Untersuchungen zur Genexpression in Amyloplasten der Kartoffel (Solanum tuberosum L.) und Ansätze zur Plastidentransformation

In der vorliegenden Arbeit wurde die Genexpression in Amyloplasten der Kartoffel auf Ebene der Transkription, Transkriptakkumulation und Translation untersucht. Die Analysen ergaben, dass in Amyloplasten aus Knollen mit einem Durchmesser von 0,8 cm hauptsächlich Haushaltsgene und in Amyloplasten aus Knollen mit einem Durchmesser von 1,5 – 2 cm vorwiegend das psbA Gen und das ribosomale Operon transkribiert werden. In Amyloplasten ist nicht die in Proplastiden vorherrschende NEP (nucleus encoded RNA polymerase) für die Transkription verantwortlich, sondern die in Chloroplasten vorherrschende PEP (plastid encoded RNA polymerase). Die akkumulierende RNA weist in Amyloplasten eine hohe Stabilität auf. Auf Ebene der Translation konnte gezeigt werden, dass in Amyloplasten Polysomen assemblieren. Allerdings sind in der polysomalen RNA-Fraktion nur geringe Mengen an mRNA zu finden, woraus auf eine geringe Translationsaktivität zu schliessen ist. Ultrastrukturelle Untersuchungen weisen darauf hin, dass die Amyloplasten sich aus frühen Stadien der Chloroplastenentwicklung differenzieren

The Reddening-Free Decline Rate Versus Luminosity Relationship for Type Ia Supernovae

We develop a method for estimating the host galaxy dust extinction for type Ia supernovae based on an observational coincidence first noted by Lira (1995), who found that the B-V evolution during the period from 30-90 days after V maximum is remarkably similar for all events, regardless of light curve shape. This fact is used to calibrate the dependence of the B(max)-V(max) and V(max)-I(max) colors on the light curve decline rate parameter delta-m15, which can, in turn, be used to separately estimate the host galaxy extinction. Using these methods to eliminate the effects of reddening, we reexamine the functional form of the decline rate versus luminosity relationship and provide an updated estimate of the Hubble constant of Ho = 63.3 +- 2.2(internal) +- 3.5(external) km/s/Mpc.Comment: 32 pages, 10 figures, AJ 1999 in pres

Novel Pyridine-Based Hydroxamates and 2'-Aminoanilides as Histone Deacetylase Inhibitors: Biochemical Profile and Anticancer Activity

Starting from the N-hydroxy-3-(4-(2-phenylbutanoyl)amino)phenyl)acrylamide 5b previously described by us as HDAC inhibitor, we prepared four aza-analogues of 5b (6-8, 9b) as regioisomers containing the pyridine nucleus. A preliminary screening against mHDAC1 highlighted the N-hydroxy-5-(2-(2-phenylbutanoyl)amino)pyridyl)acrylamide 9b as the most potent inhibitor. Thus, we further developed both pyridylacrylic- and nicotinic-based hydroxamates (9a, 9c-f, and 11a-f) and 2'-aminoanilides (10a-f and 12a-f), related to 9b, to be tested against HDACs. Among them, the nicotinic hydroxamate 11d displayed subnanomolar potency (IC50: 0.5 nM) and selectivity up to 34000-fold over HDAC4 and from 100- to 1300-fold over all the other tested HDAC isoforms. The 2'-aminoanilides were class I-selective HDAC inhibitors, generally more potent against HDAC3, with the nicotinic anilide 12d being the most effective (IC50HDAC3 = 0.113 μM). When tested in U937 leukemia cells, the hydroxamates 9e, 11c, and 11d blocked over 80% cells in G2/M phase, whereas the anilides did not alter the cell cycle progress. In the same cell line, the hydroxamate 11c and the anilide 10b induced about 30% apoptosis, and the anilide 12c displayed about 40% cytodifferentiation. Finally, the most potent compounds in leukemia cells 9b, 11c, 10b, 10e, and 12c were also tested in K562, HCT116, and A549 cancer cells, displaying antiproliferative IC50 values at single-digit to sub-micromolar level

Comparison of Pittsburgh compound B and florbetapir in cross-sectional and longitudinal studies.

IntroductionQuantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B-based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design.MethodsPittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally.ResultsGlobal amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers.DiscussionAlthough the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers

Intrinsic antibacterial activity of nanoparticles made of β-cyclodextrins potentiates their effect as drug nanocarriers against tuberculosis

Multi-drug-resistant tuberculosis (TB) is a major public health problem, concerning about half a million cases each year. Patients hardly adhere to the current strict treatment consisting of more than 10 000 tablets over a 2-year period. There is a clear need for efficient and better formulated medications. We have previously shown that nanoparticles made of cross-linked poly-β-cyclodextrins (pβCD) are efficient vehicles for pulmonary delivery of powerful combinations of anti-TB drugs. Here, we report that in addition to being efficient drug carriers, pβCD nanoparticles are endowed with intrinsic antibacterial properties. Empty pβCD nanoparticles are able to impair Mycobacterium tuberculosis (Mtb) establishment after pulmonary administration in mice. pβCD hamper colonization of macrophages by Mtb by interfering with lipid rafts, without inducing toxicity. Moreover, pβCD provoke macrophage apoptosis, leading to depletion of infected cells, thus creating a lung microenvironment detrimental to Mtb persistence. Taken together, our results suggest that pβCD nanoparticles loaded or not with antibiotics have an antibacterial action on their own and could be used as a carrier in drug regimen formulations effective against TB.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Resting state network profiles of Alzheimer disease and frontotemporal dementia: A preliminary examination

