Probing the metalloproteome: an 8-mercaptoquinoline motif enriches minichromosome maintenance complex components as significant metalloprotein targets in live cells.

Affinity-based probes are valuable tools for detecting binding interactions between small molecules and proteins in complex biological environments. Metalloproteins are a class of therapeutically significant biomolecules which bind metal ions as part of key structural or catalytic domains and are compelling targets for study. However, there is currently a limited range of chemical tools suitable for profiling the metalloproteome. Here, we describe the preparation and application of a novel, photoactivatable affinity-based probe for detection of a subset of previously challenging to engage metalloproteins. The probe, bearing an 8-mercaptoquinoline metal chelator, was anticipated to engage several zinc metalloproteins, including the 26S-proteasome subunit Rpn11. Upon translation of the labelling experiment to mammalian cell lysate and live cell experiments, proteomic analysis revealed that several metalloproteins were competitively enriched. The diazirine probe SMK-24 was found to effectively enrich multiple components of the minichromosome maintenance complex, a zinc metalloprotein assembly with helicase activity essential to DNA replication. Cell cycle analysis experiments revealed that HEK293 cells treated with SMK-24 experienced stalling in G0/G1 phase, consistent with inactivation of the DNA helicase complex. This work represents an important contribution to the library of cell-permeable chemical tools for studying a collection of metalloproteins for which no previous probe existed.

Boosting the Impact of EFMC Young Scientists Network Through the Creation of Working Groups.

The establishment of the Young Scientists Network (YSN) by the European Federation for Medicinal Chemistry (EFMC) served as a proactive response to the evolving landscape of the scientific community. The YSN aims to assist early-career medicinal chemists and chemical biologists by responding to emerging themes, such as the influence of social media, shifts in gender balance within the scientific population, and evolving educational opportunities. The YSN also ensures that the upcoming generation of scientists actively contributes to shape the EFMC's strategic direction while addressing their specific needs. Initially conceived as a general concept, YSN has evolved into a proactive and dynamic team which demonstrates a tangible impact. To boost the impact of the YSN and involve additional motivated young scientists, we have adopted a novel organization, and structured the team in seven working groups (WGs). Herein, we will discuss the tasks of the different WGs as well as the activities planned for the near future. We believe this structure will strengthen the pivotal role YSN has already played in serving medicinal chemists and chemical biologists in Europe. The YSN now has the structure and motivation to pave the way to attract young scientists across Europe and to give them the stage within EFMC.

Flipping the Switch: Innovations in Inducible Probes for Protein Profiling.

Over the past two decades, activity-based probes have enabled a range of discoveries, including the characterization of new enzymes and drug targets. However, their suitability in some labeling experiments can be limited by nonspecific reactivity, poor membrane permeability, or high toxicity. One method for overcoming these issues is through the development of "inducible" activity-based probes. These probes are added to samples in an unreactive state and require in situ transformation to their active form before labeling can occur. In this Review, we discuss a variety of approaches to inducible activity-based probe design, different means of probe activation, and the advancements that have resulted from these applications. Additionally, we highlight recent developments which may provide opportunities for future inducible activity-based probe innovations.

The best practice tariff and hip fractures: How can Northern Ireland keep up?

INTRODUCTION: Current hip fractures guidelines recommend surgery within 36 h of admission. The 2011 National Hip Fracture Database (NHFD) report shows our institute has the fewest patients meeting this target (9%). Northern Irelands' exclusion from the "Best Practice Tariff" means no incentive-led treatment or prioritisation of hip fracture patients. METHOD: We performed a systematic review of post-operative results to highlight deficiencies in delivery of patient care. We reviewed 702 patients admitted between September 2009 and April 2012. Patients were prospectively identified and added to our Fracture Outcome and Research Database (FORD). Results were compared to national average values from the NHFD. RESULTS: 16.7% of patients met the 36-h target to theatre compared to the UK average of 66%. 81.7% underwent a pre-operative orthogeriatric review. The main reasons for surgical delay were inadequate theatre space (58%) and medically unfit patients (29%). After exclusion of medically unfit patients, medically fit patients were divided into delayed surgery and not delayed categories. Medically fit patients who had delayed surgery had inferior outcomes- longer hospital stay and higher mortality as an inpatient and at 30 days. CONCLUSION: Without a change in funding, Northern Ireland will struggle to compete with the UK mainland and decrease mortality in this patient group.

Salter Harris Fractures of the Distal Femur: Learning Points From Two Cases Compared.

Salter Harris-type injuries of the distal femur should be treated as a dislocation of the knee and therefore as a medical emergency. Senior medical staff should be involved early, ankle-brachial index ratio should be measured in all patients and the clinician should have a high index of suspicion for a vascular injury. Ideally reduction, stabilization, and vascular repair, if necessary, should be carried out within 6 hours of the initial event. There should be a low threshold for fasciotomies. These 2 cases demonstrate the importance of having a high index of suspicion for vascular injury and the need for continued reassessment.