Probing Disaccharide Binding to Triplatin as Models for Tumor Cell Heparan Sulfate (GAG) Interactions.

In this study, we have used [1H, 15N] NMR spectroscopy to investigate the interactions of the trinuclear platinum anticancer drug triplatin (1) (1,0,1/t,t,t or BBR3464) with site-specific sulfated and carboxylated disaccharides. Specifically, the disaccharides GlcNS(6S)-GlcA (I) and GlcNS(6S)-IdoA(2S) (II) are useful models of longer-chain glycosaminoglycans (GAGs) such as heparan sulfate (HS). For both the reactions of 15N-1 with I and II, equilibrium conditions were achieved more slowly (65 h) compared to the reaction with the monosaccharide GlcNS(6S) (9 h). The data suggest both carboxylate and sulfate binding of disaccharide I to the Pt with the sulfato species accounting for <1% of the total species at equilibrium. The rate constant for sulfate displacement of the aqua ligand (kL2) is 4 times higher than the analogous rate constant for carboxylate displacement (kL1). There are marked differences in the equilibrium concentrations of the chlorido, aqua, and carboxy-bound species for reactions with the two disaccharides, notably a significantly higher concentration of carboxylate-bound species for II, where sulfate-bound species were barely detectable. The trend mirrors that reported for the corresponding dinuclear platinum complex 1,1/t,t, where the rate constant for sulfate displacement of the aqua ligand was 3 times higher than that for acetate. Also similar to what we observed for the reactions of 1,1/t,t with the simple anions, aquation of the sulfato group is rapid, and the rate constant k-L2 is 3 orders of magnitude higher than that for displacement of the carboxylate (k-L1). Molecular dynamics calculations suggest that extra hydrogen-bonding interactions with the more sulfated disaccharide II may prevent or diminish sulfate binding of the triplatin moiety. The overall results suggest that Pt-O donor interactions should be considered in any full description of platinum complex cellular chemistry.

Causal attributions and OCD treatment response: A linguistic analysis of OCD patients' self-reported etiological explanations in intensive residential treatment.

In the present study, 43 obsessive-compulsive disorder (OCD) patients receiving cognitive-behavior therapy (CBT)/exposure and response prevention (ERP) in an intensive residential treatment program responded to an open-ended question about causal attributions (i.e., personal explanations for the etiology of their OCD) at baseline and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) at baseline and treatment discharge. Baseline self-reported responses about causal attributions were qualitatively coded to derive predictors (biological/genetic, environmental, psychological, and interactional attributions). Predictors were entered into a binary logistic regression with Y-BOCS responder status (at least partial response [≥25% pre-post reduction] vs. no response) as the outcome. After controlling for length of stay and number of comorbid psychiatric diagnoses, only biological/genetic attributions uniquely predicted increased odds of treatment response, odds ratio = 10.04, p = 0.03. Biological/genetic attributions may reduce self-blame for symptoms or increase expectancy violation likelihood during treatment, thereby improving odds of response. Clinicians should assess OCD patients' causal attributions as part of routine clinical care to hopefully optimize treatment outcomes.

Online Video Teletherapy Treatment of Obsessive-Compulsive Disorder Using Exposure and Response Prevention: Clinical Outcomes From a Retrospective Longitudinal Observational Study.

BACKGROUND: Exposure and response prevention, a type of cognitive-behavioral therapy, is an effective first-line treatment for obsessive-compulsive disorder (OCD). Despite extensive evidence of the efficacy of exposure and response prevention (ERP) from clinical studies and in real-world samples, it is still underused as a treatment. This is likely due to the limits to access to care that include the availability of adequately trained therapists, as well as geographical location, time, and cost barriers. To address these, NOCD created a digital behavioral health treatment for OCD using ERP delivered via video teletherapy and with technology-assisted elements including app-based therapy tools and between-session therapist messaging. OBJECTIVE: We examined treatment outcomes in a large naturalistic sample of 3552 adults with a primary OCD diagnosis who received NOCD treatment. METHODS: The treatment model consisted of twice-weekly, live, face-to-face video teletherapy ERP for 3 weeks, followed by 6 weeks of once-weekly brief video teletherapy check-ins for 30 minutes. Assessments were conducted at baseline, at midpoint after completion of 3 weeks of twice-weekly sessions, and at the end of 6 weeks of brief check-ins (endpoint). Longitudinal assessments were also obtained at 3, 6, 9, and 12 months after endpoint. RESULTS: Treatment resulted in clinically and statistically significant improvements, with a 43.4% mean reduction in obsessive-compulsive symptoms (g=1.0; 95% CI 0.93 to 1.03) and a 62.9% response rate. Treatment also resulted in a 44.2% mean reduction in depression, a 47.8% mean reduction in anxiety, and a 37.3% mean reduction in stress symptoms. Quality of life improved by a mean of 22.7%. Reduction in OCD symptoms and response rates were similar for those with mild, moderate, or severe symptoms. The mean duration of treatment was 11.5 (SD 4.0) weeks, and the mean total therapist time was 10.6 (SD 1.1) hours. Improvements were maintained at 3, 6, 9, and 12 months. CONCLUSIONS: In this sample, representing the largest reported treated cohort of patients with OCD to date, video teletherapy treatment demonstrated effectiveness in reducing obsessive-compulsive and comorbid symptoms and improved quality of life. Further, it achieved meaningful results in less than half the total therapist time compared with standard once-weekly outpatient treatment, an efficiency that represents substantial monetary and time savings. The effect size was large and similar to studies of in-person ERP. This technology-assisted remote treatment is readily accessible for patients, offering an advancement in the field in the dissemination of effective evidence-based care for OCD.

