A molecular docking exploration of the large extracellular loop of tetraspanin CD81 with small molecules.

Tetraspanin CD81 is a transmembrane protein used as a co-receptor by different viruses and implicated in some cancer and inflammatory diseases. The design of therapeutic small molecules targeting CD81 lags behind monoclonal antibodies and peptides but different synthetic and natural products binding to CD81 have been identified. We have investigated the interaction between synthetic compounds and CD81, considering both the cholesterol-bound full-length receptor and a truncated protein corresponding to the large extracellular loop (LEL) of the tetraspanin. They represent the closed and open conformations of the protein, respectively. Stable complexes were characterized with bi-aryl compounds (notably the quinolinone-benzothiazole 6) and atypical molecules bearing a 1-amino-boraadamantane scaffold well adapted to interact with CD81 (5a-d). In each case, the mode of binding to CD81 was analyzed, the binding sites identified and the molecular contacts determined. The narrow intra-LEL binding site of CD81 can accommodate the elongated bi-aryl 6 but not a series of isosteric compounds with a bis(bicyclic) scaffold. The bora-adamantane derivatives appeared to bind well to CD81, but essentially to the external surface of the protein loop. The binding selectivity of the compounds was assessed comparing binding to the LEL of tetraspanins CD81, CD9 and Tspan15. A net preference for CD81 over CD9 was evidenced, but the LEL of Tspan15 also provided a suitable binding site for the compounds, notably for the bora-adamantane derivatives. This work provides an aid to the identification and design of tetraspanin-binding small molecules, underlining the distinct behavior of the open and closed conformation of the protein for drug binding. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00203-6.

The Role of Electron-Donating Subunits in Cross-Linked BODIPY Polymer Films.

A new method for synthesizing cross-linked 4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes (BODIPYs) using a radical-based thiol-ene click reaction is developed. This method is simple, efficient, and cost-effective, and it produces polymers with unique optical, electrochemical, and surface morphology properties. Significant blue shifts in absorption and photoinduced electron transfer in emissions are observed in the cross-linked BODIPY thin films. Cross-linking also leads to the restriction of conjugation, which results in the breakage of the terminal vinyl group, an increase in the oxidation potential, and a slight upshift in the HOMO position. As a result, the electrochemical band gap is widened from 1.88 to 1.94 eV for polymer bearing N,N-dimethylamino-BODIPY and from 1.97 to 2.02 eV for polymer bearing N,N-diphenylamino-BODIPY moieties. Monomer thin films form planar surfaces due to crystallinity, while amorphous cross-linked BODIPY polymers form more rough surfaces. Additionally, photopatterning on the film surface is successfully performed using different patterned masks. This new method for synthesizing cross-linked BODIPYs has the potential to be used in a variety of applications, including organic electronics, bioimaging, and photocatalysis.

Bora-alkenes: Metal Coordination and Reactions with BH-boranes.

The neutral N-heterocyclic carbene stabilized bora-alkene 1, conveniently prepared by a BH borenium/hydroboration route, forms stable copper, gold or palladium π-complexes. The polar bora-alkene B=C system undergoes regioselective hydroboration reactions with the (C6 F5 )2 BH or C6 F5 BH2 ⋅ SMe2 boranes. The latter reaction involves a subsequent rearrangement that leads to internal hydride vs. isothiocyanate substituent exchange at the borane pair.

Citric acid esterified Glutinous Assam bora rice starch enhances disintegration and dissolution efficiency of model drug.

The current work was designed to study the starch's physicochemical attributes, tablet disintegration and dissolution efficiency and its derivatives obtained from the glutinous Assam bora rice (G-ABR) variety of Assam, Northeast India. Starch was isolated by a simple protein denaturation method, and a starch derivative was prepared through citric acid modification. G-ABRS and citrated G-ABRS were characterized through FTIR, DSC, XRD and SEM. The rate of consolidation, consolidation index, angle of internal friction, packing rearrangement and cohesive properties were determined to investigate their applications as functional excipients in pharmaceutical industries. G-ABRS and citrated G-ABRS exhibited better packing rearrangement and cohesive properties than standard corn starch. Furthermore, immediate release of API from the tablet compact was observed when the starch concentration increased from 1 to 5 %, indicating facilitation of the tablet compact disintegration. Therefore, G-ABRS and citrated G-ABRS are potentially functional and sustainable materials for pharmaceutical industries.

