The roles of sphingosine kinase 2 in behaviour, myelination and protection against Alzheimer’s disease

Sphingosine 1-phos¬phate (S1P) is a po¬tent vasculo- and neuro-pro¬tective signalling lipid that pro¬motes neuro¬trophic growth factor ex¬pression and pre-synaptic acetylcholine and glu¬tam¬ate release. It signals through its own family of five G-protein coupled receptors. S1P is synthesised by sphingosine kinase 1 and 2 (SK1/2). Our research group demonstrated pro-nounced loss of S1P and SK2 activity early in Alz¬heimer’s dis¬ease (AD) patho¬genesis, leading us to speculate that loss of S1P sensitises to AD de¬velop¬ment. Paradoxically, SK2 was reported to mediate amyloid β (Aβ) formation from amyloid precursor protein (APP) in vitro, which implies a role for this enzyme in promoting AD pathology. In this study we investigated the consequences of global SK2 knockout (SK2Δ) on neurological functions, particularly in the context of myelination and Alzheimer’s disease. We first examined behavioural effects of SK2 deletion in the absence of pathology. We then crossed SK2Δ mice to the J20 mouse model of familial AD amyloidosis to test whether SK2 deficiency synergises with amyloid beta (Aβ) in pro¬moting AD. S1P levels were reduced 85-90% in brains of SK2Δ mice, indicating that SK2 is responsible for the majority of S1P synthesis in the brain. SK2Δ mice displayed notably higher freezing response when placed in a novel context in the fear conditioning paradigm, independently of the fear stimulus, indicating a general anxiety phenotype in this strain. In agreement with a role in amyloid formation, SK2 deficiency re¬duced Aβ content, plaque burden, and reactive astrogliosis in J20 mice. This was as¬so¬ci¬ated with sig¬nifi¬cant impro-vements in hyper¬synchronous activity and cross-frequency coupling measured by hippo¬campal electro¬encephalo¬graphy. However, SK2-deficient J20 mice exhibited severe hypo¬mye¬lina¬tion in the hippo¬campus and cortex, hippo¬campal atrophy, and sig¬nifi¬cant deficits in the Y-maze and social novelty memory tests, when com¬pared to the J20 or SK2Δ strains. We also uncovered a significant hypomyelination phenotype in SK2Δ mice, leading us to investigate the role of S1P receptors in myelination, and particularly the oligodendrocyte-specific S1PR5 receptor. Female SK2Δ mice were administered the S1PR5-selective agonist A-971432 or S1PR1/5 dual-agonist Siponimod, to determine if activation of these receptors would preserve myelination. Despite observing pronounced myelin depletion in male SK2Δ mice, no such impairments were identified in female SK2Δ mice. Nonetheless, a significant increase of understudied 18:2 base sphingadiene lipids was observed in both male and female SK2Δ mice. As myelin is comprised 80% of lipids, further investigation on the potential impact of these 18:2 lipids on myelin structural integrity is required. In summary, SK2-generated S1P was required for oligodendrocyte survival in an AD mouse model, yet was paradoxically also an important endogenous regulator of Aβ formation. These results urge consideration of the importance of myelin loss as a driver of neurodegeneration in AD. Future work should further investigate the different hypomyelination phenotypes in male and female SK2Δ mice, including any potential interaction between sex hormones and SK2-generated S1P in myelination

SEIPIN Regulates Lipid Droplet Expansion and Adipocyte Development by Modulating the Activity of Glycerol-3-phosphate Acyltransferase

Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) is caused by loss-of-function mutations in SEIPIN, a protein implicated in both adipogenesis and lipid droplet expansion but whose molecular function remains obscure. Here, we identify physical and functional interactions between SEIPIN and microsomal isoforms of glycerol-3-phosphate acyltransferase (GPAT) in multiple organisms. Compared to controls, GPAT activity was elevated in SEIPIN-deficient cells and tissues and GPAT kinetic values were altered. Increased GPAT activity appears to underpin the block in adipogenesis and abnormal lipid droplet morphology associated with SEIPIN loss. Overexpression of Gpat3 blocked adipogenesis, and Gpat3 knockdown in SEIPIN-deficient preadipocytes partially restored differentiation. GPAT overexpression in yeast, preadipocytes, and fly salivary glands also formed supersized lipid droplets. Finally, pharmacological inhibition of GPAT in Seipin-/- mouse preadipocytes partially restored adipogenesis. These data identify SEIPIN as an evolutionarily conserved regulator of microsomal GPAT and suggest that GPAT inhibitors might be useful for the treatment of human BSCL2 patients

