Microglia either promote or restrain TRAIL-mediated excitotoxicity caused by Aß1-42 oligomers.

BACKGROUND: Alzheimer's disease (AD) features progressive neurodegeneration and microglial activation that results in dementia and cognitive decline. The release of soluble amyloid (Aß) oligomers into the extracellular space is an early feature of AD pathology. This can promote excitotoxicity and microglial activation. Microglia can adopt several activation states with various functional outcomes. Protective microglial activation states have been identified in response to Aß plaque pathology in vivo. However, the role of microglia and immune mediators in neurotoxicity induced by soluble Aß oligomers is unclear. Further, there remains a need to identify druggable molecular targets that promote protective microglial states to slow or prevent the progression of AD. METHODS: Hippocampal entorhinal brain slice culture (HEBSC) was employed to study mechanisms of Aß1-42 oligomer-induced neurotoxicity as well as the role of microglia. The roles of glutamate hyperexcitation and immune signaling in Aß-induced neurotoxicity were assessed using MK801 and neutralizing antibodies to the TNF-related apoptosis-inducing ligand (TRAIL) respectively. Microglial activation state was manipulated using Gi-hM4di designer receptor exclusively activated by designer drugs (DREADDs), microglial depletion with the colony-stimulating factor 1 receptor (CSF1R) antagonist PLX3397, and microglial repopulation (PLX3397 withdrawal). Proteomic changes were assessed by LC-MS/MS in microglia isolated from control, repopulated, or Aß-treated HEBSCs. RESULTS: Neurotoxicity induced by soluble Aß1-42 oligomers involves glutamatergic hyperexcitation caused by the proinflammatory mediator and death receptor ligand TRAIL. Microglia were found to have the ability to both promote and restrain Aß-induced toxicity. Induction of microglial Gi-signaling with hM4di to prevent pro-inflammatory activation blunted Aß neurotoxicity, while microglial depletion with CSF1R antagonism worsened neurotoxicity caused by Aß as well as TRAIL. HEBSCs with repopulated microglia, however, showed a near complete resistance to Aß-induced neurotoxicity. Comparison of microglial proteomes revealed that repopulated microglia have a baseline anti-inflammatory and trophic phenotype with a predicted pathway activation that is nearly opposite that of Aß-exposed microglia. mTORC2 and IRF7 were identified as potential targets for intervention. CONCLUSION: Microglia are key mediators of both protection and neurodegeneration in response to Aß. Polarizing microglia toward a protective state could be used as a preventative strategy against Aß-induced neurotoxicity.

Alcohol, HMGB1, and Innate Immune Signaling in the Brain.