BODIPYs in PDT: A Journey through the Most Interesting Molecules Produced in the Last 10 Years.

Over the past 30 years, photodynamic therapy (PDT) has shown great development. In the clinical setting the few approved molecules belong almost exclusively to the porphyrin family; but in the scientific field, in recent years many researchers have been interested in other families of photosensitizers, among which BODIPY has shown particular interest. BODIPY is the acronym for 4,4-difluoro-4-bora-3a, 4a-diaza-s-indacene, and is a family of molecules well-known for their properties in the field of imaging. In order for these molecules to be used in PDT, a structural modification is necessary which involves the introduction of heavy atoms, such as bromine and iodine, in the beta positions of the pyrrole ring; this change favors the intersystem crossing, and increases the 1O2 yield. This mini review focused on a series of structural changes made to BODIPYs to further increase 1O2 production and bioavailability by improving cell targeting or photoactivity efficiency.

Galactose conjugated boron dipyrromethene and hydrogen bonding promoted J-aggregates for efficiently targeted NIR-II fluorescence assistant photothermal therapy.

It is essential to develop novel multifunctional and easily synthesized stable NIR-II fluorescent probes to guide photothermal therapy for tumors. Here, we propose a new strategy to construct boron dipyrromethene (BODIPY) J-aggregates by intermolecular hydrogen bonding (H-bond) and π-π stacking interactions to achieve fluorescence emission in the second near-infrared window (NIR-II, 1000-1700 nm). A novel meso-benzamide galactose hexanoate-BODIPY (Gal-OH-BDP) amphiphilic small molecular dye was synthesized and it formed nanoparticles spontaneously in aqueous solution with a maximum emission wavelength near 1060 nm, which works as a smart nanomedicine for targeting NIR-II imaging-guided photothermal therapy (PTT) of hepatocellular carcinoma. Galactose not only provided hydrogen bonds to regulate the aggregation pattern of the molecules but also effectively targeted hepatocellular carcinoma cells and promoted the formation of well-dispersed nanoparticles of dye molecules due to their hydrophilicity. Moreover, due to high photothermal conversion efficiency (PCE = 55%), Gal-OH-BDP NPs achieve galactose-targeted NIR-II imaging and PTT, which is important for the precise diagnosis and treatment of tumors (Scheme 1). In the present research work, H-bond was introduced for the first time into BODIPY for building J-aggregates to achieve the NIR-II fluorescence.

Quantifying Positional Isomers (QPI) by Top-Down Mass Spectrometry.

Proteomics has exposed a plethora of posttranslational modifications, but demonstrating functional relevance requires new approaches. Top-down proteomics of intact proteins has the potential to fully characterize protein modifications in terms of amount, site(s), and the order in which they are deposited on the protein; information that so far has been elusive to extract by shotgun proteomics. Data acquisition and analysis of intact multimodified proteins have however been a major challenge, in particular for positional isomers that carry the same number of modifications at different sites. Solutions were previously proposed to extract this information from fragmentation spectra, but these have so far mainly been limited to peptides and have entailed a large degree of manual interpretation. Here, we apply high-resolution Orbitrap fusion top-down analyses in combination with bioinformatics approaches to attempt to characterize multiple modified proteins and quantify positional isomers. Automated covalent fragment ion type definition, detection of mass precision and accuracy, and extensive use of replicate spectra increase sequence coverage and drive down false fragment assignments from 10% to 1.5%. Such improved performance in fragment assignment is key to localize and quantify modifications from fragment spectra. The method is tested by investigating positional isomers of Ubiquitin mixed in known concentrations, which results in quantification of high ratios at very low standard errors of the mean (<5%), as well as with synthetic phosphorylated peptides. Application to multiphosphorylated Bora provides an estimation of the so far unknown stoichiometry of the known set of phosphosites and uncovers new sites from hyperphosphorylated Bora.