OpenFraming: open-sourced tool for computational framing analysis of multilingual data

When journalists cover a news story, they can cover the story from multiple angles or perspectives. These perspectives are called “frames,” and usage of one frame or another may influence public perception and opinion of the issue at hand. We develop a web-based system for analyzing frames in multilingual text documents. We propose and guide users through a five-step end-to-end computational framing analysis framework grounded in media framing theory in communication research. Users can use the framework to analyze multilingual text data, starting from the exploration of frames in user’s corpora and through review of previous framing literature (step 1-3) to frame classification (step 4) and prediction (step 5). The framework combines unsupervised and supervised machine learning and leverages a state-of-the-art (SoTA) multilingual language model, which can significantly enhance frame prediction performance while requiring a considerably small sample of manual annotations. Through the interactive website, anyone can perform the proposed computational framing analysis, making advanced computational analysis available to researchers without a programming background and bridging the digital divide within the communication research discipline in particular and the academic community in general. The system is available online at http://www.openframing.org, via an API http://www.openframing.org:5000/docs/, or through our GitHub page https://github.com/vibss2397/openFraming.Published versio

A 3D study on the amplification of regional haze and particle growth by local emissions

The role of new particle formation (NPF) events and their contribution to haze formation through subsequent growth in polluted megacities is still controversial. To improve the understanding of the sources, meteorological conditions, and chemistry behind air pollution, we performed simultaneous measurements of aerosol composition and particle number size distributions at ground level and at 260 m in central Beijing, China, during a total of 4 months in 2015-2017. Our measurements show a pronounced decoupling of gas-to-particle conversion between the two heights, leading to different haze processes in terms of particle size distributions and chemical compositions. The development of haze was initiated by the growth of freshly formed particles at both heights, whereas the more severe haze at ground level was connected directly to local primary particles and gaseous precursors leading to higher particle growth rates. The particle growth creates a feedback loop, in which a further development of haze increases the atmospheric stability, which in turn strengthens the persisting apparent decoupling between the two heights and increases the severity of haze at ground level. Moreover, we complemented our field observations with model analyses, which suggest that the growth of NPF-originated particles accounted up to similar to 60% of the accumulation mode particles in the Beijing-Tianjin-Hebei area during haze conditions. The results suggest that a reduction in anthropogenic gaseous precursors, suppressing particle growth, is a critical step for alleviating haze although the number concentration of freshly formed particles (3-40 nm) via NPF does not reduce after emission controls.Peer reviewe

Is reducing new particle formation a plausible solution to mitigate particulate air pollution in Beijing and other Chinese megacities?

Atmospheric gas-to-particle conversion is a crucial or even dominant contributor to haze formation in Chinese megacities in terms of aerosol number, surface area and mass. Based on our comprehensive observations in Beijing during 15 January 2018-31 March 2019, we are able to show that 80-90% of the aerosol mass (PM2.5) was formed via atmospheric reactions during the haze days and over 65% of the number concentration of haze particles resulted from new particle formation (NPF). Furthermore, the haze formation was faster when the subsequent growth of newly formed particles was enhanced. Our findings suggest that in practice almost all present-day haze episodes originate from NPF, mainly since the direct emission of primary particles in Beijing has considerably decreased during recent years. We also show that reducing the subsequent growth rate of freshly formed particles by a factor of 3-5 would delay the buildup of haze episodes by 1-3 days. Actually, this delay would decrease the length of each haze episode, so that the number of annual haze days could be approximately halved. Such improvement in air quality can be achieved with targeted reduction of gas-phase precursors for NPF, mainly dimethyl amine and ammonia, and further reductions of SO2 emissions. Furthermore, reduction of anthropogenic organic and inorganic precursor emissions would slow down the growth rate of newly-formed particles and consequently reduce the haze formation.Peer reviewe

The Enigmatic Origin of Bovine mtDNA Haplogroup R: Sporadic Interbreeding or an Independent Event of Bos primigenius Domestication in Italy?