PURPOSE: Binge drinking (i.e., consuming enough alcohol to achieve a blood ethanol concentration of 80 mg/dL, approximately 4-5 drinks within 2 hours), particularly in early adolescence, can promote progressive increases in alcohol drinking and alcohol-related problems that develop into compulsive use in the chronic relapsing disease, alcohol use disorder (AUD). Over the past decade, neuroimmune signaling has been discovered to contribute to alcohol-induced changes in drinking, mood, and neurodegeneration. This review presents a mechanistic hypothesis supporting high mobility group box protein 1 (HMGB1) and Toll-like receptor (TLR) signaling as key elements of alcohol-induced neuroimmune signaling across glia and neurons, which shifts gene transcription and synapses, altering neuronal networks that contribute to the development of AUD. This hypothesis may help guide further research on prevention and treatment. SEARCH METHODS: The authors used the search terms "HMGB1 protein," "alcohol," and "brain" across PubMed, Scopus, and Embase to find articles published between 1991 and 2023. SEARCH RESULTS: The database search found 54 references in PubMed, 47 in Scopus, and 105 in Embase. A total of about 100 articles were included. DISCUSSION AND CONCLUSIONS: In the brain, immune signaling molecules play a role in normal development that differs from their functions in inflammation and the immune response, although cellular receptors and signaling are shared. In adults, pro-inflammatory signals have emerged as contributing to brain adaptation in stress, depression, AUD, and neurodegenerative diseases. HMGB1, a cytokine-like signaling protein released from activated cells, including neurons, is hypothesized to activate pro-inflammatory signals through TLRs that contribute to adaptations to binge and chronic heavy drinking. HMGB1 alone and in heteromers with other molecules activates TLRs and other immune receptors that spread signaling across neurons and glia. Both blood and brain levels of HMGB1 increase with ethanol exposure. In rats, an adolescent intermittent ethanol (AIE) binge drinking model persistently increases brain HMGB1 and its receptors; alters microglia, forebrain cholinergic neurons, and neuronal networks; and increases alcohol drinking and anxiety while disrupting cognition. Studies of human postmortem AUD brain have found elevated levels of HMGB1 and TLRs. These signals reduce cholinergic neurons, whereas microglia, the brain's immune cells, are activated by binge drinking. Microglia regulate synapses through complement proteins that can change networks affected by AIE that increase drinking, contributing to risks for AUD. Anti-inflammatory drugs, exercise, cholinesterase inhibitors, and histone deacetylase epigenetic inhibitors prevent and reverse the AIE-induced pathology. Further, HMGB1 antagonists and other anti-inflammatory treatments may provide new therapies for alcohol misuse and AUD. Collectively, these findings suggest that restoring the innate immune signaling balance is central to recovering from alcohol-related pathology.

Thermal profiles of Cicindelidia haemorrhagica (Coleoptera: Cicindelidae) activity in hot springs in Yellowstone National Park.

The wetsalts tiger beetle, Cicindelidia haemorrhagica (LeConte) (Coleoptera: Cicindelidae), is found in several active thermal hot spring areas in Yellowstone National Park (YNP) where substrate surface temperatures can exceed 50 °C. However, relationships between surface temperatures and the time adults spend on them remain poorly understood. Therefore, we characterized thermal profiles of Dragon Spring and Rabbit Creek, 2 thermally active research sites containing C. haemorrhagica in YNP, to quantify the time adults spend at different surface temperatures. We took 58 thermal video recordings of adults over 6 total days of observation ranging from 10 to 15 min for each adult. Thermal video analysis results indicated a positive relationship between the total time adult beetles spent on surface temperatures from Dragon Spring and Rabbit Creek as temperatures increased from 20 °C. Once surface temperatures exceeded 40 °C, the total time spent at those surface temperatures declined. Adults were recorded on substrates exceeding 50 °C at one of the 2 research locations. Rabbit Creek had substantially more instances of adults present with surface temperatures exceeding 40 °C, including one individual on a surface temperature of 61.5 °C. There were 3 instances of beetles spending more than 4 min at a particular surface temperature, all within the preferred range of 30-40 °C. Our thermal profile results and previous behavioral observations suggest that adults may be resistant to the heat produced from the thermal waters that influence the substrate temperatures but may not be subject to high surface temperatures as previously reported.

Development Modeling of Phormia regina (Diptera: Calliphoridae).

A series of experiments were conducted on Phormia regina, a forensically important blow fly species, that met the requirements needed to create statistically valid development models. Experiments were conducted over 11 temperatures (7.5 to 32.5 °C, at 2.5 °C intervals) with a 16:8 L:D cycle. Experimental units contained 20 eggs, 10 g of beef liver, and 2.5 cm of sand. Each life stage (egg to adult) had five sampling times. Each sampling time was replicated four times for a total of 20 measurements per life stage. For each sampling time, the cups were pulled from the chambers, and the stage of each maggot was documented morphologically through posterior spiracular slits and cephalopharyngeal development. Data were normally distributed with the later larval (L3m) and pupation stages having the most variation within and transitioning between stages, particularly between 12.5 °C and 20.0 °C. The biological minimum was between 10.0 °C and 12.5 °C, with little egg development and no egg emergence at 7.5 °C and no maturation past L1 at 10.0 °C. Phormia regina did not display increased mortality associated with the upper temperature of 32.5 °C. The development data generated illustrate the advantages of large data sets in modeling blow fly development and the need for curvilinear models in describing development at environmental temperatures near the biological minima and maxima.

