Neuroligin-3 interaction with CSPG4 regulates normal and malignant glial precursors through PIEZO1.

Glioma pathophysiology is robustly regulated by interactions with neurons. Key to these interactions is the role of neuroligin-3 (NLGN3), a synaptic adhesion molecule shed in response to neuronal activity that functions as a paracrine factor crucial for glioma growth. Here, we elucidate the mechanistic pathway whereby shed NLGN3 interacts with glioma and their normal glial counterpart.

Two parallel lineage-committed progenitors contribute to the developing brain.

The hindbrain is a life-sustaining brain region. In one model, a common neural progenitor generates all brain regions. Here our studies of mouse embryos and human pluripotent stem cells (hPSCs) support a different model: two parallel brain progenitors emerge simultaneously during gastrulation, anterior neural ectoderm (forebrain/midbrain progenitor) and posterior neural ectoderm (hindbrain progenitor).

Cholinergic neuronal activity promotes diffuse midline glioma growth through muscarinic signaling.

Glutamatergic neuronal activity promotes proliferation of both oligodendrocyte precursor cells (OPCs) and gliomas, including diffuse midline glioma (DMG). However, the role of neuromodulatory brainstem neurons projecting to midline structures where DMGs arise remains unexplored. Here, we demonstrate that midbrain cholinergic neuronal activity modulates OPC and DMG proliferation in a circuit-dependent manner.

Salience Signaling and Stimulus Scaling of Ventral Tegmental Area Glutamate Neuron Subtypes.

Ventral tegmental area (VTA) glutamatergic neurons participate in reward, aversion, drug-seeking, and stress. Subsets of these neurons cotransmit glutamate and GABA (VGluT2VGaT neurons), transmit glutamate without GABA (VGluT2VGaT neurons), or cotransmit glutamate and dopamine (VGluT2TH neurons), but whether these molecularly distinct subpopulations show behavior-related differences is not wholly understood. We identified in male and female mice that VGluT2 subpopulations are sensitive to the reward value in unique ways.

GABAergic neuron-to-glioma synapses in diffuse midline gliomas.

High-grade gliomas (HGGs) are the leading cause of brain cancer-related death. HGGs include clinically, anatomically and molecularly distinct subtypes that stratify into diffuse midline gliomas (DMGs), such as H3K27M-altered diffuse intrinsic pontine glioma, and hemispheric HGGs, such as IDH wild-type glioblastoma. Neuronal activity drives glioma progression through paracrine signalling and neuron-to-glioma synapses.

Cholinergic Neuronal Activity Promotes Diffuse Midline Glioma Growth through Muscarinic Signaling.

Neuronal activity promotes the proliferation of healthy oligodendrocyte precursor cells (OPC) and their malignant counterparts, gliomas. Many gliomas arise from and closely resemble oligodendroglial lineage precursors, including diffuse midline glioma (DMG), a cancer affecting midline structures such as the thalamus, brainstem and spinal cord. In DMG, glutamatergic and GABAergic neuronal activity promotes progression through both paracrine signaling and through bona-fide neuron-to-glioma synapses.

Salience signaling and stimulus scaling of ventral tegmental area glutamate neuron subtypes.

Ventral tegmental area (VTA) glutamatergic neurons participate in reward, aversion, drug-seeking, and stress. Subsets of VTA VGluT2+ neurons are capable of co-transmitting glutamate and GABA (VGluT2+VGaT+ neurons), transmitting glutamate without GABA (VGluT2+VGaT- neurons), or co-transmitting glutamate and dopamine (VGluT2+TH+ neurons), but whether these molecularly distinct subpopulations show behavior-related differences is not wholly understood. We identified that neuronal activity of each VGluT2+ subpopulation is sensitive to reward value but signaled this in different ways.

MPFL reconstruction with proximal rather than distal femoral tunnel position leads to less favorable short-term results.

Background: This study aimed to compare the clinical and radiological outcomes of medial patellofemoral ligament (MPFL) reconstruction (MPFLR) between anatomic femoral tunnel positions: proximal (near adductor tubercle [AT]) and distal (near medial epicondyle [ME]).

Hypothesis: MPFLR with the proximal femoral tunnel position has worse clinical and radiological outcomes than those with the distal femoral tunnel position.

Patients And Methods: Fifty-five patients who underwent isolated MPFLR with proximal or distal femoral tunnels with at least 2 years of follow-up were retrospectively analyzed.

Correlation between oxygen flow-controlled resistive switching and capacitance behavior in gallium oxide memristors grown via RF sputtering.

We studied on the bipolar resistive switching (RS)-dependent capacitance of GaO memristors, grown using controlled oxygen flow via a radio frequency sputtering process. The Ag/GaO/Pt memristor structure was employed to investigate the capacitance changes associated with RS behavior and oxygen concentration. In the low-resistance state (LRS), capacitance increased by over 60 times compared to the high-resistance state (HRS).

Glioma synapses recruit mechanisms of adaptive plasticity.

The role of the nervous system in the regulation of cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine signalling factors such as neuroligin-3 and brain-derived neurotrophic factor (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. The consequent glioma cell membrane depolarization drives tumour proliferation.