OBJECTIVES/SPECIFIC AIMS: Recent evidence from resting-state fMRI studies have shown that brain network connectivity is altered in patients with neurodegenerative disorders. However, few studies have examined the complete connectivity patterns of these well-reported RSNs using a whole brain approach and how they compare between dementias. Here, we used advanced connectomic approaches to examine the connectivity of RSNs in Alzheimer disease (AD), Frontotemporal dementia (FTD), and age-matched control participants. METHODS/STUDY POPULATION: In total, 44 participants [27 controls (66.4±7.6 years), 13 AD (68.5.63±13.9 years), 4 FTD (59.575±12.2 years)] from an ongoing study at Indiana University School of Medicine were used. Resting-state fMRI data was processed using an in-house pipeline modeled after Power et al. (2014). Images were parcellated into 278 regions of interest (ROI) based on Shen et al. (2013). Connectivity between each ROI pair was described by Pearson correlation coefficient. Brain regions were grouped into 7 canonical RSNs as described by Yeo et al. (2015). Pearson correlation values were then averaged across pairs of ROIs in each network and averaged across individuals in each group. These values were used to determine relative expression of FC in each RSN (intranetwork) and create RSN profiles for each group. RESULTS/ANTICIPATED RESULTS: Our findings support previous literature which shows that limbic networks are disrupted in FTLD participants compared with AD and age-matched controls. In addition, interactions between different RSNs was also examined and a significant difference between controls and AD subjects was found between FP and DMN RSNs. Similarly, previous literature has reported a disruption between executive (frontoparietal) network and default mode network in AD compared with controls. DISCUSSION/SIGNIFICANCE OF IMPACT: Our approach allows us to create profiles that could help compare intranetwork FC in different neurodegenerative diseases. Future work with expanded samples will help us to draw more substantial conclusions regarding differences, if any, in the connectivity patterns between RSNs in various neurodegenerative diseases

Demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy: an international cohort study and individual participant data meta-analysis

Background: Posterior cortical atrophy is a rare syndrome characterised by early, prominent, and progressive impairment in visuoperceptual and visuospatial processing. The disorder has been associated with underlying neuropathological features of Alzheimer's disease, but large-scale biomarker and neuropathological studies are scarce. We aimed to describe demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy in a large international cohort.// Methods: We searched PubMed between database inception and Aug 1, 2021, for all published research studies on posterior cortical atrophy and related terms. We identified research centres from these studies and requested deidentified, individual participant data (published and unpublished) that had been obtained at the first diagnostic visit from the corresponding authors of the studies or heads of the research centres. Inclusion criteria were a clinical diagnosis of posterior cortical atrophy as defined by the local centre and availability of Alzheimer's disease biomarkers (PET or CSF), or a diagnosis made at autopsy. Not all individuals with posterior cortical atrophy fulfilled consensus criteria, being diagnosed using centre-specific procedures or before development of consensus criteria. We obtained demographic, clinical, biofluid, neuroimaging, and neuropathological data. Mean values for continuous variables were combined using the inverse variance meta-analysis method; only research centres with more than one participant for a variable were included. Pooled proportions were calculated for binary variables using a restricted maximum likelihood model. Heterogeneity was quantified using I2.// Findings: We identified 55 research centres from 1353 papers, with 29 centres responding to our request. An additional seven centres were recruited by advertising via the Alzheimer's Association. We obtained data for 1092 individuals who were evaluated at 36 research centres in 16 countries, the other sites having not responded to our initial invitation to participate to the study. Mean age at symptom onset was 59·4 years (95% CI 58·9–59·8; I2=77%), 60% (56–64; I2=35%) were women, and 80% (72–89; I2=98%) presented with posterior cortical atrophy pure syndrome. Amyloid β in CSF (536 participants from 28 centres) was positive in 81% (95% CI 75–87; I2=78%), whereas phosphorylated tau in CSF (503 participants from 29 centres) was positive in 65% (56–75; I2=87%). Amyloid-PET (299 participants from 24 centres) was positive in 94% (95% CI 90–97; I2=15%), whereas tau-PET (170 participants from 13 centres) was positive in 97% (93–100; I2=12%). At autopsy (145 participants from 13 centres), the most frequent neuropathological diagnosis was Alzheimer's disease (94%, 95% CI 90–97; I2=0%), with common co-pathologies of cerebral amyloid angiopathy (71%, 54–88; I2=89%), Lewy body disease (44%, 25–62; I2=77%), and cerebrovascular injury (42%, 24–60; I2=88%).// Interpretation: These data indicate that posterior cortical atrophy typically presents as a pure, young-onset dementia syndrome that is highly specific for underlying Alzheimer's disease pathology. Further work is needed to understand what drives cognitive vulnerability and progression rates by investigating the contribution of sex, genetics, premorbid cognitive strengths and weaknesses, and brain network integrity

Characterisation of age and polarity at onset in bipolar disorder

Background Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses