aux orchestrates the phosphorylation-dependent assembly of the lysosomal V-ATPase in glia and contributes to SNCA/α-synuclein degradation.

Glia contribute to the neuropathology of Parkinson disease (PD), but how they react opposingly to be beneficial or detrimental under pathological conditions, like promoting or eliminating SNCA/α-syn (synuclein alpha) inclusions, remains elusive. Here we present evidence that aux (auxilin), the homolog of the PD risk factor GAK (cyclin G associated kinase), regulates the lysosomal degradation of SNCA/α-syn in glia. Lack of glial GAK/aux increases the lysosome number and size, regulates lysosomal acidification and hydrolase activity, and ultimately blocks the degradation of substrates including SNCA/α-syn.

SPIRIT-DEFINE explanation and elaboration: recommendations for enhancing quality and impact of early phase dose-finding clinical trials protocols.

Unlabelled: Transparent and accurate reporting in early phase dose-finding (EPDF) clinical trials is crucial for informing subsequent larger trials. The SPIRIT statement, designed for trial protocol content, does not adequately cover the distinctive features of EPDF trials. Recent findings indicate that the protocol contents in past EPDF trials frequently lacked completeness and clarity.

CONSORT-DEFINE explanation and elaboration: recommendations for enhancing reporting quality and impact of early phase dose-finding clinical trials.

Unlabelled: Early phase dose-finding (EPDF) trials are key in the development of novel therapies, with their findings directly informing subsequent clinical development phases and providing valuable insights for reverse translation. Comprehensive and transparent reporting of these studies is critical for their accurate and critical interpretation, which may improve and expedite therapeutic development. However, quality of reporting of design characteristics and results from EPDF trials is often variable and incomplete.

Regional brain iron correlates with transcriptional and cellular signatures in Alzheimer's disease.

Introduction: The link between overload brain iron and transcriptional/cellular signatures in Alzheimer's disease (AD) remains inconclusive.

Methods: Iron deposition in 41 cortical and subcortical regions of 30 AD patients and 26 healthy controls (HCs) was measured using quantitative susceptibility mapping (QSM). The expression of 15,633 genes was estimated in the same regions using transcriptomic data from the Allen Human Brain Atlas (AHBA).

Behavioral Cetology in the 19th Century: Thomas Beale, Henry Cheever, Thomas Southwell and Their Role in Awakening a Cetacean Protection Consciousness.

Although naturalists have devoted attention to cetaceans since Antiquity, it was only in the 19th century that cetology underwent a true explosion. Three key cetological works of this period are The Natural History of the Sperm Whale (1839) by Thomas Beale, The Whaleman's Adventures in the Southern Ocean (1850) by Henry Cheever and The Seals and Whales of the British Seas (1881) by Thomas Southwell. Importantly, these three works did not only represent fundamental compendia of scientific knowledge of cetaceans, but also had a crucial role in awakening a cetacean protection consciousness.

The Effects of Blue Light on Locomotion and Cognition in Early Adult Drosophila melanogaster.

Artificial light sources, particularly blue light, have raised concerns about their impact on biological health and behavior. In this study, we explored the effects of blue light on the locomotion and cognitive functions of early adult Drosophila melanogaster. Our experiments were conducted in a custom-designed behavioral arena to assess how blue light influences these parameters.

RetroFun-RVS: A Retrospective Family-Based Framework for Rare Variant Analysis Incorporating Functional Annotations.

A large proportion of genetic variations involved in complex diseases are rare and located within noncoding regions, making the interpretation of underlying biological mechanisms a daunting task. Although technical and methodological progress has been made to annotate the genome, current disease-rare-variant association tests incorporating such annotations suffer from two major limitations. First, they are generally restricted to case-control designs of unrelated individuals, which often require tens or hundreds of thousands of individuals to achieve sufficient power.

Modeling Sporadic Progressive Supranuclear Palsy in 3D Midbrain Organoids: Recapitulating Disease Features for In Vitro Diagnosis and Drug Discovery.

Objective: Progressive Supranuclear Palsy (PSP) is a severe neurodegenerative disease characterized by tangles of hyperphosphorylated tau protein and tufted astrocytes. Developing treatments for PSP is challenging due to the lack of disease models reproducing its key pathological features. This study aimed to model sporadic PSP-Richardson's syndrome (PSP-RS) using multi-donor midbrain organoids (MOs).

Harmonic analysis and optimization for closed-loop superconducting shim coils of 7 T MRI magnet.

Background: High-resolution brain imaging is crucial in clinical diagnosis and neuroscience, with ultra-high field strength MRI systems ( ) offering significant advantages for imaging neuronal microstructures. However, achieving magnetic field homogeneity is challenging due to engineering faults during the installation of superconducting strip windings and the primary magnet.

Purpose: This study aims to design and optimize active superconducting shim coils for a 7 T animal MRI system, focusing on the impact of safety margin, size, and adjustability of the second-order shim coils on the MRI system's optimization.

NLRX1 limits inflammatory neurodegeneration in the anterior visual pathway.

Chronic innate immune activation in the central nervous system (CNS) significantly contributes to neurodegeneration in progressive multiple sclerosis (MS). Using multiple experimental autoimmune encephalomyelitis (EAE) models, we discovered that NLRX1 protects neurons in the anterior visual pathway from inflammatory neurodegeneration. We quantified retinal ganglion cell (RGC) density and optic nerve axonal degeneration, gliosis, and T-cell infiltration in Nlrx1 and wild-type (WT) EAE mice and found increased RGC loss and axonal injury in Nlrx1 mice compared to WT mice in both active immunization EAE and spontaneous opticospinal encephalomyelitis (OSE) models.

Marigold: a machine learning-based web app for zebrafish pose tracking.

Background: High-throughput behavioral analysis is important for drug discovery, toxicological studies, and the modeling of neurological disorders such as autism and epilepsy. Zebrafish embryos and larvae are ideal for such applications because they are spawned in large clutches, develop rapidly, feature a relatively simple nervous system, and have orthologs to many human disease genes. However, existing software for video-based behavioral analysis can be incompatible with recordings that contain dynamic backgrounds or foreign objects, lack support for multiwell formats, require expensive hardware, and/or demand considerable programming expertise.

NPT100-18A rescues mitochondrial oxidative stress and neuronal degeneration in human iPSC-based Parkinson's model.

Background: Parkinson's disease (PD) is a neurodegenerative disorder characterized by protein aggregates mostly consisting of misfolded alpha-synuclein (αSyn). Progressive degeneration of midbrain dopaminergic neurons (mDANs) and nigrostriatal projections results in severe motor symptoms. While the preferential loss of mDANs has not been fully understood yet, the cell type-specific vulnerability has been linked to a unique intracellular milieu, influenced by dopamine metabolism, high demand for mitochondrial activity, and increased level of oxidative stress (OS).

Aging disrupts the coordination between mRNA and protein expression in mouse and human midbrain.

Age-related dopamine (DA) neuron loss is a primary feature of Parkinson's disease. However, whether similar biological processes occur during healthy aging, but to a lesser degree, remains unclear. We therefore determined whether midbrain DA neurons degenerate during aging in mice and humans.

The architecture of the human default mode network explored through cytoarchitecture, wiring and signal flow.

The default mode network (DMN) is implicated in many aspects of complex thought and behavior. Here, we leverage postmortem histology and in vivo neuroimaging to characterize the anatomy of the DMN to better understand its role in information processing and cortical communication. Our results show that the DMN is cytoarchitecturally heterogenous, containing cytoarchitectural types that are variably specialized for unimodal, heteromodal and memory-related processing.

Neural circuits underlying context-dependent competition between defensive actions in Drosophila larvae.

To ensure their survival, animals must be able to respond adaptively to threats within their environment. However, the precise neural circuit mechanisms that underlie flexible defensive behaviors remain poorly understood. Using neuronal manipulations, machine learning-based behavioral detection, electron microscopy (EM) connectomics and calcium imaging in Drosophila larvae, we map second-order interneurons that are differentially involved in the competition between defensive actions in response to competing aversive cues.

Sub-cellular population imaging tools reveal stable apical dendrites in hippocampal area CA3.

Apical and basal dendrites of pyramidal neurons receive anatomically and functionally distinct inputs, implying compartment-level functional diversity during behavior. To test this, we imaged in vivo calcium signals from soma, apical dendrites, and basal dendrites in mouse hippocampal CA3 pyramidal neurons during head-fixed navigation. To capture compartment-specific population dynamics, we developed computational tools to automatically segment dendrites and extract accurate fluorescence traces from densely labeled neurons.

Anisotropic hydrogel microelectrodes for intraspinal neural recordings in vivo.

Creating durable, motion-compliant neural interfaces is crucial for accessing dynamic tissues under in vivo conditions and linking neural activity with behaviors. Utilizing the self-alignment of nano-fillers in a polymeric matrix under repetitive tension, here, we introduce conductive carbon nanotubes with high aspect ratios into semi-crystalline polyvinyl alcohol hydrogels, and create electrically anisotropic percolation pathways through cyclic stretching. The resulting anisotropic hydrogel fibers (diameter of 187 ± 13 µm) exhibit fatigue resistance (up to 20,000 cycles at 20% strain) with a stretchability of 64.

Molecular Insights into α-Synuclein Fibrillation: A Raman Spectroscopy and Machine Learning Approach.

The aggregation of α-synuclein is crucial to the development of Lewy body diseases, including Parkinson's disease and dementia with Lewy bodies. The aggregation pathway of α-synuclein typically involves a defined sequence of nucleation, elongation, and secondary nucleation, exhibiting prion-like spreading. This study employed Raman spectroscopy and machine learning analysis, alongside complementary techniques, to characterize the biomolecular changes during the fibrillation of purified recombinant wild-type α-synuclein protein.

The number of central nervous system-driven symptoms predicts subsequent chronic primary pain: evidence from UK Biobank.

Background: Chronic primary pain describes conditions where pain is the principal problem rather than a consequence of another disease. Primary pain is thought to be primarily owing to nociplastic pain (i.e.

Selective activation of mesoscale functional circuits via multichannel infrared stimulation of cortical columns in ultra-high-field 7T MRI.

To restore vision in the blind, advances in visual cortical prosthetics (VCPs) have offered high-channel-count electrical interfaces. Here, we design a 100-fiber optical bundle interface apposed to known feature-specific (color, shape, motion, and depth) functional columns that populate the visual cortex in humans, primates, and cats. Based on a non-viral optical stimulation method (INS, infrared neural stimulation; 1,875 nm), it can deliver dynamic patterns of stimulation, is non-penetrating and non-damaging to tissue, and is movable and removable.

Analysis of TEM micrographs with deep learning reveals APOE genotype-specific associations between HDL particle diameter and Alzheimer's dementia.

High-density lipoprotein (HDL) particle diameter distribution is informative in the diagnosis of many conditions, including Alzheimer's disease (AD). However, obtaining an accurate HDL size measurement is challenging. We demonstrated the utility of measuring the diameter of more than 1,800,000 HDL particles with the deep learning model YOLOv7 (you only look once) from micrographs of 183 HDL samples, including patients with dementia or normal cognition (controls).

Resting-state microstate dynamics abnormalities in children with ADHD and co-occurring sleep problems.

Objectives: Children with attention-deficit/hyperactivity disorder often experience sleep problems, exacerbating symptoms, and cognitive deficits. However, the neurophysiological mechanisms underlying such deficits remained unclear. This study aims to use resting-state microstate analysis to investigate the neurophysiological characteristics in children with ADHD and sleep problems and explore whether neurophysiological abnormalities are associated with sleep problems.

Changes to social and healthcare providers support in the perinatal period: Impact on coping strategies, depression and anxiety.

Background: During the perinatal period, risk of depression and anxiety (D&A) increases. As in other crisis events, the COVID-19 pandemic, imposed social distancing measures, diminished social support and changes in perinatal healthcare provision which heightened this risk. This study aimed to examine how changes in social and healthcare provider support during the pandemic affected coping strategies and depression and anxiety symptoms (D&As) among perinatal women.