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There has been extensive activity exploring the doping of semiconducting two-dimensional (2D) transition metal dichalcogenides in order to tune their electronic and magnetic properties. The outcome of doping depends on various factors, including the intrinsic properties of the host material, the nature of the dopants used, their spatial distribution, as well as their interactions with other types of defects. A thorough atomic-level analysis is essential to fully understand these mechanisms. In this work, the vanadium-doped WSe 2 monolayer grown by molecular beam epitaxy is investigated using four-dimensional scanning transmission electron microscopy (4D-STEM). Through center-of-mass-based reconstruction, atomic-scale maps are produced, allowing the visualization of both the electric field and the electrostatic potential around individual V atoms. To provide quantitative insights, these results are successfully compared to multislice image simulations based on ab initio calculations, accounting for lens aberrations. Finally, a negative charge around the V dopants is detected as a drop in the electrostatic potential, unambiguously demonstrating that 4D-STEM can be used to detect and to accurately analyze single-dopant charge states in semiconducting 2D materials.

Background: Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disorder due to an autosomal recessive mutation in the survival motor neuron 1 gene (SMN1), causing degeneration of the anterior horn cells of the spinal cord and resulting in muscle atrophy. This study aimed to report on the 36-month follow-up of children with SMA treated with nusinersen before the age of 3 years. Changes in motor function, nutritional and ventilatory support, and orthopedic outcomes were evaluated at baseline and 36 months after intrathecal administration of nusinersen and correlated with SMA type and SMN2 copy number., Results: We found that 93% of the patients gained new motor skills during the 3 years-standing without help for 12 of 37 and walking with help for 11 of 37 patients harboring three SMN2 copies. No patients with two copies of SMN2 can stand alone or walk. Patients bearing three copies of SMN2 are more likely to be spared from respiratory, nutritional, and orthopedic complications than patients with two SMN2 copies., Conclusion: Children with SMA treated with nusinersen continue to make motor acquisitions at 3 years after initiation of treatment. Children with two SMN2 copies had worse motor, respiratory, and orthopedic outcomes after 3 years of treatment than children with three copies., Competing Interests: Declaration of Competing Interest JD, CV, MGGB, and UWL received funding as scientific advisory boards member from Biogen. VL, FA, JD, AI, MCN, JBD, CET, MGGB, and UWL received funding as scientific advisory boards member from Novartis. JD, CC, MGGB, and ID received funding as scientific advisory boards member from Roche. ID received funding as scientific advisory boards member from PTC therapeutics. CC, CET, and UWL received funding as scientific advisory boards member from Pfizer. VL, FA, CB, AI, JBD, CS, and ID received compensations for presentation from Novartis. FA, CB, JBD, CV, and CET received compensations for presentation from Biogen. CC received compensations for presentation from Roche. CS received compensations for presentation from PTC therapeutics and Sanofi Adventis. CC and ID received compensations for presentation from Pfizer. JBD is investigator for ongoing Roche clinical trials. MGGB is sub-investigator in SMA studies for Biogen, Novartis, and Roche. SMD, MC, and MB, declare that they have no competing interests., (Copyright © 2023. Published by Elsevier Masson SAS.)

We describe the case of a 32-year-old female who presented to the emergency department (ED) with a 3-day history of severe epigastric abdominal pain accompanied by nausea, vomiting, and constipation. Past medical history was significant for known right hydrosalpinx and previous pelvic inflammatory disease (PID), without past surgical history. Clinical examination revealed a hemodynamically stable patient with a soft but distended abdomen, tenderness in the epigastric region, without signs of peritonitis. Bloodwork including white blood cell count, electrolytes, and lactic acid was unremarkable. Initial computed tomography (CT) scan of the abdomen and pelvis with contrast demonstrated a small bowel obstruction (SBO) with a transition point in the right lower quadrant, accompanied by mesenteric edema and free fluid. Exploratory laparotomy was performed and revealed obstruction secondary to dense adhesions involving the terminal ileum, appendix, sigmoid colon, and right ovary. Lysis of adhesions, appendectomy, and excision of a right paratubal cyst were performed. Histopathology demonstrated endometriosis of the appendix and a benign paratubal cyst.

