Evidence of Pure Spin-Current Generated by Spin Pumping in Interface-Localized States in Hybrid Metal-Silicon-Metal Vertical Structures.

Due to the difficulty of growing high-quality semiconductors on ferromagnetic metals, the study of spin diffusion transport in Si was limited to lateral geometry devices. In this work, by using an ultrahigh-vacuum wafer-bonding technique, we have successfully fabricated metal-semiconductor-metal CoFeB/MgO/Si/Pt vertical structures. We hereby demonstrate pure spin-current injection and transport in the perpendicular current flow geometry over a distance larger than 2 µm in n-type Si at room temperature. In those experiments, a pure propagating spin current is generated via ferromagnetic resonance spin pumping and converted into a measurable voltage by using the inverse spin Hall effect occurring in the top Pt layer. A systematic study varying both Si and MgO thicknesses reveals the important role played by the localized states at the MgO-Si interface for the spin-current generation. Proximity effects involving indirect exchange interactions between the ferromagnet and the MgO-Si interface states appears to be a prerequisite to establishing the necessary out-of-equilibrium spin population in Si under the spin-pumping action.

GABAB receptors in neocortical and hippocampal pyramidal neurons are coupled to different potassium channels.

Classically, GABAB receptors are thought to regulate neuronal excitability via G-protein-coupled inwardly rectifying potassium (GIRK) channels. Recent data, however, indicate that GABAB receptors can also activate two-pore domain potassium channels. Here, we investigate which potassium channels are coupled to GABAB receptors in rat neocortical layer 5 and hippocampal CA1 pyramidal neurons. Bath application of the non-specific GIRK channel blocker barium (200 µm) abolished outward currents evoked by GABAB receptors in CA1 pyramidal, but only partially blocked GABAB responses in layer 5 neurons. Layer 5 and CA1 pyramidal neurons also showed differential sensitivity to tertiapin-Q, a specific GIRK channel blocker. Tertiapin-Q partially blocked GABAB responses in CA1 pyramidal neurons, but was ineffective in blocking GABAB responses in neocortical layer 5 neurons. Consistent with the idea that GABAB receptors are coupled to two-pore domain potassium channels, the non-specific blockers quinidine and bupivacaine partially blocked GABAB responses in both layer 5 and CA1 neurons. Finally, we show that lowering external pH, as occurs in hypoxia, blocks the component of GABAB responses mediated by two-pore domain potassium channels in neocortical layer 5 pyramidal neurons, while at the same time revealing a GIRK channel component. These data indicate that GABAB receptors in neocortical layer 5 and hippocampal CA1 pyramidal neurons are coupled to different channels, with this coupling pH dependent on neocortical layer 5 pyramidal neurons. This pH dependency may act to maintain constant levels of GABAB inhibition during hypoxia by enhancing GIRK channel function following a reduction in two-pore domain potassium channel activity.

Combining Multiscale Approaches for the Structure Determination of an Iron Layered Oxysulfate: Sr4Fe2.5O7.25(SO4)0.5.

The new iron layered oxysulfate Sr4Fe2.5O7.25(SO4)0.5 has been prepared by a solid-state reaction in closed ampules into the form of ceramics and single crystals. Its atomic structure has been solved by means of spectroscopy, diffraction techniques, and high-resolution electron microscopy. Sr4Fe2.5O7.25(SO4)0.5 is a layered structure that derives from the Ruddelsden-Popper (RP) phases with the layer stacking sequence SrO/SrFeO2.5/SrFe0.5(SO4)0.5O1.25/SrFeO2.5. Within the mixed Fe3+/SO42- layer, the sulfur atoms are slightly shifted from the B site of the perovskite and each sulfate group shares two corners with iron pyramids in the basal plan without any order phenomenon. The electronic conductivity is thermally activated, while no ionic conductivity is detected.

Thermal spin current from a ferromagnet to silicon by Seebeck spin tunnelling.

