An elastic siderophore synthetase and rubbery substrates assemble multimeric linear and macrocyclic hydroxamic acid metal chelators.

The trihydroxamic acid bacterial siderophore desferrioxamine B (DFOB, 1) produced by the DesABCD biosynthetic cluster coordinates metals beyond Fe(iii), which identifies potential to modify this chelator type to broaden metal sequestration and/or delivery applications. Rather than producing discrete chelators by total chemical synthesis from native monomers including -hydroxy--succinyl-cadaverine (HSC, 2), the recombinant siderophore synthetase from CNB-440 (DesD) was used with different substrate combinations to produce biocombinatorial mixtures of hydroxamic acid chelators. The mixtures were screened with Ga(iii) or Zr(iv) as surrogates of immunological positron emission tomography (PET) imaging radiometals Ga(iii) or Zr(iv) to inform known or new coordination chemistry.

The production of siderophore analogues using precursor-directed biosynthesis.

Siderophores are low-molecular-weight organic bacterial and fungal secondary metabolites that form high affinity complexes with Fe(III). These Fe(III)-siderophore complexes are part of the siderophore-mediated Fe(III) uptake mechanism, which is the most widespread strategy used by microbes to access sufficient iron for growth. Microbial competition for limited iron is met by biosynthetic gene clusters that encode for the biosynthesis of siderophores with variable molecular scaffolds and iron binding motifs.

A first-in-class dual-chelator theranostic agent designed for use with imaging-therapy radiometal pairs of different elements.

A covalent adduct of DFOB and DOTA separated by a l-lysine residue (DFOB-l-Lys- -DOTA) exhibited remarkable regioselective metal binding, with {H}-C NMR spectral shifts supporting Zr(iv) coordinating to the DFOB unit, and Lu(iii) coordinating to the DOTA unit. This first-in-class, dual-chelator theranostic design could enable the use of imaging-therapy radiometal pairs of different elements, such as Zr for positron emission tomography (PET) imaging and Lu for low-energy β-particle radiation therapy. DFOB-l-Lys- -DOTA was elaborated with an amine-terminated polyethylene glycol extender unit (PEG4) to give DFOB- -(PEG4)-l-Lys- -DOTA (compound D2) to enable installation of a phenyl-isothiocyanate group (Ph-NCS) for subsequent monoclonal antibody (mAb) conjugation (mAb = HuJ591).

A Mild and Modular Approach to the Total Synthesis of Desferrioxamine B.

A mild and modular approach to the total synthesis of the WHO-listed essential medicine desferrioxamine B is described. Hydroxamic acid fragments were installed under mild conditions, a generalized divergent acylation procedure used to access two monomer precursors, and a transfer hydrogenation reaction used to unmask the hydroxamic acid moieties. Desferrioxamine B was generated over ten linear steps as the formate salt in 17% overall yield using standard amide coupling conditions or in 13% overall yield using microwave-assisted amide coupling conditions.

Processes of change in a randomized clinical trial of radically open dialectical behavior therapy (RO DBT) for adults with treatment-refractory depression.

Objective: Radically open dialectical behavior therapy (RO DBT) is an empirically supported psychotherapy for treatment-refractory depression (TRD) that targets psychological inflexibility and interpersonal functioning within the context of maladaptive overcontrol. However, it is unknown whether change in these mechanistic processes is associated with decreased symptoms. This study tested whether change in psychological inflexibility and interpersonal functioning is associated with change in depressive symptoms in RO DBT.

A first-in-human study of [Ga]Ga-CDI: a positron emitting radiopharmaceutical for imaging tumour cell death.

Purpose: This study assesses human biodistribution, radiation dosimetry, safety and tumour uptake of cell death indicator labelled with Ga ([Ga]Ga-CDI), a novel radiopharmaceutical that can image multiple forms of cell death.

Methods: Five participants with at least one extracranial site of solid malignancy > 2 cm and no active cancer treatment in the 8 weeks prior to the study were enrolled. Participants were administered 205 ± 4.

Adding a diazo-transfer reagent to culture to generate secondary metabolite probes for click chemistry.

Converting discrete microbial metabolites into chemical probes for chemical biology and medicinal chemistry studies is typically preceded by lengthy purification and chemical derivatization processes. Standard practice involves purifying the target microbial metabolite from culture, followed by derivatization and/or conjugation chemistry to convert the pure metabolite into a tagged species. This multistep approach can pose difficulties in generating useful yields of chemical probes, particularly in the case of low-abundant metabolites, as common in metabolomes.