Pathogenic mutations in mitochondrial DNA (mtDNA) compromise cellular metabolism, contributing to cellular heterogeneity and disease. Diverse mutations are associated with diverse clinical phenotypes, suggesting distinct organ- and cell-type-specific metabolic vulnerabilities. Here we establish a multi-omics approach to quantify deletions in mtDNA alongside cell state features in single cells derived from six patients across the phenotypic spectrum of single large-scale mtDNA deletions (SLSMDs). By profiling 206,663 cells, we reveal the dynamics of pathogenic mtDNA deletion heteroplasmy consistent with purifying selection and distinct metabolic vulnerabilities across T-cell states in vivo and validate these observations in vitro. By extending analyses to hematopoietic and erythroid progenitors, we reveal mtDNA dynamics and cell-type-specific gene regulatory adaptations, demonstrating the context-dependence of perturbing mitochondrial genomic integrity. Collectively, we report pathogenic mtDNA heteroplasmy dynamics of individual blood and immune cells across lineages, demonstrating the power of single-cell multi-omics for revealing fundamental properties of mitochondrial genetics., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

We report on large spin-filtering effects in epitaxial graphene-based spin valves, strongly enhanced in our specific multilayer case. Our results were obtained by the effective association of chemical vapor deposited (CVD) multilayer graphene with a high quality epitaxial Ni(111) ferromagnetic spin source. We highlight that the Ni(111) spin source electrode crystallinity and metallic state are preserved and stabilized by multilayer graphene CVD growth. Complete nanometric spin valve junctions are fabricated using a local probe indentation process, and spin properties are extracted from the graphene-protected ferromagnetic electrode through the use of a reference Al 2 O 3 /Co spin analyzer. Strikingly, spin-transport measurements in these structures give rise to large negative tunnel magneto-resistance TMR = -160%, pointing to a particularly large spin polarization for the Ni(111)/Gr interface P Ni/Gr , evaluated up to -98%. We then discuss an emerging physical picture of graphene-ferromagnet systems, sustained both by experimental data and ab initio calculations, intimately combining efficient spin filtering effects arising (i) from the bulk band structure of the graphene layers purifying the extracted spin direction, (ii) from the hybridization effects modulating the amplitude of spin polarized scattering states over the first few graphene layers at the interface, and (iii) from the epitaxial interfacial matching of the graphene layers with the spin-polarized Ni surface selecting well-defined spin polarized channels. Importantly, these main spin selection effects are shown to be either cooperating or competing, explaining why our transport results were not observed before. Overall, this study unveils a path to harness the full potential of low Resitance.Area (RA) graphene interfaces in efficient spin-based devices.

Mitochondria are organelles with vital functions in almost all eukaryotic cells. Often described as the cellular 'powerhouses' due to their essential role in aerobic oxidative phosphorylation, mitochondria perform many other essential functions beyond energy production. As signaling organelles, mitochondria communicate with the nucleus and other organelles to help maintain cellular homeostasis, allow cellular adaptation to diverse stresses, and help steer cell fate decisions during development. Mitochondria have taken center stage in the research of normal and pathological processes, including normal tissue homeostasis and metabolism, neurodegeneration, immunity and infectious diseases. The central role that mitochondria assume within cells is evidenced by the broad impact of mitochondrial diseases, caused by defects in either mitochondrial or nuclear genes encoding for mitochondrial proteins, on different organ systems. In this Review, we will provide the reader with a foundation of the mitochondrial 'hardware', the mitochondrion itself, with its specific dynamics, quality control mechanisms and cross-organelle communication, including its roles as a driver of an innate immune response, all with a focus on development, disease and aging. We will further discuss how mitochondrial DNA is inherited, how its mutation affects cell and organismal fitness, and current therapeutic approaches for mitochondrial diseases in both model organisms and humans., Competing Interests: Competing interests L.I.Z. is a founder of and holds stock in Fate Therapeutics, Camp4 Therapeutics and Scholar Rock, and is a consultant to Celularity. All other authors declare no competing interests., (© 2021. Published by The Company of Biologists Ltd.)