Unintended Pregnancy and Associated Factors Among HIV Positive Women in Ilu Aba Bora zone, South Western Ethiopia: A Facility-Based Cross-Sectional Study.

BACKGROUND: Unintended pregnancy reflects the existence of unprotected sex. Understanding factors associated with unintended pregnancy among HIV-positive women is very important to design strategies for the prevention of further transmission and infection with the virus. However, there is scarce information in this regard. Given the degree of HIV prevalence among women and the current antiretroviral therapy scale up in Ethiopia, it is important to understand factors associated with un-intended pregnancy in order to prevent mother to child HIV transmission (MTCT). METHODS: An institution-based cross-sectional study design was employed. The sample size was 353; all HIV/AIDS sero-positive reproductive age group (15-49) women having any pregnancy history after their diagnosis and having started HAART were included and simple random sampling was used to select study participants. Data collection period was from March 9 to April 13, 2019. RESULTS: The prevalence of unintended pregnancy among the participants was 40.9%. In the multivariate logistic regression, unemployment (AOR, 3.36; 95% CI: 1.55-7.26), not being knowledgeable on MTCT and prevention of MTCT (PMTCT) (AOR, 3.18; 95% CI: 1.92-5.24), and having had no discussion on reproductive health issues (AOR, 1.83; 95% CI: 1.09-3.07) are factors significantly associated with unintended pregnancy occurrence among HIV-positive women on antiretroviral therapy. CONCLUSION AND RECOMMENDATION: The prevalence of unintended pregnancy among the women in the study is high. To avoid unintended pregnancies, HIV-infected women need access to effective family planning services and risk reduction discussions during routine care visits.

Binding mode analysis of ABCA7 for the prediction of novel Alzheimer's disease therapeutics.

The adenosine-triphosphate-(ATP)-binding cassette (ABC) transporter ABCA7 is a genetic risk factor for Alzheimer's disease (AD). Defective ABCA7 promotes AD development and/or progression. Unfortunately, ABCA7 belongs to the group of 'under-studied' ABC transporters that cannot be addressed by small-molecules. However, such small-molecules would allow for the exploration of ABCA7 as pharmacological target for the development of new AD diagnostics and therapeutics. Pan-ABC transporter modulators inherit the potential to explore under-studied ABC transporters as novel pharmacological targets by potentially binding to the proposed 'multitarget binding site'. Using the recently reported cryogenic-electron microscopy (cryo-EM) structures of ABCA1 and ABCA4, a homology model of ABCA7 has been generated. A set of novel, diverse, and potent pan-ABC transporter inhibitors has been docked to this ABCA7 homology model for the discovery of the multitarget binding site. Subsequently, application of pharmacophore modelling identified the essential pharmacophore features of these compounds that may support the rational drug design of innovative diagnostics and therapeutics against AD.

A New Species of Tetragona Lepeletier & Serville, 1828 from the "truncata group" and New Distribution Records of T. truncata Moure, 1971 (Hymenoptera: Apidae).

Tetragona Lepeletier & Serville is a genus of stingless bees with 14 recognized species occurring from Mexico to Argentina. The genus is characterized by velvety genal area, mesotibial spur present, and propodeal triangle glabrous. Within the genus, the truncata species group (T. truncata Moure and T. atahualpa sp. nov.) is characterized by worker metabasitarsus with posterior angle rounded and the mandible with two short teeth of similar length. Tetragona truncata is reported with new records for Ecuador (Napo and Orellana), Peru (Huánuco, Loreto, and San Martín), and Brazil (Acre [Rio Branco] and Tocantins [Itacá, Lizarda and Palmas]). In addition, T. atahualpa sp. nov. is described as a new species from regions of altitudes above 1,800 m in Colombia (Boyacá), Ecuador (Napo, Zamora-Chinchipe), and Peru (Pasco). We illustrate and discuss the identification of these two species.

