Kynurenic acid (KYNA), an astrocyte-derived metabolite, antagonizes the α7 nicotinic acetylcholine receptor (α7nAChR) and, possibly, the glycine co-agonist site of the NMDA receptor at endogenous ...brain concentrations. As both receptors are involved in cognitive processes, KYNA elevations may aggravate, whereas reductions may improve, cognitive functions. We tested this hypothesis in rats by examining the effects of acute up- or downregulation of endogenous KYNA on extracellular glutamate in the hippocampus and on performance in the Morris water maze (MWM). Applied directly by reverse dialysis, KYNA (30-300 nM) reduced, whereas the specific kynurenine aminotransferase-II inhibitor (S)-4-(ethylsulfonyl)benzoylalanine (ESBA; 0.3-3 mM) raised, extracellular glutamate levels in the hippocampus. Co-application of KYNA (100 nM) with ESBA (1 mM) prevented the ESBA-induced glutamate increase. Comparable effects on hippocampal glutamate levels were seen after intra-cerebroventricular (i.c.v.) application of the KYNA precursor kynurenine (1 mM, 10 μl) or ESBA (10 mM, 10 μl), respectively. In separate animals, i.c.v. treatment with kynurenine impaired, whereas i.c.v. ESBA improved, performance in the MWM. I.c.v. co-application of KYNA (10 μM) eliminated the pro-cognitive effects of ESBA. Collectively, these studies show that KYNA serves as an endogenous modulator of extracellular glutamate in the hippocampus and regulates hippocampus-related cognitive function. Our results suggest that pharmacological interventions leading to acute reductions in hippocampal KYNA constitute an effective strategy for cognitive improvement. This approach might be especially useful in the treatment of cognitive deficits in neurological and psychiatric diseases that are associated with increased brain KYNA levels.
Seasonal influenza vaccines confer protection against specific viral strains but have restricted breadth that limits their protective efficacy. The H1 and H3 subtypes of influenza A virus cause most ...of the seasonal epidemics observed in humans and are the major drivers of influenza A virus-associated mortality. The consequences of pandemic spread of COVID-19 underscore the public health importance of prospective vaccine development. Here, we show that headless hemagglutinin (HA) stabilized-stem immunogens presented on ferritin nanoparticles elicit broadly neutralizing antibody (bnAb) responses to diverse H1 and H3 viruses in nonhuman primates (NHPs) when delivered with a squalene-based oil-in-water emulsion adjuvant, AF03. The neutralization potency and breadth of antibodies isolated from NHPs were comparable to human bnAbs and extended to mismatched heterosubtypic influenza viruses. Although NHPs lack the immunoglobulin germline VH1-69 residues associated with the most prevalent human stem-directed bnAbs, other gene families compensated to generate bnAbs. Isolation and structural analyses of vaccine-induced bnAbs revealed extensive interaction with the fusion peptide on the HA stem, which is essential for viral entry. Antibodies elicited by these headless HA stabilized-stem vaccines neutralized diverse H1 and H3 influenza viruses and shared a mode of recognition analogous to human bnAbs, suggesting that these vaccines have the potential to confer broadly protective immunity against diverse viruses responsible for seasonal and pandemic influenza infections in humans.
At endogenous brain concentrations, the astrocyte-derived metabolite kynurenic acid (KYNA) antagonizes the alpha 7 nicotinic acetylcholine receptor and, possibly, the glycine co-agonist site of the ...NMDA receptor. The functions of these two receptors, which are intimately involved in synaptic plasticity and cognitive processes, may, therefore, be enhanced by reductions in brain KYNA levels. This concept was tested in mice with a targeted deletion of kynurenine aminotransferase II (KAT II), a major biosynthetic enzyme of brain KYNA. At 21 days of age, KAT II knock-out mice had reduced hippocampal KYNA levels (-71%) and showed significantly increased performance in three cognitive paradigms that rely in part on the integrity of hippocampal function, namely object exploration and recognition, passive avoidance, and spatial discrimination. Moreover, compared with wild-type controls, hippocampal slices from KAT II-deficient mice showed a significant increase in the amplitude of long-term potentiation in vitro. These functional changes were accompanied by reduced extracellular KYNA (-66%) and increased extracellular glutamate (+51%) concentrations, measured by hippocampal microdialysis in vivo. Taken together, a picture emerges in which a reduction in the astrocytic formation of KYNA increases glutamatergic tone in the hippocampus and enhances cognitive abilities and synaptic plasticity. Our studies raise the prospect that interventions aimed specifically at reducing KYNA formation in the brain may constitute a promising molecular strategy for cognitive improvement in health and disease.
Worldwide, there are nearly 10 million new cases of dementia annually, of which Alzheimer's disease (AD) is the most common. New measures are needed to improve the diagnosis of individuals with ...cognitive impairment due to various etiologies. Here, we report a deep learning framework that accomplishes multiple diagnostic steps in successive fashion to identify persons with normal cognition (NC), mild cognitive impairment (MCI), AD, and non-AD dementias (nADD). We demonstrate a range of models capable of accepting flexible combinations of routinely collected clinical information, including demographics, medical history, neuropsychological testing, neuroimaging, and functional assessments. We then show that these frameworks compare favorably with the diagnostic accuracy of practicing neurologists and neuroradiologists. Lastly, we apply interpretability methods in computer vision to show that disease-specific patterns detected by our models track distinct patterns of degenerative changes throughout the brain and correspond closely with the presence of neuropathological lesions on autopsy. Our work demonstrates methodologies for validating computational predictions with established standards of medical diagnosis.