We present a growth process relying on pulsed laser deposition for the elaboration of complex van der Waals heterostructures on large scales, at a 400 °C CMOS-compatible temperature. Illustratively, we define a multilayer quantum well geometry through successive in situ growths, leading to WSe 2 being encapsulated into WS 2 layers. The structural constitution of the quantum well geometry is confirmed by Raman spectroscopy combined with transmission electron microscopy. The large-scale high homogeneity of the resulting 2D van der Waals heterostructure is also validated by macro- and microscale Raman mappings. We illustrate the benefit of this integrative in situ approach by showing the structural preservation of even the most fragile 2D layers once encapsulated in a van der Waals heterostructure. Finally, we fabricate a vertical tunneling device based on these large-scale layers and discuss the clear signature of electronic transport controlled by the quantum well configuration with ab initio calculations in support. The flexibility of this direct growth approach, with multilayer stacks being built in a single run, allows for the definition of complex 2D heterostructures barely accessible with usual exfoliation or transfer techniques of 2D materials. Reminiscent of the III-V semiconductors' successful exploitation, our approach unlocks virtually infinite combinations of large 2D material families in any complex van der Waals heterostructure design.

Objective: The aims of our study were to describe the evolution of interstitial lung disease (ILD) extent on HRCT scan in systemic sclerosis (SSc), to identify baseline prognostic factors associated with ILD evolution and to assess whether the evolution of pulmonary function tests (PFTs) correlated with this evolution., Methods: 58 SSc with ILD (SSc-ILD) patients were included. All HRCT scans and PFTs available were collected. We modelized PFTs and HRCT scans evolution using linear mixed model with random effect., Results: Patients underwent a median number of 3 HRCT scans (total n = 203) and 5 PFTs (total n = 329), during a mean follow-up of 5.3 ± 4.9 years. Mean SSc duration was 2.5 ± 3.1 years at the diagnosis of ILD. Mean baseline ILD extent was 32.3 ± 28.7%. We found a significant mean progression of ILD extent on serial HRCT scans of 0.92 ± 0.36% per year (p = 0.018). Male sex, diffuse cutaneous SSc (dcSSc), presence of anti-topoisomerase 1 antibodies, a higher DLCO, limited ILD and a low coarseness score at baseline in bivariate analysis, and presence of antitopoisomerase 1 antibodies and a coarseness score of 0 in multivariate analysis, were associated with faster progression of ILD extent over time There was a significant correlation between the progression of ILD extent and the decline of DLCO but only a trend for FVC. ILD extent at baseline and during follow-up was associated with survival., Conclusion: Male sex, dcSSc, anti-topoisomerase 1 antibodies and a less severe ILD at baseline were associated with a faster progression of ILD over time. Evolution of DLCO significantly correlated with change in ILD extent on HRCT scan. Our study helps defining the profile of patients at risk of experiencing a progression of ILD on HRCT scans., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We report on spin transport in state-of-the-art epitaxial monolayer graphene based 2D-magnetic tunnel junctions (2D-MTJs). In our measurements, supported by ab-initio calculations, the strength of interaction between ferromagnetic electrodes and graphene monolayers is shown to fundamentally control the resulting spin signal. In particular, by switching the graphene/ferromagnet interaction, spin transport reveals magneto-resistance signal MR > 80% in junctions with low resistance × area products. Descriptions based only on a simple K-point filtering picture (i.e. MR increase with the number of layers) are not sufficient to predict the behavior of our devices. We emphasize that hybridization effects need to be taken into account to fully grasp the spin properties (such as spin dependent density of states) when 2D materials are used as ultimately thin interfaces. While this is only a first demonstration, we thus introduce the fruitful potential of spin manipulation by proximity effect at the hybridized 2D material / ferromagnet interface for 2D-MTJs.

We present an overview of the onetep program for linear-scaling density functional theory (DFT) calculations with large basis set (plane-wave) accuracy on parallel computers. The DFT energy is computed from the density matrix, which is constructed from spatially localized orbitals we call Non-orthogonal Generalized Wannier Functions (NGWFs), expressed in terms of periodic sinc (psinc) functions. During the calculation, both the density matrix and the NGWFs are optimized with localization constraints. By taking advantage of localization, onetep is able to perform calculations including thousands of atoms with computational effort, which scales linearly with the number or atoms. The code has a large and diverse range of capabilities, explored in this paper, including different boundary conditions, various exchange-correlation functionals (with and without exact exchange), finite electronic temperature methods for metallic systems, methods for strongly correlated systems, molecular dynamics, vibrational calculations, time-dependent DFT, electronic transport, core loss spectroscopy, implicit solvation, quantum mechanical (QM)/molecular mechanical and QM-in-QM embedding, density of states calculations, distributed multipole analysis, and methods for partitioning charges and interactions between fragments. Calculations with onetep provide unique insights into large and complex systems that require an accurate atomic-level description, ranging from biomolecular to chemical, to materials, and to physical problems, as we show with a small selection of illustrative examples. onetep has always aimed to be at the cutting edge of method and software developments, and it serves as a platform for developing new methods of electronic structure simulation. We therefore conclude by describing some of the challenges and directions for its future developments and applications.