Heat generation by electric current, which is ubiquitous in electronic devices and circuits, raises energy consumption and will become increasingly problematic in future generations of high-density electronics. The control and re-use of heat are therefore important topics for existing and emerging technologies, including spintronics. Recently it was reported that heat flow within a ferromagnet can produce a flow of spin angular momentum-a spin current-and an associated voltage. This spin Seebeck effect has been observed in metallic, insulating and semiconductor ferromagnets with temperature gradients across them. Here we describe and report the demonstration of Seebeck spin tunnelling-a distinctly different thermal spin flow, of purely interfacial nature-generated in a tunnel contact between electrodes of different temperatures when at least one of the electrodes is a ferromagnet. The Seebeck spin current is governed by the energy derivative of the tunnel spin polarization. By exploiting this in ferromagnet-oxide-silicon tunnel junctions, we observe thermal transfer of spins from the ferromagnet to the silicon without a net tunnel charge current. The induced spin accumulation scales linearly with heating power and changes sign when the temperature differential is reversed. This thermal spin current can be used by itself, or in combination with electrical spin injection, to increase device efficiency. The results highlight the engineering of heat transport in spintronic devices and facilitate the functional use of heat.

Reliability, Validity, and Clinical Utility of the Dominic Interactive for Adolescents-RevisedA DSM-5-Based Self-Report Screen for Mental Disorders, Borderline Personality Traits, and Suicidality.

OBJECTIVES: The Dominic Interactive for Adolescents-Revised (DIA-R) is a multimedia self-report screen for 9 mental disorders, borderline personality traits, and suicidality defined by the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders ( DSM-5). This study aimed to examine the reliability and the validity of this instrument. METHODS: French- and English-speaking adolescents aged 12 to 15 years ( N = 447) were recruited from schools and clinical settings in Montreal and were evaluated twice. The internal consistency was estimated by Cronbach alpha coefficients and the test-retest reliability by intraclass correlation coefficients. Cutoff points on the DIA-R scales were determined by using clinically relevant measures for defining external validation criteria: the Schedule for Affective Disorders and Schizophrenia for School-Aged Children, the Beck Hopelessness Scale, and the Abbreviated-Diagnostic Interview for Borderlines. Receiver operating characteristic (ROC) analyses provided accuracy estimates (area under the ROC curve, sensitivity, specificity, likelihood ratio) to evaluate the ability of the DIA-R scales to predict external criteria. RESULTS: For most of the DIA-R scales, reliability coefficients were excellent or moderate. High or moderate accuracy estimates from ROC analyses demonstrated the ability of the DIA-R thresholds to predict psychopathological conditions. These thresholds were generally capable to discriminate between clinical and school subsamples. However, the validity of the obsessions/compulsions scale was too low. CONCLUSIONS: Findings clearly support the reliability and the validity of the DIA-R. This instrument may be useful to assess a wide range of adolescents' mental health problems in the continuum of services. This conclusion applies to all scales, except the obsessions/compulsions one.

Oxidative DNA Damage and Repair in the Radioresistant Archaeon Thermococcus gammatolerans.

The hyperthermophilic archaeon Thermococcus gammatolerans can resist huge doses of γ-irradiation, up to 5.0 kGy, without loss of viability. The potential to withstand such harsh conditions is probably due to complementary passive and active mechanisms, including repair of damaged chromosomes. In this work, we documented the formation and repair of oxidative DNA lesions in T. gammatolerans. The basal level of the oxidized nucleoside, 8-oxo-2'-deoxyguanosine (8-oxo-dGuo), was established at 9.2 (± 0.9) 8-oxo-dGuo per 106 nucleosides, a higher level than those usually measured in eukaryotic cells or bacteria. A significant increase in oxidative damage, i.e., up to 24.2 (± 8.0) 8-oxo-dGuo/106 nucleosides, was measured for T. gammatolerans exposed to a 5.0 kGy dose of γ-rays. Surprisingly, the yield of radiation-induced modifications was lower than those previously observed for human cells exposed to doses corresponding to a few grays. One hour after irradiation, 8-oxo-dGuo levels were significantly reduced, indicating an efficient repair. Two putative base excision repair (BER) enzymes, TGAM_1277 and TGAM_1653, were demonstrated both by proteomics and transcriptomics to be present in the cells without exposure to ionizing radiation. Their transcripts were moderately upregulated after gamma irradiation. After heterologous production and purification of these enzymes, biochemical assays based on electrophoresis and MALDI-TOF (matrix-assisted laser desorption ionization-time of flight) mass spectrometry indicated that both have a ß-elimination cleavage activity. TGAM_1653 repairs 8-oxo-dGuo, whereas TGAM_1277 is also able to remove lesions affecting pyrimidines (1-[2-deoxy-ß-d-erythro-pentofuranosyl]-5-hydroxyhydantoin (5-OH-dHyd) and 1-[2-deoxy-ß-d-erythro-pentofuranosyl]-5-hydroxy-5-methylhydantoin (5-OH-5-Me-dHyd)). This work showed that in normal growth conditions or in the presence of a strong oxidative stress, T. gammatolerans has the potential to rapidly reduce the extent of DNA oxidation, with at least these two BER enzymes as bodyguards with distinct substrate ranges.

