Rapid spin changes around a magnetar fast radio burst.

Magnetars are neutron stars with extremely high magnetic fields (≳1014 gauss) that exhibit various X-ray phenomena such as sporadic subsecond bursts, long-term persistent flux enhancements and variable rotation-period derivative1,2. In 2020, a fast radio burst (FRB), akin to cosmological millisecond-duration radio bursts, was detected from the Galactic magnetar SGR 1935+2154 (refs. 3-5), confirming the long-suspected association between some FRBs and magnetars. However, the mechanism for FRB generation in magnetars remains unclear. Here we report the X-ray observation of two glitches in SGR 1935+2154 within a time interval of approximately nine hours, bracketing an FRB that occurred on 14 October 20226,7. Each glitch involved a significant increase in the magnetar's spin frequency, being among the largest abrupt changes in neutron-star rotation8-10 observed so far. Between the glitches, the magnetar exhibited a rapid spin-down phase, accompanied by an increase and subsequent decline in its persistent X-ray emission and burst rate. We postulate that a strong, ephemeral, magnetospheric wind11 provides the torque that rapidly slows the star's rotation. The trigger for the first glitch couples the star's crust to its magnetosphere, enhances the various X-ray signals and spawns the wind that alters magnetospheric conditions that might produce the FRB.

Considerations for establishing and maintaining international research collaboration: the example of chemotherapy-induced peripheral neurotoxicity (CIPN)-a white paper.

PURPOSE: This white paper provides guidance regarding the process for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research. METHODS: An international multidisciplinary group of CIPN scientists, clinicians, research administrators, and legal experts have pooled their collective knowledge regarding recommendations for establishing and maintaining international collaboration to foster advancement of CIPN science. RESULTS: Experts provide recommendations in 10 categories: (1) preclinical and (2) clinical research collaboration; (3) collaborators and consortiums; (4) communication; (5) funding; (6) international regulatory standards; (7) staff training; (8) data management, quality control, and data sharing; (9) dissemination across disciplines and countries; and (10) additional recommendations about feasibility, policy, and mentorship. CONCLUSION: Recommendations to establish and maintain international CIPN research collaboration will promote the inclusion of more diverse research participants, increasing consideration of cultural and genetic factors that are essential to inform innovative precision medicine interventions and propel scientific discovery to benefit cancer survivors worldwide. RELEVANCE TO INFORM RESEARCH POLICY: Our suggested guidelines for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research set forth a challenge to multinational science, clinical, and policy leaders to (1) develop simple, streamlined research designs; (2) address logistical barriers; (3) simplify and standardize regulatory requirements across countries; (4) increase funding to support international collaboration; and (5) foster faculty mentorship.

Treponema denticola Has the Potential to Cause Neurodegeneration in the Midbrain via the Periodontal Route of Infection-Narrative Review.

Alzheimer's disease (AD) is a neurodegenerative disease and the most common example of dementia. The neuropathological features of AD are the abnormal deposition of extracellular amyloid-ß (Aß) and intraneuronal neurofibrillary tangles with hyperphosphorylated tau protein. It is recognized that AD starts in the frontal cerebral cortex, and then it progresses to the entorhinal cortex, the hippocampus, and the rest of the brain. However, some studies on animals suggest that AD could also progress in the reverse order starting from the midbrain and then spreading to the frontal cortex. Spirochetes are neurotrophic: From a peripheral route of infection, they can reach the brain via the midbrain. Their direct and indirect effect via the interaction of their virulence factors and the microglia potentially leads to the host peripheral nerve, the midbrain (especially the locus coeruleus), and cortical damage. On this basis, this review aims to discuss the hypothesis of the ability of Treponema denticola to damage the peripheral axons in the periodontal ligament, to evade the complemental pathway and microglial immune response, to determine the cytoskeletal impairment and therefore causing the axonal transport disruption, an altered mitochondrial migration and the consequent neuronal apoptosis. Further insights about the central neurodegeneration mechanism and Treponema denticola's resistance to the immune response when aggregated in biofilm and its quorum sensing are suggested as a pathogenetic model for the advanced stages of AD.

