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Inducing a magnetic gap at the Dirac point of the topological surface state (TSS) in a 3D topological insulator (TI) is a route to dissipationless charge and spin currents. Ideally, magnetic order is present only at the surface and not in the bulk, e.g. through proximity of a ferromagnetic (FM) layer. However, such a proximity-induced Dirac mass gap has not been observed, likely due to insufficient overlap of TSS and the FM subsystem. Here, we take a different approach, namely FM extension, using a thin film of the 3D TI Bi\\(_2\\)Te\\(_3\\), interfaced with a monolayer of the lattice-matched van der Waals ferromagnet MnBi\\(_2\\)Te\\(_4\\). Robust 2D ferromagnetism with out-of-plane anisotropy and a critical temperature of \\(\\text{T}_\\text{c}\\approx\\)~15 K is demonstrated by X-ray magnetic dichroism and electrical transport measurements. Using angle-resolved photoelectron spectroscopy, we observe the opening of a sizable magnetic gap in the 2D FM phase, while the surface remains gapless in the paramagnetic phase above T\\(_c\\). This sizable gap indicates a relocation of the TSS to the FM ordered Mn moments near the surface, which leads to a large mutual overlap.

Using angle-resolved photoelectron spectroscopy (ARPES), we investigate the surface electronic structure of the magnetic van der Waals compounds MnBi\\(_4\\)Te\\(_7\\) and MnBi\\(_6\\)Te\\(_{10}\\), the \\(n=\\)~1 and 2 members of a modular (Bi\\(_2\\)Te\\(_3\\))\\(_n\\)(MnBi\\(_2\\)Te\\(_4\\)) series, which have attracted recent interest as intrinsic magnetic topological insulators. Combining circular dichroic, spin-resolved and photon-energy-dependent ARPES measurements with calculations based on density functional theory, we unveil complex momentum-dependent orbital and spin textures in the surface electronic structure and disentangle topological from trivial surface bands. We find that the Dirac-cone dispersion of the topologial surface state is strongly perturbed by hybridization with valence-band states for Bi\\(_2\\)Te\\(_3\\)-terminated surfaces but remains preserved for MnBi\\(_2\\)Te\\(_4\\)-terminated surfaces. Our results firmly establish the topologically non-trivial nature of these magnetic van der Waals materials and indicate that the possibility of realizing a quantized anomalous Hall conductivity depends on surface termination.

The layered van der Waals antiferromagnet MnBi\\(_2\\)Te\\(_4\\) has been predicted to combine the band ordering of archetypical topological insulators such as Bi\\(_2\\)Te\\(_3\\) with the magnetism of Mn, making this material a viable candidate for the realization of various magnetic topological states. We have systematically investigated the surface electronic structure of MnBi\\(_2\\)Te\\(_4\\)(0001) single crystals by use of spin- and angle-resolved photoelectron spectroscopy experiments. In line with theoretical predictions, the results reveal a surface state in the bulk band gap and they provide evidence for the influence of exchange interaction and spin-orbit coupling on the surface electronic structure.

Invasions of alien plants are typically studied as invasions of individual species, yet interactions between plants and symbiotic fungi (mutualists and potential pathogens) affect plant survival, physiological traits, and reproduction and hence invasion success. Studies show that plant–fungal associations are frequently key drivers of plant invasion success and impact, but clear conceptual frameworks and integration across studies are needed to move beyond a series of case studies towards a more predictive understanding. Here, we consider linked plant–fungal invasions from the perspective of plant and fungal origin, simplified to the least complex representations or ‘motifs’. By characterizing these interaction motifs, parallels in invasion processes between pathogen and mutualist fungi become clear, although the outcomes are often opposite in effect. These interaction motifs provide hypotheses for fungal-driven dynamics behind observed plant invasion trajectories. In some situations, the effects of plant–fungal interactions are inconsistent or negligible. Variability in when and where different interaction motifs matter may be driven by specificity in the plant–fungal interaction, the size of the effect of the symbiosis (negative to positive) on plants and the dependence (obligate to facultative) of the plant−fungal interaction. Linked plant–fungal invasions can transform communities and ecosystem function, with potential for persistent legacies preventing ecosystem restoration.