We report on spin transport in WS 2 -based 2D-magnetic tunnel junctions (2D-MTJs), unveiling a band structure spin filtering effect specific to the transition metal dichalcogenides (TMDCs) family. WS 2 mono-, bi-, and trilayers are derived by a chemical vapor deposition process and further characterized by Raman spectroscopy, atomic force microscopy (AFM), and photoluminescence spectroscopy. The WS 2 layers are then integrated in complete Co/Al 2 O 3 /WS 2 /Co MTJ hybrid spin-valve structures. We make use of a tunnel Co/Al 2 O 3 spin analyzer to probe the extracted spin-polarized current from the WS 2 /Co interface and its evolution as a function of WS 2 layer thicknesses. For monolayer WS 2 , our technological approach enables the extraction of the largest spin signal reported for a TMDC-based spin valve, corresponding to a spin polarization of P Co/WS 2 = 12%. Interestingly, for bi- and trilayer WS 2 , the spin signal is reversed, which indicates a switch in the mechanism of interfacial spin extraction. With the support of ab initio calculations, we propose a model to address the experimentally measured inversion of the spin polarization based on the change in the WS 2 band structure while going from monolayer (direct bandgap) to bilayer (indirect bandgap). These experiments illustrate the rich potential of the families of semiconducting 2D materials for the control of spin currents in 2D-MTJs.

Graphene grown by chemical vapor deposition (CVD) is the most promising material for industrial-scale applications based on graphene monolayers. It also holds promise for spintronics; despite being polycrystalline, spin transport in CVD graphene has been measured over lengths up to 30 μm, which is on par with the best measurements made in single-crystal graphene. These results suggest that grain boundaries (GBs) in CVD graphene, while impeding charge transport, may have little effect on spin transport. However, to date very little is known about the true impact of disordered networks of GBs on spin relaxation. Here, by using first-principles simulations, we derive an effective tight-binding model of graphene GBs in the presence of spin-orbit coupling (SOC), which we then use to evaluate spin transport in realistic morphologies of polycrystalline graphene. The spin diffusion length is found to be independent of the grain size, and it is determined only by the strength of the substrate-induced SOC. This result is consistent with the D'yakonov-Perel' mechanism of spin relaxation in the diffusive regime, but we find that it also holds in the presence of quantum interference. These results clarify the role played by GBs and demonstrate that the average grain size does not dictate the upper limit for spin transport in CVD-grown graphene, a result of fundamental importance for optimizing large-scale graphene-based spintronic devices.

We report on the integration of atomically thin 2D insulating hexagonal boron nitride (h-BN) tunnel barriers into magnetic tunnel junctions (2D-MTJs) by fabricating two illustrative systems (Co/h-BN/Co and Co/h-BN/Fe) and by discussing h-BN potential for metallic spin filtering. The h-BN is directly grown by chemical vapor deposition on prepatterned Co and Fe stripes. Spin-transport measurements reveal tunnel magneto-resistances in these h-BN-based MTJs as high as 12% for Co/h-BN/h-BN/Co and 50% for Co/h-BN/Fe. We analyze the spin polarizations of h-BN/Co and h-BN/Fe interfaces extracted from experimental spin signals in light of spin filtering at hybrid chemisorbed/physisorbed h-BN, with support of ab initio calculations. These experiments illustrate the strong potential of h-BN for MTJs and are expected to ignite further investigations of 2D materials for large signal spin devices.