Locus Coeruleus Dysfunction and Trigeminal Mesencephalic Nucleus Degeneration: A Cue for Periodontal Infection Mediated Damage in Alzheimer's Disease?

Alzheimer's disease (AD) is a leading neurodegenerative disease with deteriorating cognition as its main clinical sign. In addition to the clinical history, it is characterized by the presence of two neuropathological hallmark lesions; amyloid-beta (Aß) and neurofibrillary tangles (NFTs), identified in the brain at post-mortem in specific anatomical areas. Recently, it was discovered that NFTs occur initially in the subcortical nuclei, such as the locus coeruleus in the pons, and are said to spread from there to the cerebral cortices and the hippocampus. This contrasts with the prior acceptance of their neuropathology in the enthorinal cortex and the hippocampus. The Braak staging system places the accumulation of phosphorylated tau (p-tau) binding to NFTs in the locus coeruleus and other subcortical nuclei to precede stages I-IV. The locus coeruleus plays diverse psychological and physiological roles within the human body including rapid eye movement sleep disorder, schizophrenia, anxiety, and depression, regulation of sleep-wake cycles, attention, memory, mood, and behavior, which correlates with AD clinical behavior. In addition, the locus coeruleus regulates cardiovascular, respiratory, and gastrointestinal activities, which have only recently been associated with AD by modern day research enabling the wider understanding of AD development via comorbidities and microbial dysbiosis. The focus of this narrative review is to explore the modes of neurodegeneration taking place in the locus coeruleus during the natural aging process of the trigeminal nerve connections from the teeth and microbial dysbiosis, and to postulate a pathogenetic mechanism due to periodontal damage and/or infection focused on Treponema denticola.

The Mechanistic Pathways of Periodontal Pathogens Entering the Brain: The Potential Role of Treponema denticola in Tracing Alzheimer's Disease Pathology.

Alzheimer's Disease (AD) is a complex neurodegenerative disease and remains the most common form of dementia. The pathological features include amyloid (Aß) accumulation, neurofibrillary tangles (NFTs), neural and synaptic loss, microglial cell activation, and an increased blood-brain barrier permeability. One longstanding hypothesis suggests that a microbial etiology is key to AD initiation. Among the various periodontal microorganisms, Porphyromonas gingivalis has been considered the keystone agent to potentially correlate with AD, due to its influence on systemic inflammation. P. gingivalis together with Treponema denticola and Tannerella forsythia belong to the red complex consortium of bacteria advocated to sustain periodontitis within a local dysbiosis and a host response alteration. Since the implication of P. gingivalis in the pathogenesis of AD, evidence has emerged of T. denticola clusters in some AD brain tissue sections. This narrative review explored the potential mode of spirochetes entry into the AD brain for tracing pathology. Spirochetes are slow-growing bacteria, which can hide within ganglia for many years. It is this feature in combination with the ability of these bacteria to evade the hosts' immune responses that may account for a long lag phase between infection and plausible AD disease symptoms. As the locus coeruleus has direct connection between the trigeminal nuclei to periodontal free nerve endings and proprioceptors with the central nervous system, it is plausible that they could initiate AD pathology from this anatomical region.

Periodontitis as a Risk Factor for Alzheimer's Disease: The Experimental Journey So Far, with Hope of Therapy.

