Role of age and neuroinflammation in the mechanism of cognitive deficits in sickle cell disease

This study aims to determine whether sickle cell mice could recapitulate features of cognitive and neurobehavioral impairment observed in sickle cell patients and whether neuroinflammation could be a potential therapeutic target as in other non-sickle cell disease-related cognitive dysfunction. Cognitive (learning and memory) and behavioral (anxiety) deficits in 13- and later 6-month-old male Townes humanized sickle cell (SS) and matched control (AA) mice were evaluated using novel object recognition (NOR) and fear conditioning tests. Immunohistochemistry was performed to quantify peripheral immune cell (CD45⁺) and activated microglia (Iba1⁺) as markers of neuroinflammation in the dentate and peri-dentate gyrus areas. We evaluated cell fate by measuring 5''-bromodeoxyuridine and doublecortin fluorescence and phenotyped proliferating cells using either glial fibrillary acid protein (GFAP⁺), neuronal nuclei (NeuN⁺), CD45⁺, and Iba1⁺. In addition, Golgi-Cox staining was used to assess markers of neuroplasticity (dendritic spine density and morphology and density of dendrite arbors) on cortical and hippocampal pyramidal neurons. Compared to matched AA controls, 13-month-old SS mice showed significant evidence of cognitive and behavioral deficit on NOR and fear conditioning tests. Also, SS mice had significantly higher density of CD45⁺ and activated microglia cells (i.e. more evidence of neuroinflammation) in the dentate and peri-dentate gyrus area. Additionally, SS mice had significantly lower dendritic spine density, but a higher proportion of immature dendritic spines. Treatment of 13-month-old SS mice with minocycline resulted in improvement of cognitive and behavioral deficit compared to matched vehicle-treated SS mice. Also, treated SS mice had significantly fewer CD45⁺ and activated microglia cells (i.e. less evidence of neuroinflammation) in the dentate and peri-dentate gyrus, as well as a significant improvement in markers of neuroplasticity.Impact statementThis study provides crucial information that could be helpful in the development of new or repurposing of existing therapies for the treatment of cognitive deficit in individuals with sickle cell disease (SCD). Its impact is in demonstrating for the first time that neuroinflammation and along with abnormal neuroplasticity are among the underlying mechanism of cognitive and behavioral deficits in SCD and that drugs such as minocycline which targets these pathophysiological mechanisms could be repurposed for the treatment of this life altering complication of SCD.     

Bioethics in the Malay‐Muslim Community in Malaysia: A Study on the Formulation of Fatwa on Genetically Modified Food by the National Fatwa Council

The field of bioethics aims to ensure that modern scientific and technological advancements have been primarily developed for the benefits of humankind. This field is deeply rooted in the traditions of Western moral philosophy and socio‐political theory. With respect to the view that the practice of bioethics in certain community should incorporate religious and cultural elements, this paper attempts to expound bioethical tradition of the Malay‐Muslim community in Malaysia, with shedding light on the mechanism used by the National Fatwa Council to evaluate whether an application of biological sciences is ethical or not. By using the application of the genetically modified food as a case study, this study has found that the council had reviewed the basic guidelines in the main references of shari'ah in order to make decision on the permissibility of the application. The fatwa is made after having consultation with the experts in science field. The council has taken all factors into consideration and given priority to the general aim of shari'ah which to serve the interests of mankind and to save them from harm.     

Regeneration im Pankreas der Ratte nach Alloxanschädigung

Zusammenfassung Im Pankreas ausgewachsener Ratten wurden nach Alloxanschädigung Regenerationsherde beobachtet und beschrieben. Sie bestehen in einem büschelförmigen Aussprossen kleiner Gänge an umschriebenen Stellen des Organes, die in ein retikuläres Bindegewebe eingebettet sind. In analoger Weise wie bei der ontogenetischen Entwicklung des Pankreas aus den primitiven Drüsenschläuchen, kommt es auch im Bereiche der Gangwucherungen zur Neubildung von Inselgewebe.     

The effect of kinetin on the indoleacetic acid level and indoleacetic acid oxidase activity in roots of young plants

Kinetin treatment increased the extractable IAA content in roots of young plants of Phaseolus vulgaris L., Zea mays L. and Avena sativa L. The highest increase was obtained with roots of beans and the lowest with oat roots. Maize was intermediate between these two species. Kinetin treatment decreased the activity of IAA-oxidase but the correlation between the decrease of the activity of this enzyme and the increase in the level of IAA was not good. The decrease of the oxidase activity was greatest in oat roots where kinetin had very little effect on the IAA level, and was rather small in bean roots, where kinetin treatment significantly increased the IAA level.     

