Melatonin and probiotic administration ameliorated hyperglycaemia, oxidative stress, and enhanced cytoprotective effect on beta-cells of diabetic rats.

Objective: The study aimed at investigating the effects of administering melatonin and a probiotic to streptozotocin-induced diabetic rats on hyperglycaemia, oxidative stress biomarkers and beta-cells. Design: Type 1 diabetes was induced in 5 months-old male Wistar rats by single intraperitoneal (i.p.) administration of freshly-prepared STZ (60 mg/kg body weight). Six groups of 10 rats were used and treated once daily for six weeks; (1) Healthy control: normal saline only; (2) Pre-treated with Melatonin (MEL); (3) Diabetic control; (4) Diabetic + Treated with MEL; (5) Diabetic + Treated with Probiotic (Prob); (6) Diabetic + Treated with MEL + Prob. Blood glucose, body weight, activities of antioxidant enzymes and malondialdehyde concentration in serum and tissues, reduced glutathione and immunohistochemical assay. Data obtained were expressed as mean ± standard error of the mean (Mean ± SEM) and subjected to ANOVA followed by Tukey's post hoc test. Results: Melatonin + Probiotic significantly decreased blood glucose concentrations in diabetic treated rats, compared to the diabetic control rats. MEL + Probiotic increased (p < 0.05) superoxide dismutase activity in serum and liver of diabetic rats. MEL + Probiotic reduced (p < 0.05) malondialdehyde concentration in the serum, liver and kidneys, respectively. MEL + Probiotic treated diabetic rats displayed islets with much greater content of insulin. Conclusion: Melatonin + Probiotic combination was more effective in mitigating hyperglycaemia, oxidative stress, and exerted cytoprotective effect on the beta-cells.

Identifying modifiable factors and their joint effect on dementia risk in the UK Biobank.

Previous hypothesis-driven research has identified many risk factors linked to dementia. However, the multiplicity and co-occurrence of risk factors have been underestimated. Here we analysed data of 344,324 participants from the UK Biobank with 15 yr of follow-up data for 210 modifiable risk factors. We first conducted an exposure-wide association study and then combined factors associated with dementia to generate composite scores for different domains. We then evaluated their joint associations with dementia in a multivariate Cox model. We estimated the potential impact of eliminating the unfavourable profiles of risk domains on dementia using population attributable fraction. The associations varied by domain, with lifestyle (16.6%), medical history (14.0%) and socioeconomic status (13.5%) contributing to the majority of dementia cases. Overall, we estimated that up to 47.0%-72.6% of dementia cases could be prevented.

Lung function and risk of incident dementia: A prospective cohort study of 431,834 individuals.

BACKGROUND: Whether lung function prospectively affects cognitive brain health independent of their overlapping factors remains largely unknown. This study aimed to investigate the longitudinal association between decreased lung function and cognitive brain health and to explore underlying biological and brain structural mechanisms. METHODS: This population-based cohort included 43,1834 non-demented participants with spirometry from the UK Biobank. Cox proportional hazard models were fitted to estimate the risk of incident dementia for individuals with low lung function. Mediation models were regressed to explore the underlying mechanisms driven by inflammatory markers, oxygen-carrying indices, metabolites, and brain structures. FINDINGS: During a follow-up of 3,736,181 person-years (mean follow-up 8.65 years), 5,622 participants (1.30 %) developed all-cause dementia, which consisted of 2,511 Alzheimer's dementia (AD) and 1,308 Vascular Dementia (VD) cases. Per unit decrease in lung function measure was each associated with increased risk for all-cause dementia (forced expiratory volume in 1 s [liter]: hazard ratio [HR, 95 %CI], 1.24 [1.14-1.34], P = 1.10 × 10-07; forced vital capacity [liter]: 1.16 [1.08-1.24], P = 2.04 × 10-05; peak expiratory flow [liter/min]: 1.0013 [1.0010-1.0017], P = 2.73 × 10-13). Low lung function generated similar hazard estimates for AD and VD risks. As underlying biological mechanisms, systematic inflammatory markers, oxygen-carrying indices, and specific metabolites mediated the effects of lung function on dementia risks. Besides, brain grey and white matter patterns mostly affected in dementia were substantially changed with lung function. INTERPRETATION: Life-course risk for incident dementia was modulated by individual lung function. Maintaining optimal lung function is useful for healthy aging and dementia prevention.

