The Role of the Mucus Barrier in Digestion

Mucus forms a protective layer across a variety of epithelial surfaces. In the gastrointestinal (GI) tract, the barrier has to permit the uptake of nutrients, while excluding potential hazards, such as pathogenic bacteria. In this short review article, we look at recent literature on the structure, location, and properties of the mammalian intestinal secreted mucins and the mucus layer they form over a wide range of length scales. In particular, we look at the structure of the gel-forming glycoprotein MUC2, the primary intestinal secreted mucin, and the influence this has on the properties of the mucus layer. We show that, even at the level of the protein backbone, MUC2 is highly heterogeneous and that this is reflected in the networks it forms. It is evident that a combination of charge and pore size determines what can diffuse through the layer to the underlying gut epithelium. This information is important for the targeted delivery of bioactive molecules, including nutrients and pharmaceuticals, and for understanding how GI health is maintained

Neurosteroid Activation of GABA-A Receptors: A Potential Treatment Target for Symptoms in Primary Biliary Cholangitis?

\ua9 2022 Aaron Wetten et al. Background and Aims. A third of patients with primary biliary cholangitis (PBC) experience poorly understood cognitive symptoms, with a significant impact on quality of life (QOL), and no effective medical treatment. Allopregnanolone, a neurosteroid, is a positive allosteric modulator of gamma-aminobutyricacid-A (GABA-A) receptors, associated with disordered mood, cognition, and memory. This study explored associations between allopregnanolone and a disease-specific QOL scoring system (PBC-40) in PBC patients. Method. Serum allopregnanolone levels were measured in 120 phenotyped PBC patients and 40 age and gender-matched healthy controls. PBC subjects completed the PBC-40 at recruitment. Serum allopregnanolone levels were compared across PBC-40 domains for those with none/mild symptoms versus severe symptoms. Results. There were no overall differences in allopregnanolone levels between healthy controls (median = 0.03 ng/ml (IQR = 0.025)) and PBC patients (0.031 (0.42), p=0.42). Within the PBC cohort, higher allopregnanolone levels were observed in younger patients (r (120) = -0.53, p<0.001) but not healthy controls (r (39) = -0.21, p=0.21). Allopregnanolone levels were elevated in the PBC-40 domains, cognition (u = 1034, p=0.02), emotional (u = 1374, p=0.004), and itch (u = 795, p=0.03). Severe cognitive symptoms associated with a younger age: severe (50 (12)) vs. none (60 (13); u = 423 p=0.001). Conclusion. Elevated serum allopregnanolone is associated with severe cognitive, emotional, and itch symptoms in PBC, in keeping with its known action on GABA-A receptors. Existing novel compounds targeting allopregnanolone could offer new therapies in severely symptomatic PBC, satisfying a significant unmet need

Vitamin D and subsequent all-age and premature mortality: a systematic review

<br>Background: All-cause mortality in the population < 65 years is 30% higher in Glasgow than in equally deprived Liverpool and Manchester. We investigated a hypothesis that low vitamin D in this population may be associated with premature mortality via a systematic review and meta-analysis.</br> <br>Methods: Medline, EMBASE, Web of Science, the Cochrane Library and grey literature sources were searched until February 2012 for relevant studies. Summary statistics were combined in an age-stratified meta-analysis.</br> <br>Results: Nine studies were included in the meta-analysis, representing 24,297 participants, 5,324 of whom died during follow-up. The pooled hazard ratio for low compared to high vitamin D demonstrated a significant inverse association (HR 1.19, 95% CI 1.12-1.27) between vitamin D levels and all-cause mortality after adjustment for available confounders. In an age-stratified meta-analysis, the hazard ratio for older participants was 1.25 (95% CI 1.14-1.36) and for younger participants 1.12 (95% CI 1.01-1.24).</br> <br>Conclusions: Low vitamin D status is inversely associated with all-cause mortality but the risk is higher amongst older individuals and the relationship is prone to residual confounding. Further studies investigating the association between vitamin D deficiency and all-cause mortality in younger adults with adjustment for all important confounders (or using randomised trials of supplementation) are required to clarify this relationship.</br&gt

Albuminuria and Microalbuminuria as Predictors of Cognitive Performance in a General Population: An 11-Year Follow-Up Study

Microalbuminuria, defined as urine albumin-to-creatinine ratio (UACR)> 3.0 mg/mmol and 3.0 mg/mmol), and cognitive impairment. Previous studies on microalbuminuria, albuminuria, and cognition in the middle-aged have not provided repeated cognitive testing at different time-points. We hypothesized that albuminuria (micro-plus macroalbuminuria) and microalbuminuria would predict cognitive decline independently of previously reported risk factors for cognitive decline, including cardiovascular risk factors. In addition, we hypothesized that UACR levels even below the cut-off for microalbuminuria might be associated with cognitive functioning. These hypotheses were tested in the Finnish nationwide, population-based Health 2000 Survey (n = 5,921, mean age 52.6, 55.0% women), and its follow-up, Health 2011 (n = 3,687, mean age at baseline 49.3, 55.6% women). Linear regression analysis was used to determine the associations between measures of albuminuria and cognitive performance. Cognitive functions were assessed with verbal fluency, word-list learning, word-list delayed recall (at baseline and at follow-up), and with simple and visual choice reaction time tests (at baseline only). Here, we show that micro-plus macroalbuminuria associated with poorer wordlist learning and a slower reaction time at baseline, with poorer word-list learning at follow-up, and with a steeper decline in word-list learning during 11 years after multivariate adjustments. Also, higher continuous UACR consistently associated with poorer verbal fluency at levels below microalbuminuria. These results suggest that UACR might have value in evaluating the risk for cognitive decline

Manganese as a Probe of Fungal Degradation of Wood

Transition state metals, such as manganese (Mn) and iron (Fe), have been reported to be involved in fungal degradation of wood (Ellis, 1959; Shortl

Genetic Tests for Ecological and Allopatric Speciation in Anoles on an Island Archipelago

From Darwin's study of the Galapagos and Wallace's study of Indonesia, islands have played an important role in evolutionary investigations, and radiations within archipelagos are readily interpreted as supporting the conventional view of allopatric speciation. Even during the ongoing paradigm shift towards other modes of speciation, island radiations, such as the Lesser Antillean anoles, are thought to exemplify this process. Geological and molecular phylogenetic evidence show that, in this archipelago, Martinique anoles provide several examples of secondary contact of island species. Four precursor island species, with up to 8 mybp divergence, met when their islands coalesced to form the current island of Martinique. Moreover, adjacent anole populations also show marked adaptation to distinct habitat zonation, allowing both allopatric and ecological speciation to be tested in this system. We take advantage of this opportunity of replicated island coalescence and independent ecological adaptation to carry out an extensive population genetic study of hypervariable neutral nuclear markers to show that even after these very substantial periods of spatial isolation these putative allospecies show less reproductive isolation than conspecific populations in adjacent habitats in all three cases of subsequent island coalescence. The degree of genetic interchange shows that while there is always a significant genetic signature of past allopatry, and this may be quite strong if the selection regime allows, there is no case of complete allopatric speciation, in spite of the strong primae facie case for it. Importantly there is greater genetic isolation across the xeric/rainforest ecotone than is associated with any secondary contact. This rejects the development of reproductive isolation in allopatric divergence, but supports the potential for ecological speciation, even though full speciation has not been achieved in this case. It also explains the paucity of anole species in the Lesser Antilles compared to the Greater Antilles

Multi-centre parallel arm randomised controlled trial to assess the effectiveness and cost-effectiveness of a group-based cognitive behavioural approach to managing fatigue in people with multiple sclerosis