As part of efforts to reduce pressure on the Amazon and other biomes, one approach considered by Brazilian authorities and scientists is more intensive use of the soils of the interior of the northeast of the country, which are generally sandy, with low contents of organic matter and low water holding capacity and are frequently affected by severe droughts. In this work, biochars produced from waste biomasses were tested for the improvement of these soils. The highest BET (Brunauer-Emmett-Teller) specific surface areas were observed for all biochars. In the pH range studied, the water hyacinth plants (WH) sample showed the most negative zeta potentials, as well as the highest water holding capacity (WHC) values, while the zeta potentials of two quartzarenic neosol soils were consistent with their WHC values. The results suggested that despite the effect of porosity on water retention, the zeta potential could be associated with the presence of negative charges by which hydrated cationic counterions were absorbed and retained. The surface energy and its polar and dispersive components were associated with water retention, with sugar cane bagasse, orange peel, and water hyacinth biochars presenting higher SE values and larger polar components.

The transcriptional scaffolds C-terminal Binding Proteins (CtBP) 1 and 2 are overexpressed and act as oncogenic dependencies in multiple cancers but importantly encode a chemically targetable dehydrogenase domain. CtBP promotes survival of high grade serous ovarian carcinoma (HGSOC) cells by repressing expression of Death Receptors (DR) 4 and 5, which activate caspase 8-dependent apoptosis. We have previously developed a series of substrate competitive CtBP dehydrogenase inhibitors active in multiple cell and preclinical solid tumor models. In the current study, we validated CtBP1 and 2 overexpression in a longitudinal series of primary and metastatic/recurrent HGSOC cases. Our lead CtBP dehydrogenase inhibitor, JW-98, induced apoptosis and exhibited variable single agent IC 50 values in HGSOC cell lines. Importantly, depletion of nicotinamide adenine dinucleotide (NAD) species using the NAD synthesis inhibitor GMX1778 strikingly sensitized HGSOC cells to JW-98 treatment. Mechanistically, the JW-98/GMX1778 combination effectively abrogated CtBP dimerization that requires stoichiometric levels of intracellular NAD and is required for CtBP’s oncogenic transcriptional activities. Highlighting translational potential in late-stage HGSOC, combined JW-98/GMX1778 treatment of platinum-resistant OVCAR3 HGSOC mouse xenografts abrogated tumor growth without observable toxicity. Combined inhibition of CtBP and NAD synthesis represents a novel therapeutic strategy that could improve outcomes in chemoresistant HGSOC.

Current therapeutic strategies for Parkinson’s disease (PD) aim to delay progression or replace damaged neurons by restoring the original neuronal structures. The poor regenerative capacity of neural tissue highlights the need for the development of cellular environments to model the pathogenesis of PD. In the current work, we have characterised the growth, survival and response to PD mimetics of human SH-SY5Y neuroblastoma and U-87MG glioblastoma cell lines cultured on polyacrylonitrile (PAN) and Jeffamine® doped polyacrylonitrile (PJ) nano-scaffolds. Differentiation induced by a range of agents was evaluated by immunoassays of neural protein biomarkers. PAN and PJ nanofibre scaffolds provided suitable three-dimensional (3D) environment to support the growth, differentiation and network formation of dopaminergic neuron- and astrocyte-like cell populations, respectively. The scaffolds selectively supported the survival and differentiation of both cell populations with prolonged neuronal survival when exposed to PD mimetics in the presence of astrocytes in a co-culture model. Such 3D nanoscaffold-based assays could aid our understanding of the molecular basis of PD mimetic-induced Parkinsonism and the discovery of neuroprotective agents.

