{\mathbb{Z}_{2}} Invariants of Topological Insulators as Geometric Obstructions

We consider a gapped periodic quantum system with time-reversal symmetry of fermionic (or odd) type, i.e. the time-reversal operator squares to \({-\mathbb{1}}\). We investigate the existence of periodic and time-reversal invariant Bloch frames in dimensions 2 and 3. In 2d, the obstruction to the existence of such a frame is shown to be encoded in a \({\mathbb{Z}_2}\)-valued topological invariant, which can be computed by a simple algorithm. We prove that the latter agrees with the Fu-Kane index. In 3d, instead, four \({\mathbb{Z}_2}\) invariants emerge from the construction, again related to the Fu-Kane-Mele indices. When no topological obstruction is present, we provide a constructive algorithm yielding explicitly a periodic and time-reversal invariant Bloch frame. The result is formulated in an abstract setting, so that it applies both to discrete models and to continuous ones.     

Biodegradable Passion Fruit‐Like Nano‐Architectures as Carriers for Cisplatin Prodrug

Accumulation of inorganic nanostructures in the excretory system organs increases their likelihood of toxicity and interference with common medical diagnoses. Thus, one of the major concerns regarding their clinical translation is related to their persistence in organisms. Here the authors demonstrate that nano‐architectures composed by hollow silica nanocapsules embedding arrays of ultrasmall gold nanoparticles undergo biodegradation in cellular environment affording small, potentially clearable building blocks. Furthermore, the authors present their exploitation in glutathione‐triggered release of covalently loaded cisplatin prodrug. This endogenously triggered release leads to high cytotoxicity to human pancreatic carcinoma cells, setting the way for promising applications to synergistic dual chemo/radio‐therapy and radio‐imaging.     

Combining Solid-State NMR with Structural and Biophysical Techniques to Design Challenging Protein-Drug Conjugates

Several protein-drug conjugates are currently being used in cancer therapy. These conjugates rely on cytotoxic organic compounds that are covalently attached to the carrier proteins or that interact with them via non-covalent interactions. Human transthyretin (TTR), a physiological protein, has already been identified as a possible carrier protein for the delivery of cytotoxic drugs. Here we show the structure-guided development of a new stable cytotoxic molecule based on a known strong binder of TTR and a well-established anticancer drug. This example is used to demonstrate the importance of the integration of multiple biophysical and structural techniques, encompassing microscale thermophoresis, X-ray crystallography and NMR. In particular, we show that solid-state NMR has the ability to reveal effects caused by ligand binding which are more easily relatable to structural and dynamical alterations that impact the stability of macromolecular complexes.     

Spleen SORT LNP Generated in situ CAR T Cells Extend Survival in a Mouse Model of Lymphoreplete B Cell Lymphoma

Chimeric Antigen Receptor (CAR) T cell immunotherapy is revolutionizing treatment for patients suffering from B-cell lymphoma (BL). However, the current method of CAR T cell production is complicated and expensive, requiring collection of patient blood to enrich the T cell population, ex vivo engineering/activation, and quality assessment before the patient can receive the treatment. Herein we leverage Spleen Selective ORgan Targeted (SORT) Lipid Nanoparticles (LNPs) to produce CAR T cells in situ and bypass the extensive and laborious process currently used. Optimized Spleen SORT LNPs containing 10 % 18 : 1 PA transfected CD3+, CD8+, and CD4+ T cells in wild-type mice. Spleen SORT LNPs delivered Cre recombinase mRNA and CAR encoding mRNA to T cells in reporter mice and in a lymphoreplete B cell lymphoma model (respectively) after intravenous injection without the need for active targeting ligands. Moreover, in situ CAR T cells increased the overall survival of mice with a less aggressive form of B cell lymphoma. In addition, in situ transfected CAR T cells reduced tumor metastasis to the liver by increasing tumor infiltrating lymphocytes. Overall, these results offer a promising alternative method for CAR T cell production with pre-clinical potential to treat hematological malignancies.     

Complementary heterogeneous/homogeneous protocols for the synthesis of densely functionalized benzo[d]sultams: C-C bond formation by intramolecular nucleophilic aromatic fluorine displacement

Polyfunctionalized benzo[d]sultams 7 and 8, which contain an alpha-amino acid unit, have been synthesized from the corresponding open chain (pentafluorobenzene)sulfonamides 4 by complementary solid-liquid phase transfer catalysis (SL-PTC) and homogeneous protocols. The cyclization step proceeds through the intramolecular nucleophilic displacement of an aromatic fluorine atom.     

