Feed-forward stimulation of CAMK2 by the oncogenic pseudokinase PEAK1 generates a therapeutically "actionable" signalling axis in triple negative breast cancer.

The PEAK family of pseudokinases, comprising PEAK1-3, are signalling scaffolds that play oncogenic roles in several poor prognosis human cancers, including triple negative breast cancer (TNBC). However, therapeutic targeting of pseudokinases is challenging due to their lack of catalytic activity. To address this, we screened for PEAK1 effectors by affinity purification and mass spectrometry, identifying calcium/calmodulin-dependent protein kinase 2 (CAMK2)D and CAMK2G.

The Evaluation and Management of Methimazole-Induced Agranulocytosis in the Pediatric Patient: A Case Report and Review of the Literature.

Introduction: Agranulocytosis is a rare, but serious complication of methimazole (MMI) use for Graves' disease (GD). Treatment requires discontinuation of MMI, and the use of propylthiouracil (PTU) is also contraindicated. Few reports exist about the optimal alternative treatment regimens for the management of thyrotoxicosis in these medically complex patients in the pediatric population.

Structural mapping of PEAK pseudokinase interactions identifies 14-3-3 as a molecular switch for PEAK3 signaling.

PEAK pseudokinases regulate cell migration, invasion and proliferation by recruiting key signaling proteins to the cytoskeleton. Despite lacking catalytic activity, alteration in their expression level is associated with several aggressive cancers. Here, we elucidate the molecular details of key PEAK signaling interactions with the adapter proteins CrkII and Grb2 and the scaffold protein 14-3-3.

The unifying catalytic mechanism of the RING-between-RING E3 ubiquitin ligase family.

The RING-between-RING (RBR) E3 ubiquitin ligase family in humans comprises 14 members and is defined by a two-step catalytic mechanism in which ubiquitin is first transferred from an E2 ubiquitin-conjugating enzyme to the RBR active site and then to the substrate. To define the core features of this catalytic mechanism, we here structurally and biochemically characterise the two RBRs HOIL-1 and RNF216. Crystal structures of both enzymes in their RBR/E2-Ub/Ub transthiolation complexes capturing the first catalytic step, together with complementary functional experiments, reveal the defining features of the RBR catalytic mechanism.

Hyperparathyroidism in a Fracture Population.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder that results in excess parathyroid hormone (PTH) secretion and hypercalcemia. PHPT is usually caused by an adenoma and its presentation is often asymptomatic, though it can negatively impact the skeleton via osteoporosis mostly affecting cortical bone and fracture. The diagnosis of PHPT is made by clinical presentation and biochemical and hormonal assessment.

Serologic phenotypes distinguish systemic lupus erythematosus patients developing interstitial lung disease and/or myositis.

Objectives: To determine if serologic phenotypes could be identified in systemic lupus erythematosus patients developing interstitial lung disease (ILD) and/or myositis.

Methods: Adult SLE patients (without myositis/ILD at baseline) had annual assessments and serum sampling between 2000 and 2017. New-onset ILD was identified using the SDI pulmonary fibrosis item.

Structural basis of K63-ubiquitin chain formation by the Gordon-Holmes syndrome RBR E3 ubiquitin ligase RNF216.

An increasing number of genetic diseases are linked to deregulation of E3 ubiquitin ligases. Loss-of-function mutations in the RING-between-RING (RBR) family E3 ligase RNF216 (TRIAD3) cause Gordon-Holmes syndrome (GHS) and related neurodegenerative diseases. Functionally, RNF216 assembles K63-linked ubiquitin chains and has been implicated in regulation of innate immunity signaling pathways and synaptic plasticity.

Activation mechanism of PINK1.

Mutations in the protein kinase PINK1 lead to defects in mitophagy and cause autosomal recessive early onset Parkinson's disease. PINK1 has many unique features that enable it to phosphorylate ubiquitin and the ubiquitin-like domain of Parkin. Structural analysis of PINK1 from diverse insect species with and without ubiquitin provided snapshots of distinct structural states yet did not explain how PINK1 is activated.

Myositis in systemic lupus erythematosus.

Objectives: Myositis is an infrequent feature of SLE and may often be overlooked. We aimed to estimate the incidence of myositis in SLE, and to determine demographic and clinical factors associated with it.

Methods: Within our lupus cohort, we identified potential myositis cases using the SLICC Damage Index for muscle atrophy or weakness, the SLEDAI-2K item for myositis, and annually measured serum creatinine kinase.

Unusual appearance of an adrenal ganglioneuroma.

Ganglioneuromas are rare tumors that occur spontaneously or arise from a poorly differentiated neuroblastic tumor. Although they are typically described in the pediatric population, they can occur in adults. Ganglioneuromas are often discovered incidentally and their typical imaging appearance, although non-specific, is that of a well-defined solid mass.

Chain reactions: molecular mechanisms of RBR ubiquitin ligases.

Ubiquitination is a fundamental post-translational modification that regulates almost all aspects of cellular signalling and is ultimately catalysed by the action of E3 ubiquitin ligases. The RING-between-RING (RBR) family of E3 ligases encompasses 14 distinct human enzymes that are defined by a unique domain organisation and catalytic mechanism. Detailed characterisation of several RBR ligase family members in the last decade has revealed common structural and mechanistic features.

Increased yield and CO sequestration potential with the C cereal Sorghum bicolor cultivated in basaltic rock dust-amended agricultural soil.

Land-based enhanced rock weathering (ERW) is a biogeochemical carbon dioxide removal (CDR) strategy aiming to accelerate natural geological processes of carbon sequestration through application of crushed silicate rocks, such as basalt, to croplands and forested landscapes. However, the efficacy of the approach when undertaken with basalt, and its potential co-benefits for agriculture, require experimental and field evaluation. Here we report that amending a UK clay-loam agricultural soil with a high loading (10 kg/m ) of relatively coarse-grained crushed basalt significantly increased the yield (21 ± 9.

