We further document the wide applicability of this method by applying it to other enzymes systems where we have run covalent inhibitor programs.Cyclic dinucleotides (CDNs) could activate stimulator of interferon genes (STING) protein to produce type I interferon and other pro-inflammation cytokines in mammalian cells. To explore new types of potentially efficient STING activators targeting all five major hSTING variants (WT, R232H, HAQ, AQ and R293Q), we here reported the synthesis of a total of 19 inosine-containing CDNs based on the combinations of hypoxanthine with four natural bases (A, G, C and U) and three phosphodiester linkage backbones (3'-3', 2'-3', 2'-2'). The IFN-β induction results showed that all of the 2'-3' and 2'-2' CDNs linked by inosine and purine nucleosides favored the stacking interaction with Y167 and R238 residues of hSTING protein, and several CDNs constructed by hypoxanthine and pyrimidine like c[I(2',5')U(2',5')] could also activate all five hSTING variants. The molecular dynamic simulation and the isothermal titration calorimetric (ITC) assay further demonstrated the potential of cAIMP isomers with 2'-5' phosphate to form the hydrogen binding with R232 and R238 residues of hSTING in an entropically driven manner compared to cGAMP isomers. It would be promising to exploit novel inosine-mixed CDNs as activators of hSTING variants in immune therapy.Drugs with a covalent mechanism of action benefit from enhanced potency, selectivity, and in vivo efficacy. Historically, the only covalent drugs on the market have been covalent small molecules. However, many proteins and protein-protein interactions cannot be targeted by small molecules due to their lack of small molecule binding pockets, and are thus deemed "undruggable." In order to drug the undruggable, peptide and protein therapeutics that can better bind to flat protein surfaces have been developed. Until recently, peptide and protein therapeutics have had noncovalent mechanisms of action. The recent advancement of unnatural amino acid chemistry, along with the development of better and more specific electrophilic warheads, has allowed for the application of covalent mechanisms to peptide and protein drugs. Covalent peptide and protein therapeutics have the potential to benefit from the same advantages that covalent small molecules have over their noncovalent counterparts. Here we provide a brief overview of the chemistry that makes this advancement possible, as well as examples of covalent peptides and the first covalent protein drug. These examples successfully crosslink their target proteins and have beneficial therapeutic effects.As abnormal PI3K signaling is a feature of many types of cancer, the development of orally active PI3K inhibitors is of great significance for targeted cancer therapy. Through integrating strategies of reducing aromatic character/increasing the fraction of sp3 carbons together with scaffold hopping, we designed and synthesized two new series of thieno[2,3-d]pyrimidine and thiazolo[5,4-d]pyrimidine derivatives for use as PI3K inhibitors. Our structure-activity relationship studies led to the identification of thieno[2,3-d]pyrimidine 6a and thiazolo[5,4-d]pyrimidine 7a, which exhibited remarkable nanomolar PI3K potency, good antiproliferative activity, favorable pharmacokinetic properties and significant in vivo anti-cancer efficacy. Notably, thiazolo[5,4-d]pyrimidine 7a had better anti-cancer activity than thieno[2,3-d]pyrimidine 6a and is worthy of further pre-clinical evaluation for its use in cancer treatment.As a continuation of our previous work, a series of new phenyl acrylamide derivatives (4Aa-g, 4Ba-t, 5 and 6a-c) were designed and synthesized as non-nucleoside anti-HBV agents. Among them, compound 4Bs could potently inhibit HBV DNA replication in wild-type and lamivudine (3TC)/entecavir resistant HBV mutant strains with IC50 values of 0.19 and 0.18 μM, respectively. Notably, the selective index value of 4Bs was above 526, indicating the favorable safety profile. Interestingly, unlike nucleoside analogue 3TC, 4Bs could significantly inhibit 3.5 kb pgRNA expression. https://www.selleckchem.com/products/gsk467.html Molecular docking study revealed that 4Bs could fit well into the dimer-dimer interface of HBV core protein by hydrophobic, π-π and H-bond interactions. Considering the potent anti-HBV activity, low toxicity and diverse anti-HBV mechanism from that of nucleoside anti-HBV agent 3TC, compound 4Bs might be a promising lead to develop novel non-nucleoside anti-HBV therapeutic agents, and warranted further investigation.
