EEG resting-state networks in Alzheimer’s disease associated with clinical symptoms

Alzheimer’s disease (AD) is a progressive neuropsychiatric disease affecting many elderly people and is characterized by progressive cognitive impairment of memory, visuospatial, and executive functions. As the elderly population is growing, the number of AD patients is increasing considerably. There is currently growing interest in determining AD’s cognitive dysfunction markers. We used exact low-resolution-brain-electromagnetic-tomography independent-component-analysis (eLORETA-ICA) to assess activities of five electroencephalography resting-state-networks (EEG-RSNs) in 90 drug-free AD patients and 11 drug-free patients with mild-cognitive-impairment due to AD (ADMCI). Compared to 147 healthy subjects, the AD/ADMCI patients showed significantly decreased activities in the memory network and occipital alpha activity, where the age difference between the AD/ADMCI and healthy groups was corrected by linear regression analysis. Furthermore, the age-corrected EEG-RSN activities showed correlations with cognitive function test scores in AD/ADMCI. In particular, decreased memory network activity showed correlations with worse total cognitive scores for both Mini-Mental-State-Examination (MMSE) and Alzheimer’s Disease-Assessment-Scale-cognitive-component-Japanese version (ADAS-J cog) including worse sub-scores for orientation, registration, repetition, word recognition and ideational praxis. Our results indicate that AD affects specific EEG-RSNs and deteriorated network activity causes symptoms. Overall, eLORETA-ICA is a useful, non-invasive tool for assessing EEG-functional-network activities and provides better understanding of the neurophysiological mechanisms underlying the disease

Development of an apolipoprotein E mimetic peptide–lipid conjugate for efficient brain delivery of liposomes

Liposomes are versatile carriers that can encapsulate various drugs; however, for delivery to the brain, they must be modified with a targeting ligand or other modifications to provide blood–brain barrier (BBB) permeability, while avoiding rapid clearance by reticuloendothelial systems through polyethylene glycol (PEG) modification. BBB-penetrating peptides act as brain-targeting ligands. In this study, to achieve efficient brain delivery of liposomes, we screened the functionality of eight BBB-penetrating peptides reported previously, based on high-throughput quantitative evaluation methods with in vitro BBB permeability evaluation system using Transwell, in situ brain perfusion system, and others. For apolipoprotein E mimetic tandem dimer peptide (ApoEdp), which showed the best brain-targeting and BBB permeability in the comparative evaluation of eight peptides, its lipid conjugate with serine–glycine (SG)5 spacer (ApoEdp-SG-lipid) was newly synthesized and ApoEdp-modified PEGylated liposomes were prepared. ApoEdp-modified PEGylated liposomes were effectively associated with human brain capillary endothelial cells via the ApoEdp sequence and permeated the membrane in an in vitro BBB model. Moreover, ApoEdp-modified PEGylated liposomes accumulated in the brain 3.9-fold higher than PEGylated liposomes in mice. In addition, the ability of ApoEdp-modified PEGylated liposomes to localize beyond the BBB into the brain parenchyma in mice was demonstrated via three-dimensional imaging with tissue clearing. These results suggest that ApoEdp-SG-lipid modification is an effective approach for endowing PEGylated liposomes with the brain-targeting ability and BBB permeability

Host selection of hematophagous leeches (Haemadipsa japonica): Implications for iDNA studies

The development of an efficient and cost‐effective method for monitoring animal populations or biodiversity is urgently needed, and invertebrate‐derived DNA (iDNA) may offer a promising tool for assessing the diversity and other ecological information of vertebrates. We studied the host species of a hematophagous leech (Haemadipsa japonica) in Yakushima by genetic barcoding and compared the results with those for mammal composition revealed by camera trapping. We analyzed 119 samples using two sets of primers by Sanger sequencing and one set of primer by next generation sequencing. The proportion of the samples that were successfully sequenced and identified to at least one species was 11.8–24.3%, depending on the three different methods. In all of these three methods, most of the samples were identified as sika deer (18/20, 6/15 and 16/29) or human (2/20, 7/15 and 21/29). The nonhuman mammal host species composition was significantly different from that estimated by camera trapping. Sika deer was the main host, which may be related with their high abundance, large body size and terrestriality. Ten samples included DNA derived from multiple species of vertebrates. This may be due to the contamination of human DNA, but we also found DNA from deer, Japanese macaque and a frog in the same samples, suggesting the mixture of the two meals in the gut of the leech. Using H. japonica‐derived iDNA would not be suitable to make an inventory of species, but it may be useful to collect genetic information on the targeted species, due to their high host selectivity