Sleep-Wake Patterns of Adolescents with Borderline Personality Disorder and Bipolar Disorder.

Sleep-wake patterns are rarely examined in adolescents with borderline personality disorder (BPD) or bipolar disorder (BD). Within a developmental perspective, this study explores the sleep-wake cycle of adolescents aged 12-17 years with BPD or BD and healthy controls (HC) during periods with and without entrainment by school/work schedules. Eighteen euthymic BPD, six euthymic BD, and 20 HC adolescents wore wrist actigraphy during nine consecutive days to assess sleep-wake patterns. During school/work days, BPD adolescents spent more time awake when they were in bed compared to HC and BD adolescents (p = 0.039). On schedule-free days, BPD and BD youths spent more time in bed compared to HC adolescents (p = 0.015). BPD adolescents woke up over 1 h later compared to HC (p = 0.003). Total sleep time was more variable between nights in BPD adolescents compared to the HC group (p = 0.031). Future research should explore if sleep-wake pattern disruptions are a cause or a consequence of BPD symptomatology in adolescents. Addressing sleep-wake pattern during clinical assessment and treatment of BPD adolescents may potentially reduce their symptoms; this therapeutic effect still needs to be evaluated.

Long-lasting spinal oxytocin analgesia is ensured by the stimulation of allopregnanolone synthesis which potentiates GABA(A) receptor-mediated synaptic inhibition.

Hypothalamospinal control of spinal pain processing by oxytocin (OT) has received a lot of attention in recent years because of its potency to reduce pain symptoms in inflammatory and neuropathic conditions. However, cellular and molecular mechanisms underlying OT spinal antinociception are still poorly understood. In this study, we used biochemical, electrophysiological, and behavioral approaches to demonstrate that OT levels are elevated in the spinal cord of rats exhibiting pain symptoms, 24 h after the induction of inflammation with an intraplantar injection of λ-carrageenan. Using a selective OT receptor antagonist, we demonstrate that this elevated OT content is responsible for a tonic analgesia exerted on both mechanical and thermal modalities. This phenomenon appeared to be mediated by an OT receptor-mediated stimulation of neurosteroidogenesis, which leads to an increase in GABA(A) receptor-mediated synaptic inhibition in lamina II spinal cord neurons. We also provide evidence that this novel mechanism of OT-mediated spinal antinociception may be controlled by extracellular signal-related protein kinases, ERK1/2, after OT receptor activation. The oxytocinergic inhibitory control of spinal pain processing is emerging as an interesting target for future therapies since it recruits several molecular mechanisms, which are likely to exert a long-lasting analgesia through nongenomic and possibly genomic effects.

DNA binding of the p21 repressor ZBTB2 is inhibited by cytosine hydroxymethylation.

Recent studies have demonstrated that the modified base 5-hydroxymethylcytosine (5-hmC) is detectable at various rates in DNA extracted from human tissues. This oxidative product of 5-methylcytosine (5-mC) constitutes a new and important actor of epigenetic mechanisms. We designed a DNA pull down assay to trap and identify nuclear proteins bound to 5-hmC and/or 5-mC. We applied this strategy to three cancerous cell lines (HeLa, SH-SY5Y and UT7-MPL) in which we also measured 5-mC and 5-hmC levels by HPLC-MS/MS. We found that the putative oncoprotein Zinc finger and BTB domain-containing protein 2 (ZBTB2) is associated with methylated DNA sequences and that this interaction is inhibited by the presence of 5-hmC replacing 5-mC. As published data mention ZBTB2 recognition of p21 regulating sequences, we verified that this sequence specific binding was also alleviated by 5-hmC. ZBTB2 being considered as a multifunctional cell proliferation activator, notably through p21 repression, this work points out new epigenetic processes potentially involved in carcinogenesis.