Self-assembly dynamics of modular homoditopic bis-calix[5]arenes and long-chain alpha,omega-alkanediyldiammonium components

Homoditopic building blocks 1, featuring two pi-rich cone-like calix[5]arene moieties connected at their narrow rims by a rigid o-, m-, or p-xylyl spacer in a centrosymmetric divergent arrangement, show a remarkable tendency to spontaneously and reversibly self-assemble with the complementary homoditopic alpha,omega-alkanediyldiammonium dipicrate guest salts C8-C12 x 2Pic through iterative intermolecular inclusion events, forming supramolecular assemblies whose composition and dynamics strongly depend upon the length of the connector, the geometry of the spacer, as well as the concentration and/or molar ratios between the two components. (1)H NMR spectroscopy and ESI-MS studies of 1/C(n) x 2Pic modular homoditopic pairs support the formation of discrete (bis)-endo-cavity assemblies with the shorter C8 and C9 connectors, and/or (poly)capsular assemblies with the longer C10-C12 components under appropriate concentrations and molar ratios (50 mM equimolar solutions). (1)H NMR titration experiments and diffusion NMR studies provide clear evidence for the self-assembly dynamics of the complementary pairs here investigated.     

Structural characterizations of lipids A by MS/MS of doubly charged ions on a hybrid linear ion trap/orbitrap mass spectrometer

Here, a new 'one pot' and fast approach is described, based on electrospray ionization (ESI) of negative ions by using a hybrid linear ion trap/orbitrap mass spectrometer (LTQ/orbitrap) for MS and MS/MS analysis. By this method the distribution of the primary and secondary acyl residues of the intact lipid A is inferred by analysis of the ESI spectra measured in positive and negative mode. The analysis of these data allows an unequivocal assignment of the fatty acid distribution. This methodology was successfully tested on two different lipid A with known structures, deriving from the Agrobacterium tumefaciens and Escherichia coli lipopolysaccharides (LPS).     

Computer-assisted protein domain boundary prediction using the DomPred server

Domain prediction from sequence is a particularly challenging task, and currently, a large variety of different methodologies are employed to tackle the task. Here we try to classify these diverse approaches into a number of broad categories. Completely automatic domain prediction from sequence alone is currently fraught with problems, but this should not be so surprising since human experts currently have significant disagreement on domain assignment even when given the structures. It can be argued that we should only test the domain prediction methods on benchmark data that human experts agree upon and this is the approach we take in this paper. Even for the data sets on which human experts agree, automatic structure-based domain assignment still cannot always agree, and so again it is still unlikely that domain prediction methods will reliably obtain correct results completely automatically. We make the argument that computer-assisted domain prediction is a more achievable goal. With this aim in mind, we present the DomPred server. This server provides the user with the results from two completely different categories of method (DPS and DomSSEA). In this paper, each method is individually benchmarked against one of the latest domain prediction benchmarks to provide information about their respective reliabilities. A variety of different benchmark scores are employed since the accuracy of a domain prediction method depends critically on what types of results one wishes to obtain (single/multi-domain classification, domain number, residue linker positions, etc.). Also both of these methods, implemented within the DomPred server, can suggest alternative domain predictions, allowing the user to make the final decision based on these results and applying their own background knowledge to the problem. The DomPred server is available from the URL:http://bioinf.cs.ucl.ac.uk/software.html.     

EQUILIBRIUM MODELING OF PSEUDOMONAD AGGREGATION AND PARTITIONING TO DOLOMITE†

Bioremediation is a common treatment technology considered for the remediation of many toxic and hazardous waste sites. In order for this technology to be successfully implemented, the mobility and adhesion characteristics of the microorganisms must be understood. This study explored the surface and adhesion characteristics of two pseudomonads: Pseudomonas aeruginosa Olin and P. fluorescens rib:lux. In general, the Lewis acid/base character of these microorganisms dominated surface thermodynamics. In both cases partitioning to dolomite, a common mineral, was predicted to be greatest in the stationary phase. In the log growth and decay phases, the Lewis acid/base interaction energy was repulsive for both organisms. The stationary phase for both microbes exhibited a reversal of the Lewis acid/base energy to attractive. Although the magnitude of the various surface energy components differed between the microorganism, it is remarkable that the Lewis acid/base energy exhibited similar behavior.