ACPs were developed for the elements H, B, C, N, O, F, Si, P, S, and Cl. The ACP parameters were determined using an extensive training set of 118655 data points, mostly of complete basis set coupled-cluster level quality. The target molecular properties for the ACP-corrected methods include noncovalent interaction energies, molecular conformational energies, reaction energies, barrier heights, and bond separation energies. The ACPs were tested first on the training set and then on a validation set of 42567 additional data points. We show that the ACP-corrected methods can predict the target molecular properties with accuracy close to complete basis set wavefunction theory methods, but at a computational cost of double-ζ DFT methods. This makes the new BLYP/6-31G*-ACP, M06-2X/6-31G*-ACP, and CAM-B3LYP/6-31G*-ACP methods uniquely suited to the calculation of noncovalent, thermochemical, and kinetic properties in large molecular systems.A set of three Cr-dimer compounds, Cr2Q2(en)4X2 (Q S, Se; X Br, Cl; en ethylenediamine), with monoatomic chalcogenide bridges have been synthesized via a single-step solvothermal route. Chalcogenide linkers mediate magnetic exchange between Cr3+ centers, while bidentate ethylenediamine ligands complete the distorted octahedral coordination of Cr centers. Unlike the compounds previously reported, none of the chalcogenide atoms are connected to extra ligands. Magnetic susceptibility studies indicate antiferromagnetic coupling between Cr3+ centers, which are moderate in Cr2Se2(en)4X2 and stronger in Cr2S2(en)4Cl2. Fitting the magnetic data requires a biquadratic exchange term. High-frequency EPR spectra showing characteristic signals due to coupled S = 1 spin states could be interpreted in terms of the "giant spin" Hamiltonian. A fourth compound, Cr2Se8(en)4, has a single diatomic Se bridge connecting the two Cr3+ centers and shows weak ferromagnetic exchange interactions. This work demonstrates the tunability in strength and type of exchange interactions between metal centers by manipulating the interatomic distances and number of bridging chalcogenide linkers.Poly(l-alanine-co-l-lysine)-graft-trehalose (PAKT) was synthesized as a natural antifreezing glycopolypeptide (AFGP)-mimicking cryoprotectant for cryopreservation of mesenchymal stem cells (MSCs). FTIR and circular dichroism spectra indicated that the content of the α-helical structure of PAK decreased after conjugation with trehalose. Two protocols were investigated in cryopreservation of MSCs to prove the significance of the intracellularly delivered PAKT. In protocol I, MSCs were cryopreserved at -196 °C for 7 days by a slow-cooling procedure in the presence of both PAKT and free trehalose. In protocol II, MSCs were preincubated at 37 °C in a PAKT solution, followed by cryopreservation at -196 °C in the presence of free trehalose for 7 days by the slow-cooling procedure. Polymer and trehalose concentrations were varied by 0.0-1.0 and 0.0-15.0 wt %, respectively. Cell recovery was significantly improved by protocol II with preincubation of the cells in the PAKT solution. The recovered cells from protocol II exhibited excellent proliferation and maintained multilineage potentials into osteogenic, chondrogenic, and adipogenic differentiation, similar to MSCs recovered from cryopreservation in the traditional 10% dimethyl sulfoxide system. Ice recrystallization inhibition (IRI) activity of the polymers/trehalose contributed to cell recovery; however, intracellularly delivered PEG-PAKT was the major contributor to the enhanced cell recovery in protocol II. Inhibitor studies suggested that macropinocytosis and caveolin-dependent endocytosis are the main mechanisms for the intracellular delivery of PEG-PAKT. 1H NMR and FTIR spectra suggested that the intracellular PEG-PAKTs interact with water and stabilize the cells during cryopreservation.Climate change will stress urban sanitation systems. Although urban sanitation uses various infrastructure types and service systems, current research appears skewed toward a small subset of cases. We conducted a systematic literature review to critically appraise the evidence for climate change impacts on all urban sanitation system types. We included road-based transport networks, an essential part of fecal sludge management systems. We combined the evidence on climate change impacts with the existing knowledge about modes of urban sanitation failures. We found a predominance of studies that assess climate impacts on centralized sewerage in high-income contexts. The implications of climate change for urban nonsewered and complex, fragmented, and (partially) decentralized sanitation systems remain under-researched. In addition, the understanding of the impacts of climate change on urban sanitation systems fails to take a comprehensive citywide perspective considering interdependencies with other sectors and combinations of climate effects. We conclude that the evidence for climate change impacts on urban sanitation systems is weak. To date, research neither adequately represents the variety of urban sanitation infrastructure and service systems nor reflects the operational and management challenges of already stressed systems.Bacterial DnaK is an ATP-dependent molecular chaperone important for maintaining cellular proteostasis in concert with cofactor proteins. The cofactor DnaJ delivers non-native client proteins to DnaK and activates its ATPase activity, which is required for protein folding. In the bacterial pathogen Mycobacterium tuberculosis, DnaK is assisted by two DnaJs, DnaJ1 and DnaJ2. Functional protein-protein interactions (PPIs) between DnaK and at least one DnaJ are essential for survival of mycobacteria; hence, these PPIs represent untapped antibacterial targets. Here, we synthesize peptide-based