Periodontitis and Alzheimer's disease (AD) exist globally within the adult population. Given that the risk of AD incidence doubles within 10 years from the time of periodontal disease diagnosis, there is a window of opportunity for slowing down or preventing AD by risk-reduction-based intervention. Literature appraisal on the shared risk factors of these diseases suggests a shift to a healthy lifestyle would be beneficial. Generalised (chronic) periodontitis with an established dysbiotic polymicrobial aetiology affects the tooth supporting tissues with eventual tooth loss. The cause of AD remains unknown, however two neurohistopathological lesions - amyloid-beta plaques and neurofibrillary tangles, together with the clinical history, provide AD diagnosis at autopsy. Historically, prominence was given to the two hallmark lesions but now emphasis is placed on cerebral inflammation and what triggers it. Low socioeconomic status promotes poor lifestyles that compromise oral and personal hygiene along with reliance on poor dietary intake. Taken together with advancing age and a declining immune protection, these risk factors may negatively impact on periodontitis and AD. These factors also provide a tangible solution to controlling pathogenic bacteria indigenous to the oral and gastrointestinal tract microbioes in vulnerable subjects. The focus here is on Porphyromonas gingivalis, one of several important bacterial pathogens associated with both periodontitis and AD. Recent research has enabled advances in our knowledge of the armoury of P. gingivalis via reproduction of all clinical and neuropathological hallmark lesions of AD and chronic periodontal disease in vitro and in vivo experimental models, thus paving the way for better future management.

Enhanced x-ray emission coinciding with giant radio pulses from the Crab Pulsar.

Giant radio pulses (GRPs) are sporadic bursts emitted by some pulsars that last a few microseconds and are hundreds to thousands of times brighter than regular pulses from these sources. The only GRP-associated emission outside of radio wavelengths is from the Crab Pulsar, where optical emission is enhanced by a few percentage points during GRPs. We observed the Crab Pulsar simultaneously at x-ray and radio wavelengths, finding enhancement of the x-ray emission by 3.8 ± 0.7% (a 5.4σ detection) coinciding with GRPs. This implies that the total emitted energy from GRPs is tens to hundreds of times higher than previously known. We discuss the implications for the pulsar emission mechanism and extragalactic fast radio bursts.

Multi-TeV Emission From the Vela Pulsar.

Pulsed emission from the Vela pulsar at energies above 3 TeV has recently been detected by the H.E.S.S. II air-Cherenkov telescope. We present a model for the broad-band spectrum of Vela from infra-red (IR) to beyond 10 TeV. Recent simulations of the global pulsar magnetosphere have shown that most of the particle acceleration occurs in the equatorial current sheet outside the light cylinder and that the magnetic field structure is nearly force-free for younger pulsars. We adopt this picture to compute the radiation from both electron-positron pairs produced in polar cap cascades and from primary particles accelerated in the separatrix and current sheet. The synchrotron spectrum from pairs resonantly absorbing radio photons at relatively low altitude can account for the observed IR-optical emission. We set the parallel electric field in the current sheet to produce the Fermi GeV emission through curvature radiation, producing particles with energies of 30-60 TeV. These particles then produce Very-High-Energy emission up to around 30 TeV through inverse-Compton scattering of the IR-Optical emission. We present model spectra and light curves that can match the IR-Optical, GeV and make predictions for the multi-TeV emission.

Exploring the Association between Alzheimer's Disease, Oral Health, Microbial Endocrinology and Nutrition.

Longitudinal monitoring of patients suggests a causal link between chronic periodontitis and the development of Alzheimer's disease (AD). However, the explanation of how periodontitis can lead to dementia remains unclear. A working hypothesis links extrinsic inflammation as a secondary cause of AD. This hypothesis suggests a compromised oral hygiene leads to a dysbiotic oral microbiome whereby Porphyromonas gingivalis, a keystone periodontal pathogen, with its companion species, orchestrates immune subversion in the host. Brushing and chewing on teeth supported by already injured soft tissues leads to bacteremias. As a result, a persistent systemic inflammatory response develops to periodontal pathogens. The pathogens, and the host's inflammatory response, subsequently lead to the initiation and progression of multiple metabolic and inflammatory co-morbidities, including AD. Insufficient levels of essential micronutrients can lead to microbial dysbiosis through the growth of periodontal pathogens such as demonstrated for P. gingivalis under low hemin bioavailability. An individual's diet also defines the consortium of microbial communities that take up residency in the oral and gastrointestinal (GI) tract microbiomes. Their imbalance can lead to behavioral changes. For example, probiotics enriched in Lactobacillus genus of bacteria, when ingested, exert some anti-inflammatory influence through common host/bacterial neurochemicals, both locally, and through sensory signaling back to the brain. Early life dietary behaviors may cause an imbalance in the host/microbial endocrinology through a dietary intake incompatible with a healthy GI tract microbiome later in life. This imbalance in host/microbial endocrinology may have a lasting impact on mental health. This observation opens up an opportunity to explore the mechanisms, which may underlie the previously detected relationship between diet, oral/GI microbial communities, to anxiety, cognition and sleep patterns. This review suggests healthy diet based interventions that together with improved life style/behavioral changes may reduce and/or delay the incidence of AD.