Voltage-Driven Fluorine Motion for Novel Organic Spintronic Memristor.

Integrating tunneling magnetoresistance (TMR) effect in memristors is a long-term aspiration because it allows to realize multifunctional devices, such as multi-state memory and tunable plasticity for synaptic function. However, the reported TMR in different multiferroic tunnel junctions is limited to 100%. This work demonstrates a giant TMR of -266% in La0.6Sr0.4MnO3(LSMO)/poly(vinylidene fluoride)(PVDF)/Co memristor with thin organic barrier. Different from the ferroelectricity-based memristors, this work discovers that the voltage-driven florine (F) motion in the junction generates a huge reversible resistivity change up to 106% with nanosecond (ns) timescale. Removing F from PVDF layer suppresses the dipole field in the tunneling barrier, thereby significantly enhances the TMR. Furthermore, the TMR can be tuned by different polarizing voltage due to the strong modification of spin-polarization at the LSMO/PVDF interface upon F doping. Combining of high TMR in the organic memristor paves the way to develop high-performance multifunctional devices for storage and neuromorphic applications.

Juvenile bipolar disorder and suicidality: a review of the last 10 years of literature.

Although children and adolescents with bipolar disorder (BD) are at elevated risk for suicide, little research to date has been conducted on suicidality in this population. The purpose of this descriptive review of the past 10 years of scientific literature on suicidality in youths with BD was to identify the risk and protective factors associated with this phenomenon, and to discuss the implications for research and clinical practice. Searches on Medline and PsycINFO databases for the period from early 2002 to mid-2012 yielded 16 relevant articles, which were subsequently explored using an analysis grid. Note that the authors employed a consensus analysis approach at all stages of the review. Four primary categories of risk factors for suicidality in youths with BD were identified: demographic (age and gender), clinical (depression, mixed state or mixed features specifier, mania, anxiety disorders, psychotic symptoms, and substance abuse), psychological (cyclothymic temperament, hopelessness, poor anger management, low self-esteem, external locus of control, impulsivity and aggressiveness, previous suicide attempts, and history of suicide ideation, non-suicidal self-injurious behaviors and past psychiatric hospitalization), and family/social (family history of attempted suicide, family history of depression, low quality of life, poor family functioning, stressful life events, physical/sexual abuse, and social withdrawal). Youths with BD who experienced more complex symptomatic profiles were at greater risk of suicidality. Few protective factors associated with suicidality have been studied among youths with BD. One protective factor was found in this descriptive literature review: the positive effects of dialectical behavior therapy. This article allows a better appreciation of the risk and protective factors associated with suicidality among youth with BD. Greater awareness of risk factors is the first step in suicide prevention.

A Delphi consensus among experts on assessment and treatment of disruptive mood dysregulation disorder.

Objective: The aim of this study was to explore consensus among clinicians and researchers on how to assess and treat Disruptive Mood Dysregulation Disorder (DMDD). Methods: The Delphi method was used to organize data collected from an initial sample of 23 child psychiatrists and psychologists. Three rounds of closed/open questions were needed to achieve the objective. Results: Fifteen experts in the field completed the whole study. Finally, 122 proposals were validated and 5 were rejected. Globally, consensus was more easily reached on items regarding assessment than on those regarding treatment. Specifically, experts agreed that intensity, frequency, and impact of DMDD symptoms needed to be measured across settings, including with parents, siblings, peers, and teachers. While a low level of consensus emerged regarding optimal pharmacological treatment, the use of psychoeducation, behavior-focused therapies (e.g., dialectical behavior therapy, chain analysis, exposure, relaxation), and systemic approaches (parent management training, family therapy, parent-child interaction therapy) met with a high degree of consensus. Conclusion: This study presents recommendations that reached a certain degree of consensus among researchers and clinicians regarding the assessment and treatment of youths with DMDD. These findings may be useful to clinicians working with this population and to researchers since they also highlight non-consensual areas that need to be further investigated.