To assess the safety and efficacy of CT-guided microwave ablation (MWA) of hepatocellular carcinoma (HCC) near large blood vessels and the diaphragm by analyzing procedural complications and local tumor progression (LTP).

From October 2013 through January 2019, 80 patients (54 males and 26 females) with 136 tumors who underwent CT-guided MWA of HCC were included in this retrospective analysis. MWA was performed on 43 perivascular HCC (≤5mm from a vessel measuring ≥5mm in diameter), 38 subdiaphragmatic HCC (≤5mm from diaphragm), and 64 control HCC. Risk factors for local tumor progression (LTP), overall survival, and complications were analyzed using the Chi-square and Cox proportional hazards model methods.

The technical success rate of MWA was 100%. Complication incidence was not significantly different between perivascular and control tumors (20.9% vs 10.9%; p=0.155) or between subdiaphragmatic and control tumors (21.1% vs 10.9%; p=0.163). The effect of lesion location on LTP disappeared while controlling for age and lesion size. There was no significant difference in median survival time between patients who had only control tumors (38.8months) compared to patients with at least one perivascular or subdiaphragmatic tumor (42.5months; p=0.098).

CT-guided percutaneous MWA of perivascular and subdiaphragmatic HCC tumors is safe and effective. The local tumor recurrence and survival was not significantly different compared to control tumors.
CT-guided percutaneous MWA of perivascular and subdiaphragmatic HCC tumors is safe and effective. The local tumor recurrence and survival was not significantly different compared to control tumors.

Microbial lipids play a critical role in the pathogenesis of infectious diseases by modulating the host cell membrane properties, including lipid/protein diffusion and membrane organization. Mycobacterium tuberculosis (Mtb) synthesizes various chemically distinct lipids that are exposed on its outer membrane and interact with host cell membranes. However, the effects of the structurally diverse Mtb lipids on the host cell membrane properties to fine-tune the host cellular response remain unknown. In this study, we employed membrane biophysics and cell biology to assess the effects of different Mtb lipids on cell membrane mechanics, lipid diffusion, and the cytoskeleton of THP-1 macrophages. We found that Mtb lipids modulate macrophage membrane properties, actin cytoskeleton, and biochemical processes, such as protein phosphorylation and lipid peroxidation, in a virulence lipid-selective manner. These results emphasize that Mtb can fine-tune its interactions with the host cells governed by modulating the lipid profile on its surface. These observations provide a novel lipid-centric paradigm of Mtb pathogenesis that is amenable to pharmacological inhibition and could promote the development of robust biomarkers of Mtb infection and pathogenesis.Cytotoxic frog antimicrobial peptide Temporin L (TempL) is an attractive molecule for the design of lead antimicrobial agents due to its short size and versatile biological activities. However, noncytotoxic TempL variants with desirable biological activities have rarely been reported. TempL analogue Q3K,TempL is water-soluble and possesses a significant antiendotoxin property along with comparable cytotoxicity to TempL. A phenylalanine residue, located at the hydrophobic face of Q3K,TempL and the "d" position of its phenylalanine zipper sequence, was replaced with a cationic lysine residue. This analogue, Q3K,F8K,TempL, showed reduced hydrophobic moment and was noncytotoxic with lower antimicrobial activity. Interestingly, swapping between tryptophan at the fourth and serine at the sixth positions turned Q3K,F8K,TempL totally amphipathic as reflected by its helical wheel projection with clusters of hydrophobic and hydrophilic residues and the highest hydrophobic moment among these peptides. Surprisingly, this analogue, SW,Q3K,F8K,TempL, was as noncytotoxic as Q3K,F8K,TempL but showed augmented antimicrobial and antiendotoxin properties, comparable to that of TempL and Q3K,TempL. SW,Q3K,F8K,TempL exhibited appreciable survival of mice against P. aeruginosa infection and a lipopolysaccharide (LPS) challenge. Unlike TempL and Q3K,TempL, SW,Q3K,F8K,TempL adopted an unordered secondary structure in bacterial membrane mimetic lipid vesicles and did not permeabilize them or depolarize the bacterial membrane. Overall, the