A Click Chemistry Approach to Targeted DNA Crosslinking with cis-Platinum(II)-Modified Triplex-Forming Oligonucleotides.

Limitations of clinical platinum(II) therapeutics include systemic toxicity and inherent resistance. Modern approaches, therefore, seek new ways to deliver active platinum(II) to discrete nucleic acid targets. In the field of antigene therapy, triplex-forming oligonucleotides (TFOs) have attracted interest for their ability to specifically recognise extended duplex DNA targets. Here, we report a click chemistry based approach that combines alkyne-modified TFOs with azide-bearing cis-platinum(II) complexes-based on cisplatin, oxaliplatin, and carboplatin motifs-to generate a library of PtII -TFO hybrids. These constructs can be assembled modularly and enable directed platinum(II) crosslinking to purine nucleobases on the target sequence under the guidance of the TFO. By covalently incorporating modifications of thiazole orange-a known DNA-intercalating fluorophore-into PtII -TFOs constructs, enhanced target binding and discrimination between target and off-target sequences was achieved.

Understanding the effects of reductionist biological views of eating disorder etiology on patient attitudes and behavior.

While eating disorders were historically considered to be a result of psychological or environmental causes, current evidence suggests that eating disorders are the product of complex gene-environment interactions wherein heritable vulnerabilities are activated by multiple exposures to environmental stimuli over the lifespan. Despite the fact that this integrated biopsychosocial etiological view of eating disorders is accepted among many professionals in the eating disorder field, evidence suggests that the general public and some clinicians are susceptible to dualist, or reductionist, views of psychopathology. Currently, little is known about (a) the prevalence of reductionist biological views of eating disorder etiology in those with eating disorders (this view attributes the cause of eating disorders to predominantly biological factors but does not acknowledge psychosocial factors as important contributors), (b) the effects of reductionist biological views on clinical outcomes, and (c) the most effective methods for modifying these views. In this article, we present the results of a preliminary investigation on the relationship between perceived causes of eating disorders and the attitudes and behaviors of those with eating disorders. We then go on to propose specific avenues for further research on uncovering the effects of reductionist biological views of eating disorder etiology.

Registered report: Initial development and validation of the eating disorders safety behavior scale.

Anxiety and eating disorders (EDs) often co-occur, prompting calls to explore anxiety-related maintenance processes in ED samples. Safety behaviors, which function to prevent a feared outcome from occurring or to reduce anxiety associated with a feared stimulus, are observed across anxiety disorders and, along with overt avoidance behaviors, are an important target in treatment. Data suggest that individuals with EDs also engage in safety behaviors. However, no existing assessments provide a comprehensive measure of eating-disorder-specific overt avoidance and safety behaviors. The goal of this Stage 1 Registered Report is to develop a comprehensive self-report measure of ED-specific safety behaviors. In Study 1, we will recruit 50 women with EDs to complete the scale and provide feedback on the response scale. Feedback from these participants will be used to refine the measure. In Study 2, we will evaluate the psychometric properties of the measure in a large sample of women with EDs (n dependent on the size of measurement) and a community sample without current or a history of ED symptoms. We will explore the measure factor structure, known-groups validity by comparing scores from women with EDs to healthy controls, internal consistency, and convergent and divergent validity with other psychological instruments.