PAQR4 regulates adipocyte function and systemic metabolic health by mediating ceramide levels.

PAQR4 is an orphan receptor in the PAQR family with an unknown function in metabolism. Here, we identify a critical role of PAQR4 in maintaining adipose tissue function and whole-body metabolic health. We demonstrate that expression of Paqr4 specifically in adipocytes, in an inducible and reversible fashion, leads to partial lipodystrophy, hyperglycaemia and hyperinsulinaemia, which is ameliorated by wild-type adipose tissue transplants or leptin treatment. By contrast, deletion of Paqr4 in adipocytes improves healthy adipose remodelling and glucose homoeostasis in diet-induced obesity. Mechanistically, PAQR4 regulates ceramide levels by mediating the stability of ceramide synthases (CERS2 and CERS5) and, thus, their activities. Overactivation of the PQAR4-CERS axis causes ceramide accumulation and impairs adipose tissue function through suppressing adipogenesis and triggering adipocyte de-differentiation. Blocking de novo ceramide biosynthesis rescues PAQR4-induced metabolic defects. Collectively, our findings suggest a critical function of PAQR4 in regulating cellular ceramide homoeostasis and targeting PAQR4 offers an approach for the treatment of metabolic disorders.

Blue Light Compromises Bacterial ß-Lactamases Activity to Overcome ß-Lactam Resistance.

OBJECTIVE: In this study, we evaluated the effectiveness of antimicrobial blue light (aBL; 410 nm wavelength) against ß-lactamase-carrying bacteria and the effect of aBL on the activity of ß-lactamases. METHODS: Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae strains carrying ß-lactamases as well as a purified ß-lactamase enzymes were studied. ß-lactamase activity was assessed using a chromogenic cephalosporin hydrolysis assay. Additionally, we evaluated the role of porphyrins in the photoreaction, as well as protein degradation by sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Finally, we investigated the bactericidal effect of combined aBL-ceftazidime exposure against a metallo-ß-lactamase expressing P. aeruginosa strain. RESULTS: Our study demonstrated that aBL effectively killed ß-lactamase-producing bacteria and reduced ß-lactamase activity. After an aBL exposure of 1.52 J/cm2, a 50% reduction in enzymatic activity was observed in P. aeruginosa. Additionally, we found a 40% decrease in the photoreaction activity of porphyrins following an aBL exposure of 64.8 J/cm2. We also revealed that aBL reduced ß-lactamase activity via protein degradation (after 136.4 J/cm2). Additionally, aBL markedly improved the bactericidal effect of ceftazidime (by >4-log10) in the metallo-ß-lactamase P. aeruginosa strain. CONCLUSION: Our results provide evidence that aBL compromises bacterial ß-lactamase activity, offering a potential approach to overcome ß-lactam resistance in bacteria.

Loss of neuronal lysosomal acid lipase drives amyloid pathology in Alzheimer's disease.

Underlying drivers of late-onset Alzheimer's disease (LOAD) pathology remain unknown. However, multiple biologically diverse risk factors share a common pathological progression. To identify convergent molecular abnormalities that drive LOAD pathogenesis we compared two common midlife risk factors for LOAD, heavy alcohol use and obesity. This revealed that disrupted lipophagy is an underlying cause of LOAD pathogenesis. Both exposures reduced lysosomal flux, with a loss of neuronal lysosomal acid lipase (LAL). This resulted in neuronal lysosomal lipid (NLL) accumulation, which opposed Aß localization to lysosomes. Neuronal LAL loss both preceded (with aging) and promoted (targeted knockdown) Aß pathology and cognitive deficits in AD mice. The addition of recombinant LAL ex vivo and neuronal LAL overexpression in vivo prevented amyloid increases and improved cognition. In WT mice, neuronal LAL declined with aging and correlated negatively with entorhinal Aß. In healthy human brain, LAL also declined with age, suggesting this contributes to the age-related vulnerability for AD. In human LOAD LAL was further reduced, correlated negatively with Aß1-42, and occurred with polymerase pausing at the LAL gene. Together, this finds that the loss of neuronal LAL promotes NLL accumulation to impede degradation of Aß in neuronal lysosomes to drive AD amyloid pathology.