Objective: Studies of early-onset systemic lupus erythematosus (SLE) have identified monogenic forms of the disease. The primary objective of this study was to compare the clinical and laboratory features of the first patients included in the GENIAL/LUMUGENE cohort to those reported in previous publications. The secondary objective was to determine whether subgroups with a distinctive pattern of clinical and biological features are seen in predominantly genetic forms of SLE., Methods: GENIAL/LUMUGENE is a French nationwide study of the clinical, immunological, and genetic features of juvenile-onset SLE (clinicaltrials.gov #NCT01992666). Clinical and laboratory data from the first 64 patients younger than 18 years who were included in the first part of the study were collected retrospectively. Predefined criteria were used to divide the patients into three subgroups: syndromic SLE (n=10) and familial SLE (n=12) - both presumed to have a strong genetic component - and other forms of early-onset SLE (n=42)., Results: The predefined criteria for identifying subgroups based on knowledge of the clinical and epidemiological features of monogenic SLE showed a significantly younger age at onset in syndromic SLE (P<0.05) and a lower frequency of joint manifestations in familial SLE., Conclusions: In this study, clinical and epidemiological data alone failed to identify a specific patient subgroup characterized by the same disease presentation or progression. This result may be related to the small sample size or indicate marked heterogeneity of juvenile-onset SLE. Genetic studies using new sequencing techniques in these patients might identify genetic factors responsible for marked phenotypic variability., (Copyright © 2016. Published by Elsevier SAS.)

Mutations in mtDNA lead to muscular and neurological diseases and are linked to aging. The most frequent aberrancy is the "common deletion" that involves a 4,977-bp region flanked by 13-bp repeats. To investigate the basis of this deletion, we developed a single-molecule mtDNA combing method. The analysis of replicating mtDNA molecules provided in vivo evidence in support of the asymmetric mode of replication. Furthermore, we observed frequent fork stalling at the junction of the common deletion, suggesting that impaired replication triggers the formation of this toxic lesion. In parallel experiments, we employed mito-TALENs to induce breaks in distinct loci of the mitochondrial genome and found that breaks adjacent to the 5' repeat trigger the common deletion. Interestingly, this process was mediated by the mitochondrial replisome independent of canonical DSB repair. Altogether, our data underscore a unique replication-dependent repair pathway that leads to the mitochondrial common deletion., (Copyright © 2017 Elsevier Inc. All rights reserved.)

HTLV-1 creates a chronic health condition that involves moderate to severe pain with a negative impact on quality of life (QoL). There is no consensus on which attitudes to pain are more related to the worsening of QoL in HTLV-1 infected patients. The aim of this study was to investigate the correlation between QoL and multidimensional aspects of pain in patients with HTLV-1. A cross-sectional study was conducted in Salvador, Bahia, Brazil. The study included individuals diagnosed with HTLV-1. The Short Form 36 Questionnaire was used to analyze QoL, and the Brief Pain Inventory was used to assess multidimensional aspects of pain. The mean pain intensity was 4.88±3.06 on the visual pain scale, and the average impact on QoL corresponded to a loss of approximately 40%. Moderate to high correlations between pain intensity and all domains of QoL were observed and compared reaction attitudes for general activity, mood, ability to walk, ability to work, relationships, sleep, and ability to enjoy life (r>0.40; p<0.05). Moderate correlations were found between all domains of QoL, pain intensity, and reactive attitudes to pain. The greatest pain intensity impacts involved difficulty to walk and to work, and interpersonal relationships in the emotional aspect of QoL., (Copyright © 2016 Sociedade Brasileira de Infectologia. Published by Elsevier Editora Ltda. All rights reserved.)

Density functional theory molecular dynamics (DFT-MD) provides an efficient framework for accurately computing several types of spectra. The major benefit of DFT-MD approaches lies in the ability to naturally take into account the effects of temperature and anharmonicity, without having to introduce any ad hoc or a posteriori corrections. Consequently, computational spectroscopy based on DFT-MD approaches plays a pivotal role in the understanding and assignment of experimental peaks and bands at finite temperature, particularly in the case of floppy molecules. Linear-scaling DFT methods can be used to study large and complex systems, such as peptides, DNA strands, amorphous solids, and molecules in solution. Here, we present the implementation of DFT-MD IR spectroscopy in the ONETEP linear-scaling code. In addition, two methods for partitioning the dipole moment within the ONETEP framework are presented. Dipole moment partitioning allows us to compute spectra of molecules in solution, which fully include the effects of the solvent, while at the same time removing the solvent contribution from the spectra.