Coenzyme Q (CoQ or ubiquinone) serves as an essential redox-active lipid in respiratory electron and proton transport during cellular energy metabolism. CoQ also functions as a membrane-localized ...antioxidant protecting cells against lipid peroxidation. CoQ deficiency is associated with multiple human diseases; CoQ10 supplementation in particular has noted cardioprotective benefits. In Saccharomyces cerevisiae, Coq10, a putative START domain protein, is believed to chaperone CoQ to sites where it functions. Yeast coq10 deletion mutants (coq10Δ) synthesize CoQ inefficiently during log phase growth and are respiratory defective and sensitive to oxidative stress. Humans have two orthologs of yeast COQ10, COQ10A and COQ10B. Here, we tested the human co-orthologs for their ability to rescue the yeast mutant. We showed that expression of either human ortholog, COQ10A or COQ10B, rescues yeast coq10Δ mutant phenotypes, restoring the function of respiratory-dependent growth on a nonfermentable carbon source and sensitivity to oxidative stress induced by treatment with PUFAs. These effects indicate a strong functional conservation of Coq10 across different organisms. However, neither COQ10A nor COQ10B restored CoQ biosynthesis when expressed in the yeast coq10Δ mutant. The involvement of yeast Coq10 in CoQ biosynthesis may rely on its interactions with another protein, possibly Coq11, which is not found in humans. Coexpression analyses of yeast COQ10 and human COQ10A and COQ10B provide additional insights to functions of these START domain proteins and their potential roles in other biologic pathways.
GRB 221009A: The BOAT Burns, Eric; Svinkin, Dmitry; Fenimore, Edward ...
Astrophysical journal. Letters,
03/2023, Volume:
946, Issue:
1
Journal Article
Peer reviewed
Open access
Abstract GRB 221009A has been referred to as the brightest of all time (BOAT). We investigate the veracity of this statement by comparing it with a half century of prompt gamma-ray burst ...observations. This burst is the brightest ever detected by the measures of peak flux and fluence. Unexpectedly, GRB 221009A has the highest isotropic-equivalent total energy ever identified, while the peak luminosity is at the ∼99th percentile of the known distribution. We explore how such a burst can be powered and discuss potential implications for ultralong and high-redshift gamma-ray bursts. By geometric extrapolation of the total fluence and peak flux distributions, GRB 221009A appears to be a once-in-10,000-year event. Thus, it is almost certainly not the BOAT over all of cosmic history; it may be the brightest gamma-ray burst since human civilization began.
Rumination and its related mental phenomena share associated impairments in cognition, such as executive functions and attentional processes across different clinical conditions (e.g., in psychotic ...disorders). In recent decades, however, the notion of rumination has been increasingly narrowed to the "self-focused" type in depressive disorders. A closer review of the literature shows that rumination may be construed as a broader process characterized by repetitive thoughts about certain mental contents that interfere with one's daily activities, not only limited to those related to "self". A further examination of the construct of rumination beyond the narrowly focused depressive rumination would help expand intervention opportunities for mental disorders in today's context. We first review the development of the clinical construct of rumination with regard to its historical roots and its roles in psychopathology. This builds the foundation for the introduction of the "Flow Model of Rumination (FMR)", which conceptualizes rumination as a disruption of a smooth flow of mental contents in conscious experience that depends on the coordinated interactions between intention, memory, affect, and external events. The conceptual review concludes with a discussion of the impact of rapid technological advances (such as smartphones) on rumination. Particularly in contemporary societies today, a broader consideration of rumination not only from a cognition viewpoint, but also incorporating a human-device interaction perspective, is necessitated. The implications of the FMR in contemporary mental health practice are discussed.
Correspondence to Prof. Mindie H Nguyen, Stanford University Medical Center; Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, CA 94305, USA; mindiehn@stanford.edu ; Prof. ...Fanpu Ji, Department of Infectious Diseases, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China; jifanpu1979@163.com We read with interest the article by Dufour et al.1 The authors were to be commended for their comprehensive review on the presentations, pathophysiology and prognosis of COVID-19 in patients with chronic liver disease. Notably, the authors included data from multicentre and nationwide cohort studies to suggest decompensated cirrhosis as an independent risk factor for severe COVID-19 and death.1–6 However, while excess death from COVID-19 among patients with cirrhosis is important, the non-COVID-19-related excess death is integral in considering the degree of care disruption and delayed presentation, especially for those before 65 years of age. ...using the CDC WONDER website of the US National Vital Statistic System, which includes over 99% of deaths annually, we evaluated the percentage of excess years of potential life loss (YPLL) among individuals with cirrhosis during the pandemic and how much of these excess YPLL were directly versus indirectly related to COVID-19. ALD, alcohol-associated liver disease; HBV, hepatitis B virus infection; HCV, hepatitis C virus infection; NAFLD, non-alcoholic fatty liver disease; YPLL, years of potential life lost. ...returning to normal’ of healthcare access and reception should be the goal for all stakeholders.
Our aim was to evaluate the impact of race/ethnicity on cirrhosis-related premature death during the COVID-19 pandemic.
We obtained cirrhosis-related death data (n = 872,965, January 1, 2012-December ...31, 2021) from the US National Vital Statistic System to calculate age-standardized mortality rates and years of potential life lost (YPLL) for premature death aged 25-64 years.
Significant racial/ethnic disparity in cirrhosis-related age-standardized mortality rates was noted prepandemic but widened during the pandemic, with the highest excess YPLL for the non-Hispanic American Indian/American Native (2020: 41.0%; 2021: 68.8%) followed by other minority groups (28.7%-45.1%), and the non-Hispanic White the lowest (2020: 20.7%; 2021: 31.6%). COVID-19 constituted >30% of the excess YPLLs for Hispanic and non-Hispanic American Indian/American Native in 2020, compared with 11.1% for non-Hispanic White.
Ethnic minorities with cirrhosis experienced a disproportionate excess death and YPLLs in 2020-2021.
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