Impaired one carbon metabolism and DNA methylation in alcohol toxicity

Excessive alcohol consumption is a prominent problem and one of the major causes of mortality and morbidity around the world. Long‐term, heavy alcohol consumption is associated with a number of deleterious health consequences, such as cancer, heart and liver disease, a variety of neurological, cognitive, and behavioral deficits. Alcohol consumption is also associated with developmental defects. The causes of alcohol‐induced toxicity are presently unclear. One of the mechanisms underlying alcohol toxicity has to do with its interaction with folic acid/homocysteine or one‐carbon metabolism (OCM). OCM is a major donor of methyl groups for methylation, particularly DNA methylation critical for epigenetic regulation of gene expression, and its disturbance may compromise DNA methylation, thereby affecting gene expression. OCM disturbance mediated by nutrient deficits is a well‐known risk factor for various disorders and developmental defects (e.g., neural tube defects). In this review, we summarize the role of OCM disturbance and associated epigenetic aberrations in chronic alcohol‐induced toxicity.

     

Invertebrate assemblages of pools in arid‐land streams have high functional redundancy and are resistant to severe drying

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Sulfenic acid chemistry,detection and cellular lifetime

Background

Reactive oxygen species-mediated cysteine sulfenic acid modification has emerged as an important regulatory mechanism in cell signaling. The stability of sulfenic acid in proteins is dictated by the local microenvironment and ability of antioxidants to reduce this modification. Several techniques for detecting this cysteine modification have been developed, including direct and in situ methods.

Scope of review

This review presents a historical discussion of sulfenic acid chemistry and highlights key examples of this modification in proteins. A comprehensive survey of available detection techniques with advantages and limitations is discussed. Finally, issues pertaining to rates of sulfenic acid formation, reduction, and chemical trapping methods are also covered.

Major conclusions

Early chemical models of sulfenic acid yielded important insights into the unique reactivity of this species. Subsequent pioneering studies led to the characterization of sulfenic acid formation in proteins. In parallel, the discovery of oxidant-mediated cell signaling pathways and pathological oxidative stress has led to significant interest in methods to detect these modifications. Advanced methods allow for direct chemical trapping of protein sulfenic acids directly in cells and tissues. At the same time, many sulfenic acids are short-lived and the reactivity of current probes must be improved to sample these species, while at the same time, preserving their chemical selectivity. Inhibitors with binding scaffolds can be rationally designed to target sulfenic acid modifications in specific proteins.

General significance

Ever increasing roles for protein sulfenic acids have been uncovered in physiology and pathology. A more complete understanding of sulfenic acid-mediated regulatory mechanisms will continue to require rigorous and new chemical insights. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn.     

Climate‐driven spatial mismatches between British orchards and their pollinators: increased risks of pollination deficits

Understanding how climate change can affect crop‐pollinator systems helps predict potential geographical mismatches between a crop and its pollinators, and therefore identify areas vulnerable to loss of pollination services. We examined the distribution of orchard species (apples, pears, plums and other top fruits) and their pollinators in Great Britain, for present and future climatic conditions projected for 2050 under the SRES A1B Emissions Scenario. We used a relative index of pollinator availability as a proxy for pollination service. At present, there is a large spatial overlap between orchards and their pollinators, but predictions for 2050 revealed that the most suitable areas for orchards corresponded to low pollinator availability. However, we found that pollinator availability may persist in areas currently used for fruit production, which are predicted to provide suboptimal environmental suitability for orchard species in the future. Our results may be used to identify mitigation options to safeguard orchard production against the risk of pollination failure in Great Britain over the next 50 years; for instance, choosing fruit tree varieties that are adapted to future climatic conditions, or boosting wild pollinators through improving landscape resources. Our approach can be readily applied to other regions and crop systems, and expanded to include different climatic scenarios.     