Acetyl-CoA-Mediated Post-Biosynthetic Modification of Desferrioxamine B Generates - and N--Acetylated Isomers Controlled by a pH Switch.

Biosynthesis of the hydroxamic acid siderophore desferrioxamine D (DFOD, ), which is the -acetylated analogue of desferrioxamine B (DFOB, ), has been delineated. Enzyme-independent Ac-CoA-mediated -acetylation of produced , in addition to three constitutional isomers containing an N--acetyl group installed at either one of the three hydroxamic acid groups of . The formation of -Ac-DFOB (DFOD, ) and the composite of N--acetylated isomers N--Ac-DFOB[001] (), N--Ac-DFOB[010] (), and N--Ac-DFOB[100] () (defined as the N--Ac motif positioned within the terminal amine, internal, or -acetylated region of , respectively), was pH-dependent, with - dominant at pH < 8.

Ethical and Legal Guidance for Mental Health Practitioners Who Wish to Conduct Research in a Private Practice Setting.

Mental health practitioners, even when they have research training, rarely contribute to the scientific literature. One reason for this may be that they need help addressing the ethical and legal issues they encounter as they contemplate undertaking research in a clinical practice setting. To address that need, we offer several types of guidance for conducting research in a private practice setting in a way that meets high ethical and legal standards.

Directing macrocyclic architecture using iron(III)-, gallium(III)-, or zirconium(IV)-assisted ring closure of linear dimeric endo-hydroxamic acid ligands.

Dimeric hydroxamic acid macrocycles are a subclass of bacterial siderophores produced for iron acquisition. Limited yields from natural sources provides the impetus to develop synthetic routes to improve access to these compounds, which have potential utility in metal ion binding applications in the environment and medicine. This work has examined the role of metal ions in forming pre-complexes with linear endo-hydroxamic acid (endo-HXA) ligands bearing terminal amine and carboxylic acid groups optimally configured for in situ ring closure reactions.

Radically Open Dialectical Behavior Therapy (RO DBT) in the treatment of perfectionism: A case study.

We present the case of an adult male ("Jake") with chronic Anorexia Nervosa, buttressed by dysfunctional levels of perfectionism and aggravated by long-standing mood and anxiety disturbance, successfully treated with Radically Open Dialectical Behavior Therapy (RO DBT). RO DBT is an evidence-based, transdiagnostic psychotherapy designed to address perfectionistic overcontrolled coping through teaching flexibility, openness, and healthy self-doubt. We illustrate this treatment approach by means of describing its application to this case, including discussing core RO DBT treatment strategies and providing sample dialogues.

Immobilized Metal Affinity Chromatography as a Drug Discovery Platform for Metalloenzyme Inhibitors.

Immobilized metal-ion affinity chromatography (IMAC) used to purify recombinant proteins features a resin-bound 1:1 Ni(II)-iminodiacetic acid (IDA) complex. This hemi-saturated Ni(II)-IDA system containing exchangeable sites at the metal ion is re-cast as a surrogate of a coordinatively-unsaturated metalloenzyme active site, with utility for selecting compounds with metal-binding groups from mixtures as potential metalloenzyme inhibitors. Exchanging Ni(II) for other metal ions could broaden the scope of metalloenzyme target.

Incidence and treatment of positive pelvic sidewall lymph nodes in patients with rectal cancer.

Aim: The involvement of pelvic sidewall (PSW) lymph nodes in rectal cancer is a marker of locally advanced disease and poor prognosis. Eastern countries generally advocate lateral lymph node dissection (LLND) over the Western approach of neoadjuvant chemoradiotherapy and more limited surgery. The aim of this study was to evaluate how these advanced cancers were treated in three UK Health Boards.

Radically Open Dialectical Behavior Therapy: Social Signaling, Transdiagnostic Utility and Current Evidence.

At the core of an overcontrolled personality and coping style is a tendency to have too much self-control, exhibiting as behavioral and cognitive inflexibility, high inhibition of emotion, high detail-focused processing and perfectionism, and a lack of social connectedness. Overcontrol underlies a wide variety of psychiatric illnesses and as such, an innovative transdiagnostic therapy called Radically Open Dialectical Behavior Therapy (RO DBT) has been developed to treat disorders characterized by overcontrol. RO DBT targets maladaptive social signaling in order to help individuals "rejoin the tribe," hypothesizing that increasing social connectedness by means of targeting social signaling is the central mechanism of change in treatment.

Azido-Desferrioxamine Siderophores as Functional Click-Chemistry Probes Generated in Culture upon Adding a Diazo-Transfer Reagent.