CONSPECTUS: Graphene-related nanostructures stand out as exceptional materials due to both their wide range of properties and their expanse of interest in both applied and fundamental research. They are good examples of nanoscale materials for which the properties do not necessarily replicate those of the bulk. For the description and the understanding of their properties, it is clear that a general quantum-mechanical approach is mandatory. The remarkable result of density functional theory (DFT) is that the quantum-mechanical description of materials at the ground state is made amenable to simulations at a relatively low computational cost. The knowledge of materials has undergone a revolution after the introduction of DFT as an unrivaled instrument for the investigation of materials properties through computer experiments. Their deeper understanding comes from a variety of tools developed from concepts intrinsically present in DFT, notably the total energy and the charge density. Such tools allow the prediction of a diverse set of physicochemical properties relevant for material scientists. This Account lays out an example-driven tour through the achievements of ground-state DFT applied to the description of graphene-related nanostructures and to the deep understanding of their outstanding properties. After a brief introduction to DFT, the survey starts with the determination of the most basic properties that can be obtained from DFT, that is, band structures, lattice parameters, and spin ground state. Next follows an exploration of how total energies of different systems can give information about relative stability, formation energies, and reaction paths. Exploiting the derivatives of the energy with respect to displacements leads the way toward the extraction of vibrational and mechanical properties. In addition, a close examination of the charge density gives information about charge transfer mechanisms, which can be linked to chemical reactivity. The ground state density and Hamiltonian finally connect to the concepts behind transport phenomena, which drive much of the application-oriented research on graphene and graphene-related nanostructures. In each section, a selection of cases that are of current importance are used to illustrate the use and relevance of DFT-based techniques. In summary, this Account presents an introductory landscape of the possibilities of ground-state DFT for the study of graphene-related nanostructures. The prospect is rich, and the use of DFT for the study of graphene-related nanostructures will continue to be fruitful for the advancement of these and other materials.

Background: The interleukin-8 chemokine (IL-8) G-protein coupled receptor CXCR2 governs pro-inflammatory and pro-angiogenic responses in leukocytes and endothelial cells. At a molecular standpoint, CXCR2 is widely reported to operate through calcium flux, phosphoinoisitide 3 kinase (PI3K) and mitogen-activated protein kinase (MAPK). While CXCR2 trafficking is suspected to be intertwined with its signaling, the exact mechanism is not fully elucidated., Results: Here, we identified the lysine 327 within the CXCR2 C-terminal tail as a key residue for ubiquitination, internalization, and signaling. First, the substitution to an arginine of K327 mutation was associated with a reduction in CXCR2 poly-ubiquitination. While WT CXCR2 was rapidly internalized following IL-8 administration, K327R mutant remained at the plasma membrane. Finally, K327R mutant failed to promote the recruitment of β-arrestin2, as estimated by imagery and bioluminescence resonance transfer. As a consequence, the activation of intracellular signaling, including both early events such as ERK phosphorylation and the increase in calcium flux, and the latter activation of the AP1 and NF-κB transcription factors, was blunted., Conclusions: Overall, our results demonstrate that CXCR2 ubiquitination on K327 residue modulates agonist-activated CXCR2 cell sorting and intracellular signaling. Thus, the inhibition of K327 ubiquitination might emerge as an effective mean to curb exacerbated CXCR2 signaling in several pathological conditions, such as inflammatory diseases and cancer.

Antigen receptor-mediated nuclear factor κB (NF-κB) activation relies on the formation of a large multi-protein complex that contains CARMA1, BCL10, and MALT1 (CBM complex). This signalosome is pirated in the activated B-cell-like subgroup of diffuse large B-cell lymphoma (ABC DLBCL) to drive aberrant NF-κB activation, thereby promoting cell survival and propagation. Using an unbiased proteomic approach, we screened for additional components of the CBM in lymphocytes. We found that the linear ubiquitin chain assembly complex (LUBAC), which was previously linked to cytokine-mediated NF-κB activation, dynamically integrates the CBM and marshals NF-κB optimal activation following antigen receptor ligation independently of its catalytic activity. The LUBAC also participates in preassembled CBM complex in cells derived from ABC DLBCL. Silencing the LUBAC reduced NF-κB activation and was toxic in ABC DLBCL cell lines. Thus, our findings reveal a role for the LUBAC during lymphocyte activation and in B-cell malignancy.