Family accommodation in eating disorders: a preliminary examination of correlates with familial burden and cognitive-behavioral treatment outcome.

Previous research suggests caregivers of individuals with eating disorders (EDs) may attempt to reduce family strain by engaging in accommodation and enabling behaviors to avoid conflict or alleviate stress of the affected individual. Moreover, families often reorganize life around the ED, reinforcing ED behaviors and exacerbating family dysfunction and caregiver distress. However, limited research has examined how accommodation relates to caregivers' distress, family functioning, and treatment outcomes. The current study provides an initial evaluation of these associations among treatment-seeking individuals with EDs and their family members. Forty family members of individuals receiving cognitive behavioral therapy for EDs in a residential treatment setting completed the Accommodation and Enabling Scale for Eating Disorders (AESED) and measures of anxiety (Patient-Reported Outcomes Measurement Information System anxiety scale) and family functioning (Family Assessment Device; FAD) at the time of their family member's treatment admission. Eighteen patients completed the Eating Disorder Examination-Questionnaire (EDE-Q) at admission and discharge. AESED scores were positively associated with family member anxiety, FAD roles, FAD behavioral control, and higher patient EDE-Q global scores at discharge. Findings provide preliminary evidence that greater family accommodation not only relates to poorer family functioning, but uniquely relates to worse ED treatment outcome.

On the Biology of Werner's Complex.

Werner's Complex, as a cationic coordination complex (CCC), has hitherto unappreciated biological properties derived from its binding affinity to highly anionic biomolecules such as glycosaminoglycans (GAGs) and nucleic acids. Competitive inhibitor and spectroscopic assays confirm the high affinity to GAGs heparin, heparan sulfate (HS), and its pentasaccharide mimetic Fondaparinux (FPX). Functional consequences of this affinity include inhibition of FPX cleavage by bacterial heparinase and mammalian heparanase enzymes with inhibition of cellular invasion and migration. Werner's Complex is a very efficient condensing agent for DNA and tRNA. In proof-of-principle for translational implications, it is demonstrated to display antiviral activity against human cytomegalovirus (HCMV) at micromolar concentrations with promising selectivity. Exploitation of non-covalent hydrogen-bonding and electrostatic interactions has motivated the unprecedented discovery of these properties, opening new avenues of research for this iconic compound.

Conformational Modulation of Iduronic Acid-Containing Sulfated Glycosaminoglycans by a Polynuclear Platinum Compound and Implications for Development of Antimetastatic Platinum Drugs.

1 H NMR spectroscopic studies on the 1:1 adduct of the pentasaccharide Fondaparinux (FPX) and the substitution-inert polynuclear platinum complex TriplatinNC show significant modulation of geometry around the glycosidic linkages of the FPX constituent monosaccharides. FPX is a valid model for the highly sulfated cell signalling molecule heparan sulfate (HS). The conformational ratio of the 1 C4 :2 S0 forms of the FPX residue IdoA(2S) is altered from ca. 35:65 (free FPX) to ca. 75:25 in the adduct; the first demonstration of a small molecule affecting conformational changes on a HS oligosaccharide. Functional consequences of such binding are suggested to be inhibition of HS cleavage in MDA-MB-231 triple-negative breast cancer (TNBC) cells. We further describe inhibition of metastasis by TriplatinNC in the TNBC 4T1 syngeneic tumour model. Our work provides insight into a novel approach for design of platinum drugs (and coordination compounds in general) with intrinsic anti-metastatic potential.

Substitution-Inert Polynuclear Platinum Complexes Inhibit Reverse Transcription Preferentially in RNA Triplex-Forming Templates.

RNA triplexes are significant tertiary structure motifs that are found in many functional RNAs. Hence, small molecules capable of recognition, binding, and stabilization of the triple-helical RNA structures are emerging as attractive potential molecular biology tools and therapeutic agents. Here, we utilize methods of molecular biology and biophysics to study the interactions of a series of antitumor substitution-inert polynuclear platinum complexes (SI-PPCs) with triple-helical RNA structures. We show that SI-PPCs recognize and stabilize RNA triplexes and inhibit reverse transcription preferentially in the RNA template prone to the triplex formation. These so far unexplored properties of SI-PPCs suggest that the targeting of triple-stranded regions in RNA might contribute to the biological effects of SI-PPCs.

The open versus blind weight conundrum: A multisite randomized controlled trial across multiple levels of patient care for anorexia nervosa.