results demonstrate the design of a nontoxic TempL analogue that possesses clusters of hydrophobic and hydrophilic residues with impaired secondary structure and shows a nonmembrane-lytic mechanism and in vivo antiendotoxin and antimicrobial activities. This paradigm of design of antimicrobial peptide with clusters of hydrophobic and hydrophilic residues and high hydrophobic moment but low secondary structure could be attempted further.Praziquantel is the only widely available drug to treat schistosomiasis. With very few candidates currently in the drug development pipeline, there is an urgent need to discover and develop novel antischistosomal drugs. https://www.selleckchem.com/products/Rosuvastatin-calcium(Crestor).html In this regard, the pyrido[1,2-a]benzimidazole (PBI) scaffold has emerged as a promising chemotype in hit-to-lead efforts. Here, we report a novel series of antischistosomal PBIs with potent in vitro activity (IC50 values of 0.08-1.43 μM) against Schistosoma mansoni newly transformed schistosomula and adult worms. Moreover, the current PBIs demonstrated good hepatic microsomal stability (>70% of drug remaining after 30 min) and were nontoxic to the Chinese hamster ovarian and human liver HepG2 cells, though toxicity (selectivity index, SI less then 10) against the rat L6 myoblast cell line was observed. The compounds showed a small therapeutic window but were efficacious in vivo, exhibiting moderate to high worm burden reductions of 35.8-89.6% in S. mansoni-infected mice.The discovery of novel drug candidates with anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) potential is critical for the control of the global COVID-19 pandemic. Artemisinin, an old antimalarial drug derived from Chinese herbs, has saved millions of lives. Artemisinins are a cluster of artemisinin-related drugs developed for the treatment of malaria and have been reported to have multiple pharmacological activities, including anticancer, antiviral, and immune modulation. Considering the reported broad-spectrum antiviral potential of artemisinins, researchers are interested in whether they could be used to combat COVID-19. We systematically evaluated the anti-SARS-CoV-2 activities of nine artemisinin-related compounds in vitro and carried out a time-of-drug-addition assay to explore their antiviral mode of action. Finally, a pharmacokinetic prediction model was established to predict the therapeutic potential of selected compounds against COVID-19. Arteannuin B showed the highest anti-SARS-CoV-2 potential with an EC50 of 10.28 ± 1.12 μM. Artesunate and dihydroartemisinin showed similar EC50 values of 12.98 ± 5.30 μM and 13.31 ± 1.24 μM, respectively, which could be clinically achieved in plasma after intravenous administration. Interestingly, although an EC50 of 23.17 ± 3.22 μM was not prominent among the tested compounds, lumefantrine showed therapeutic promise due to high plasma and lung drug concentrations after multiple dosing. Further mode of action analysis revealed that arteannuin B and lumefantrine acted at the post-entry step of SARS-CoV-2 infection. This research highlights the anti-SARS-CoV-2 potential of artemisinins and provides leading candidates for anti-SARS-CoV-2 drug research and development.Colistin is an antibiotic of last resort used to treat infections caused by multidrug-resistant Gram-negative bacterial pathogens. The recent surge in reported cases of colistin-resistant infections urgently calls for fast and reliable diagnostic methods, which can be used for the facile detection and proper treatment of these challenging infections. A major mechanism of colistin resistance involves phosphoethanolamine (PE) modification of lipopolysaccharide (LPS), the molecular target of colistin. This LPS modification mechanism has been recently reported to be transferrable via a plasmid-carried mcr-1 gene, which is particularly concerning as it may readily confer colistin resistance to a wide array of bacterial pathogens. To develop molecular tools to allow facile detection of colistin resistance, we have herein enlisted a novel phage library that incorporates dynamic covalent warheads to recognize PE modifications on bacterial cells. Screening of this chemically modified phage library against colistin-resistant pathogens revealed a number of peptide probes that readily differentiate colistin-resistant bacterial strains from their colistin-susceptible counterparts.