Bacillus thuringiensis strains isolated from Qatari soil, synthesizing δ-endotoxins highly active against the disease vector insect Aedes aegypti Bora Bora.

Bacillus thuringiensis (Bt) is a Gram-positive soil bacterium that has been recognized as an effective bioinsecticide active against plant, animal and human pathogenic and disease vector insects. During its sporulation phase, Bt produces crystals consisting of δ-endotoxins, which upon ingestion kill specifically insect larvae. Bt subsp. israelensis (Bti) is very active against dipteran insects. Bti based bioinsecticides are considered as a sustainable solution to control the Dipteran insects responsible of plant, animal and human diseases. In this study, Bti strains isolated from Qatar soil were analyzed for their insecticidal activities against the dipteran insect Aedes aegypti Bora Bora (Culicidae, Diptera) and for their δ-endotoxins yields per cell. Among the local Bti strains, four exceptional strains producing spherical crystals, were found to be more insecticidal than the reference strain Bti H14. When tested for their δ-endotoxin yield, the Bti QBT217 strain, producing typical spherical crystals and having the best insecticidal activity, was recognized as the best candidate strain for potential bioinsecticide production and biological control of dipteran insects, particularly the disease vector insect A. aegypti.

BORA regulates cell proliferation and migration in bladder cancer.

BACKGROUND: Bladder cancer is having a gradually increasing incidence in China. Except for the traditional chemotherapy drugs, there are no emerging new drugs for almost 30 years in bladder cancer. New potential therapeutic targets and biomarkers are urgently needed. METHODS: BORA is the activator of kinase Aurora A and plays an important role in cell cycle progression. To investigate the function of BORA in BCa, we established BORA knockdown and overexpression cell models for in vitro studies, xenograft and pulmonary metastasis mouse models for in vivo studies. RESULTS: Our results indicated that BORA was upregulated in human bladder cancer (BCa) compared to the normal bladder and paracancerous tissues at transcriptional and translational levels. We found that BORA was positively related to BCa cell proliferation. Furthermore, BORA knockdown induced cell cycle arrest in G2/M phase while BORA overexpression decreased the proportion of cells in G2/M, associated with PLK1-CDC25C-CDK1 alteration. Interestingly, we observed that knockdown of BORA inhibited BCa cell migration and invasion, accompanied with alterations of epithelial-mesenchymal transition (EMT) pathway related proteins. In vivo studies confirmed the inhibition effect of BORA knockdown on BCa cell growth and migration. CONCLUSIONS: Our study indicates that BORA regulates BCa cell cycle and growth, meanwhile influences cell motility by EMT, and could be a novel biomarker and potential therapeutic target in BCa.

Aurora Borealis (Bora), Which Promotes Plk1 Activation by Aurora A, Has an Oncogenic Role in Ovarian Cancer.

Identifying novel actionable factors that critically contribute to tumorigenesis is essential in ovarian cancer, an aggressive and disseminative tumor, with limited therapeutic options available. Here we show that Aurora Borealis (BORA), a mitotic protein that plays a key role in activating the master mitotic kinase polo-like kinase 1 (PLK1), has an oncogenic role in ovarian cancer. Gain and loss of function assays on mouse models and ex vivo patient-derived ascites cultures revealed an oncogenic role of BORA in tumor development and a transcriptome-analysis in clinically representative models depicted BORA's role in survival, dissemination and inflammatory cancer related-pathways. Importantly, combinatory treatments of FDA-approved inhibitors against oncogenic downstream effectors of BORA displayed synergistic effect in ovarian cancer models, offering promising therapeutic value. Altogether, our findings uncovered for the first time a critical role of BORA in the viability of human cancer cells providing potential novel therapeutic opportunities for ovarian cancer management.

The impact of tunnel mutations on enzymatic catalysis depends on the tunnel-substrate complementarity and the rate-limiting step.

