Sequence-selective detection of double-stranded DNA sequences using pyrrole-imidazole polyamide microarrays

We describe a microarray format that can detect double-stranded DNA sequences with a high degree of sequence selectivity. Cyclooctyne-derivatized pyrrole-imidazole polyamides were immobilized on azide-modified glass substrates using microcontact printing and a strain-promoted azide-alkyne cycloaddition (SPAAC) reaction. These polyamide-immobilized substrates selectively detected a seven-base-pair binding site incorporated within a double-stranded oligodeoxyribonucleotide sequence even in the presence of an excess of a sequence with a single-base-pair mismatc

Regional desynchronization of microglial activity is associated with cognitive decline in Alzheimer’s disease

Background Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker. Methods To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization. Results Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia. Conclusion Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression

Timing of initial arrival at the breeding site predicts age at first reproduction in a long-lived migratory bird

In long-lived vertebrates, individuals generally visit potential breeding areas or populations during one or more seasons before reproducing for the first time. During these years of prospecting, they select a future breeding site, colony, or mate and improve various skills and their physical condition to meet the requirements of reproduction. One precondition of successful reproduction is arrival in time on the breeding grounds. Here, we study the intricate links among the date of initial spring arrival, body mass, sex, and the age of first breeding in the common tern Sterna hirundo, a long-lived migratory colonial seabird. The study is based on a unique, individual-based, long-term dataset of sexed birds, marked with transponders, which allow recording their individual arrival, overall attendance, and clutch initiation remotely and automatically year by year over the entire lifetime at the natal colony site. We show that the seasonal date of initial arrival at the breeding grounds predicts the individual age at first reproduction, which mostly occurs years later. Late first-time arrivals remain delayed birds throughout subsequent years. Our findings reveal that timing of arrival at the site of reproduction and timing of reproduction itself are coherent parameters of individual quality, which are linked with the prospects of the breeding career and may have consequences for fitness