Robust expansion of phylogeny for fast-growing genome sequence data

Massive sequencing of SARS-CoV-2 genomes has led to a great demand for adding new samples to a reference phylogeny instead of building the tree from scratch. To address such challenge, we proposed an algorithm TIPars by integrating parsimony analysis with pre-computed ancestral sequences. Compared to four state-of-the-art methods on four benchmark datasets (SARS-CoV-2, Influenza virus, Newcastle disease virus and 16S rRNA genes), TIPars achieved the best performance in most tests. It took only 21 seconds to insert 100 SARS-CoV-2 genomes to a 100k-taxa reference tree using near 1.4 gigabytes of memory. Its efficient and accurate phylogenetic placements and incrementation for phylogenies with highly similar and divergent sequences suggest that it will be useful in a wide range of studies including pathogen molecular epidemiology, microbiome diversity and systematics.

Peptide Scanning of SARS-CoV and SARS-CoV-2 Spike Protein Subunit 1 Reveals Potential Additional Receptor Binding Sites

The binding of SARS-CoV and SARS-CoV-2 to the ACE2 receptor on human cells is mediated by the spike protein subunit 1 (S1) on the virus surfaces, while the receptor binding domains (RBDs) of S1 are the major determinants for the interaction with ACE2 and dominant targets of neutralizing antibodies. However, at the virus-host interface, additional biomolecular interactions, although being relatively weak in affinity and low in specificity, could also contribute to viral attachment and play important roles in gain- or loss-of-function mutations. In this work, we performed a peptide scanning of the S1 domains of SARS-CoV and SARS-CoV-2 by synthesizing 972 16-mer native and mutated peptide fragments using a high throughput in situ array synthesis technology. By probing the array using fluorescently labelled ACE2, a number of previously unknown potential receptor binding sites of S1 have been revealed. 20 peptides were synthesized using solid phase peptide synthesis, in order to validate and quantify their binding to ACE2. Four ACE2-binding peptides were selected, to investigate whether they can be assembled through a biotinylated peptide/neutravidin system to achieve high affinity to ACE2. A number of constructs exhibited high affinity to ACE2 with Kd values of pM to low nM.

Dynamic perioperative variation of neutrophil-to-lymphocyte ratio as an independent prognosis factor following lobectomy for NSCLC.

Inflammation plays a key role in malignant tumor progression. The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation and, as such, high isolated pretreatment NLR has been shown to be associated with worse long-term outcomes. The aim of the present study is to evaluate the prognostic value of pre- and post-operative NLR in relation to mortality and recurrence rates in patients undergoing lung lobectomy for NSCLC. A single-center retrospective analysis of 534 lobectomies was performed between 2009 and 2018. NLR was measured in two opportunities: 1 month prior to surgery and 1-4 months after. Primary outcomes were overall survival (OS) and recurrence-free survival (RFS). Secondary outcomes were variables associated with mortality and recurrence. The study sample included 264 lobectomies. Independent predictors of OS were ASA 3/4 (p = 0.041) and open surgical approach (p = 0.042). Adjuvant chemotherapy (p = 0.002) and pathological N 1/2-stage (p = 0.0015) were associated with RFS. Delta NLR correlated with OS (p = 0.042) and RFS (p < 0.001). Patients were divided into three delta NLR categories: delta NLR < 0, delta NLR 0-0.5 and delta NLR > 0.5. Increasing delta NLR was significantly associated with worse OS (p < 0.001) and RFS (p < 0.001). Dynamic behaviour of NLR assessed through delta NLR is a useful tool that potentially allows predicting mortality and recurrence outcomes in patients undergoing lung lobectomy for NSCLC and may be more informative than static baseline values.

A Machine Learning Approach to Identify a Circulating MicroRNA Signature for Alzheimer Disease.

BACKGROUND: Accurate diagnosis of Alzheimer disease (AD) involving less invasive molecular procedures and at reasonable cost is an unmet medical need. We identified a serum miRNA signature for AD that is less invasive than a measure in cerebrospinal fluid. METHODS: From the Oxford Project to Investigate Memory and Aging (OPTIMA) study, 96 serum samples were profiled by a multiplex (>500 analytes) microRNA (miRNA) reverse transcription quantitative PCR analysis, including 51 controls, 32 samples from patients with AD, and 13 samples from patients with mild cognitive impairment (MCI). Clinical diagnosis of a subset of AD and the controls was confirmed by postmortem (PM) histologic examination of brain tissue. In a machine learning approach, the AD and control samples were split 70:30 as the training and test cohorts. A multivariate random forest statistical analysis was applied to construct and test a miRNA signature for AD identification. In addition, the MCI participants were included in the test cohort to assess whether the signature can identify early AD patients. RESULTS: A 12-miRNA signature for AD identification was constructed in the training cohort, demonstrating 76.0% accuracy in the independent test cohort with 90.0% sensitivity and 66.7% specificity. The signature, however, was not able to identify MCI participants. With a subset of AD and control participants with PM-confirmed diagnosis status, a separate 12-miRNA signature was constructed. Although sample size was limited, the PM-confirmed signature demonstrated improved accuracy of 85.7%, largely owing to improved specificity of 80.0% with comparable sensitivity of 88.9%. CONCLUSION: Although additional and more diverse cohorts are needed for further clinical validation of the robustness, the miRNA signature appears to be a promising blood test to diagnose AD.