Use of neurological criteria to declare death in children.

Accurate determination of death is a necessary responsibility of the medical profession. Brain death, or death by neurological criteria (DNC), can be legally declared after the determination of permanent loss of clinical brain function, including the capacity for consciousness, brainstem reflexes, and the ability to breathe spontaneously. Despite longstanding debates over the exact definition of brain death or DNC and how it is determined, most middle- and high-income countries have compatible medical protocols and legal policies for brain death or DNC. This review summarizes the 2023 updated guidelines for brain death or DNC determination, which integrate adult and pediatric diagnostic criteria. We discuss the clinical challenges related to brain death or DNC determination in infants and young children. We emphasize that physicians must follow the standardized and meticulous evaluation processes outlined in these guidelines to reduce diagnostic error and ensure no false positive determinations. An essential component of the brain death or DNC evaluation is appropriate and transparent communication with families. Ongoing efforts to promote consistency and legal uniformity in the declaration of death are needed.

The Enigma of Methanol Synthesis by Cu/ZnO/Al2O3-Based Catalysts.

The activity and durability of the Cu/ZnO/Al2O3 (CZA) catalyst formulation for methanol synthesis from CO/CO2/H2 feeds far exceed the sum of its individual components. As such, this ternary catalytic system is a prime example of synergy in catalysis, one that has been employed for the large scale commercial production of methanol since its inception in the mid 1960s with precious little alteration to its original formulation. Methanol is a key building block of the chemical industry. It is also an attractive energy storage molecule, which can also be produced from CO2 and H2 alone, making efficient use of sequestered CO2. As such, this somewhat unusual catalyst formulation has an enormous role to play in the modern chemical industry and the world of global economics, to which the correspondingly voluminous and ongoing research, which began in the 1920s, attests. Yet, despite this commercial success, and while research aimed at understanding how this formulation functions has continued throughout the decades, a comprehensive and universally agreed upon understanding of how this material achieves what it does has yet to be realized. After nigh on a century of research into CZA catalysts, the purpose of this Review is to appraise what has been achieved to date, and to show how, and how far, the field has evolved. To do so, this Review evaluates the research regarding this catalyst formulation in a chronological order and critically assesses the validity and novelty of various hypotheses and claims that have been made over the years. Ultimately, the Review attempts to derive a holistic summary of what the current body of literature tells us about the fundamental sources of the synergies at work within the CZA catalyst and, from this, suggest ways in which the field may yet be further advanced.

Hippocampal sclerosis and temporal lobe epilepsy following febrile status epilepticus: The FEBSTAT study.