Can Better Management of Periodontal Disease Delay the Onset and Progression of Alzheimer's Disease?

A risk factor relationship exists between periodontal disease and Alzheimer's disease (AD) via tooth loss, and improved memory following dental intervention. This links the microbial contribution from indigenous oral periodontal pathogens to the manifestation of chronic conditions, such as AD. Here, we use Porphyromonas gingivalis infection to illustrate its effect on mental health. P. gingivalis infection, in its primary sub-gingival niche, can cause polymicrobial synergy and dysbiosis. Dysbiosis describes the residency of select commensals from the oral cavity following co-aggregation around the dominant keystone pathogen, such as P. gingivalis, to gain greater virulence. The initial process involves P. gingivalis disturbing neutrophil mediated innate immune responses in the healthy gingivae and then downregulating adaptive immune cell differentiation and development to invade, and subsequently, establish new dysbiotic bacterial communities. Immune responses affect the host in general and functionally via dietary adjustments caused by tooth loss. Studies from animals orally infected with P. gingivalis confirm this bacterium can transmigrate to distant organ sites (the brain) and contribute toward peripheral and intracerebral inflammation, and compromise vascular and microvascular integrity. In another study, P. gingivalis infection caused sleep pattern disturbances by altering glial cell light/dark molecular clock activity, and this, in turn, can affect the clearance of danger associated molecular patterns, such as amyloid-ß, via the glymphatic system. Since P. gingivalis can transmigrate to the brain and modulate organ-specific inflammatory innate and adaptive immune responses, this paper explores whether better management of indigenous periodontal bacteria could delay/prevent the onset and/or progression of dementia.

CONSTRAINING RELATIVISTIC BOW SHOCK PROPERTIES IN ROTATION-POWERED MILLISECOND PULSAR BINARIES.

Multiwavelength followup of unidentified Fermi sources has vastly expanded the number of known galactic-field "black widow" and "redback" millisecond pulsar binaries. Focusing on their rotation-powered state, we interpret the radio to X-ray phenomenology in a consistent framework. We advocate the existence of two distinct modes differing in their intrabinary shock orientation, distinguished by the phase-centering of the double-peaked X-ray orbital modulation originating from mildly-relativistic Doppler boosting. By constructing a geometric model for radio eclipses, we constrain the shock geometry as functions of binary inclination and shock stand-off R0. We develop synthetic X-ray synchrotron orbital light curves and explore the model parameter space allowed by radio eclipse constraints applied on archetypal systems B1957+20 and J1023+0038. For B1957+20, from radio eclipses the stand-off is R0 ~ 0.15-0.3 fraction of binary separation from the companion center, depending on the orbit inclination. Constructed X-ray light curves for B1957+20 using these values are qualitatively consistent with those observed, and we find occultation of the shock by the companion as a minor influence, demanding significant Doppler factors to yield double peaks. For J1023+0038, radio eclipses imply R0 ≲ 0.4 while X-ray light curves suggest 0.1 ≲ R0 ≲ 0.3 (from the pulsar). Degeneracies in the model parameter space encourage further development to include transport considerations. Generically, the spatial variation along the shock of the underlying electron power-law index should yield energy-dependence in the shape of light curves motivating future X-ray phase-resolved spectroscopic studies to probe the unknown physics of pulsar winds and relativistic shock acceleration therein.