Somatic and dendritic GABA(B) receptors regulate neuronal excitability via different mechanisms.

GABA(B) receptors play a key role in regulating neuronal excitability in the brain. Whereas the impact of somatic GABA(B) receptors on neuronal excitability has been studied in some detail, much less is known about the role of dendritic GABA(B) receptors. Here, we investigate the impact of GABA(B) receptor activation on the somato-dendritic excitability of layer 5 pyramidal neurons in the rat barrel cortex. Activation of GABA(B) receptors led to hyperpolarization and a decrease in membrane resistance that was greatest at somatic and proximal dendritic locations. These effects were occluded by low concentrations of barium (100 µM), suggesting that they are mediated by potassium channels. In contrast, activation of dendritic GABA(B) receptors decreased the width of backpropagating action potential (APs) and abolished dendritic calcium electrogenesis, indicating that dendritic GABA(B) receptors regulate excitability, primarily via inhibition of voltage-dependent calcium channels. These distinct actions of somatic and dendritic GABA(B) receptors regulated neuronal output in different ways. Activation of somatic GABA(B) receptors led to a reduction in neuronal output, primarily by increasing the AP rheobase, whereas activation of dendritic GABA(B) receptors blocked burst firing, decreasing AP output in the absence of a significant change in somatic membrane properties. Taken together, our results show that GABA(B) receptors regulate somatic and dendritic excitability of cortical pyramidal neurons via different cellular mechanisms. Somatic GABA(B) receptors activate potassium channels, leading primarily to a subtractive or shunting form of inhibition, whereas dendritic GABA(B) receptors inhibit dendritic calcium electrogenesis, leading to a reduction in bursting firing.

Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial.

BACKGROUND: Chemotherapy is the standard of care for advanced stages of non-small-cell lung cancer (NSCLC). TG4010 is a targeted immunotherapy based on a poxvirus (modified vaccinia virus Ankara) that codes for MUC1 tumour-associated antigen and interleukin 2. This study assessed TG4010 in combination with first-line chemotherapy in advanced NSCLC. METHODS: 148 patients with advanced (stage IIIB [wet] or IV) NSCLC expressing MUC1 by immunohistochemistry, and with performance status 0 or 1, were enrolled in parallel groups in this open-label, phase 2B study. 74 patients were allocated to the combination therapy group, and received TG4010 (10(8) plaque forming units) plus cisplatin (75 mg/m(2) on day 1) and gemcitabine (1250 mg/m(2) on days 1 and 8) repeated every 3 weeks for up to six cycles. 74 patients allocated to the control group received the same chemotherapy alone. Patients were allocated using a dynamic minimisation procedure stratified by centre, performance status, and disease stage. The primary endpoint was 6-month progression-free survival (PFS), with a target rate of 40% or higher in the experimental group. Analyses were done on an intention-to-treat basis. This study is completed and is registered with ClinicalTrials.gov, number NCT00415818. FINDINGS: 6-month PFS was 43·2% (32 of 74; 95% CI 33·4-53·5) in the TG4010 plus chemotherapy group, and 35·1% (26 of 74; 25·9-45·3) in the chemotherapy alone group. Fever, abdominal pain, and injection-site pain of any grade according to National Cancer Institute Common Toxicity Criteria were more common in the TG4010 group than in the chemotherapy alone group: 17 of 73 patients (23·3%) versus six of 72 (8·3%), 12 (16·4%) versus two (2·8%), and four (5·5%) versus zero (0%), respectively. The most common grade 3-4 adverse events were neutropenia (33 [45·2%] of patients in the TG4010 plus chemotherapy group vs 31 [43·1%] in the chemotherapy alone group) and fatigue (18 [24·7%] vs 13 [18·1%]); the only grade 3-4 events that differed significantly between groups were anorexia (three [4·1%] vs 10 [13·9%]) and pleural effusion (none vs four [5·6%]). 38 of 73 patients (52·1%) in the TG4010 plus chemotherapy group and 34 of 72 (47·2%) in the chemotherapy alone group had at least one serious adverse event. INTERPRETATION: This phase 2B study suggests that TG4010 enhances the effect of chemotherapy in advanced NSCLC. A confirmatory phase 2B-3 trial has been initiated. FUNDING: Transgene SA, Advanced Diagnostics for New Therapeutic Approaches (ADNA)/OSEO.