OBJECTIVE: This study was undertaken to determine whether hippocampal T2 hyperintensity predicts sequelae of febrile status epilepticus, including hippocampal atrophy, sclerosis, and mesial temporal lobe epilepsy. METHODS: Acute magnetic resonance imaging (MRI) was obtained within a mean of 4.4 (SD = 5.5, median = 2.0) days after febrile status on >200 infants with follow-up MRI at approximately 1, 5, and 10 years. Hippocampal size, morphology, and T2 signal intensity were scored visually by neuroradiologists blinded to clinical details. Hippocampal volumetry provided quantitative measurement. Upon the occurrence of two or more unprovoked seizures, subjects were reassessed for epilepsy. Hippocampal volumes were normalized using total brain volumes. RESULTS: Fourteen of 22 subjects with acute hippocampal T2 hyperintensity returned for follow-up MRI, and 10 developed definite hippocampal sclerosis, which persisted through the 10-year follow-up. Hippocampi appearing normal initially remained normal on visual inspection. However, in subjects with normal-appearing hippocampi, volumetrics indicated that male, but not female, hippocampi were smaller than controls, but increasing hippocampal asymmetry was not seen following febrile status. Forty-four subjects developed epilepsy; six developed mesial temporal lobe epilepsy and, of the six, two had definite, two had equivocal, and two had no hippocampal sclerosis. Only one subject developed mesial temporal epilepsy without initial hyperintensity, and that subject had hippocampal malrotation. Ten-year cumulative incidence of all types of epilepsy, including mesial temporal epilepsy, was highest in subjects with initial T2 hyperintensity and lowest in those with normal signal and no other brain abnormalities. SIGNIFICANCE: Hippocampal T2 hyperintensity following febrile status epilepticus predicted hippocampal sclerosis and significant likelihood of mesial temporal lobe epilepsy. Normal hippocampal appearance in the acute postictal MRI was followed by maintained normal appearance, symmetric growth, and lower risk of epilepsy. Volumetric measurement detected mildly decreased hippocampal volume in males with febrile status.

Quantifying Förster Resonance Energy Transfer from Single Perovskite Quantum Dots to Organic Dyes.

Colloidal quantum dots (QDs) are promising regenerable photoredox catalysts offering broadly tunable redox potentials along with high absorption coefficients. QDs have thus far been examined for various organic transformations, water splitting, and CO2 reduction. Vast opportunities emerge from coupling QDs with other homogeneous catalysts, such as transition metal complexes or organic dyes, into hybrid nanoassemblies exploiting energy transfer (ET), leveraging a large absorption cross-section of QDs and long-lived triplet states of cocatalysts. However, a thorough understanding and further engineering of the complex operational mechanisms of hybrid nanoassemblies require simultaneously controlling the surface chemistry of the QDs and probing dynamics at sufficient spatiotemporal resolution. Here, we probe the ET from single lead halide perovskite QDs, capped by alkylphospholipid ligands, to organic dye molecules employing single-particle photoluminescence spectroscopy with single-photon resolution. We identify a Förster-type ET by spatial, temporal, and photon-photon correlations in the QD and dye emission. Discrete quenching steps in the acceptor emission reveal stochastic photobleaching events of individual organic dyes, allowing a precise quantification of the transfer efficiency, which is >70% for QD-dye complexes with strong donor-acceptor spectral overlap. Our work explores the processes occurring at the QD/molecule interface and demonstrates the feasibility of sensitizing organic photocatalysts with QDs.

A case report of riboflavin transporter deficiency: A novel heterozygous pathogenic variant in the SLC52A3 gene.

Riboflavin transporter deficiency (RTD) is a neurodegenerative disorder that presents from infancy to adulthood with a progressive axonal neuropathy characterized by a variety of neurologic symptoms including hearing loss, weakness, bulbar palsy, and respiratory insufficiency. Pathogenic variants in SLC52A2 and SLC52A3 are implicated in the pathogenesis of RTD type 2 and 3, respectively. Early identification of this disorder is critical, as it is treatable with riboflavin supplementation. We describe a 16-year-old female with a phenotype consistent with RTD3 found to have a novel heterozygous SLC52A3 variant. Though RTD is typically considered an autosomal recessive condition, her heterozygous variant was thought to be disease causing after further genetic analysis and given her improvement in response to riboflavin supplementation. This case highlights the importance of reinterpretation of genetic testing, particularly when there is a high clinical suspicion for disease.

An integrative taxonomy study reveals a rare new species of the genus Creptotrema (Trematoda: Allocreadiidae) in an endangered frog in South America.