OBJECTIVE: Anorexia nervosa (AN) is a disorder characterized by a profound fear of weight gain, resulting in significant weight loss, as well as behavioral symptoms that interfere with weight normalization. In concert, weight gain remains a proximal goal of treatment, and patient weighing is a critical component of treatment. However, divergent approaches exist in how patient weighing is undertaken in clinical practice. The aim of this study is to investigate the impact of a brief course of open weighing (sharing weight data with patients) versus blind weighing (not sharing weight data with patients) on distress around being weighed and AN symptom severity. METHOD: 216 patients with AN and atypical AN will be randomized to receive 4 weeks of open or blind weighing practices across residential, intensive outpatient, and outpatient treatment settings, within the context of manualized empirically supported treatment. Following 4 weeks of open or blind weighing, all patients will be enrolled into open weighing practices. Primary outcomes of interest will be patient-reported distress around being weighed at week 5 and eating disorder symptom severity at week 5. Secondary outcomes will assess weight prediction error, intolerance of uncertainty, and the fear of food. DISCUSSION: No best practice guidelines exist in determining optimal practices around weighing patients with AN. This multisite randomized controlled trial will provide the first known data on the impact of open versus blind weighing practices upon weight-related distress and AN symptom severity.

Cognitive-behavioral therapy in the time of coronavirus: Clinician tips for working with eating disorders via telehealth when face-to-face meetings are not possible.

OBJECTIVE: The coronavirus pandemic has led to a dramatically different way of working for many therapists working with eating disorders, where telehealth has suddenly become the norm. However, many clinicians feel ill equipped to deliver therapy via telehealth, while adhering to evidence-based interventions. This article draws together clinician experiences of the issues that should be attended to, and how to address them within a telehealth framework. METHOD: Seventy clinical colleagues of the authors were emailed and invited to share their concerns online about how to deliver cognitive-behavioral therapy for eating disorders (CBT-ED) via telehealth, and how to adapt clinical practice to deal with the problems that they and others had encountered. After 96 hr, all the suggestions that had been shared by 22 clinicians were collated to provide timely advice for other clinicians. RESULTS: A range of themes emerged from the online discussion. A large proportion were general clinical and practical domains (patient and therapist concerns about telehealth; technical issues in implementing telehealth; changes in the environment), but there were also specific considerations and clinical recommendations about the delivery of CBT-ED methods. DISCUSSION: Through interaction and sharing of ideas, clinicians across the world produced a substantial number of recommendations about how to use telehealth to work with people with eating disorders while remaining on track with evidence-based practice. These are shared to assist clinicians over the period of changed practice.

Molecular methods for assessment of non-covalent metallodrug-DNA interactions.

The binding of small molecule metallodrugs to discrete regions of nucleic acids is an important branch of medicinal chemistry and the nature of these interactions, allied with sequence selectivity, forms part of the backbone of modern medicinal inorganic chemistry research. In this tutorial review we describe a range of molecular methods currently employed within our laboratories to explore novel metallodrug-DNA interactions. At the outset, an introduction to DNA from a structural perspective is provided along with descriptions of non-covalent DNA recognition focusing on intercalation, insertion, and phosphate binding. Molecular methods, described from a non-expert perspective, to identify non-covalent and pre-associative nucleic acid recognition are then demonstrated using a variety of techniques including direct (non-optical) and indirect (optical) methods. Direct methods include: X-ray crystallography; NMR spectroscopy; mass spectrometry; and viscosity while indirect approaches detail: competitive inhibition experiments; fluorescence and absorbance spectroscopy; circular dichroism; and electrophoresis-based techniques. For each method described we provide an overview of the technique, a detailed examination of results obtained and relevant follow-on of advanced biophysical/analytical techniques. To achieve this, a selection of relevant copper(ii) and platinum(ii) complexes developed within our laboratories are discussed and are compared, where possible, to classical DNA binding agents. Applying these molecular methods enables us to determine structure-activity factors important to rational metallodrug design. In many cases, combinations of molecular methods are required to comprehensively elucidate new metallodrug-DNA interactions and, from a drug discovery perspective, coupling this data with cellular responses helps to inform understanding of how metallodrug-DNA binding interactions manifest cytotoxic action.

Substitution-Inert Polynuclear Platinum Complexes Act as Potent Inducers of Condensation/Aggregation of Short Single- and Double-Stranded DNA and RNA Oligonucleotides.

