Lithium reduces apoptosis and autophagy after neonatal hypoxia–ischemia

Lithium is used in the treatment of bipolar mood disorder. Reportedly, lithium can be neuroprotective in models of adult brain ischemia. The purpose of this study was to evaluate the effects of lithium in a model of neonatal hypoxic–ischemic brain injury. Nine-day-old male rats were subjected to unilateral hypoxia–ischemia (HI) and 2 mmol/kg lithium chloride was injected i.p. immediately after the insult. Additional lithium injections, 1 mmol/kg, were administered at 24-h intervals. Pups were killed 6, 24 or 72 h after HI. Lithium reduced the infarct volume from 24.7±2.9 to 13.8±3.3 mm3 (44.1%) and total tissue loss (degeneration + lack of growth) from 67.4±4.4 to 38.4±5.9 mm3 (43.1%) compared with vehicle at 72 h after HI. Injury was reduced in the cortex, hippocampus, thalamus and striatum. Lithium reduced the ischemia-induced dephosphorylation of glycogen synthase kinase-3β and extracellular signal-regulated kinase, the activation of calpain and caspase-3, the mitochondrial release of cytochrome c and apoptosis-inducing factor, as well as autophagy. We conclude that lithium could mitigate the brain injury after HI by inhibiting neuronal apoptosis. The lithium doses used were in the same range as those used in bipolar patients, suggesting that lithium might be safely used for the avoidance of neonatal brain injury

Early structural and functional defects in synapses and myelinated axons in stratum lacunosum moleculare in two preclinical models for tauopaty

The stratum lacunosum moleculare (SLM) is the connection hub between entorhinal cortex and hippocampus, two brain regions that are most vulnerable in Alzheimer’s disease. We recently identified a specific synaptic deficit of Nectin-3 in transgenic models for tauopathy. Here we defined cognitive impairment and electrophysiological problems in the SLM of Tau.P301L mice, which corroborated the structural defects in synapses and dendritic spines. Reduced diffusion of DiI from the ERC to the hippocampus indicated defective myelinated axonal pathways. Ultrastructurally, myelinated axons in the temporoammonic pathway (TA) that connects ERC to CA1 were damaged in Tau.P301L mice at young age. Unexpectedly, the myelin defects were even more severe in bigenic biGT mice that co-express GSK3β with Tau.P301L in neurons. Combined, our data demonstrate that neuronal expression of protein Tau profoundly affected the functional and structural organization of the entorhinal-hippocampal complex, in particular synapses and myelinated axons in the SLM. White matter pathology deserves further attention in patients suffering from tauopathy and Alzheimer’s disease

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Writing with molecules on molecular printboards

Nanotechnology aspires to create functional materials with characteristic dimensions of the order 1–100 nm. One requirement to make nanotechnology work is to precisely position molecules and nanoparticles on surfaces, so that they may be addressed and manipulated for bottom-up construction of nanoscale devices. Here we review the concept of a “molecular printboard”. A molecular printboard is a monolayer of host molecules on a solid substrate on which guest molecules can be attached with control over position, binding strength, and binding dynamics. To this end, cyclodextrins were immobilized in monomolecular layers on gold, on silicon wafers and on glass. Guest molecules (for example, adamantane and ferrocene derivatives) bind to these host surfaces through supramolecular, hydrophobic inclusion interaction. Multivalent interactions are exploited to tune the binding strength and dynamics of the interaction of guest molecules with the printboard. Molecules can be positioned onto the printboard using supramolecular microcontact printing and supramolecular dip-pen nanolithography due to the specific interaction between the ‘ink’ and the substrate. In this way, nanoscale patterns can be written and erased on the printboard. Currently, the molecular printboard is exploited for nanofabrication, for example in combination with electroless deposition of metals and by means of supramolecular layer-by-layer depositio