During an ecological study with a near-endangered anuran in Brazil, the Schmidt's Spinythumb frog, Crossodactylus schmidti Gallardo, 1961, we were given a chance to analyze the gastrointestinal tract of a few individuals for parasites. In this paper, we describe a new species of an allocreadiid trematode of the genus Creptotrema Travassos, Artigas & Pereira, 1928, which possesses a unique trait among allocreadiids (i.e., a bivalve shell-like muscular structure at the opening of the ventral sucker); the new species represents the fourth species of allocreadiid trematode parasitizing amphibians. Besides, the new species is distinguished from other congeners by the combination of characters such as the body size, ventral sucker size, cirrus-sac size, and by having small eggs. DNA sequences through the 28S rDNA and COI mtDNA further corroborated the distinction of the new species. Phylogenetic analyses placed the newly generated sequences in a monophyletic clade together with all other sequenced species of Creptotrema. Genetic divergences between the new species and other Creptotrema spp. varied from 2.0 to 4.2% for 28S rDNA, and 15.1 to 16.8% for COI mtDNA, providing robust validation for the recognition of the new species. Even though allocreadiids are mainly parasites of freshwater fishes, our results confirm anurans as hosts of trematodes of this family. Additionally, we propose the reallocation of Auriculostoma ocloya Liquin, Gilardoni, Cremonte, Saravia, Cristóbal & Davies, 2022 to the genus Creptotrema. This study increases the known diversity of allocreadiids and contributes to our understanding of their evolutionary relationships, host-parasite relationships, and biogeographic history.

Colloidal Aziridinium Lead Bromide Quantum Dots.

The compositional engineering of lead-halide perovskite nanocrystals (NCs) via the A-site cation represents a lever to fine-tune their structural and electronic properties. However, the presently available chemical space remains minimal since, thus far, only three A-site cations have been reported to favor the formation of stable lead-halide perovskite NCs, i.e., Cs+, formamidinium (FA), and methylammonium (MA). Inspired by recent reports on bulk single crystals with aziridinium (AZ) as the A-site cation, we present a facile colloidal synthesis of AZPbBr3 NCs with a narrow size distribution and size tunability down to 4 nm, producing quantum dots (QDs) in the regime of strong quantum confinement. NMR and Raman spectroscopies confirm the stabilization of the AZ cations in the locally distorted cubic structure. AZPbBr3 QDs exhibit bright photoluminescence with quantum efficiencies of up to 80%. Stabilized with cationic and zwitterionic capping ligands, single AZPbBr3 QDs exhibit stable single-photon emission, which is another essential attribute of QDs. In particular, didodecyldimethylammonium bromide and 2-octyldodecyl-phosphoethanolamine ligands afford AZPbBr3 QDs with high spectral stability at both room and cryogenic temperatures, reduced blinking with a characteristic ON fraction larger than 85%, and high single-photon purity (g(2)(0) = 0.1), all comparable to the best-reported values for MAPbBr3 and FAPbBr3 QDs of the same size.

Heavy metal movement through insect food chains in pristine thermal springs of Yellowstone National Park.

Yellowstone National Park thermal features regularly discharge various heavy metals and metalloids. These metals are taken up by microorganisms that often form mats in thermal springs. These microbial mats also serve as food sources for invertebrate assemblages. To examine how heavy metals move through insect food webs associated with hot springs, two sites were selected for this study. Dragon-Beowulf Hot Springs, acid-sulfate chloride springs, have a pH of 2.9, water temperatures above 70 °C, and populations of thermophilic bacterial, archaeal, and algal mats. Rabbit Creek Hot Springs, alkaline springs, have a pH of up to 9, some water temperatures in excess of 60 °C, and are populated with thermophilic and phototrophic bacterial mats. Mats in both hydrothermal systems form the trophic base and support active metal transfer to terrestrial food chains. In both types of springs, invertebrates bioaccumulated heavy metals including chromium, manganese, cobalt, nickel, copper, cadmium, mercury, tin and lead, and the metalloids arsenic, selenium, and antimony resulting from consuming the algal and bacterial mat biomass. At least two orders of magnitude increase in concentrations were observed in the ephydrid shore fly Paracoenia turbida, as compared to the mats for all metals except antimony, mercury, and lead. The highest bioaccumulation factor (BAF) of 729 was observed for chromium. At the other end of the food web, the invertebrate apex predator, Cicindelidia haemorrhagica, had at least a 10-fold BAF for all metals at some location-year combinations, except with antimony. Of other taxa, high BAFs were observed with zinc for Nebria sp. (2180) and for Salda littoralis (1080). This accumulation, occurring between primary producer and primary consumer trophic levels at both springs, is biomagnified through the trophic web. These observations suggest trace metals enter the geothermal food web through the microbial mat community and are then transferred through the food chain. Also, while bioaccumulation of arsenic is uncommon, we observed five instances of increases near or exceeding 10-fold: Odontomyia sp. larvae (13.6), P. turbida (34.8), C. haemorrhagica (9.7), Rhagovelia distincta (16.3), and Ambrysus mormon (42.8).