Abstract (provisional) Background Fatigue is one of the most commonly reported and debilitating symptoms of multiple sclerosis (MS); approximately two-thirds of people with MS consider it to be one of their three most troubling symptoms. It may limit or prevent participation in everyday activities, work, leisure, and social pursuits, reduce psychological well-being and is one of the key precipitants of early retirement. Energy effectiveness approaches have been shown to be effective in reducing MS-fatigue, increasing self-efficacy and improving quality of life. Cognitive behavioural approaches have been found to be effective for managing fatigue in other conditions, such as chronic fatigue syndrome, and more recently, in MS. The aim of this pragmatic trial is to evaluate the clinical and cost-effectiveness of a recently developed group-based fatigue management intervention (that blends cognitive behavioural and energy effectiveness approaches) compared with current local practice. Methods This is a multi-centre parallel arm block-randomised controlled trial (RCT) of a six session group-based fatigue management intervention, delivered by health professionals, compared with current local practice. 180 consenting adults with a confirmed diagnosis of MS and significant fatigue levels, recruited via secondary/primary care or newsletters/websites, will be randomised to receive the fatigue management intervention or current local practice. An economic evaluation will be undertaken alongside the trial. Primary outcomes are fatigue severity, self-efficacy and disease-specific quality of life. Secondary outcomes include fatigue impact, general quality of life, mood, activity patterns, and cost-effectiveness. Outcomes in those receiving the fatigue management intervention will be measured 1 week prior to, and 1, 4, and 12 months after the intervention (and at equivalent times in those receiving current local practice). A qualitative component will examine what aspects of the fatigue management intervention participants found helpful/unhelpful and barriers to change. Discussion This trial is the fourth stage of a research programme that has followed the Medical Research Council guidance for developing and evaluating complex interventions. What makes the intervention unique is that it blends cognitive behavioural and energy effectiveness approaches. A potential strength of the intervention is that it could be integrated into existing service delivery models as it has been designed to be delivered by staff already working with people with MS. Service users will be involved throughout this research. Trial registration: Current Controlled Trials ISRCTN7651747

Factors associated with time delay to carotid stenting in patients with a symptomatic carotid artery stenosis

Treatment of a symptomatic stenosis is known to be most beneficial within 14 days after the presenting event but this can frequently not be achieved in daily practice. The aim of this study was the assessment of factors responsible for this time delay to treatment. A retrospective analysis of a prospective two-center CAS database was carried out to investigate the potential factors that influence a delayed CAS treatment. Of 374 patients with a symptomatic carotid stenosis, 59.1% were treated beyond ≥14 days. A retinal TIA event (OR = 3.59, 95% CI 1.47–8.74, p < 0.01) was found to be a predictor for a delayed treatment, whereas the year of the intervention (OR = 0.32, 95% CI 0.20–0.50, p < 0.01) and a contralateral carotid occlusion (OR = 0.42, 95% CI 0.21–0.86, p = 0.02) were predictive of an early treatment. Similarly, within the subgroup of patients with transient symptoms, the year of the intervention (OR = 0.28, 95% CI 0.14–0.59, p < 0.01) was associated with an early treatment, whereas a retinal TIA as the qualifying event (OR = 6.96, 95% CI 2.37–20.47, p < 0.01) was associated with a delayed treatment. Treatment delay was most pronounced in patients with an amaurosis fugax, whereas a contralateral carotid occlusion led to an early intervention. Although CAS is increasingly performed faster in the last years, there is still scope for an even more accelerated treatment strategy, which might prevent future recurrent strokes prior to treatment

Reading during the composition of multi-sentence texts: an eye-movement study

Writers composing multi-sentence texts have immediate access to a visual representation of what they have written. Little is known about the detail of writers’ eye movements within this text during production. We describe two experiments in which competent adult writers’ eye-movements were tracked while performing short expository writing tasks. These are contrasted with conditions in which participants read and evaluated researcher-provided texts. Writers spent a mean of around 13% of their time looking back into their text. Initiation of these look-back sequences was strongly predicted by linguistically important boundaries in their ongoing production (e.g., writers were much more likely to look back immediately prior to starting a new sentence). 36% of look-back sequences were associated with sustained reading and the remainder with less patterned forward and backward saccades between words ("hopping"). Fixation and gaze durations and the presence of word-length effects suggested lexical processing of fixated words in both reading and hopping sequences. Word frequency effects were not present when writers read their own text. Findings demonstrate the technical possibility and potential value of examining writers’ fixations within their just-written text. We suggest that these fixations do not serve solely, or even primarily, in monitoring for error, but play an important role in planning ongoing production

Spiral and Interlocking Grain in Eucalyptus Dunnii

Spiral grain in 181 trees from a 9-year-old plantation-grown Eucalyptus dunnii was normally distributed with mean 0.33 degrees (to the left) and standard deviation 1.7 degrees, and was affected by family and by crown asymmetry. Interlocking grain was common, exhibiting a mean amplitude of 3.4 degrees (standard deviation 1.5 degrees) and a mean wavelength of 39 mm (standard deviation 12 mm). The relatively large amplitude of interlocking grain means that most trees will have spiral grain that alternates between left and right during each year. The wavelength of interlocking grain is influenced by tree size, but amplitude of interlocking is under genetic control. Both spiral grain and the amplitude of any interlocking were heritable (h2 = 0.99 and 0.63 respectively)