Resistance of Pseudomonas pseudomallei to Normal Human Serum Bactericidal Action

The effect of human normal serum (HNS) on Pseudomonas pseudomallei was determined. It is apparent from our data that the organism is resistant to the normal serum bactericidal mechanism. Ancillary experiments to confirm this serum-resistant property of P. pseudomallei were done by examining the effects of growth phase conditions of the bacteria (i.e., logarithmic and stationary phases) and different buffered systems used as diluent in our bactericidal assay. Results obtained showed similar degree of resistance to serum bactericidal killing by 5 strains of the organisms tested. The possible survival advantage of serum-resistant property to P. pseudomallei as bacterial pathogens known to invade the blood stream is discussed.     

Molten Globule-Triggered Inactivation of a Thermostable and Solvent Stable Lipase in Hydrophilic Solvents

The use of lipase in hydrophilic solvent is usually hampered by inactivation. The solvent stability of a recombinant solvent stable lipase isolated from thermostable Bacillus sp. strain 42 (Lip 42), in DMSO and methanol were studied at different solvent-water compositions. The enzymatic activities were retained in up to 45% v/v solvent compositions. The near-UV CD spectra indicated that tertiary structures were perturbed at 60% v/v and above. Far-UV CD in methanol indicated the secondary structure in Lip 42 was retained throughout all solvent compositions. Fluorescence studies indicated formations of molten globules in solvent compositions of 60% v/v and above. The enzyme was able to retain its secondary structures in the presence of methanol; however, there was a general reduction in β-sheet and an increase in α-helix contents. The H-bonding arrangements triggered in methanol and DMSO, respectively, caused different forms of tertiary structure perturbations on Lip 42, despite both showing partial denaturation with molten globule formations.     

DNA polymorphisms and linkage disequilibrium in the angiotensinogen gene

A number of recent studies have implicated the angiotensinogen gene in the aetiology of essential hypertension in Caucasian, Japanese and African Caribbean subjects. We have genotyped 153 healthy white Caucasian subjects at a dinucleotide repeat polymorphism and seven diallelic sites in the coding or flanking regions of the angiotensinogen gene, including one polymorphism not previously studied. We have also documented patterns of linkage disequilibrium between polymorphisms. There is evidence of variation in the frequency of several mutations when compared with published results from other Caucasian control populations, possibly due to cryptic ethnic differences between these groups. This should be considered in the design and interpretation of studies of the angiotensinogen gene. Received: 10 November 1995 / Revised: 25 March 1996     

Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study

BackgroundIncreased vitamin D levels, as reflected by 25-hydroxy vitamin D (25OHD) measurements, have been proposed to protect against COVID-19 based on in vitro, observational, and ecological studies. However, vitamin D levels are associated with many confounding variables, and thus associations described to date may not be causal. Vitamin D Mendelian randomization (MR) studies have provided results that are concordant with large-scale vitamin D randomized trials. Here, we used 2-sample MR to assess evidence supporting a causal effect of circulating 25OHD levels on COVID-19 susceptibility and severity.Methods and findingsGenetic variants strongly associated with 25OHD levels in a genome-wide association study (GWAS) of 443,734 participants of European ancestry (including 401,460 from the UK Biobank) were used as instrumental variables. GWASs of COVID-19 susceptibility, hospitalization, and severe disease from the COVID-19 Host Genetics Initiative were used as outcome GWASs. These included up to 14,134 individuals with COVID-19, and up to 1,284,876 without COVID-19, from up to 11 countries. SARS-CoV-2 positivity was determined by laboratory testing or medical chart review. Population controls without COVID-19 were also included in the control groups for all outcomes, including hospitalization and severe disease. Analyses were restricted to individuals of European descent when possible. Using inverse-weighted MR, genetically increased 25OHD levels by 1 standard deviation on the logarithmic scale had no significant association with COVID-19 susceptibility (odds ratio [OR] = 0.95; 95% CI 0.84, 1.08; p = 0.44), hospitalization (OR = 1.09; 95% CI: 0.89, 1.33; p = 0.41), and severe disease (OR = 0.97; 95% CI: 0.77, 1.22; p = 0.77). We used an additional 6 meta-analytic methods, as well as conducting sensitivity analyses after removal of variants at risk of horizontal pleiotropy, and obtained similar results. These results may be limited by weak instrument bias in some analyses. Further, our results do not apply to individuals with vitamin D deficiency.ConclusionsIn this 2-sample MR study, we did not observe evidence to support an association between 25OHD levels and COVID-19 susceptibility, severity, or hospitalization. Hence, vitamin D supplementation as a means of protecting against worsened COVID-19 outcomes is not supported by genetic evidence. Other therapeutic or preventative avenues should be given higher priority for COVID-19 randomized controlled trials.

In a Mendelian randomization analysis, Guillaume Butler-Laporte, Tomoki Nakanishi, and colleages study genetic evidence for a relationship between vitamin D and COVID-19 outcomes.