Post-thyroidectomy emergency room visits and readmissions: Assessment from the Collaborative Endocrine Surgery Quality Improvement Program (CESQIP).

Background: This study analyzed independent factors associated with post-thyroidectomy Emergency Room (ER) visits and Hospital Readmissions (HR).

Methods: This is a retrospective review from the CESQIP registry of 8381 thyroidectomy patients by 173 surgeons at 46 institutions. A total of 7142 ER visits and 7265 HR were analyzed.

Surviving in a Hostile World: Plant Strategies to Resist Pests and Diseases.

As primary producers, plants are under constant pressure to defend themselves against potentially deadly pathogens and herbivores. In this review, we describe short- and long-term strategies that enable plants to cope with these stresses. Apart from internal immunological strategies that involve physiological and (epi)genetic modifications at the cellular level, plants also employ external strategies that rely on recruitment of beneficial organisms.

Metabolic regulation of the maize rhizobiome by benzoxazinoids.

The rhizobiome is an important regulator of plant growth and health. Plants shape their rhizobiome communities through production and release of primary and secondary root metabolites. Benzoxazinoids (BXs) are common tryptophan-derived secondary metabolites in grasses that regulate belowground and aboveground biotic interactions.

Are drivers of root-associated fungal community structure context specific?

The composition and structure of plant-root-associated fungal communities are determined by local abiotic and biotic conditions. However, the relative influence and identity of relationships to abiotic and biotic factors may differ across environmental and ecological contexts, and fungal functional groups. Thus, understanding which aspects of root-associated fungal community ecology generalise across contexts is the first step towards a more predictive framework.

Impacts of Atmospheric CO and Soil Nutritional Value on Plant Responses to Rhizosphere Colonization by Soil Bacteria.

Concerns over rising atmospheric CO concentrations have led to growing interest in the effects of global change on plant-microbe interactions. As a primary substrate of plant metabolism, atmospheric CO influences below-ground carbon allocation and root exudation chemistry, potentially affecting rhizosphere interactions with beneficial soil microbes. In this study, we have examined the effects of different atmospheric CO concentrations on Arabidopsis rhizosphere colonization by the rhizobacterial strain WCS417 and the saprophytic strain KT2440.

Arbuscular mycorrhizal fungal communities and global change: an uncertain future.

Arbuscular mycorrhizal (AM) fungi are amongst the most common and functionally important symbionts of terrestrial plants and are highly likely to be affected by global change. The potential consequences of this on plant growth and carbon and nutrient cycling has led to a growing demand for their inclusion in global change models. However, our understanding of their responses to environmental change remains limited.

The Effects of Arbuscular Mycorrhizal Fungal Colonisation on Nutrient Status, Growth, Productivity, and Canker Resistance of Apple ().

We assess whether arbuscular mycorrhizal fungi (AMF) improve growth, nutritional status, phenology, flower and fruit production, and disease resistance in woody perennial crops using apple ( as a study system. In a fully factorial experiment, young trees were grown for 3 years with or without AMF ( and ), and with industrial standard fertiliser applications or restricted fertiliser (10% of standard). We use two commercial scions (Dabinett and Michelin) and rootstocks (MM111 and MM106).

Processes and Outcomes of a Community-Based Participatory Research-Driven Health Needs Assessment: A Tool for Moving Health Disparity Reporting to Evidence-Based Action.

Background: The community-based participatory research (CBPR)-driven health needs assessment was a tool used to inform community-led, -implemented, and -sustained research and prevention strategies.

Methods: The Morehouse School of Medicine Prevention Research Center (MSM PRC) research and prevention initiatives are implemented in direct response to priorities identified through this process and tool. Led by a community-majority coalition board, the assessment coupled state and city secondary data with primary survey data collected by and from community residents.

Lost in diversity: the interactions between soil-borne fungi, biodiversity and plant productivity.

There is consensus that plant species richness enhances plant productivity within natural grasslands, but the underlying drivers remain debated. Recently, differential accumulation of soil-borne fungal pathogens across the plant diversity gradient has been proposed as a cause of this pattern. However, the below-ground environment has generally been treated as a 'black box' in biodiversity experiments, leaving these fungi unidentified.

Molecular characterization of latent GDF8 reveals mechanisms of activation.

Growth/differentiation factor 8 (GDF8), or myostatin, negatively regulates muscle mass. GDF8 is held in a latent state through interactions with its N-terminal prodomain, much like TGF-β. Using a combination of small-angle X-ray scattering and mutagenesis, we characterized the interactions of GDF8 with its prodomain.

Structure of the human myostatin precursor and determinants of growth factor latency.

Myostatin, a key regulator of muscle mass in vertebrates, is biosynthesised as a latent precursor in muscle and is activated by sequential proteolysis of the pro-domain. To investigate the molecular mechanism by which pro-myostatin remains latent, we have determined the structure of unprocessed pro-myostatin and analysed the properties of the protein in its different forms. Crystal structures and SAXS analyses show that pro-myostatin adopts an open, V-shaped structure with a domain-swapped arrangement.

Outpatient Total Thyroidectomy Is Safe for Moderate-Volume Surgeons.

Traditionally, total thyroidectomy (TT) was an inpatient procedure, but recent trends indicate that patients are often discharged on the day of surgery. This has been proven safe for high-volume surgeons but has not been studied for low (<10 TT per year) and moderate volume surgeons (<24 TT per year). Retrospective review was performed for 414 total thyroidectomies between 2005 and 2013.