Responses of the insular cortex (IC) and amygdala to stimuli of positive and negative valence are altered in patients with anxiety disorders. However, neural coding of both anxiety and valence by IC neurons remains unknown. Using fiber photometry recordings in mice, we uncover a selective increase of activity in IC projection neurons of the anterior (aIC), but not posterior (pIC) section, when animals are exploring anxiogenic spaces, and this activity is proportional to the level of anxiety of mice. Neurons in aIC also respond to stimuli of positive and negative valence, and the strength of response to strong negative stimuli is proportional to mice levels of anxiety. Using ex vivo electrophysiology, we characterized the IC connection to the basolateral amygdala (BLA), and employed projection-specific optogenetics to reveal anxiogenic properties of aIC-BLA neurons. Finally, we identified that aIC-BLA neurons are activated in anxiogenic spaces, as well as in response to aversive stimuli, and that both activities are positively correlated. Altogether, we identified a common neurobiological substrate linking negative valence with anxiety-related information and behaviors, which provides a starting point to understand how alterations of these neural populations contribute to psychiatric disorders. The existence of a common substrate for emotional valence and anxiety remained elusive. Here we show that excitatory neurons of the anterior insular cortex (aIC), including neurons projecting to the basolateral amygdala (aIC-BLA) encode both states.

Diet-induced obesity reduces dopaminergic neurotransmission in the nucleus accumbens (NAc), and stressful weight loss interventions could promote cravings for palatable foods high in fat and sugar that stimulate dopamine. Activation of κ-opioid receptors (KORs) reduces synaptic dopamine, but contribution of KORs to lower dopamine tone after dietary changes is unknown. Therefore, the purpose of this study was to determine the function of KORs in C57BL/6 mice that consumed a 60% high-fat diet (HFD) for six weeks followed by replacement of HFD with a control 10% fat diet for one day or one week. HFD replacement induced voluntary caloric restriction and weight loss. However, fast-scan cyclic voltammetry revealed no differences in baseline dopamine parameters, whereas sex effects were revealed during KOR stimulation. NAc core dopamine release was reduced by KOR agonism after one day of HFD replacement in females but after one week of HFD replacement in males. Further, elevated plus-maze testing revealed no diet effects during HFD replacement on overt anxiety. These results suggest that KORs reduce NAc dopamine tone and increase food-related anxiety during dietary weight loss interventions that could subsequently promote palatable food cravings and inhibit weight loss.

VM202 is a plasmid DNA encoding two isoforms of hepatocyte growth factor (HGF). A previous phase II study in subjects with painful diabetic peripheral neuropathy (DPN) showed significant reductions in pain. A phase III study was conducted to evaluate the safety and efficacy of VM202 in DPN. The trial was conducted in two parts, one for 9 months (DPN 3‐1) with 500 subjects (VM202: 336 subjects; and placebo: 164) and a preplanned subset of 101 subjects (VM202: 65 subjects; and placebo: 36) with a noninterventional extension to 12 months (DPN 3‐1b). VM202 or placebo was administered to calf muscles on days 0 and 14, and on days 90 and 104. The primary end point in DPN 3‐1 was change from baseline in the mean 24‐h Numerical Rating Scale (NRS) pain score. In DPN 3‐1b, the primary end point was safety, whereas the secondary efficacy end point was change in the mean pain score. VM202 was well‐tolerated in both studies without significant adverse events. VM202 failed to meet its efficacy end points in DPN 3‐1. In DPN 3‐1b, however, VM202 showed significant and clinically meaningful pain reduction versus placebo. Pain reduction in DPN 3‐1b was even greater in subjects not receiving gabapentin or pregabalin, confirming an observation noted in the phase II study. In DPN 3‐1b, symptomatic relief was maintained for 8 months after the last injection suggesting that VM202 treatment might change disease progression. Despite the perplexing discrepancy between the two studies, the safety and long‐lasting pain‐relieving effects of VM202 observed in DPN 3‐1b warrant another rigorous phase III study. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Current therapies for painful diabetic peripheral neuropathy (DPN) are palliative and do not target the underlying mechanisms. Moreover, symptomatic relief is often limited with existing neuropathic pain drugs. Thus, there is a great medical need for safer and effective treatments for DPN. WHAT QUESTION DID THIS STUDY ADDRESS? Can nonviral gene delivery of hepatocyte growth factor reduce pain in patients with DPN and potentially modify progression of the disorder? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Nonviral gene therapy can be used safely and practically to treat DPN. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? As the first gene medicine to enter advanced clinical trials for the treatment of DPN, this study provides the proof of concept of an entirely new potential approach to the disorder.