Geometrical influence on the non-biomimetic heterolytic splitting of H2 by bio-inspired [FeFe]-hydrogenase complexes: a rare example of inverted frustrated Lewis pair based reactivity.

Despite the high levels of interest in the synthesis of bio-inspired [FeFe]-hydrogenase complexes, H2 oxidation, which is one specific aspect of hydrogenase enzymatic activity, is not observed for most reported complexes. To attempt H-H bond cleavage, two disubstituted diiron dithiolate complexes in the form of [Fe2(µ-pdt)L2(CO)4] (L: PMe3, dmpe) have been used to play the non-biomimetic role of a Lewis base, with frustrated Lewis pairs (FLPs) formed in the presence of B(C6F5)3 Lewis acid. These unprecedented FLPs, based on the bimetallic Lewis base partner, allow the heterolytic splitting of the H2 molecule, forming a protonated diiron cation and hydrido-borate anion. The substitution, symmetrical or asymmetrical, of two phosphine ligands at the diiron dithiolate core induces a strong difference in the H2 bond cleavage abilities, with the FLP based on the first complex being more efficient than the second. DFT investigations examined the different mechanistic pathways involving each accessible isomer and rationalized the experimental findings. One of the main DFT results highlights that the iron site acting as a Lewis base for the asymmetrical complex is the {Fe(CO)3} subunit, which is less electron-rich than the {FeL(CO)2} site of the symmetrical complex, diminishing the reactivity towards H2. Calculations relating to the different mechanistic pathways revealed the presence of a terminal hydride intermediate at the apical site of a rotated {Fe(CO)3} site, which is experimentally observed, and a semi-bridging hydride intermediate from H2 activation at the Fe-Fe site; these are responsible for a favourable back-reaction, reducing the conversion yield observed in the case of the asymmetrical complex. The use of two equivalents of Lewis acid allows for more complete and faster H2 bond cleavage due to the encapsulation of the hydrido-borate species by a second borane, favouring the reactivity of each FLP, in agreement with DFT calculations.

A rapid multiplex cell-free assay on biochip to evaluate functional aspects of double-strand break repair.

The repair of DNA double-strand breaks (DSBs) involves interdependent molecular pathways, of which the choice is crucial for a cell's fate when facing a damage. Growing evidence points toward the fact that DSB repair capacities correlate with disease aggressiveness, treatment response and treatment-related toxicities in cancer. Scientific and medical communities need more easy-to-use and efficient tools to rapidly estimate DSB repair capacities from a tissue, enable routine-accessible treatment personalization, and hopefully, improve survival. Here, we propose a new functional biochip assay (NEXT-SPOT) that characterizes DSB repair-engaged cellular pathways and provides qualitative and quantitative information on the contribution of several pathways in less than 2 h, from 10 mg of cell lysates. We introduce the NEXT-SPOT technology, detail the molecular characterizations of different repair steps occurring on the biochip, and show examples of DSB repair profiling using three cancer cell lines treated or not with a DSB-inducer (doxorubicin) and/or a DNA repair inhibitor (RAD51 inhibitor; DNA-PK inhibitor; PARP inhibitor). Among others, we demonstrate that NEXT-SPOT can accurately detect decreased activities in strand invasion and end-joining mechanisms following DNA-PK or RAD51 inhibition in DNA-PK-proficient cell lines. This approach offers an all-in-one reliable strategy to consider DSB repair capacities as predictive biomarkers easily translatable to the clinic.

Development and Initial Validation of the Disruptive Mood Dysregulation Disorder Questionnaire Among Adolescents From Clinic Settings.