Medium Diradical Character, Small Hole and Electron Reorganization Energies and Ambipolar Transistors in Difluorenoheteroles

Four difluorenoheteroleshavinga centralquinoidalcore with the heteroringvaryingas furan,thiophene,its dioxidederivativeand pyrrolehave shownto be mediumcharacterdiradicals.Solid-statestructures,optical,photophysical,magnetic,and electrochemicalpropertieshave been discussedin termsof diradicalcharacter,variationof aromaticcharacterand captoda-tive effects(electronaffinity).Organicfield-effecttran-sistors(OFETs)have been prepared,showingbalancedholeand electronmobilitiesof the orderof103cm2V1s1or ambipolarchargetransportwhichisfirst inferredfrom their redoxamphoterism.Quantumchemicalcalculationsshow that the electricalbehaviorisoriginatedfrom the mediumdiradicalcharacterwhichproducessimilarreorganizationenergiesfor hole andelectrontransports.The visionof a diradicalas simulta-neouslybearingpseudo-holeand pseudo-electronde-fects might justifythe reducedvaluesof reorganizationenergiesfor both regimes.Structure-functionrelation-ships betweendiradicaland ambipolarelectricalbehav-ior are revealed.The authorsthankthe SpanishMinistryof ScienceandInnovation(projectsMINECO/FEDERPGC2018-098533-B-100,and PID2019-110305GB-I00),the Junta de Andalucíaand GeneralidadValenciana,Spain (UMA18FEDERJA057,P18-FR-4549and Prometeo/2019/076)and JSPS KAKENHIgrant (JP21K05042for S.-i.K.,JP21K04995and JP21H05489for R.K., JP21H01887and JP20K21173for M.N.).S.-i.K.gratefullyacknowledgesthe AsahiGlassFoundationforfinancialsupport.We also thankthe ResearchCentralServices(SCAI)of the Universityof Málaga,UnidaddeEspectroscopíaVibracional(Dra. Capely Dr. Zafra)andUnidadde OpticaNo-Linealy EspectroscopíaUltrarápida(Dr. Román).This work was partiallysupportedby theCooperativeResearchProgram“NetworkJoint ResearchCenterfor Materialsand Devices”(KyushuUniversity).WethankProf. ShuheiHigashibayashi(KeioUniversity)forassistancewith synthesis.Mass spectrometricdata werecollectedat HiroshimaUniversity(N-BARD:Ms. TomokoAmimoto).Theoreticalcalculationswere partlyperformedusing ResearchCenterfor ComputationalScience(R-CCS),Okazaki,Japan.F.N and Y.D. acknowledgesupportfrom“Valutazionedella Ricercadi Ateneo”(VRA)—Universityof Bologna.Y.D. acknowledgesMinisterodell’Universitàedella Ricerca(MUR)for her Ph.D. fellowship. Funding for open access charge: Universidad de Málaga / CBU

The RRM domain of poly(A)-specific ribonuclease has a noncanonical binding site for mRNA cap analog recognition

The degradation of the poly(A) tail is crucial for posttranscriptional gene regulation and for quality control of mRNA. Poly(A)-specific ribonuclease (PARN) is one of the major mammalian 3′ specific exo-ribonucleases involved in the degradation of the mRNA poly(A) tail, and it is also involved in the regulation of translation in early embryonic development. The interaction between PARN and the m7GpppG cap of mRNA plays a key role in stimulating the rate of deadenylation. Here we report the solution structures of the cap-binding domain of mouse PARN with and without the m7GpppG cap analog. The structure of the cap-binding domain adopts the RNA recognition motif (RRM) with a characteristic α-helical extension at its C-terminus, which covers the β-sheet surface (hereafter referred to as PARN RRM). In the complex structure of PARN RRM with the cap analog, the base of the N7-methyl guanosine (m7G) of the cap analog stacks with the solvent-exposed aromatic side chain of the distinctive tryptophan residue 468, located at the C-terminal end of the second β-strand. These unique structural features in PARN RRM reveal a novel cap-binding mode, which is distinct from the nucleotide recognition mode of the canonical RRM domains