A central question in the circadian biology field concerns the mechanisms that translate ~24‐hr oscillations of the molecular clock into overt rhythms. Drosophila melanogaster is a powerful system ...that provided the first understanding of how molecular clocks are generated and is now illuminating the neural basis of circadian behavior. The identity of ~150 clock neurons in the Drosophila brain and their roles in shaping circadian rhythms of locomotor activity have been described before. This review summarizes mechanisms that transmit time‐of‐day signals from the clock, within the clock network as well as downstream of it. We also discuss the identification of functional multisynaptic circuits between clock neurons and output neurons that regulate locomotor activity.
Circadian pacemaking is a result of individually rhythmic clock neurons synchronized across a circuit. In the circadian system of Drosophila melanogaster, rhythmic neuronal activity also propagates downstream of the central clock neurons, s‐LNvs, to output circuits that regulate behavioral rhythms.
Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease that results in motor dysfunction and death, generally from respiratory failure. 90% of ALS cases are sporadic with no ...known cause. Familial cases have been linked with mutations in several disparate classes of genes, including those involved in DNA/RNA metabolism, protein misfolding, oxidative stress and the cytoskeleton, leading to the proposition that ALS could be a multi-factorial disease. However, alterations in excitability have been reported in all types of ALS cases, and may be a common disease mechanism predisposing neurons to degeneration. Excitotoxicity has long been suspected as a mediator in the disease process, and may arise from changes in synaptic inputs, or alterations in the excitability of the neurons being stimulated. Although the glutamatergic system is widely recognised as a therapeutic avenue with the potential to extend lifespan and delay disease onset, the causes of altered excitability in ALS are currently unclear and warrant further investigation. This article reviews current evidence of alterations to excitatory and inhibitory signalling in the cortex and spinal cord, and in the intrinsic excitability of motor neurons, in ALS.
Intronic expansion of a hexanucleotide GGGGCC repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene is the major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal ...dementia. However, the cellular function of the C9ORF72 protein remains unknown. Here, we demonstrate that C9ORF72 regulates endosomal trafficking. C9ORF72 colocalized with Rab proteins implicated in autophagy and endocytic transport: Rab1, Rab5, Rab7 and Rab11 in neuronal cell lines, primary cortical neurons and human spinal cord motor neurons, consistent with previous predictions that C9ORF72 bears Rab guanine exchange factor activity. Consistent with this notion, C9ORF72 was present in the extracellular space and as cytoplasmic vesicles. Depletion of C9ORF72 using siRNA inhibited transport of Shiga toxin from the plasma membrane to Golgi apparatus, internalization of TrkB receptor and altered the ratio of autophagosome marker light chain 3 (LC3) II:LC3I, indicating that C9ORF72 regulates endocytosis and autophagy. C9ORF72 also colocalized with ubiquilin-2 and LC3-positive vesicles, and co-migrated with lysosome-stained vesicles in neuronal cell lines, providing further evidence that C9ORF72 regulates autophagy. Investigation of proteins interacting with C9ORF72 using mass spectrometry identified other proteins implicated in ALS; ubiquilin-2 and heterogeneous nuclear ribonucleoproteins, hnRNPA2/B1 and hnRNPA1, and actin. Treatment of cells overexpressing C9ORF72 with proteasome inhibitors induced the formation of stress granules positive for hnRNPA1 and hnRNPA2/B1. Immunohistochemistry of C9ORF72 ALS patient motor neurons revealed increased colocalization between C9ORF72 and Rab7 and Rab11 compared with controls, suggesting possible dysregulation of trafficking in patients bearing the C9ORF72 repeat expansion. Hence, this study identifies a role for C9ORF72 in Rab-mediated cellular trafficking.