A smaller sludge surface area is also found more significant on vacuum drying.Implications Drying the sludge under low pressure shortens the drying time. It is possible to reach higher solid material ratio under low pressure. Time, temperature, and surface areas of sludge are effective parameters in vacuum drying.Dictyostelids are a monophyletic group of sorocarp-forming social amoebae in the major eukaryotic division Amoebozoa. Members of this taxon, which is made up of almost 200 described species, are common in terrestrial soils globally. Still, the alpha diversity is not well known in many areas, and new species are frequently recovered. The highest species richness is found in the tropics. Here, five new species are described from soil samples collected in Madagascar. These species-Cavenderia basinodulosa, C. canoespora, Heterostelium radiatum, H. versatile, and Raperostelium stabile-are described based on both morphological characteristics and molecular data, with sequence data from the rDNA small subunit (SSU). The five new species are morphologically disparate, ranging from relatively small, robust taxa such as R. stabile to taxa with variable morphologies such as the larger H. https://www.selleckchem.com/products/AZD0530.html radiatum and H. versatile and the yellow-tinted and irregularly branched species C. canoespora and C. basinulosa. These new species, together with earlier work where 13 other species were described from the island, suggest that there is a range of genetically diverse and highly morphologically variable dictyostelid taxa occurring on Madagascar, suggesting biogeographic patterns even within these very small organisms.Several labels, such as neuroticism, negative emotionality, and dispositional negativity, indicate a broad dimension of psychopathology. However, largely separate, often disorder-specific research lines have developed that focus on different cognitive and affective characteristics that are associated with this dimension, such as perseverative cognition (worry, rumination), reduced autobiographical memory specificity, compromised fear learning, and enhanced somatic-symptom reporting. In this article, we present a theoretical perspective within a predictive-processing framework in which we trace these phenotypically different characteristics back to a common underlying "better-safe-than-sorry" processing strategy. This implies information processing that tends to be low in sensory-perceptual detail, which allows threat-related categorical priors to dominate conscious experience and for chronic uncertainty/surprise because of a stagnated error-reduction process. This common information-processing strategy has beneficial effects in the short term but important costs in the long term. From this perspective, we suggest that the phenomenally distinct cognitive and affective psychopathological characteristics mentioned above represent the same basic processing heuristic of the brain and are only different in relation to the particular type of information involved (e.g., in working memory, in autobiographical memory, in the external and internal world). Clinical implications of this view are discussed.Gymnosporangium is a group of plant fungal pathogens that cause rust diseases on many economically important fruit trees. Most Gymnosporangium are heteroecious and demicyclic, producing four morphologically diverse spore stages on two taxonomically unrelated host plants, the Cupressaceae and Rosaceae. The complex life cycle and heteroecism make it difficult to investigate the species within Gymnosporangium. To determine the taxonomy, phylogeny, and species diversity of Gymnosporangium in China, a large collection of 672 specimens were analyzed using a combination of morphological observations and phylogenetic analyses. In total, 27 Gymnosporangium species from China are documented here, including 22 known species, one new combination, one new record, and three new species. The study also documents a novel aeciospore surface structure with an irregular surface that is described here as "surfy."
Covalent inhibition of target proteins using high affinity ligands bearing weakly electrophilic warheads is being adopted increasingly as design strategy in the discovery of novel therapeutics, and several covalent drugs have now received regulatory approval for indications in oncology. Experience to date with targeted covalent inhibitors has led to a number of design principles that underlie the safety and efficacy of this increasingly important class of molecules.

A review is provided of the current status of the covalent drug approach, emphasizing the unique benefits and attendant risks associated with reversible and irreversible binders. Areas of application beyond inhibition of tyrosine kinases are presented, and design considerations to de-risk covalent inhibitors with respect to undesirable off-target effects are discussed.

