Chronic, progressive retinal diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa, arise from genetic and environmental perturbations of cellular ...and tissue homeostasis. These disruptions accumulate with repeated exposures to stress over time, leading to progressive visual impairment and, in many cases, legal blindness. Despite decades of research, therapeutic options for the millions of patients suffering from these disorders remain severely limited, especially for treating earlier stages of pathogenesis when the opportunity to preserve the retinal structure and visual function is greatest. To address this urgent, unmet medical need, we employed a systems pharmacology platform for therapeutic development. Through integrative single-cell transcriptomics, proteomics, and phosphoproteomics, we identified universal molecular mechanisms across distinct models of age-related and inherited retinal degenerations, characterized by impaired physiological resilience to stress. Here, we report that selective, targeted pharmacological inhibition of cyclic nucleotide phosphodiesterases (PDEs), which serve as critical regulatory nodes that modulate intracellular second messenger signaling pathways, stabilized the transcriptome, proteome, and phosphoproteome through downstream activation of protective mechanisms coupled with synergistic inhibition of degenerative processes. This therapeutic intervention enhanced resilience to acute and chronic forms of stress in the degenerating retina, thus preserving tissue structure and function across various models of age-related and inherited retinal disease. Taken together, these findings exemplify a systems pharmacology approach to drug discovery and development, revealing a new class of therapeutics with potential clinical utility in the treatment or prevention of the most common causes of blindness.
Please see the correct author order here: Citation: Figlerowicz M, Urbanowicz A, Lewandowski D, Jodynis-Liebert J, Sadowski C (2013) Correction: Functional Insights into Recombinant TROSPA Protein ...from Ixodes ricinus.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lyme disease (also called borreliosis) is a prevalent chronic disease transmitted by ticks and caused by Borrelia burgdorferi s. l. spirochete. At least one tick protein, namely TROSPA from I. ...scapularis, commonly occurring in the USA, was shown to be required for colonization of the vector by bacteria. Located in the tick gut, TROSPA interacts with the spirochete outer surface protein A (OspA) and initiates the tick colonization. Ixodes ricinus is a primary vector involved in B. burgdorferi s. l. transmission in most European countries. In this study, we characterized the capacities of recombinant TROSPA protein from I. ricinus to interact with OspA from different Borrelia species and to induce an immune response in animals. We also showed that the N-terminal part of TROSPA (a putative transmembrane domain) is not involved in the interaction with OspA and that reduction of the total negative charge on the TROSPA protein impaired TROSPA-OspA binding. In general, the data presented in this paper indicate that recombinant TROSPA protein retains the capacity to form a complex with OspA and induces a significant level of IgG in orally immunized rats. Thus, I. ricinus TROSPA may be considered a good candidate component for an animal vaccine against Borrelia.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The ribosome builds proteins by joining together amino acids in an order determined by messenger RNA. Here, we report on the design, synthesis, and operation of an artificial small-molecule machine ...that travels along a molecular strand, picking up amino acids that block its path, to synthesize a peptide in a sequence-specific manner. The chemical structure is based on a rotaxane, a molecular ring threaded onto a molecular axle. The ring carries a thiolate group that iteratively removes amino acids in order from the strand and transfers them to a peptide-elongation site through native chemical ligation. The synthesis is demonstrated with ∼10 18 molecular machines acting in parallel; this process generates milligram quantities of a peptide with a single sequence confirmed by tandem mass spectrometry.
Full text
Available for:
BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The precise adjustment of the polariton condensate flow under incoherent excitation conditions is an indispensable prerequisite for polariton-based logic gate operations. In this report, an ...all-optical approach for steering the motion of a polariton condensate using only nonresonant excitation is demonstrated. We create arbitrarily shaped functional potentials by means of a spatial light modulator, which allow for tailoring the condensate state and guiding a propagating condensate along reconfigurable pathways. Additional numerical simulations confirm the experimental observations and elucidate the interaction effects between background carriers and polariton condensates.
Full text
Available for:
CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Measuring various biochemical and cellular components in the blood is a routine procedure in clinical practice. Human serum contains hundreds of diverse proteins secreted from all cells and tissues ...in healthy and diseased states. Moreover, some serum proteins have specific strong interactions with other blood components, but most interactions are probably weak and transient. One of the serum proteins is butyrylcholinesterase (BChE), an enzyme existing mainly as a glycosylated soluble tetramer that plays an important role in the metabolism of many drugs. Our results suggest that BChE interacts with plasma proteins and forms much larger complexes than predicted from the molecular weight of the BChE tetramer. To investigate and isolate such complexes, we developed a two-step strategy to find specific protein–protein interactions by combining native size-exclusion chromatography (SEC) with affinity chromatography with the resin that specifically binds BChE. Second, to confirm protein complexes′ specificity, we fractionated blood serum proteins by density gradient ultracentrifugation followed by co-immunoprecipitation with anti-BChE monoclonal antibodies. The proteins coisolated in complexes with BChE were identified by mass spectroscopy. These binding studies revealed that BChE interacts with a number of proteins in the human serum. Some of these interactions seem to be more stable than transient. BChE copurification with ApoA-I and the density of some fractions containing BChE corresponding to high-density lipoprotein cholesterol (HDL) during ultracentrifugation suggest its interactions with HDL. Moreover, we observed lower BChE plasma activity in individuals with severely reduced HDL levels (≤20 mg/dL). The presented two-step methodology for determination of the BChE interactions can facilitate further analysis of such complexes, especially from the brain tissue, where BChE could be involved in the pathogenesis and progression of AD.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Objectives
The lack of systematic evidence on neuroimaging findings in motor neuron diseases (MND) hampers the diagnostic utility of magnetic resonance imaging (MRI). Thus, we aimed at performing a ...systematic review and meta-analysis of MRI features in MND including their histopathological correlation.
Methods
In a comprehensive literature search, out of 5941 unique publications, 223 records assessing brain and spinal cord MRI findings in MND were eligible for a qualitative synthesis. 21 records were included in a random effect model meta-analysis.
Results
Our meta-analysis shows that both T2-hyperintensities along the corticospinal tracts (CST) and motor cortex T2
*
-hypointensitites, also called “motor band sign”, are more prevalent in ALS patients compared to controls OR 2.21 (95%-CI: 1.40–3.49) and 10.85 (95%-CI: 3.74–31.44), respectively. These two imaging findings correlate to focal axonal degeneration/myelin pallor or glial iron deposition on histopathology, respectively. Additionally, certain clinical MND phenotypes such as amyotrophic lateral sclerosis (ALS) seem to present with distinct CNS atrophy patterns.
Conclusions
Although CST T2-hyperintensities and the “motor band sign” are non-specific imaging features, they can be leveraged for diagnostic workup of suspected MND cases, together with certain brain atrophy patterns. Collectively, this study provides high-grade evidence for the usefulness of MRI in the diagnostic workup of suspected MND cases.
Systematic review registration
https://www.crd.york.ac.uk/PROSPERO/
, identifier: CRD42020182682.
PDF