BACKGROUND: When domestic taurine cattle diffused from the Fertile Crescent, local wild aurochsen (Bos primigenius) were still numerous. Moreover, aurochsen and introduced cattle often coexisted for millennia, thus providing potential conditions not only for spontaneous interbreeding, but also for pastoralists to create secondary domestication centers involving local aurochs populations. Recent mitochondrial genomes analyses revealed that not all modern taurine mtDNAs belong to the shallow macro-haplogroup T of Near Eastern origin, as demonstrated by the detection of three branches (P, Q and R) radiating prior to the T node in the bovine phylogeny. These uncommon haplogroups represent excellent tools to evaluate if sporadic interbreeding or even additional events of cattle domestication occurred. METHODOLOGY: The survey of the mitochondrial DNA (mtDNA) control-region variation of 1,747 bovine samples (1,128 new and 619 from previous studies) belonging to 37 European breeds allowed the identification of 16 novel non-T mtDNAs, which after complete genome sequencing were confirmed as members of haplogroups Q and R. These mtDNAs were then integrated in a phylogenetic tree encompassing all available P, Q and R complete mtDNA sequences. CONCLUSIONS: Phylogenetic analyses of 28 mitochondrial genomes belonging to haplogroups P (N = 2), Q (N = 16) and R (N = 10) together with an extensive survey of all previously published mtDNA datasets revealed major similarities between haplogroups Q and T. Therefore, Q most likely represents an additional minor lineage domesticated in the Near East together with the founders of the T subhaplogroups. Whereas, haplogroup R is found, at least for the moment, only in Italy and nowhere else, either in modern or ancient samples, thus supporting an origin from European aurochsen. Haplogroup R could have been acquired through sporadic interbreeding of wild and domestic animals, but our data do not rule out the possibility of a local and secondary event of B. primigenius domestication in Italy

Mitogenomes from Egyptian Cattle Breeds: New Clues on the Origin of Haplogroup Q and the Early Spread of Bos taurus from the Near East

Background Genetic studies support the scenario that Bos taurus domestication occurred in the Near East during the Neolithic transition about 10 thousand years (ky) ago, with the likely exception of a minor secondary event in Italy. However, despite the proven effectiveness of whole mitochondrial genome data in providing valuable information concerning the origin of taurine cattle, until now no population surveys have been carried out at the level of mitogenomes in local breeds from the Near East or surrounding areas. Egypt is in close geographic and cultural proximity to the Near East, in particular the Nile Delta region, and was one of the first neighboring areas to adopt the Neolithic package. Thus, a survey of mitogenome variation of autochthonous taurine breeds from the Nile Delta region might provide new insights on the early spread of cattle rearing outside the Near East. Methodology Using Illumina high-throughput sequencing we characterized the mitogenomes from two cattle breeds, Menofi (N = 17) and Domiaty (N = 14), from the Nile Delta region. Phylogenetic and Bayesian analyses were subsequently performed. Conclusions Phylogenetic analyses of the 31 mitogenomes confirmed the prevalence of haplogroup T1, similar to most African cattle breeds, but showed also high frequencies for haplogroups T2, T3 and Q1, and an extremely high haplotype diversity, while Bayesian skyline plots pointed to a main episode of population growth ~12.5 ky ago. Comparisons of Nile Delta mitogenomes with those from other geographic areas revealed that (i) most Egyptian mtDNAs are probably direct local derivatives from the founder domestic herds which first arrived from the Near East and the extent of gene flow from and towards the Nile Delta region was limited after the initial founding event(s); (ii) haplogroup Q1 was among these founders, thus proving that it underwent domestication in the Near East together with the founders of the T clades

The effect of COVID-19 restrictions on atmospheric new particle formation in Beijing

During the COVID-19 lockdown, the dramatic reduction of anthropogenic emissions provided a unique opportunity to investigate the effects of reduced anthropogenic activity and primary emissions on atmospheric chemical processes and the consequent formation of secondary pollutants. Here, we utilize comprehensive observations to examine the response of atmospheric new particle formation (NPF) to the changes in the atmospheric chemical cocktail. We find that the main clustering process was unaffected by the drastically reduced traffic emissions, and the formation rate of 1.5 nm particles remained unaltered. However, particle survival probability was enhanced due to an increased particle growth rate (GR) during the lockdown period, explaining the enhanced NPF activity in earlier studies. For GR at 1.5-3 nm, sulfuric acid (SA) was the main contributor at high temperatures, whilst there were unaccounted contributing vapors at low temperatures. For GR at 3-7 and 7-15 nm, oxygenated organic molecules (OOMs) played a major role. Surprisingly, OOM composition and volatility were insensitive to the large change of atmospheric NOx concentration; instead the associated high particle growth rates and high OOM concentration during the lockdown period were mostly caused by the enhanced atmospheric oxidative capacity. Overall, our findings suggest a limited role of traffic emissions in NPF.Peer reviewe