High selectivity for the intended protein target has emerged as a key consideration in mitigating safety risks associated with widespread proteome reactivity. Powerful chemical proteomics-based techniques are now available to assess selectivity in a drug discovery setting. Optimizing pharmacokinetics to capitalize on the intrinsically high potency of covalent drugs should lead to low daily doses and greater safety margins, while minimizing susceptibility to metabolic activation likewise will attenuate the risk of covalent drug toxicity.
High selectivity for the intended protein target has emerged as a key consideration in mitigating safety risks associated with widespread proteome reactivity. Powerful chemical proteomics-based techniques are now available to assess selectivity in a drug discovery setting. Optimizing pharmacokinetics to capitalize on the intrinsically high potency of covalent drugs should lead to low daily doses and greater safety margins, while minimizing susceptibility to metabolic activation likewise will attenuate the risk of covalent drug toxicity.
Literature on clinical note mining has highlighted the superiority of machine learning (ML) over hand-crafted rules. Nevertheless, most studies assume the availability of large training sets, which is rarely the case. For this reason, in the clinical setting, rules are still common. We suggest 2 methods to leverage the knowledge encoded in pre-existing rules to inform ML decisions and obtain high performance, even with scarce annotations.

We collected 501 prostate pathology reports from 6 American hospitals. Reports were split into 2,711 core segments, annotated with 20 attributes describing the histology, grade, extension, and location of tumors. The data set was split by institutions to generate a cross-institutional evaluation setting. We assessed 4 systems, namely a rule-based approach, an ML model, and 2 hybrid systems integrating the previous methods a Rule as Feature model and a Classifier Confidence model. Several ML algorithms were tested, including logistic regression (LR), support vector machine (SVM), and eXtreme gradient boosting (XGB).

In the multivariable hierarchical regression, depression, frequency of use, and higher PCQ scores were associated with higher PPUS scores, although only the latter two remained significant in the final model. Understanding the risk factors via more frequent screening for PPU will help with the development of treatment protocols for this problematic behavior.The development of drug-resistant bacteria, as well as multidrug-resistant pathogens related to substantial mortality, is an important global health threat. The wide range of biological activities and the wealthy use of coumarin-containing drugs in the clinic have encouraged more and more interest in this class of heterocycles. Various coumarin-based antibiotic hybrids have been developed in the last decade and most of them exhibited potential antibacterial potency. This present review summarizes the current innovations of coumarin-based derivatives with potential antibacterial activities against a variety of Gram-negative and Gram-positive bacteria discussing various aspects of structure-activity relationship (SAR). The improved SAR will provide further insight into the rational improvement of coumarin hybrids with astounding strength against multidrug-resistant bacteria.The aryl hydrocarbon receptor (AhR) is a chemical sensor upregulating the transcription of responsive genes associated with endocrine homeostasis, oxidative balance and diverse metabolic, immunological and inflammatory processes, which have raised the pharmacological interest on its modulation. Herein, a novel set of 32 unsymmetrical triarylmethane (TAM) class of structures has been synthesized, characterized and their AhR transcriptional activity evaluated using a cell-based assay. Eight of the assayed TAM compounds (14, 15, 18, 19, 21, 22, 25, 28) exhibited AhR agonism but none of them showed antagonist effects. TAMs bearing benzotrifluoride, naphthol or heteroaromatic (indole, quinoline or thiophene) rings seem to be prone to AhR activation unlike phenyl substituted or benzotriazole derivatives. A molecular docking analysis with the AhR ligand binding domain (LBD) showed similarities in the binding mode and in the interactions of the most potent TAM identified 4-(pyridin-2-yl (thiophen-2-yl)methyl)phenol (22) compared to the endogenous AhR agonist 5,11-dihydroindolo[3,2-b]carbazole-12-carbaldehyde (FICZ). Finally, in silico predictions of physicochemical and biopharmaceutical properties for the most potent agonistic compounds were performed and these exhibited acceptable druglikeness and good ADME profiles. To our knowledge, this is the first study assessing the AhR modulatory effects of unsymmetrical TAM class of compounds.Targeted covalent inhibitors represent a viable strategy to