This work aimed to undertake the in situ conversion of the terminal amine groups of bacterial desferrioxamine (DFO) siderophores, including desferrioxamine B (DFOB), to azide groups to enable downstream click chemistry. Initial studies trialed a precursor-directed biosynthesis (PDB) approach. Supplementing Streptomyces pilosus culture with blunt-end azido/amine non-native substrates designed to replace 1,5-diaminopentane as the native diamine substrate in the terminal amine position of DFOB did not produce azido-DFOB.

Exploring hydroxamic acid inhibitors of HDAC1 and HDAC2 using small molecule tools and molecular or homology modelling.

Hydroxamic acid compounds 1-10 containing a N-hydroxycinnamamide scaffold and a 4-(benzylamino)methyl cap group that was either unsubstituted (1) or substituted with one (2-4) or two (5-10) methoxy groups in variable positions were prepared as inhibitors of Zn(II)-containing histone deacetylases (HDACs). The 3,4- (9) and 3,5- (10) bis-methoxy-substituted compounds were the least potent against HeLa nuclear extract, HDAC1 and HDAC2. Molecular modelling showed methoxy groups in the 3-, 4- and 5-position, but not the 2-position, had unfavourable steric interactions with the G32-H33-P34 triad on a loop at the surface of the HDAC2 active site cavity.

-Hydroxamic Acid Monomers for the Assembly of a Suite of Non-native Dimeric Macrocyclic Siderophores Using Metal-Templated Synthesis.

An expedited synthesis of -hydroxamic acid aminocarboxylic acid (-HXA) compounds has been developed. These monomeric ligands are relevant to the synthesis of metal-macrocycle complexes using metal-templated synthesis (MTS), and the downstream production of apomacrocycles. Macrocycles can display useful drug properties and be used as ligands for radiometals in medical imaging applications, which supports methodological advances in accessing this class of molecule.

Preparation of a Dithiol-Reactive Probe for PET Imaging of Cell Death.

Conjugates of 4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid (GSAO) with optical or radionuclide probes are able to image cell death in vivo. GSAO conjugates are retained in the cytosol of dying and dead cells via the formation of covalent bonds between the As(III) ion and the thiol groups of proximal cysteine residues. Here we describe the method for preparing a NODAGA-GSAO conjugate and its radiolabeling with gallium-68 (Ga-NODAGA-GSAO) for positron-emission tomography (PET) imaging of cell death.

Analogues of desferrioxamine B (DFOB) with new properties and new functions generated using precursor-directed biosynthesis.

Desferrioxamine B (DFOB) is a siderophore native to Streptomyces pilosus biosynthesised by the DesABCD enzyme cluster as a high affinity Fe(III) chelator. Although DFOB has a long clinical history for the treatment of chronic iron overload, limitations encourage the development of new analogues. This review describes a recent body of work that has used precursor-directed biosynthesis (PDB) to access new DFOB analogues.

Engineering a cleavable disulfide bond into a natural product siderophore using precursor-directed biosynthesis.

An analogue of the bacterial siderophore desferrioxamine B (DFOB) containing a disulfide motif in the backbone was produced from Streptomyces pilosus cultures supplemented with cystamine. Cystamine competed against native 1,5-diaminopentane during assembly. DFOB-(SS)1[001] and its complexes with Fe(iii) or Ga(iii) were cleaved upon incubation with dithiothreitol.

Fluorinated Analogues of Desferrioxamine B from Precursor-Directed Biosynthesis Provide New Insight into the Capacity of DesBCD.

The siderophore desferrioxamine B (DFOB, 1) native to Streptomyces pilosus is biosynthesized by the DesABCD enzyme cluster. DesA-mediated decarboxylation of l-lysine gives 1,5-diaminopentane (DP) for processing by DesBCD. S.

The chemical biology and coordination chemistry of putrebactin, avaroferrin, bisucaberin, and alcaligin.

Dihydroxamic acid macrocyclic siderophores comprise four members: putrebactin (putH), avaroferrin (avaH), bisucaberin (bisH), and alcaligin (alcH). This mini-review collates studies of the chemical biology and coordination chemistry of these macrocycles, with an emphasis on putH. These Fe(III)-binding macrocycles are produced by selected bacteria to acquire insoluble Fe(III) from the local environment.

Double duodenal perforation following foreign body ingestion.

Intentional ingestion of a foreign body in adults is a rare clinical presentation. This case is one of a 27-year-old Sudanese man who presented having swallowed a ballpoint pen intentionally. Clinical examination and plain chest radiograph exhibited no signs indicative of perforation with only a raised C reactive protein identified on blood tests.