Transport of ligands between bulk solvent and the buried active sites is a critical event in the catalytic cycle of many enzymes. The rational design of transport pathways is far from trivial due to the lack of knowledge about the effect of mutations on ligand transport. The main and an auxiliary tunnel of haloalkane dehalogenase LinB have been previously engineered for improved dehalogenation of 1,2-dibromoethane (DBE). The first chemical step of DBE conversion was enhanced by L177W mutation in the main tunnel, but the rate-limiting product release was slowed down because the mutation blocked the main access tunnel and hindered protein dynamics. Three additional mutations W140A + F143L + I211L opened-up the auxiliary tunnel and enhanced the product release, making this four-point variant the most efficient catalyst with DBE. Here we study the impact of these mutations on the catalysis of bulky aromatic substrates, 4-(bromomethyl)-6,7-dimethoxycoumarin (COU) and 8-chloromethyl-4,4'-difluoro-3,5-dimethyl-4-bora-3a,4a-diaza-s-indacene (BDP). The rate-limiting step of DBE conversion is the product release, whereas the catalysis of COU and BDP is limited by the chemical step. The catalysis of COU is mainly impaired by the mutation L177W, whereas the conversion of BDP is affected primarily by the mutations W140A + F143L + I211L. The combined computational and kinetic analyses explain the differences in activities between the enzyme-substrate pairs. The effect of tunnel mutations on catalysis depends on the rate-limiting step, the complementarity of the tunnels with the substrates and is clearly specific for each enzyme-substrate pair.

Multi-Component Synthesis of Rare 1,3-Dihydro-1,3-azaborinine Derivatives: Application of a Bora-Nazarov Type Reaction.

The twofold hydroboration products of (Fmes)BH2 ⋅SMe2 with a series of alkynes (2-butyne, arylethynes) react with two molar equiv of 2,6-dimethylphenyl isocyanide (CN-Xyl) at 80 °C to give rare examples of 1,3-azaborinine derivatives. A mechanistic study revealed a reaction course involving insertion of one isonitrile followed by a bora-Nazarov type ring-closure reaction and subsequent isonitrile insertion to give the respective 1,3-dihydro-1,3-azaborinines 5.

Doxorubicin loaded carboxymethyl Assam bora rice starch coated superparamagnetic iron oxide nanoparticles as potential antitumor cargo.

In recent years, polysaccharide-decorated superparamagnetic iron oxide nanoparticles (SPIONs) have gained attention in the field of "nanotheranostics" with integrated diagnostic and therapeutic functions. Carboxymethyl Assam bora rice starch-stabilized SPIONs (CM-ABRS SPIONs), synthesized by co-precipitation method, has already shown exciting potential towards magnetic drug targeting potential. After establishing it as a promisable targeting carrier, the present study is focused on the next step i.e. to evaluate its In vitro anti-tumor potential by loading anticancer drug "Doxorubicin hydrochloride (DOX)" onto CM-ABRS SPIONs. DOX-loaded CM-ABRS SPIONs were physico-chemically characterized by DLS, zeta-potential, TEM, FT-IR, XRD, and VSM analysis. Spectroflourimetric analysis confirmed the maximum loading of DOX up to 6% (w/w) onto CM-ABRS SPIONs via electrostatic interactions. Further, molecular level drug performance was investigated by docking study against receptors (HER-2 and Folate receptor-α) over expressed in cancer cells and MTT assay (in MCF-7 and HeLa cell line), which conferred promisable results of DOX-CM-ABRS SPIONs as compared to standard DOX solution.

Combined QTAIM and ETS-NOCV investigation of the interactions in ClnM[PhB(NtBu)2] complexes with M = Si & Ge (n = 0), As & Sb (n = 1), Te & Po (n = 2).

In this work, the nature of the chemical interactions between the metalloid atom (M = Si, Ge, As, Sb, Te, Po) and the nitrogen atoms in the bora-amidinate (bam) complexes (ClnM[PhB(NtBu)2]) are investigated, mainly via density-based indices. The descriptors used are derived using the quantum theory of atoms in molecules and natural orbitals for chemical valence approaches. It is shown that the strongest interaction is achieved with silicon. Indeed, it is generally the lightest metalloid in a particular group of the periodic table (i.e., Si, As, and Te for groups 14-16, respectively) that exhibits the strongest bond in the bam complex. This suggests that the atomic radius of the metalloid is a useful parameter for predicting the bonding strength. Extended transition state (ETS) decomposition results indicate that the interactions are more electrostatic than due to orbital interactions.