block protein kinases involved in different disease pathologies. Although a number of computational protocols have been published for identifying druggable cysteines, experimental approaches are limited for mapping the reactivity and accessibility of these residues. Here, we present a ligand based approach using a toolbox of fragment-sized molecules with identical scaffold but equipped with diverse covalent warheads. Our library represents a unique opportunity for the efficient integration of warhead-optimization and target-validation into the covalent drug development process. Screening this probe kit against multiple kinases could experimentally characterize the accessibility and reactivity of the targeted cysteines and helped to identify suitable warheads for designed covalent inhibitors. The usefulness of this approach has been confirmed retrospectively on Janus kinase 3 (JAK3). Furthermore, representing a prospective validation, we identified Maternal embryonic leucine zipper kinase (MELK), as a tractable covalent target. Covalently labelling and biochemical inhibition of MELK would suggest an alternative covalent strategy for MELK inhibitor programs.In this paper, the compensated neutron logging is transformed into the Thermal Neutron Cross Section Logging (TNXS) to improve the application effect. Because the compensated neutron logging measures the neutron count, TNXS cannot be directly measured by the compensated neutron logging tool. Moreover, the thermal neutron ratio cannot be directly converted into the TNXS due to the influence of lithology and fluid. The ratio of thermal neutron count is related not only to the formation hydrogen index, but also to the formation density and the formation capture cross section. The density and the capture cross section of formations can be used to reduce the influence of lithology and fluid. Therefore, the thermal neutron counting ratio can be converted into the TNXS by density and the capture cross section of formations. The accuracy of the porosity calculated by the TNXS is studied based on the Monte Carlo method. The results show that the thermal neutron counting ratio can be accurately converted to the TNXS by density and the capture cross section of formations. The porosity calculated by TNXS is closer to the formation porosity than that calculated by the compensated neutron logging, especially in gas-bearing formations and complex lithologic formations.Industrial Computed Tomography (ICT) is a radiation based cross sectional imaging technique that requires a sample to be manipulated precisely in a specific geometry to acquire analytically useful data. Unlike medical CT, industrial CT may require use of gamma radiation from radio-isotopes like Co60, Cs137 etc. having higher energy radiations for penetrating through higher density and thickness of material under inspection. Data acquisition in ICT involves use of a mechanical manipulator to rotate either the specimen or the source and detectors assembly in circular and linear geometry. https://www.selleckchem.com/products/BKM-120.html Misalignment in mechanical set-up leads to significant artifacts in CT image. The effects may be even more pronounced in data acquired with discrete detector as against Linear Detector Array (LDA) because of certain built-in mechanical integrity associated with LDA. This paper discusses cross correlation based software correction method for combination of gamma ray source and NaI (Tl) scintillation detector based transmission ICT system in parallel beam CT geometry.

Convulsion is a typical symptom associated with epilepsy. Jatropha gossypifolia, a common plant in Ghana, has been used traditionally for the management of epilepsy. This study was carried out to ascertain the scientific basis for the traditional utility of Jatropha gossypifolia for various convulsive disorders and also determine the part of the plant with the most anticonvulsant activity. The anticonvulsant activity of the leaf, root, and fruit extracts in doses of 30-300 mg/kg was assessed using the picrotoxin-induced seizure models in mice. The drugs and chemical preparations used included diazepam, picrotoxin, ethanol (70%), and normal saline. GraphPad Prism 6 was used for all statistical analysis and plotting of graphs. Data were analyzed using one-way ANOVA, followed by Bonferroni's multiple comparison test. The leaf extract significantly and dose-independently reduced the frequency of myoclonic jerks (P=0.0001) and decreased the duration of clonic convulsions (P=0.019). The root extract also significantly and dose-dependently reduced the frequency of myoclonic jerks (P=0.001) but only decreased the frequency of tonic convulsions at 100 mg/kg (P=0.006). It also significantly decreased the duration of tonic convulsions (P=0.0001). The fruit extract only significantly and dose-independently reduced the frequency of myoclonic