mimetics of DnaJ1 and DnaJ2 N-terminal domains as rational inhibitors of DnaK-cofactor interactions. We find that covalently stabilized DnaJ mimetics are capable of disrupting DnaK-cofactor activity in vitro and prevent mycobacterial recovery from proteotoxic stress in vivo, leading to cell death. Since chaperones and cofactors are highly conserved, we anticipate these results will inform the design of other mimetics to modulate chaperone function across cell types.CRISPR-based gene editing is a powerful tool with great potential for applications in the treatment of many inherited and acquired diseases. The longer that CRISPR gene therapy is maintained within a patient, however, the higher the likelihood that it will result in problematic side effects such as off-target editing or immune response. One approach to mitigating these issues is to link the operation of the therapeutic system to a safety switch that autonomously disables its operation and removes the delivered therapeutics after some amount of time. https://www.selleckchem.com/products/skf-34288-hydrochloride.html We present here a simulation-based analysis of the potential for regulating the time delay of such a safety switch using one or two transcriptional regulators and/or recombinases. Combinatorial circuit generation identifies 30 potential architectures for such circuits, which we evaluate in simulation with respect to tunability, sensitivity to parameter values, and sensitivity to cell-to-cell variation. This modeling predicts one of these circuit architectures to have the desired dynamics and robustness, which can be further tested and applied in the context of CRISPR therapeutics.Top-down proteomics is challenged by the high complexity of biological samples. The coelution of intact proteins results in overlapped mass spectra, and hence, an increased peak capacity for protein separation is needed. Herein, ethane-bridged hybrid monoliths with well-defined large mesopores were successfully prepared based on the sol-gel condensation of 1,2-bis(trimethoxysilyl)ethane and tetramethoxysilane, followed by two-step base etching of the Si-O-Si domain while maintaining the Si-C-C-Si domain in the structure. Relatively homogeneous macropores of 1.1 μm and large mesopores of 24 nm were obtained, permitting fast mass transfer of large molecules and efficient diffusion without obstruction. The use of less hydrophobic C1 ligand further sharpened the peak shape and improved peak capacity. A 120 cm-long capillary column was used for top-down proteomic analysis of E. coli lysates under low backpressure with 16 MPa. High peak capacity of 646 was achieved within 240 min gradient. With MS/MS analysis, 959 proteoforms corresponding to 263 proteins could be unambiguously identified from E. coli lysates in a single run. Furthermore, to illustrate the separation performance for large proteoforms, such monoliths were applied to top-down analysis of the SEC fraction of E. coli lysates with Mw ranging from 30 to 70 kDa. With highly effective separation, 347 large proteoforms with Mw higher than 30 kDa were detected in the single 75 min run. These results showed great potential for top-down proteomic analysis in complex samples.Biomaterial-associated infection is difficult to detect and brings consequences that can lead to morbidity and mortality. Bacteria can adhere to the implant surface, grow, and form biofilms. Antimicrobial peptides (AMPs) can target and kill bacterial cells using a plethora of mechanisms of action such as rupturing the cell membrane by creating pores via depolarization with their cationic and amphipathic nature. AMPs can thus be coated onto metal implants to prevent microbial cell adhesion and growth. The aim of this systematic review was to determine the potential clinical applications of AMP-modified implants through in vivo induced infection models. Following a database search recently up to 22 January 2022 using PubMed, Web of Science and Cochrane databases, and abstract/title screening using the PRISMA framework, 24 studies remained, of which 18 were used in the random effects meta-analysis of standardized mean differences (SMD) to get effect sizes. Quality of studies was assessed using SYRCLE's risk of bd to progress toward potential clinical application.Preprocessing of liquid chromatography-mass spectrometry (LC-MS) raw data facilitates downstream statistical and biological data analyses. In the case of targeted LC-MS data, consistent recognition of chromatographic peaks is a main challenge, in particular, for low abundant signals. Fully automatic preprocessing is faster than manual peak review and does not depend on the individual operator. Here, we present the R package automRm for fully automatic preprocessing of LC-MS data recorded in MRM mode. Using machine learning (ML) for detection of chromatographic peaks and quality control of reported results enables the automatic recognition of complex patterns in raw data. In addition, this approach renders automRm generally applicable to a wide range of analytical methods including hydrophilic interaction liquid chromatography (HILIC), which is known for sample-to-sample variations in peak shape and retention time. We demonstrate the impact of the choice of training data set, of the applied ML algorithm, and of individual peak characteristics on automRm's ability to correctly report chromatographic peaks. Next, we show that automRm can replicate results obtained by manual peak review on published data. Moreover, automRm outperforms alternative software solutions regarding the variation in peak integration among replicate measurements and the number of correctly reported peaks when applied to a HILIC-MS data set. The R package is freely available from gitlab (https//gitlab.gwdg.de/joerg.buescher/automrm).