Sexually dimorphic mechanisms of VGLUT-mediated protection from dopaminergic neurodegeneration.

Parkinson's disease (PD) targets some dopamine (DA) neurons more than others. Sex differences offer insights, with females more protected from DA neurodegeneration. The mammalian vesicular glutamate transporter VGLUT2 and ortholog dVGLUT have been implicated as modulators of DA neuron resilience.

Structural basis for ion selectivity in potassium-selective channelrhodopsins.

KCR channelrhodopsins (K-selective light-gated ion channels) have received attention as potential inhibitory optogenetic tools but more broadly pose a fundamental mystery regarding how their K selectivity is achieved. Here, we present 2.5-2.

Deploying synthetic coevolution and machine learning to engineer protein-protein interactions.

Fine-tuning of protein-protein interactions occurs naturally through coevolution, but this process is difficult to recapitulate in the laboratory. We describe a platform for synthetic protein-protein coevolution that can isolate matched pairs of interacting muteins from complex libraries. This large dataset of coevolved complexes drove a systems-level analysis of molecular recognition between Z domain-affibody pairs spanning a wide range of structures, affinities, cross-reactivities, and orthogonalities, and captured a broad spectrum of coevolutionary networks.

Monosynaptic inputs to ventral tegmental area glutamate and GABA co-transmitting neurons.

A unique population of ventral tegmental area (VTA) neurons co-transmits glutamate and GABA as well as functionally signals rewarding and aversive outcomes. However, the circuit inputs to VTA VGluT2+VGaT+ neurons are unknown, limiting our understanding of the functional capabilities of these neurons. To identify the inputs to VTA VGluT2+VGaT+ neurons, we coupled monosynaptic rabies tracing with intersectional genetic targeting of VTA VGluT2+VGaT+ neurons in mice.

Effect of Posterior Tibial Slopes on Graft Survival Rates at 10 Years After Primary Single-Bundle Posterior Cruciate Ligament Reconstruction.

Background: Recent biomechanical studies have reported that stress on the posterior cruciate ligament (PCL) graft increases as the posterior tibial slope (PTS) decreases (flattened) in knees with single-bundle (SB) and double-bundle PCL reconstruction. Clinical studies of SB PCL reconstruction have shown that a flattened PTS is associated with a lesser reduction in posterior tibial translation. There is no long-term study on the clinical outcomes and graft survival rates of SB PCL reconstruction based on the medial and lateral PTSs measured on magnetic resonance imaging.

Cardiogenic control of affective behavioural state.

Emotional states influence bodily physiology, as exemplified in the top-down process by which anxiety causes faster beating of the heart. However, whether an increased heart rate might itself induce anxiety or fear responses is unclear. Physiological theories of emotion, proposed over a century ago, have considered that in general, there could be an important and even dominant flow of information from the body to the brain.

All-optical physiology resolves a synaptic basis for behavioral timescale plasticity.

Learning has been associated with modifications of synaptic and circuit properties, but the precise changes storing information in mammals have remained largely unclear. We combined genetically targeted voltage imaging with targeted optogenetic activation and silencing of pre- and post-synaptic neurons to study the mechanisms underlying hippocampal behavioral timescale plasticity. In mice navigating a virtual-reality environment, targeted optogenetic activation of individual CA1 cells at specific places induced stable representations of these places in the targeted cells.

Enhanced delivery to brain using sonosensitive liposome and microbubble with focused ultrasound.

Glioblastoma is considered one of the most aggressive and dangerous brain tumors. However, treatment of GBM has been still challenged due to blood-brain barrier (BBB). BBB prevents that the chemotherapeutic molecules are extravasated to brain.

Ultrasound-Responsive Liposomes for Targeted Drug Delivery Combined with Focused Ultrasound.

Chemotherapeutic drugs are traditionally used for the treatment of cancer. However, chemodrugs generally induce side effects and decrease anticancer effects due to indiscriminate diffusion and poor drug delivery. To overcome these limitations of chemotherapy, in this study, ultrasound-responsive liposomes were fabricated and used as drug carriers for delivering the anticancer drug doxorubicin, which was able to induce cancer cell death.

Structural basis for channel conduction in the pump-like channelrhodopsin ChRmine.

ChRmine, a recently discovered pump-like cation-conducting channelrhodopsin, exhibits puzzling properties (large photocurrents, red-shifted spectrum, and extreme light sensitivity) that have created new opportunities in optogenetics. ChRmine and its homologs function as ion channels but, by primary sequence, more closely resemble ion pump rhodopsins; mechanisms for passive channel conduction in this family have remained mysterious. Here, we present the 2.

Ideal Combination of Anatomic Tibial and Femoral Tunnel Positions for Single-Bundle ACL Reconstruction.

Background: Anatomic anterior cruciate ligament reconstruction (ACLR) is preferred over nonanatomic ACLR. However, there is no consensus on which point the tunnels should be positioned among the broad anatomic footprints.

Purpose/hypothesis: To identify the ideal combination of tibial and femoral tunnel positions according to the femoral and tibial footprints of the anteromedial (AM) and posterolateral (PL) anterior cruciate ligament bundles.