Videotaped Behavior as a Predictor of Clinical Outcome in Rhesus Macaques (Macaca mulatta)

Understanding the behavior of laboratory NHP facilitates health assessment and clinical care. We sought to characterize the behavior of critically ill rhesus macaques (Macaca mulatta) and determine whether specific behaviors or behavioral changes might facilitate the determination of prognosis and clinical endpoints. Twenty-two critically-ill subjects were videorecorded after they were removed from the outdoor breeding colony for diagnostic work-up and treatment. Subjects were categorized as survivors (n = 15) and those that were euthanized according to existing clinical endpoints (n = 7). Behavior before, during, and after cageside examination was compared between these groups with regard to the presence or absence of direct observation. This approach allowed us to determine whether these settings revealed differences between groups or masking of behaviors during direct observation. Before cageside examination, several behaviors (for example, self-grooming and anxiety behaviors) were significantly more common in surviving subjects than in euthanized subjects. Few significant differences in behavior were detectable during or after the examination. Subjects that were eventually euthanized showed more illness-related behaviors; however, not all animals requiring euthanasia showed these signs when an observer was present. Furthermore, euthanized animals spent more time in an alert posture during direct observation than at other times. Therefore, direct observation of critically ill rhesus macaques may not yield the most accurate assessment of illness severity, and using video to assess behavior may be helpful for prognosis.The assessment and recognition of pain and distress in laboratory animals is crucial to ensure welfare and high-quality research.^{6,10,12,20,23,26,28} Difficulty in identifying species-specific signs of pain and distress suggests that cageside assessment of clinical condition by an observer, as a stand-alone method, may not be an optimal method of determining prognosis in critically ill animals of some species.^10,24,26,27 The behavior of NHP, including rhesus macaques (Macaca mulatta), can be especially difficult to interpret due to their relatively stoic nature and tendency to mask clinical signs of illness in the presence of human observers.^{8,10,12,14,17} Two explanations for the tendency to mask pain, which is also observed in other species, are their status as a prey species and the need to hide weaknesses from group members.^3,17,22,23 According to the 2009 Institute for Laboratory Animal Research (ILAR) recommendations for recognizing pain and distress in nonhuman primates, “[v]iewing an animal from a distance or by video can aid in detecting subtle clinical changes.”¹² The goal of the current study was to evaluate the use of videotaped behavioral data to increase accuracy in predicting prognoses for rhesus macaques that are critically ill.A humane endpoint is defined as the earliest time at which an animal may experience unnecessary pain or distress, undue suffering, or impending death.^4,12 Both subjective and objective diagnostic criteria are currently used to define clinical and research endpoints.^{6,7,10,12,21,26,29}A myriad of diagnostics can be used for this purpose, including physical examination, cageside examination, blood assays (CBC and serum biochemistry), imaging (radiographs, ultrasound, CT, and MRI), bacterial culture and sensitivity, urinalysis, and collection of tissue samples (fine-needle aspiration and biopsy). One specific example of using clinical diagnostics to aid in the prediction of mortality in NHP involved using acid-base levels in animals with severe social trauma.¹¹ Behavioral assessment may be an important and underutilized diagnostic method for assessing pain and distress. Recent studies have evaluated the behavior, specifically facial expression, of mice to detect and assess pain.^16,19 Methods for evaluating behavior typically involve cageside examination, but assessment of behavior via videotape in the absence of an observer may also be useful.Endpoints may vary depending on species, nature of the research conducted, and assessment of degree of pain or distress. At our facility, experimental endpoints (those defined as part of a specific study) are differentiated from clinical endpoints (those determined by an animal''s health and quality of life). The veterinarian has the authority to elect euthanasia for an animal that is assessed to have reached an endpoint by either or both classifications. IACUC-approved endpoint policies have been established to aid in this decision. Criteria included in these guidelines include weight loss (excluding postpartum females and intended weight loss for obese animals), anorexia that is not responsive to treatment, diarrhea that is not responsive to treatment, and major organ failure that is not responsive to treatment. Veterinarians use cageside examination in the overall assessment of animals and to aid in the decision to euthanize.To our knowledge, the current study is the first to assess the behavior of critically ill rhesus macaques that controls for the cause of clinical presentation and to use observer presence or absence as an independent variable. To obtain information that may assist in refining clinical endpoints, we compared the behavior of critically ill rhesus macaques while an observer was absent, present, and recently present (labeled as preobservation, observation, and postobservation, respectively, in this text).We hypothesized that in comparison to in-person observation of critically ill rhesus macaques, the use of videotaping in the absence of direct observation would be more accurate in detecting differences in the behavior between those animals that eventually required euthanasia and those that did not. In addition, we hypothesized that behaviors would be suppressed (‘masked’) during direct observation, accounting for the reduced information available to the direct observer. If our hypothesis is supported, then videotaped behavior may be useful as a prognostic indicator that could be incorporated into development of clinical endpoints.     