BODIPY-based Carbonaceous Materials for High Performance Electrical Capacitive Energy Storage.

Incorporation of heteroatoms into carbon materials is crucial to tailor carbon materials' donor-acceptor properties and consequently tune their chemical and electrical performance. However, doping carbon materials with multi-heteroatoms (three or more, especially the light elements) has been rarely payed attention until now. In this work, we develop a porous organic polymer containing boron, nitrogen, fluorine elements and realize its corresponding carbonaceous materials by subsequent carbonation or KOH activation process. Electrochemical measurements results reveal that KOH activation sample (BPOP-700A) is endowed with excellent specific capacitance of 408 F g-1 in three-electrode system and an energy density over 19.2 Wh kg-1 in two-electrode system at aqueous electrolyte, which can be attributed to multi light elements (boron, nitrogen and trace fluorine) doping, favorable morphology and rational pore size distribution architecture. In addition, BPOP-700A displays well rate ability and outstanding cycle performance (10 A g-1 , 10 000 cycles, 95 % retention). Our work might give some hints in designing multi light element doping carbon materials in supercapacitor applications.

Cyclin A-cdk1-Dependent Phosphorylation of Bora Is the Triggering Factor Promoting Mitotic Entry.

Mitosis is induced by the activation of the cyclin B/cdk1 feedback loop that creates a bistable state. The triggering factor promoting active cyclin B/cdk1 switch has been assigned to cyclin B/cdk1 accumulation during G2. However, this complex is rapidly inactivated by Wee1/Myt1-dependent phosphorylation of cdk1 making unlikely a triggering role of this kinase in mitotic commitment. Here we show that cyclin A/cdk1 kinase is the factor triggering mitosis. Cyclin A/cdk1 phosphorylates Bora to promote Aurora A-dependent Plk1 phosphorylation and activation and mitotic entry. We demonstrate that Bora phosphorylation by cyclin A/cdk1 is both necessary and sufficient for mitotic commitment. Finally, we identify a site in Bora whose phosphorylation by cyclin A/cdk1 is required for mitotic entry. We constructed a mathematical model confirming the essential role of this kinase in mitotic commitment. Overall, our results uncover the molecular mechanism by which cyclin A/cdk1 triggers mitotic entry.

Carboxymethyl Assam Bora rice starch coated SPIONs: Synthesis, characterization and in vitro localization in a micro capillary for simulating a targeted drug delivery system.

Carboxymethyl Assam Bora rice starch coated superparamagnetic iron oxide nanoparticles (CM-ABRS SPIONs) were chemically synthesized by co-precipitation method and particle size reduction was controlled by high energy homogenization process. Effects of various process variables (polymer concentration, homogenization speed and cycles) were optimized on the basis of average particle size (Z-average) and polydispersity index (PDI) of CM-ABRS SPIONs. The optimized CM-ABRS SPIONs were characterized for their particle size, surface morphology, electrokinetic potential, chemical interactions, crystallinity, magnetic properties, and targeting potential in presence of external magnetic field. In vitro localization of CM-ABRS SPIONs in a suspension of FITC (Fluorescein isothiocyanate) labeled RBCs (Red blood cells; hematocrit value; 45% (v/v)) was conducted inside a square glass capillary (500 × 500 µm2 cross section) in the presence of an externally applied magnetic field (Ms = 150 mT), simulating the case of magnetic drug targeting (MDT) approach. The aggregation dynamics of CM-ABRS SPIONs inside a micro capillary was observed with respect to time (t = 0 to 600 s), which shows proportionality to time of exposure to the externally applied magnetic field. This in vitro study acts as an important platform for design and optimization of active targeted drug delivery system.