jerks (P=0.0001). It, however, showed an increase in the duration of both clonic and tonic convulsions. The study shows that the leaves and roots of Jatropha gossypifolia produce anticonvulsant activity which may be through enhancement of GABAergic transmission or activation of GABA receptors which support the traditional use of the plant to treat epileptic fits.The devastating antibacterial infections, coupled with their antibiotic resistance abilities, emphasize the need for effective antibacterial therapeutics. In this prospect, liposomal delivery systems have been employed in improving the efficacy of the antibacterial agents. The liposome-based antibiotics enhance the therapeutic potential of the new or existing antibiotics and reduce their adverse effects. The current study describes the development of sulfonium-based antibacterial lipids that demonstrate the delivery of existing antibiotics. The presence of cationic sulfonium moieties and inherent membrane targeting abilities of the lipids could help reduce the antibiotic resistance abilities of the bacteria and deliver the antibiotics to remove the infectious pathogens electively. The transmission electron microscopic images and dynamic light scattering analyses revealed the liposome formation abilities of the sulfonium-based amphiphilic compounds in the aqueous medium. The effectiveness of the compounds was like HeLa and HaCaT cells) at concentrations higher than their minimum inhibitory concentration values against S. aureus, E. coli, and MRSA. Hence, the sulfonium-based lipid exemplifies a promising framework for assimilating various warheads, and provides a potent antibacterial material.Sigma (σ) receptors represent attractive targets for the development of potential agents for the treatment of several disorders, including Alzheimer's disease and neuropathic pain. In the search for multitarget small molecules (MSMs) against such disorders, we have re-discovered chromenones as new affine σ1/σ2 ligands. https://www.selleckchem.com/products/dubs-in-1.html 6-(4-(Piperidin-1-yl)butoxy)-4H-chromen-4-one (7), a previously identified MSM with potent dual-target activities against acetylcholinesterase and monoamine oxidase B, also exhibited σ1/σ2 affinity. 6-(3-(Azepan-1-yl)propoxy)-4H-chromen-4-one (20) showed a K i value for σ1 of 27.2 nM (selectivity (σ1/σ2) = 28), combining the desired σ1 receptor affinity with a dual inhibitory capacity against both acetyl- and butyrylcholinesterase. 6-((5-Morpholinopentyl)oxy)-4H-chromen-4-one (12) was almost equipotent to S1RA, an established σ1 receptor antagonist.Antigen binding to the B-cell receptor initiates a downstream signalling pathway that contains both stimulatory and damping components. A malarial parasite-derived conformation-constrained peptide was conjugated to a signal-damping pathway inhibitor. Mice immunized with this antigen produced higher antibody levels which delayed parasitemia. This represents a new approach to antigen design.Cell cryopreservation is an essential tool for drug toxicity/function screening and transporting cell-based therapies, and is essential in most areas of biotechnology. There is a challenge, however, associated with the cryopreservation of cells in monolayer format (attached to tissue culture substrates) which gives far lower cell yields ( less then 20% typically) compared to suspension freezing. Here we investigate the mechanisms by which the protective osmolyte l-proline enhances cell-monolayer cryopreservation. Pre-incubating A549 cells with proline, prior to cryopreservation in monolayers, increased post-thaw cell yields two-fold, and the recovered cells grow faster compared to cells cryopreserved using DMSO alone. Further increases in yield were achieved by adding polymeric ice recrystallization inhibitors, which gave limited benefit in the absence of proline. Mechanistic studies demonstrated a biochemical, rather than biophysical (i.e. not affecting ice growth) mode of action. It was observed that incubating cells with proline (before freezing) transiently reduced the growth rate of the cells, which was not seen with other osmolytes (betaine and alanine). Removal of proline led to rapid growth recovery, suggesting that proline pre-conditions the cells for cold stress, but with no impact on downstream cell function. Whole cell proteomics did not reveal a single pathway or protein target but rather cells appeared to be primed for a stress response in multiple directions, which together prepare the cells for freezing. These results support the use of proline alongside standard conditions to improve post-thaw recovery of cell monolayers, which is currently considered impractical. It also demonstrates that a chemical biology approach to discovering small molecule biochemical modulators of cryopreservation may be possible, to be used alongside traditional (solvent) based cryoprotectants.