This article reviews the first twelve months of the civil disobedience movement in Myanmar following the 1 February 2021 coup d’état and its many dynamics and manifestations. Myanmar’s ‘Spring ...Revolution’ generated a shared sense of national unity—overcoming gender, ethnic, religious and class boundaries, but raising questions about the long-term sustainability of nonviolent civil resistance in a state where the military has for decades wielded political and economic power. Since the coup, Myanmar has been in turmoil, paralysed by instability which escalated after the military’s deadly crackdown on pro-democracy activists. The article charts the growth of the Civil Disobedience Movement (CDM), its multiple methods of strategic resistance and non-cooperation, and the radicalisation of the resistance agenda. It analyses the formation of the Committee Representing the Pyidaungsu Hluttaw (CRPH), the creation of the interim National Unity Government (NUG), the founding of the National Unity Consultative Council (NUCC) and the inauguration of the People’s Defence Force (PDF). It examines the implications for Myanmar when the crisis reached a more complex phase after the military’s open use of force and terror on the broader civilian population prompted the NUG to declare war on the junta, and to urge ethnic armed organisations (EAOs) and newly formed anti-junta civilian militias (PDF) to attack the State Administration Council (SAC) as a terrorist organisation. The NUG now opposes the military junta by strategic and peaceful non-cooperation, armed resistance, and international diplomacy. This paper considers whether the predominantly nonviolent civil resistance movement’s struggle for federal democracy and inclusive governance is laying the foundations for eventual transition to a fully democratic future or whether the cycles of violence will continue as the military continues to control power by using intimidation and fear. It notes that the coup has destroyed the economy and expanded Myanmar’s human rights and humanitarian crises but has also provided the opportunity for Myanmar’s people to explore diverse visions of a free, federal, democratic and accountable Myanmar. It finally examines the possibilities for future peaceful nation building, reconciliation, and the healing of the trauma of civil war.
Alzheimer's disease (AD) is a neurodegenerative disease characterised by a progressive decline in cognitive function and represents a major healthcare challenge worldwide. Increasing evidence ...indicates that mitochondrial dysfunction mediated oxidative stress plays a significant role in the pathophysiological process of AD. Therefore, the physiological activation of antioxidant enzymes that respond to increased oxidative stress is thought to prevent neuropathology. One of those endogenous defences is NADPH quinone oxidoreductase 1 (NQO1). NQO1 is a cytosolic homodimeric flavoprotein that catalyses the two-electron reduction of quinones and related molecules aimed at increasing their solubility and excretion. In line with its role as a phase II stress response protein, altered NQO1 expression is associated with several pathological conditions and disorders including AD.
This review summarizes the association between NQO1 and AD pathology. Understanding this association will provide further insight into the pathogenesis of the disease. More importantly, recent interest in drugs that affect NQO1 expression or its activity provides hope that this approach could lead to novel therapeutic options for the treatment of AD.
The endoplasmic reticulum (ER) and plasma membrane (PM) form junctions crucial to ion and lipid signaling and homeostasis. The Kv2.1 ion channel is localized at ER-PM junctions in brain neurons and ...is unique among PM proteins in its ability to remodel these specialized membrane contact sites. Here, we show that this function is conserved between Kv2.1 and Kv2.2, which differ in their biophysical properties, modulation, and cellular expression. Kv2.2 ER-PM junctions are present at sites deficient in the actin cytoskeleton, and disruption of the actin cytoskeleton affects their spatial organization. Kv2.2-containing ER-PM junctions overlap with those formed by canonical ER-PM tethers. The ability of Kv2 channels to remodel ER-PM junctions is unchanged by point mutations that eliminate their ion conduction but eliminated by point mutations within the Kv2-specific proximal restriction and clustering (PRC) domain that do not impact their ion channel function. The highly conserved PRC domain is sufficient to transfer the ER-PM junction-remodeling function to another PM protein. Last, brain neurons in Kv2 double-knockout mice have altered ER-PM junctions. Together, these findings demonstrate a conserved in vivo function for Kv2 family members in remodeling neuronal ER-PM junctions that is distinct from their canonical role as ion-conducting channels shaping neuronal excitability.
Abstract
Background
aspiration pneumonia increases hospitalisation and mortality of older people in residential aged care.
Objectives
determine potentially pathogenic microorganisms in oral specimens ...of older people with aspiration pneumonia and the effect of professional oral care in reducing aspiration pneumonia risk.
