The structural flexibility of MAD1 facilitates the assembly of the Mitotic Checkpoint Complex.

The spindle assembly checkpoint (SAC) safeguards the genome during cell division by generating an effector molecule known as the Mitotic Checkpoint Complex (MCC). The MCC comprises two subcomplexes: BUBR1:BUB3 and CDC20:MAD2, and the formation of CDC20:MAD2 is the rate-limiting step during MCC assembly. Recent studies show that the rate of CDC20:MAD2 formation is significantly accelerated by the cooperative binding of CDC20 to the SAC proteins MAD1 and BUB1.

Mitochondrial Dysfunction in Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by recessive mutations in the gene, globally affecting ~8-14 newborns per 100,000. The severity of the disease depends on the residual levels of functional survival of motor neuron protein, SMN. SMN is a ubiquitously expressed RNA binding protein involved in a plethora of cellular processes.

CDC20 assists its catalytic incorporation in the mitotic checkpoint complex.

Open (O) and closed (C) topologies of HORMA-domain proteins are respectively associated with inactive and active states of fundamental cellular pathways. The HORMA protein O-MAD2 converts to C-MAD2 upon binding CDC20. This is rate limiting for assembly of the mitotic checkpoint complex (MCC), the effector of a checkpoint required for mitotic fidelity.

Pharmacological and non-pharmacological treatments for neuropathic pain: Systematic review and French recommendations.

Neuropathic pain remains a significant unmet medical need. Several recommendations have recently been proposed concerning pharmacotherapy, neurostimulation techniques and interventional management, but no comprehensive guideline encompassing all these treatments has yet been issued. We performed a systematic review of pharmacotherapy, neurostimulation, surgery, psychotherapies and other types of therapy for peripheral or central neuropathic pain, based on studies published in peer-reviewed journals before January 2018.

Electroporated recombinant proteins as tools for in vivo functional complementation, imaging and chemical biology.

Delivery of native or chemically modified recombinant proteins into mammalian cells shows promise for functional investigations and various technological applications, but concerns that sub-cellular localization and functional integrity of delivered proteins may be affected remain high. Here, we surveyed batch electroporation as a delivery tool for single polypeptides and multi-subunit protein assemblies of the kinetochore, a spatially confined and well-studied subcellular structure. After electroporation into human cells, recombinant fluorescent Ndc80 and Mis12 multi-subunit complexes exhibited native localization, physically interacted with endogenous binding partners, and functionally complemented depleted endogenous counterparts to promote mitotic checkpoint signaling and chromosome segregation.

Development of alkyl glycerone phosphate synthase inhibitors: Structure-activity relationship and effects on ether lipids and epithelial-mesenchymal transition in cancer cells.

In aggressive tumors, alkylglyceronephosphate synthase (AGPS) controls cellular ether phospholipid utilization and metabolism to promote cancer cell proliferation and motility. SAR studies on the first-in-class AGPS inhibitor 1, discovered by our group, led to the 2,6-difluoro analog 2i which showed higher binding affinity than 1in vitro. In 231MFP cancer cells, 2i reduced ether lipids levels and cell migration rate.

[Pain, from symptom to syndrome].

Acute pain is a symptom enabling us to implement a response when faced with an attack. Chronic pain is complex and multifactorial. The care of the patient by a multidisciplinary team comprises the diagnosis of the pain and the putting in place of a treatment for each of its components.

A Phenotypic Based Target Screening Approach Delivers New Antitubercular CTP Synthetase Inhibitors.

Despite its great potential, the target-based approach has been mostly unsuccessful in tuberculosis drug discovery, while whole cell phenotypic screening has delivered several active compounds. However, for many of these hits, the cellular target has not yet been identified, thus preventing further target-based optimization of the compounds. In this context, the newly validated drug target CTP synthetase PyrG was exploited to assess a target-based approach of already known, but untargeted, antimycobacterial compounds.

Flavins as Covalent Catalysts: New Mechanisms Emerge.

With approximately 1% of proteins being flavoproteins, flavins are at the heart of a plethora of redox reactions in all areas of biology. Thanks to a series of fascinating recent discoveries, in addition to redox chemistry, covalent catalysis is now being recognized more frequently as a common strategy in flavoenzymes, with unprecedented mechanisms becoming apparent. Thus, noncanonical covalent reactions by flavins are emerging as a new pervasive concept in basic enzymology and biochemistry.

Recombinant human dihydroxyacetonephosphate acyl-transferase characterization as an integral monotopic membrane protein.

Although the precise functions of ether phospholipids are still poorly understood, significant alterations in their physiological levels are associated either to inherited disorders or to aggressive metastatic cancer. The essential precursor, alkyl-dihydroxyacetone phosphate (DHAP), for all ether phospholipids species is synthetized in two consecutive reactions performed by two enzymes sitting on the inner side of the peroxisomal membrane. Here, we report the characterization of the recombinant human DHAP acyl-transferase, which performs the first step in alkyl-DHAP synthesis.