Surface conjugation of EP67 to biodegradable nanoparticles increases the generation of long-lived mucosal and systemic memory T-cells by encapsulated protein vaccine after respiratory immunization and subsequent T-cell-mediated protection against respiratory infection.

Encapsulation of protein vaccines in biodegradable nanoparticles (NP) increases T-cell expansion after mucosal immunization but requires incorporating a suitable immunostimulant to increase long-lived memory T-cells. EP67 is a clinically viable, host-derived peptide agonist of the C5a receptor that selectively activates antigen presenting cells over neutrophils. We previously found that encapsulating EP67-conjugated CTL peptide vaccines in NP increases long-lived memory subsets of CTL after respiratory immunization. Thus, we hypothesized that alternatively conjugating EP67 to the NP surface can increase long-lived mucosal and systemic memory T-cells generated by encapsulated protein vaccines. We found that respiratory immunization of naïve female C57BL/6 mice with LPS-free ovalbumin (OVA) encapsulated in PLGA 50:50 NP (∼380 nm diameter) surface-conjugated with ∼0.1 wt% EP67 through 2 kDa PEG linkers (i) increased T-cell expansion and long-lived memory subsets of OVA323-339-specific CD4+ and OVA257-264-specific CD8a+ T-cells in the lungs (CD44HI/CD127/KLRG1) and spleen (CD44HI/CD127/KLRG1/CD62L) and (ii) decreased peak CFU of OVA-expressing L. monocytogenes (LM-OVA) in the lungs, liver, and spleen after respiratory challenge vs. encapsulation in unmodified NP. Thus, conjugating EP67 to the NP surface is one approach to increase the generation of long-lived mucosal and systemic memory T-cells by encapsulated protein vaccines after respiratory immunization.

Fading perceptual resemblance: a path for rhesus macaques (Macaca mulatta) to conceptual matching?

Cognitive, comparative, and developmental psychologists have long been intrigued by humans' and animals' capacity to respond to abstract relations like sameness and difference, because this capacity may underlie crucial aspects of cognition like analogical reasoning. Recently, this capacity has been explored in higher-order, relational matching-to-sample (RMTS) tasks in which humans and animals try to complete analogies of sameness and difference between disparate groups of items. The authors introduced a new paradigm to this area, by yoking the relational-matching cue to a perceptual-matching cue. Then, using established algorithms for shape distortion, the perceptual cue was weakened and eliminated. Humans' RMTS performance easily transcended the elimination of perceptual support. In contrast, RMTS performance by six macaques faltered as they were weaned from perceptual support. No macaque showed evidence of mature RMTS performance, even given more than 260,000 training trials during which we tried to coax a relational-matching performance from them. It is an important species difference that macaques show so hesitant a response to conceptual relations when humans respond to them so effortlessly. It raises theoretical questions about the emergence of this crucial capacity during humans' cognitive evolution and during humans' cognitive development.

Utility of the Malayalam translation of the 7- minute screen for Alzheimer's disease risk in an Indian community.

BACKGROUND: Alzheimer's disease (AD) is suspected to be currently under-diagnosed in India, thus the need for a brief, effective screening test for the condition. AIMS: We aimed to test the Malayalam translation of the 7-Minute Screen (7MS) for detecting those at high risk for AD and to report on the subscores used to derive the Alzheimer's risk score. SETTING AND DESIGN: This study was performed in Kerala State amongst young university students and elders in residential care homes. MATERIALS AND METHODS: Two hundred and eighty-two volunteers were tested, 178 young controls (aged 20-29) and 104 literate elders, (55-92 years). None were clinically diagnosed with AD. STATISTICAL ANALYSES: Elders and controls were assessed as High or Low AD Risk with the published 7MS algorithm. Performance was compared between groups with ANOVA. RESULTS: The algorithm estimated high (n=61/104) or low (n=40/104) AD risk in the elderly. Significant differences were found between controls, low- and high-risk groups on all four components of the screen (Orientation: F=131.1, Enhanced Cued Recall: F=23.4, Clock Drawing: F=65.1, Verbal Fluency: F=15.7, P<0.0001 for all) and in the risk scores (F=144.7, P<0.0001). Age and gender affected verbal fluency, orientation and clock drawing performance. The high-risk group had worse scores for orientation and better scores for memory than previously reported for AD cases in other populations. CONCLUSIONS: The 7MS may be a useful screening test for cognitive impairment in India. Suggestions are given for revising the 'risk algorithm' for more appropriate AD risk assessment in this population.

Medial artery calcification as an indicator of diabetic peripheral vascular disease.