Data Sources
PUBMED/MEDLINE, CINAHL, EMBASE, COCHRANE, PROQUEST, Google Scholar, Web of Science.
Study Eligibility Criteria
published between January 2001 and December 2019 addressing oral microorganisms, aspiration pneumonia, oral health and treatment.
Participants
people 60 years and older in residential aged care.
Study Appraisal and Synthesis Methods
the Newcastle–Ottawa Scale and the Standard Protocol Items: Recommendations for Intervention Trials checklist.
Results
twelve studies (four cross-sectional, five cohort and three intervention) reported colonisation of the oral cavity of older people by microorganisms commonly associated with respiratory infections. Aspiration pneumonia occurred less in people who received professional oral care compared with no such care. Isolation of Candida albicans, Staphylococcus aureus, methicillin-resistant S. aureus and Pseudomonas aeruginosa was related to mortality due to aspiration pneumonia. An interesting finding was isolation of Escherichia coli, a gut bacterium.
Limitations
more information may be present in publications about other co-morbidities that did not meet inclusion criteria. A high degree of heterogeneity prevented a meta-analysis. Issues included sampling size, no power and effect size calculations; different oral health assessments; how oral specimens were analysed and how aspiration pneumonia was diagnosed.
Conclusions and Implications of Key Findings
pathogenic microorganisms colonising the oral microbiome are associated with aspiration pneumonia in older people in residential care; professional oral hygiene care is useful in reducing aspiration pneumonia risk.
The mechanisms by which clock neurons in the Drosophila brain confer an ∼24-hr rhythm onto locomotor activity are unclear, but involve the neuropeptide diuretic hormone 44 (DH44), an ortholog of ...corticotropin-releasing factor. Here we identified DH44 receptor 1 as the relevant receptor for rest:activity rhythms and mapped its site of action to hugin-expressing neurons in the subesophageal zone (SEZ). We traced a circuit that extends from Dh44-expressing neurons in the pars intercerebralis (PI) through hugin+ SEZ neurons to the ventral nerve cord. Hugin neuropeptide, a neuromedin U ortholog, also regulates behavioral rhythms. The DH44 PI-Hugin SEZ circuit controls circadian locomotor activity in a daily cycle but has minimal effect on feeding rhythms, suggesting that the circadian drive to feed can be separated from circadian locomotion. These findings define a linear peptidergic circuit that links the clock to motor outputs to modulate circadian control of locomotor activity.
•DH44-R1 functions in hugin+ neurons to regulate rest:activity rhythms•A neuromedin U ortholog, Hugin, is a circadian output molecule•An LNv→DN1→DH44 PI→Hugin SEZ→VNC circuit links the clock to motor output•The DH44 PI-Hugin SEZ circuit regulates locomotor activity, but not feeding rhythms
Circadian clocks allow organisms to coordinate their behavior with time of day. King et al. demonstrate that a specific circuit comprising peptidergic neurons in Drosophila connects the central pacemaker neurons to motor outputs. Peptides released by neurons in this circuit, DH44 and Hugin, regulate rest:activity rhythms.
Neurodegenerative diseases present a progressive loss of neuronal structure and function, leading to cell death and irrecoverable brain atrophy. Most have disease-modifying therapies, in part because ...the mechanisms of neurodegeneration are yet to be defined, preventing the development of targeted therapies. To overcome this, there is a need for tools that enable a quantitative assessment of how cellular mechanisms and diverse environmental conditions contribute to disease. One such tool is genetically encodable fluorescent biosensors (GEFBs), engineered constructs encoding proteins with novel functions capable of sensing spatiotemporal changes in specific pathways, enzyme functions, or metabolite levels. GEFB technology therefore presents a plethora of unique sensing capabilities that, when coupled with induced pluripotent stem cells (iPSCs), present a powerful tool for exploring disease mechanisms and identifying novel therapeutics. In this review, we discuss different GEFBs relevant to neurodegenerative disease and how they can be used with iPSCs to illuminate unresolved questions about causes and risks for neurodegenerative disease.
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