a given sex, variability is comparable for LA but the inter-individual daily range in CBT is greater for males. To identify potential rhythmic processes contributing to these sex differences, we employed wavelet transformations across a range of periodicities (1-39 h).ConclusionsAlthough variability in circadian power is comparable between the sexes for both LA and CBT, infradian variability is greater in females and ultradian variability is greater in males. Thus, exclusion of female mice from studies because of estrous cycle variability may increase variance in investigations where only male measures are collected over a span of several hours and limit generalization of findings from males to females

The role of ATP and adenosine in the control of hepatic blood flow in the rabbit liver in vivo

BACKGROUND: The role of adenosine and ATP in the regulation of hepatic arterial blood flow in the "buffer response" was studied in vitro and in a new in vivo model in the rabbit. The model achieves portal-systemic diversion by insertion of a silicone rubber prosthesis between the portal vein and inferior vena cava and avoids alterations in systemic haemodynamics. RESULTS: Hepatic arterial (HA) blood flow increased in response to reduced portal venous (PV) blood flow, the "buffer response", from 19.4 (3.3) ml min(-1 )100 g(-1 )to 25.6 (4.3) ml min(-1 )100 g(-1 )(mean (SE), p < 0.05, Student's paired t-test). This represented a buffering capacity of 18.7 (5.2) %. Intra-portal injections of ATP or adenosine (1 micrograms kg(-1)-0.5 mg kg(-1)) elicited immediate increases in HA blood flow to give -log ED(50 )values of 2.0 and 1.7 mg kg(-1 )for ATP and adenosine respectively. Injection of ATP and adenosine had no measurable effect on PV flow. In vitro, using an isolated dual-perfused rabbit liver preparation, the addition of 8-phenyltheophylline (10 MicroMolar) to the HA and PV perfusate significantly inhibited the HA response to intra-arterial adenosine and to mid-range doses of intra-portal or intra-arterial ATP (p < 0.001). CONCLUSIONS: It is suggested that HA vasodilatation elicited by ATP may be partially mediated through activation of P(1)-purinoceptors following catabolism of ATP to adenosine

Fine-Tuning Language Models via Epistemic Neural Networks

Large language models are now part of a powerful new paradigm in machine learning. These models learn a wide range of capabilities from training on large unsupervised text corpora. In many applications, these capabilities are then fine-tuned through additional training on specialized data to improve performance in that setting. In this paper, we augment these models with an epinet: a small additional network architecture that helps to estimate model uncertainty and form an epistemic neural network (ENN). ENNs are neural networks that can know what they don't know. We show that, using an epinet to prioritize uncertain data, we can fine-tune BERT on GLUE tasks to the same performance while using 2x less data. We also investigate performance in synthetic neural network generative models designed to build understanding. In each setting, using an epinet outperforms heuristic active learning schemes

Alcohol as a Risk Factor for Type 2 Diabetes: A systematic review and meta-analysis

OBJECTIVE - To clarify the dose-response relationship between alcohol consumption and type 2 diabetes.RESEARCH DESIGN AND METHODS - A systematic computer-assisted and hand search was conducted to identify relevant articles with longitudinal design and quantitative measurement of alcohol consumption. Adjustment was made for the sick-quitter effect. We used fractional polynomials in a meta-regression to determine the dose-response relationships by sex and end point using lifetime abstainers as the reference group.RESULTS - The search revealed 20 cohort studies that met our inclusion criteria. A U-shaped relationship was found for both sexes. Compared with lifetime abstainers, the relative risk (RR) for type 2 diabetes among men was most protective when consuming 22 g/day alcohol (RR 0.87 [95% CI 0.76-1.00]) and became deleterious at just over 60 g/day alcohol (1.01 [0.71-1.44]). Among women, consumption of 24 g/day alcohol was most protective (0.60 [0.52-0.69]) and became deleterious at about 50 g/day alcohol (1.02 [0.83-1.26]).CONCLUSIONS - Our analysis confirms previous research findings that moderate alcohol consumption is protective for type 2 diabetes in men and women