Apolipoprotein E Related Co-Morbidities and Alzheimer's Disease.

The primary goal of advancement in clinical services is to provide a health care system that enhances an individual's quality of life. Incidence of diabetes mellitus, cardiovascular disease, and associated dementia coupled with the advancing age of the population, have led to an increase in the worldwide challenge to the healthcare system. In order to overcome these challenges, prior knowledge of common, reliable risk factors and their effectors is essential. Oral health constitutes one such relatively unexplored but indispensable risk factor for aforementioned co-morbidities, in the form of poor oral hygiene and tooth loss during aging. Behavioral traits such as low education, smoking, poor diet, neglect of oral health, lack of exercise, and hypertension are few of the risk factors that are shared commonly among these conditions. In addition, common genetic susceptibility traits such as the apolipoprotein E gene, together with an individual's lifestyle can also influence the development of co-morbidities such as periodontitis, atherosclerosis/stroke, diabetes, and Alzheimer's disease. This review specifically addresses the susceptibility of apolipoprotein E gene allele 4 as the plausible commonality for the etiology of co-morbidities that eventually result from periodontal diseases and ultimately progress to dementia.

Porphyromonas gingivalis Periodontal Infection and Its Putative Links with Alzheimer's Disease.

Periodontal disease (PD) and Alzheimer's disease (AD) are inflammatory conditions affecting the global adult population. In the pathogenesis of PD, subgingival complex bacterial biofilm induces inflammation that leads to connective tissue degradation and alveolar bone resorption around the teeth. In health, junctional epithelium seals the gingiva to the tooth enamel, thus preventing bacteria from entering the gingivae. Chronic PD involves major pathogens (Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia) which have an immune armoury that can circumvent host's immune surveillance to create and maintain an inflammatory mediator rich and toxic environment to grow and survive. The neurodegenerative condition, AD, is characterised by poor memory and specific hallmark proteins; periodontal pathogens are increasingly being linked with this dementing condition. It is therefore becoming important to understand associations of periodontitis with relevance to late-onset AD. The aim of this review is to discuss the relevance of finding the keystone periodontal pathogen P. gingivalis in AD brains and its plausible contribution to the aetiological hypothesis of this dementing condition.

Oral inflammation, tooth loss, risk factors, and association with progression of Alzheimer's disease.

Periodontitis is a polymicrobial chronic inflammatory disease of tooth-supporting tissues with bacterial etiology affecting all age groups, becoming chronic in a subgroup of older individuals. Periodontal pathogens Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola are implicated in the development of a number of inflammatory pathologies at remote organ sites, including Alzheimer's disease (AD). The initial inflammatory hypothesis proposed that AD hallmark proteins were the main contributors of central nervous system (CNS) inflammation. This hypothesis is expanding to include the role of infections, lifestyle, and genetic and environmental factors in the pathogenesis of AD. Periodontal disease (PD) typifies a condition that encompasses all of the above factors including pathogenic bacteria. These bacteria not only are the source of low-grade, chronic infection and inflammation that follow daily episodes of bacteremia arising from everyday tasks such as brushing, flossing teeth, chewing food, and during dental procedures, but they also disseminate into the brain from closely related anatomical pathways. The long-term effect of inflammatory mediators, pathogens, and/or their virulence factors, reaching the brain systemically or otherwise would, over time, prime the brain's own microglia in individuals who have inherent susceptibility traits. Such susceptibilities contribute to inadequate neutralization of invading agents, upon reaching the brain. This has the capacity to create a vicious cycle of sustained local inflammatory milieu resulting in the loss of cytoarchitectural integrity and vital neurons with subsequent loss of function (deterioration in memory). The possible pathways between PD and AD development are considered here, as well as environmental factors that may modulate/exacerbate AD symptoms.