OBJECTIVES: Disruptive mood dysregulation disorder (DMDD) is a new DSM-5 diagnosis. It is observed in youths and is characterized by chronic irritability and temper outbursts. This study aimed (i) to develop a brief questionnaire administered during a semi-structured interview and (ii) to assess its psychometric properties with adolescents 12-15 years old by estimating its internal consistency and its concurrent association with measures of depressive symptoms and borderline personality traits. METHODS: A 10-item questionnaire was developed based on the DSM-5 criteria and input from mental health professionals. The questionnaire was administered to 192 adolescents from youth centres, inpatient units and specialized outpatient clinics in Montreal, as were the Schedule for Affective Disorders and Schizophrenia for School-Aged Children (K-SADS-PL), the Abbreviated version of the Diagnostic Interview for Borderlines revised (Ab-DIB), and the Dominic Interactive for Adolescents-Revised (DIA-R). RESULTS: A DMDD Questionnaire among adolescents from clinic settings is obtained. The content of the instrument's items was initially developed based on DSM-5 criteria and expert judgment to ensure that this new instrument covered the theoretical concepts of DMDD in English and French. Twelve participants (6.3%) met nine or more criteria and 11 youths (5.7%) met the three main criteria of DMDD (A, C, and D), which suggested the likely presence of DMDD. The total Cronbach's alpha was 0.90. In addition, the DMDD Questionnaire was significantly associated with depressive symptoms and borderline personality traits. CONCLUSION: The reliability and concurrent validity indices suggest that the questionnaire as a decision-support tool may be used with adolescents in clinical settings. It highlights that the DSM-5 DMDD criteria seem associated with depressive symptoms and borderline personality traits. Finally, future studies will be necessary to establish more robust calculations in relation to the validity and reliability of this questionnaire.

TOX4 and its binding partners recognize DNA adducts generated by platinum anticancer drugs.

Platinating agents are commonly prescribed anticancer drugs damaging DNA. Induced lesions are recognized by a wide range of proteins. These are involved in cellular mechanisms such as DNA repair, mediation of cytotoxicity or chromatin remodeling. They therefore constitute crucial actors to understand pharmacology of these drugs. To expand our knowledge about this subproteome, we developed a ligand fishing trap coupled to high throughput proteomic tools. This trap is made of damaged plasmids attached to magnetic beads, and was exposed to cell nuclear extracts. Retained proteins were identified by nanoHPLC coupled to tandem mass spectrometry. This approach allowed us to establish a list of 38 proteins interacting with DNA adducts generated by cisplatin, oxaliplatin and satraplatin. Some of them were already known interactome members like high mobility group protein 1 (HMGB1) or the human upstream binding factor (hUBF), but we also succeeded in identifying unexpected proteins such as TOX HMG box family member 4 (TOX4), phosphatase 1 nuclear targeting subunit (PNUTS), and WD repeat-containing protein 82 (WDR82), members of a recently discovered complex. Interaction between TOX4 and platinated DNA was subsequently validated by surface plasmon resonance imaging (SPRi). These interactions highlight new cellular responses to DNA damage induced by chemotherapeutic agents.

Evaluation of DNA double-strand break repair capacity in human cells: Critical overview of current functional methods.

DNA double-strand breaks (DSBs) are highly deleterious lesions, responsible for mutagenesis, chromosomal translocation or cell death. DSB repair (DSBR) is therefore a critical part of the DNA damage response (DDR) to restore molecular and genomic integrity. In humans, this process is achieved through different pathways with various outcomes. The balance between DSB repair activities varies depending on cell types, tissues or individuals. Over the years, several methods have been developed to study variations in DSBR capacity. Here, we mainly focus on functional techniques, which provide dynamic information regarding global DSB repair proficiency or the activity of specific pathways. These methods rely on two kinds of approaches. Indirect techniques, such as pulse field gel electrophoresis (PFGE), the comet assay and immunofluorescence (IF), measure DSB repair capacity by quantifying the time-dependent decrease in DSB levels after exposure to a DNA-damaging agent. On the other hand, cell-free assays and reporter-based methods directly track the repair of an artificial DNA substrate. Each approach has intrinsic advantages and limitations and despite considerable efforts, there is currently no ideal method to quantify DSBR capacity. All techniques provide different information and can be regarded as complementary, but some studies report conflicting results. Parameters such as the type of biological material, the required equipment or the cost of analysis may also limit available options. Improving currently available methods measuring DSBR capacity would be a major step forward and we present direct applications in mechanistic studies, drug development, human biomonitoring and personalized medicine, where DSBR analysis may improve the identification of patients eligible for chemo- and radiotherapy.