Noncovalent nanoarchitectures on surfaces: from 2D to 3D nanostructures

Nanofabrication requires new methodologies for the assembly of molecular to micrometre-scale objects onto substrates in predetermined arrangements for the fabrication of two and three-dimensional nanostructures. The positioning and the organization of such structures into spatially well-defined arrays constitute a powerful strategy for the creation of materials structured at the molecular level, and to extend the desired properties of these materials to the macroscopic level. Self-assembly is the pathway that enables the formation of such structures, and the formation of multiple supramolecular interactions is the key to controlling the thermodynamics and kinetics of such assemblies. This article is devoted to some representative examples to assemble molecules and nanoparticles in solution and at surfaces based on noncovalent interactions as a tool for the construction of two and three-dimensional systems

Fabrication of three-dimensional hybrid nanostructures by an integrated process comprising nanoimprint lithography and layer-by-layer assembly

The fabrication of three-dimensional (3D) nanostructures, which have sub-100 nm dimensions in all three directions that can be changed independently for each dimension, is a key issue of nanotechnology. E-beam writing can provide high-resolution two-dimensional (2D) nanopatterns, but implementation of pattern replication methods for rapid reproduction of a master and self-assembly, to provide patterned growth of structures, is essential for the development of more general and versatile 3D nanofabrication methodologies. Here the integration of top-down nanoimprint lithography (NIL) and bottom-up layer-by-layer self-assembly (LBL-SA) are described for the preparation of 3D hybrid nanostructures. NIL provided down to sub-100nm poly(methylmethacrylate) (PMMA) structures. These were employed to fabricate patterned self-assembled monolayers of cyclodextrin (CD) host molecules on silicon oxide. The consecutive LBL-SA with adamantyl guest-functionalized dendrimers and CD-modified gold nanoparticles resulted in patterned multilayer structures with thicknesses of 3-30 nm. The x, y control by NIL and the z control (albeit the same height for all nanostructures simultaneously) by LBL-SA ultimately allowed the fabrication of circular structures with a radius of 25 nm and a thickness of 20 nm. The integration of the two methods has thus yielded a versatile 3D nanofabrication methodology comprising 10-40 process steps

Patterned, Hybrid, Multilayer Nanostructures Based on Multivalent Supramolecular Interactions\ud

Various patterning strategies have been developed to create hybrid nanostructures of dendrimers and gold nanoparticles on cyclodextrin self-assembled monolayers (CD SAMs) based on multiple supramolecular interactions using a layer-by-layer (LBL) approach. A lack of specificity of the adsorption of the dendrimer prevented the use of LBL assembly on chemically patterned SAMs, which were prepared by microcontact printing (μCP) or nanoimprint lithography (NIL). Nanotransfer printing (nTP) and nanoimprint lithography solved that problem and resulted in patterned LBL assemblies on the CD SAMs. nTP was achieved by LBL assembly on a PDMS stamp followed by transfer onto a full CD SAM. NIL-prepared PMMA patterns provided patterned CD SAMs and functioned as a physical mask for LBL assembly. For these methods, differences in thickness of the LBL assemblies were observed when compared to LBL assembly on full CD SAMs. These differences were shown not to originate from rinsing or lift-off procedures, but probably from differences in wettin

Expression of a Supramolecular Complex at a Multivalent Interface\ud

The multivalent binding of a supramolecular complex at a multivalent host surface by combining the orthogonal β-cyclodextrin (CD) host−guest and metal ion−ethylenediamine coordination motifs is described. As a heterotropic, divalent linker, an adamantyl-functionalized ethylenediamine derivative was used. This was complexed with Cu(II) or Ni(II). The binding of the complexes to a CD self-assembled monolayer (SAM) was studied as a function of pH by means of surface plasmon resonance (SPR) spectroscopy. A heterotropic, multivalent binding model at interfaces was used to quantify the multivalent enhancement at the surface. The Cu(II) complex showed divalent binding to the CD surface with an enhancement factor higher than 100 relative to the formation of the corresponding divalent complex in solution. Similar behavior was observed for the Ni(II) system. Although the Ni(II) system could potentially be trivalent, only divalent binding was observed at the CD SAMs, which was confirmed by desorption experiment