The innate and adaptive immune responses involve the stimulation of nuclear factor κB (NF-κB) transcription factors through the Lys(63) (K(63))-linked ubiquitylation of specific components of NF-κB signaling pathways. We found that ubiquitylated components of the NF-κB pathway accumulated on the cytosolic leaflet of the endoplasmic reticulum (ER) membrane after the engagement of cell-surface, proinflammatory cytokine receptors or antigen receptors. Through mass spectrometric analysis, we found that the ER-anchored protein metadherin (MTDH) was a partner for these ubiquitylated activators of NF-κB and that it directly bound to K(63)-linked polyubiquitin chains. Knockdown of MTDH inhibited the accumulation of ubiquitylated NF-κB signaling components at the ER, reduced the extent of NF-κB activation, and decreased the amount of proinflammatory cytokines produced. Our observations highlight an unexpected facet of the ER as a key subcellular gateway for NF-κB activation.

Advances in the realization of hybrid graphene/h-BN materials open new ways to control the electronic properties of graphene nanostructures. In this paper, the structural, electronic, and transport properties of heterojunctions made of bare zigzag-shaped h-BN and graphene ribbons are investigated using first-principles techniques. Our results highlight the potential of graphene/h-BN junctions for applications in spintronic devices. At first, density functional theory is used to detail the role played by the edge states and dangling bonds in the electronic and magnetic behavior of h-BN and graphene ribbons. Then, the electronic conductance of the junction is computed in the framework of Green's function-based scattering theory. In its high-spin configuration, the junction reveals a full spin polarization of the propagating carriers around the Fermi energy, and the magnitude of the transmission probability is predicted to be strongly dependent on the relative orientation of magnetic momenta in the leads.

Background: NF-κB is a master gene regulator involved in plethora of biological processes, including lymphocyte activation and proliferation. Reversible ubiquitinylation of key adaptors is required to convey the optimal activation of NF-κB. However the deubiquitinylases (DUBs), which catalyze the removal of these post-translational modifications and participate to reset the system to basal level following T-Cell receptor (TCR) engagement continue to be elucidated., Findings: Here, we performed an unbiased siRNA library screen targeting the DUBs encoded by the human genome to uncover new regulators of TCR-mediated NF-κB activation. We present evidence that knockdown of Ubiquitin-Specific Protease 34 (USP34) selectively enhanced NF-κB activation driven by TCR engagement, similarly to siRNA against the well-characterized DUB cylindromatosis (CYLD). From a molecular standpoint, USP34 silencing spared upstream signaling but led to a more pronounced degradation of the NF-κB inhibitor IκBα, and culminated with an increased DNA binding activity of the transcription factor., Conclusions: Collectively, our data unveils USP34 as a new player involved in the fine-tuning of NF-κB upon TCR stimulation.

Quantum transport properties of disordered graphene with structural defects (Stone-Wales and divacancies) are investigated using a realistic π-π* tight-binding model elaborated from ab initio calculations. Mean free paths and semiclassical conductivities are then computed as a function of the nature and density of defects (using an order-N real-space Kubo-Greenwood method). By increasing the defect density, the decay of the semiclassical conductivities is predicted to saturate to a minimum value of 4e2/πh over a large range (plateau) of carrier density (>0.5×10(14)  cm(-20). Additionally, strong contributions of quantum interferences suggest that the Anderson localization regime could be experimentally measurable for a defect density as low as 1%.

We present first-principles transport calculations of graphene nanoribbons with chemically reconstructed edge profiles. Depending on the geometry of the defect and the degree of hydrogenation, spectacularly different transport mechanisms are obtained. In the case of monohydrogenated pentagon (heptagon) defects, an effective acceptor (donor) character results in strong electron-hole conductance asymmetry. In contrast, weak backscattering is obtained for defects that preserve the benzenoid structure of graphene. Based on a tight-binding model derived from ab initio calculations, evidence for large conductance scaling fluctuations are found in disordered ribbons with lengths up to the micrometer scale.