[Use of strong opioids in chronic non-cancer pain in adults. Evidence-based recommendations from the French Society for the Study and Treatment of Pain].

Objectives: An urgent need is to improve the efficacy and safety of use of strong opioids in chronic non-cancer pain (CNCP) through responsible prescription rules supported by scientific evidence.

Methods: Clinical questions addressing the indication, the benefice, the risk and the precautions were formulated. A task force composed of physicians from several medical specialties involved in managing CNCP was charged to elaborate evidence-based recommendations.

Discovery of Inhibitors for the Ether Lipid-Generating Enzyme AGPS as Anti-Cancer Agents.

Dysregulated ether lipid metabolism is an important hallmark of cancer cells. Previous studies have reported that lowering ether lipid levels by genetic ablation of the ether lipid-generating enzyme alkyl-glycerone phosphate synthase (AGPS) lowers key structural and oncogenic ether lipid levels and alters fatty acid, glycerophospholipid, and eicosanoid metabolism to impair cancer pathogenicity, indicating that AGPS may be a potential therapeutic target for cancer. In this study, we have performed a small-molecule screen to identify candidate AGPS inhibitors.

Pain beliefs and perceptions inventory: a cross-sectional study in chronic and episodic migraine.

Objective/background: This study aims to compare differences in pain beliefs according to headache type, chronic vs episodic migraine, in a large cohort of patients, using the Pain Beliefs and Perceptions Inventory (PBPI), and to identify possible predictive factors of the same pain beliefs.

Methods: All patients referring for the first time at our center in 2011 were screened using PBPI and the Hamilton Anxiety and Depression Scale (a total of 1032 patients). PBPI is a 4-subscale questionnaire that explores a patient's personal beliefs on their subjective experience of pain.

rTMS in fibromyalgia: a randomized trial evaluating QoL and its brain metabolic substrate.

Objective: This double-blind, randomized, placebo-controlled study investigated the impact of repetitive transcranial magnetic stimulation (rTMS) on quality of life (QoL) of patients with fibromyalgia, and its possible brain metabolic substrate.

Methods: Thirty-eight patients were randomly assigned to receive high-frequency rTMS (n = 19) or sham stimulation (n = 19), applied to left primary motor cortex in 14 sessions over 10 weeks. Primary clinical outcomes were QoL changes at the end of week 11, measured using the Fibromyalgia Impact Questionnaire (FIQ).

A case vignette study to assess the knowledge of pain physicians of neuropathic cancer pain: room for improvement.

Background: In more and more countries, a specific pain education curriculum is provided to instruct pain physicians. However, there is little literature on pain education and in particularly how to evaluate their knowledge. One of the modules interesting to assess is the use of clinical practice guidelines (CPGs) by pain physicians.

Treatment for neuropathic pain in patients with cancer: comparative analysis of recommendations in national clinical practice guidelines from European countries.

Introduction: Neuropathic pain is a common symptom, present in 39% of the patients with cancer pain. Treating this type of pain is challenging, as this patient group is often frail and has comorbidities which increase the risk of side events and hence influences their quality of life. Clinical practice guidelines (CPGs) can be helpful for clinicians, especially when scientific evidence is uncertain or weak.

Diagnosing neuropathic pain in patients with cancer: comparative analysis of recommendations in national guidelines from European countries.

Background: Neuropathic pain is a prevalent symptom in patients with cancer, which needs a more specific algorithm than nociceptive pain or neuropathic pain from other origin. Clinical practice guidelines (CPGs) can be helpful in optimizing the diagnosis of neuropathic pain in patients with cancer.

Methods: In this study, 9 national CPGs in Europe on the diagnosis of neuropathic pain in patients with cancer were included.

Precursor of ether phospholipids is synthesized by a flavoenzyme through covalent catalysis.

The precursor of the essential ether phospholipids is synthesized by a peroxisomal enzyme that uses a flavin cofactor to catalyze a reaction that does not alter the redox state of the substrates. The enzyme crystal structure reveals a V-shaped active site with a narrow constriction in front of the prosthetic group. Mutations causing inborn ether phospholipid deficiency, a very severe genetic disease, target residues that are part of the catalytic center.

Guidelines for neuropathic pain management in patients with cancer: a European survey and comparison.

Unlabelled: Between 19% and 39% of patients with cancer pain suffer from neuropathic pain. Its diagnosis and treatment is still challenging. Yet, national clinical practice guidelines (CPGs) have been developed in several European countries to assist practitioners in managing these patients safely and legally.

Cardiac safety in cluster headache patients using the very high dose of verapamil (≥720 mg/day).

Use of high doses of verapamil in preventive treatment of cluster headache (CH) is limited by cardiac toxicity. We systematically assess the cardiac safety of the very high dose of verapamil (verapamil VHD) in CH patients. Our work was a study performed in two French headache centers (Marseilles-Nice) from 12/2005 to 12/2008.