Natural History of Cutaneous Human Papillomavirus (HPV) Infection in Men: The HIM Study

Accumulating evidence suggests that cutaneous human papillomavirus (HPV) infection is associated with non-melanoma skin cancer (NMSC). Little is known about the natural history of cutaneous HPV. A sub-cohort of 209 men with no NMSC history, initially enrolled in the HPV infection in men (HIM) study, were followed for a median of 12.6 months. Epidemiological data were collected through self-administered questionnaires. Cutaneous HPV DNA was measured in normal skin swabs (SS) and eyebrow hairs (EB) for 25 and 16 HPV types in genera β and γ, respectively. Any β HPV infection was more prevalent in SS (67.3%) compared to EB (56.5%, p = 0.04). Incidence in SS was higher than 20 per 1,000 person-months for HPV types 4, 5, 23, 38 and 76. Median duration of persistence of β and γ HPV infection was 8.6 and 6.1 months in EB, respectively, and 11.3 months and 6.3 months, in SS, respectively. Older age (>44 years vs. 18-30 years) was significantly associated with prevalent (SS OR = 3.0, 95% CI = 1.2–7.0) and persistent β HPV infection (EB OR = 6.1, 95% CI = 2.6–14.1). History of blistering sunburn was associated with prevalent (OR = 2.8, 95% CI = 1.3–5.8) and persistent (OR = 2.3, 95% CI = 1.2–4.6) β HPV infection in SS. Cutaneous HPV is highly prevalent in men, with age and blistering sunburn being significant risk factors for cutaneous β HPV infection.     

A Y chromosome census of the British Isles

The degree of population replacement in the British Isles associated with cultural changes has been extensively debated. Recent work has demonstrated that comparisons of genetic variation in the British Isles and on the European Continent can illuminate specific demographic processes in the history of the British Isles. For example, Wilson et al. used the similarity of Basque and Celtic Y chromosomes to argue for genetic continuity from the Upper Palaeolithic to the present in the paternal history of these populations (see also ). Differences in the Y chromosome composition of these groups also suggested genetic signatures of Norwegian influence in the Orkney Islands north of the Scottish mainland, an important center of Viking activities between 800 and 1300 A.D. More recently, Weale et al. argued for substantial Anglo-Saxon male migration into central England based on the analysis of eight British sample sets collected on an east-west transect across England and Wales. To provide a more complete assessment of the paternal genetic history of the British Isles, we have compared the Y chromosome composition of multiple geographically distant British sample sets with collections from Norway (two sites), Denmark, and Germany and with collections from central Ireland, representing, respectively, the putative invading and the indigenous populations. By analyzing 1772 Y chromosomes from 25 predominantly small urban locations, we found that different parts of the British Isles have sharply different paternal histories; the degree of population replacement and genetic continuity shows systematic variation across the sampled areas.     

Shape perception: complex contour representation in visual area V4

A recent study has put forward a physiologically plausible population model that implements a parts-based shape-coding scheme for macaque visual area V4.     

Negative feedback regulation of FGF signaling levels by Pyst1/MKP3 in chick embryos

BACKGROUND: The importance of endogenous antagonists in intracellular signal transduction pathways is becoming increasingly recognized. There is evidence in cultured mammalian cells that Pyst1/MKP3, a dual specificity protein phosphatase, specifically binds to and inactivates ERK1/2 mitogen-activated protein kinases (MAPKs). High-level Pyst1/Mkp3 expression has recently been found at many sites of known FGF signaling in mouse embryos, but the significance of this association and its function are not known. RESULTS: We have cloned chicken Pyst1/Mkp3 and show that high-level expression in neural plate correlates with active MAPK. We show that FGF signaling regulates Pyst1 expression in developing neural plate and limb bud by ablating and/or transplanting tissue sources of FGFs and by applying FGF protein or a specific FGFR inhibitor (SU5402). We further show by applying a specific MAP kinase kinase inhibitor (PD184352) that Pyst1 expression is regulated via the MAPK cascade. Overexpression of Pyst1 in chick embryos reduces levels of activated MAPK in neural plate and alters its morphology and retards limb bud outgrowth. CONCLUSIONS: Pyst1 is an inducible antagonist of FGF signaling in embryos and acts in a negative feedback loop to regulate the activity of MAPK. Our results demonstrate both the importance of MAPK signaling in neural induction and limb bud outgrowth and the critical role played by dual specificity MAP kinase phosphatases in regulating developmental outcomes in vertebrates.