Compounds condensing DNA and RNA molecules can essentially affect important biological processes including DNA replication and transcription. Here, this work shows with the aid of total intensity light scattering, gel electrophoresis, and atomic force microscopy (AFM) that the substitution-inert polynuclear platinum complexes (SI-PPCs), particularly [{trans-Pt(NH3 )2 (NH2 (CH2 )6 - NH3 + )}2 -µ-{trans-Pt(NH3 )2 (NH2 (CH2 )6 NH2 )2 }]8+ (Triplatin NC), exhibit an unprecedented high potency to condense/aggregate fragments of DNA and RNA as short as 20 base pairs. SI-PPCs condensates are distinctive from those generated by the naturally occurring polyamines (commonly used DNA compacting/condensing agents). Collectively, the results further confirm that SI-PPCs are very efficient inducers of condensation of DNA and RNA, including their short fragments that might have potential in gene therapy, biotechnology, and bionanotechnology. Moreover, the data confirm the structural advantages of the phosphate clamp, with a well-defined rigid DNA recognition motif in initiating condensation and aggregation phenomena on oligonucleotides.

A comparative network analysis of eating disorder psychopathology and co-occurring depression and anxiety symptoms before and after treatment.

BACKGROUND: Network analysis is an emerging approach in the study of psychopathology, yet few applications have been seen in eating disorders (EDs). Furthermore, little research exists regarding changes in network strength after interventions. Therefore the present study examined the network structures of ED and co-occurring depression and anxiety symptoms before and after treatment for EDs. METHOD: Participants from residential or partial hospital ED treatment programs (N = 446) completed assessments upon admission and discharge. Networks were estimated using regularized Graphical Gaussian Models using 38 items from the Eating Disorders Examination-Questionnaire, Quick Inventory of Depressive Symptomatology, and State-Trait Anxiety Inventory. RESULTS: ED symptoms with high centrality indices included a desire to lose weight, guilt about eating, shape overvaluation, and wanting an empty stomach, while restlessness, self-esteem, lack of energy, and feeling overwhelmed bridged ED to depression and anxiety symptoms. Comparisons between admission and discharge networks indicated the global network strength did not change significantly, though symptom severity decreased. Participants with denser networks at admission evidenced less change in ED symptomatology during treatment. CONCLUSIONS: Findings suggest that symptoms related to shape and weight concerns and guilt are central ED symptoms, while physical symptoms, self-esteem, and feeling overwhelmed are links that may underlie comorbidities in EDs. Results provided some support for the validity of network approaches, in that admission networks conveyed prognostic information. However, the lack of correspondence between symptom reduction and change in network strength indicates that future research is needed to examine network dynamics in the context of intervention and relapse prevention.

The facile and visualizable identification of broad-spectrum inhibitors of MDM2/p53 using co-expressed protein complexes.

MDM2 is a well-known oncoprotein overexpressed in a variety of cancers, and the identification of inhibitors that disrupt the MDM2/p53 interaction is of great interest in anticancer drug development. Here we designed a platform for the facile and visualizable identification of inhibitors of MDM2 using co-expressed protein complexes of MDM2/p53. A hexahistidine-tag on MDM2 allows the binding of the protein complex to the Ni-NTA affinity resin, while the fluorescent protein fused to p53 enables the direct visualization of the interaction of p53 with MDM2. Hence, the inhibition of the MDM2/p53 interaction can be observed with the naked eye. The assay can be set up by directly loading cell lysate to the Ni-NTA affinity resin, and no chemical modification of proteins is needed. In addition to the qualitative analyses, the binding affinity of inhibitors to the MDM2 protein can be quantified by fluorescence titration. The applications of this system have been verified using small molecules and peptide inhibitors. As a proof of concept, we screened a small library using this platform. Interestingly, two types of novel inhibitors of MDM2, including cyclohexyl-triphenylamine derivatives and platinum complexes, were identified and their binding affinities were obtained. Quantitative measurements show that these new types of inhibitors demonstrate a high binding affinity (up to Kd = 51.9 nM) to MDM2.

Substitution-Inert Polynuclear Platinum Complexes with Dangling Amines: Condensation/Aggregation of Nucleic Acids and Inhibition of DNA-Related Enzymatic Activities.