BACKGROUND: Mönckeberg sclerosis or medial artery calcification (MAC) is a well-known phenomenon associated with diabetic and other arterial disease. However, its consequence within the foot, and specifically the first dorsal metatarsal artery, has not previously been studied. MATERIALS AND METHODS: Nearly 1,000 foot x-rays were studied over a 9-month period in a busy hospital to identify the prevalence of first dorsal metatarsal artery calcification. The electronic medical notes for all the patients were reviewed to confirm which patients were known to be diabetic. The patients with positive findings were then identified and their HbA1c, creatinine, and previous foot interventions recorded. RESULTS: Of the population studied, 1.4% had medial artery calcification of the 1st dorsal metatarsal artery: 93% were known diabetics and 100% had impaired glucose tolerance (a glucose plasma concentration of greater than 7.8 mmol/l 2-hours post-glucose loading). Seventy-nine percent had required previous podiatric care for foot ulceration and 64% had required surgical intervention for their diabetic feet. MAC has a high positive predictive value (92.9% (95% CI 69.2 to 98.7)) for diabetes, with a good specificity (99.9% (95%CI 99.4 to 100)) and low false positive rate (0.1% (05%CI 0.0 to 0.6)). CONCLUSION: Medial artery calcification in the first dorsal metatarsal artery is characteristic of impaired glucose metabolism, and if seen on routine x-ray should be an indication for screening of the patient. It should also be considered as a foot-at-risk sign in the established diabetic due to the high incidence of foot ulceration and need for surgical intervention in this group.

Rate of progression of cognitive decline in Alzheimer's disease: effect of butyrylcholinesterase K gene variation.

OBJECTIVE: To determine whether individuals with Alzheimer's disease (AD) and the K variant allele of butyrylcholinesterase have a slower rate of cognitive decline than those without the K variant allele of butyrylcholinesterase. METHOD: The cognitive status of 339 community based subjects with AD was assessed with the Mini Mental State Examination at baseline and yearly over a three year follow up period. The rates of cognitive decline of subjects with and without the K variant allele were compared. RESULT: Presence of the K allele was associated with a slower average rate of cognitive decline in subjects with severe AD. CONCLUSIONS: This finding is consistent with the suggestion that the K variant of butyrylcholinesterase has an important role in disease progression in AD, and this may have implications for treatment.

Measuring serum oestradiol in women with Alzheimer's disease: the importance of the sensitivity of the assay method.

OBJECTIVE: Oestrogens could be protective against the development of Alzheimer's disease (AD) but reports on oestrogen levels in AD have been conflicting. DESIGN AND METHODS: A meta-analysis using robust regression was carried out to assess whether the sensitivity of the assays of past studies had affected the reported level of total oestradiol. We had also measured total oestradiol in women with AD (n=66) and controls (n=62) not using hormone replacement therapy. We used two assays for total oestradiol to assess the difference between sensitive (radioimmunoassay with a specific rabbit antibody: 3 pmol/l) and relatively insensitive (immunoassay: 37 pmol/l) assays. RESULTS: Meta-analysis using robust regression indicated that insensitive assays gave higher levels of total oestradiol when many samples fall below the level of sensitivity of the method. Earlier reports of low levels of total oestradiol in AD might be explained by this phenomenon, since total oestradiol levels (using the sensitive assay) in our controls were one third of those reported in the earlier studies. Using the sensitive assay we found that women with AD had significantly (P<0.01) higher levels (26+/-13 pmol/l) of total oestradiol than controls (21+/-13 pmol/l). Using the insensitive assay, there was no significant difference in the levels of total oestradiol. CONCLUSIONS: The sensitivity of the assay determines the reported value of the oestradiol levels. Studies using a sensitive assay do not report significantly lower levels of total oestradiol in women with AD. This weighs against the hypothesis that low levels of total oestradiol are a risk factor for AD.

Specific antibodies to bovine choline acetyltransferase raised in mice immunised with small amounts of partially purified enzyme.

Choline acetyltransferase was purified approximately 18,000-fold from 300 g of bovine caudate nuclei to a specific activity of 21 ?mol min mg protein. The overall procedure used was: extraction of the enzyme by high salt concentration, chromatography on carboxy-methyl-Sephadex, precipitation by ammonium sulphate, affinity chromatography on Blue-Sepharose and, finally absorption on hydroxylapatite. When the enzyme absorbed on hydroxylapatite was injected into mice, it provoked reproducibly a transient production of 'inhibitory' antibodies, followed by higher antibody titres mainly of 'non-inhibitory' type. These responses were elicited by injecting less than a total of 20 ?g of immunogen. The highest antibody titre was obtained less than 2 months following the initial immunisation. Species cross reactivity was investigated. This procedure should prove to be of value in the production of monoclonal antibodies to choline acetyltransferase.