The substitution-inert polynuclear platinum complexes (SI-PPCs) are now recognized as a distinct subclass of platinum anticancer drugs with high DNA binding affinity. Here, we investigate the effects of SI-PPCs containing dangling amine groups in place of NH3 as ligands to increase the length of the molecule and therefore overall charge and its distribution. The results obtained with the aid of biophysical techniques, such as total intensity light scattering, gel electrophoresis, and atomic force microscopy, show that addition of dangling amine groups considerably augments the ability of SI-PPCs to condense/aggregate nucleic acids. Moreover, this enhanced capability of SI-PPCs correlates with their heightened efficiency to inhibit DNA-related enzymatic activities, such as those connected with DNA transcription, catalysis of DNA relaxation by DNA topoisomerase I, and DNA synthesis catalyzed by Taq DNA polymerase. Thus, the addition of the dangling amine groups resulting in structures of SI-PPCs, which differ so markedly from the derivatives of cisplatin used in the clinic, appears to contribute to the overall biological activity of these molecules.

Glycans as Ligands in Bioinorganic Chemistry. Probing the Interaction of a Trinuclear Platinum Anticancer Complex with Defined Monosaccharide Fragments of Heparan Sulfate.

We report herein a detailed NMR study of the aquation and subsequent covalent binding of the trinuclear clinical agent [{ trans-PtCl(15NH3)2}2{µ- trans-Pt(15NH3)2(15NH2(CH2)615NH2)2}]4+ (1, 1,0,1/ t, t, t or Triplatin) with three d-glucosamine residues containing varied O-sulfate and N-sulfate or N-acetyl substitutions, which represent monosaccharide fragments present within the repeating disaccharide sequences of cell surface heparan sulfate (HS). The monosaccharides GlcNS(6S), GlcNS, and GlcNAc(6S) were synthesized in good yield from a common 4,6-diol α-methyl glucopyranoside intermediate. The reactions of 15N-1 with sodium sulfate, GlcNS(6S), GlcNS, and GlcNAc(6S) were followed by 2D [1H,15N] heteronuclear single quantum coherence (HSQC) NMR spectroscopy using conditions (298 K, pH ≈5.4) similar to those previously used for other anionic systems, allowing for a direct comparison. The equilibrium constants (p K1) for the aquation of 1 in the presence of GlcNS(6S) and GlcNS were slightly higher compared to that of the aquation in a sulfate solution, while a comparable p K1 value was observed in the presence of GlcNAc(6S). A comparison of the rate constants for sulfate displacement of the aqua ligand showed preferential binding to 2- N-sulfate compared to 6- O-sulfate but a more rapid liberation. For disulfated GlcNS(6S), equilibrium conditions were achieved rapidly (9 h) and strongly favored the dichloro form, with <2% sulfato species observed. The value of kL1 was up to 15-fold lower than that for binding to sulfate, whereas the rate constant for the reverse ligation ( k-L1) was comparable. Equilibrium conditions were achieved much more slowly (∼ 100 h) for the reactions of 1 with GlcNS and GlcNAc(6S), attributed to covalent binding also to the N-donor of the sulfamate (GlcNS) group and the O-donor of the N-acetyl [GlcNAc(6S)] group. The rate constants ( kL2) were 20-40-fold lower than that for binding to the 2- N- or 6- O-sulfate, but the binding was less reversible, so that their equilibrium concentrations (5-8%) were comparable to the 2- N- or 6- O-sulfate-bound species. The results emphasize the relevance of glycans in bioinorganic chemistry and underpin a fundamental molecular description of the HS-Pt interactions that alter the profile of platinum agents from cytotoxic to metastatic in a systematic manner.

Biological relevance of interaction of platinum drugs with O-donor ligands.

Platinum complexes with S and N-donor small molecule ligands have received much attention with respect to understanding of Pt-protein and Pt-DNA(RNA) interactions in biology. Oxygen-donor ligands have received less attention, partly due to the fact that as a hard Lewis base, oxygen-donor interactions are expected to be less favourable for the soft Lewis acid properties of Pt(II), especially. Yet, it is now clear that for a full understanding of the cellular fate of platinum complexes, a plethora of oxygen-donor interactions are possible, considering extracellular and intracellular concentrations of simple anions in buffer. Further, the importance of the general class of glycans, the third major class of biomolecules after proteins and nucleic acids, contain many specific examples of important biomolecules such as sialic acids and sulphated glycosaminoglycans capable of metal complex interactions. In this contribution we summarise some important kinetic and thermodynamic aspects of platinum-oxygen-donor ligand interactions and their relevance to examples of biomolecular interactions contributing to the overall profile of platinum (and metal complexes in general) biology.

Rapid Establishment of a Cold Chain Capacity of -60°C or Colder for the STRIVE Ebola Vaccine Trial During the Ebola Outbreak in Sierra Leone.

Clinical Trials Registration: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220].