A new species of Urocleidoides Mizelle & Price, 1964 from the gills of Schizodon nasutus Kner, 1858 (Characiformes, Anostomidae) in southeastern Brazil.

Based on an integrative approach, this study describes a new species of Urocleidoides infesting Schizodon nasutus in the Paranapanema River basin, Brazil. The new species can be distinguished from its congeners by specific morphological features, including the shape of the male copulatory organ and accessory piece, the ventral bar shape, and the shape and size of the hooks. Molecular analyses, particularly of the 28S rDNA gene, suggest a close relationship between the new species and Urocleidoides paradoxus. The phylogenetic and taxonomic arrangement of Urocleidoides is discussed, as the analyses of the 28S rDNA and COI mtDNA resolved the genus as non-monophyletic, with Diaphorocleidus, Rhinoxenus, and Cacatuocotyle nested within it. Additional morphological and molecular data of other congeneric species are required to investigate the phylogenetic position and classification of Urocleidoides. This study underscores the significance of using integrative approaches in understanding host-parasite associations and phylogenetic relationships, contributing to the description of the freshwater fish parasite biodiversity in South America, particularly in the Paranapanema river basin.

Single-photon superradiance in individual caesium lead halide quantum dots.

The brightness of an emitter is ultimately described by Fermi's golden rule, with a radiative rate proportional to its oscillator strength times the local density of photonic states. As the oscillator strength is an intrinsic material property, the quest for ever brighter emission has relied on the local density of photonic states engineering, using dielectric or plasmonic resonators1,2. By contrast, a much less explored avenue is to boost the oscillator strength, and hence the emission rate, using a collective behaviour termed superradiance. Recently, it was proposed3 that the latter can be realized using the giant oscillator-strength transitions of a weakly confined exciton in a quantum well when its coherent motion extends over many unit cells. Here we demonstrate single-photon superradiance in perovskite quantum dots with a sub-100 picosecond radiative decay time, almost as short as the reported exciton coherence time4. The characteristic dependence of radiative rates on the size, composition and temperature of the quantum dot suggests the formation of giant transition dipoles, as confirmed by effective-mass calculations. The results aid in the development of ultrabright, coherent quantum light sources and attest that quantum effects, for example, single-photon emission, persist in nanoparticles ten times larger than the exciton Bohr radius.

A scalable federated learning solution for secondary care using low-cost microcomputing: privacy-preserving development and evaluation of a COVID-19 screening test in UK hospitals.

BACKGROUND: Multicentre training could reduce biases in medical artificial intelligence (AI); however, ethical, legal, and technical considerations can constrain the ability of hospitals to share data. Federated learning enables institutions to participate in algorithm development while retaining custody of their data but uptake in hospitals has been limited, possibly as deployment requires specialist software and technical expertise at each site. We previously developed an artificial intelligence-driven screening test for COVID-19 in emergency departments, known as CURIAL-Lab, which uses vital signs and blood tests that are routinely available within 1 h of a patient's arrival. Here we aimed to federate our COVID-19 screening test by developing an easy-to-use embedded system-which we introduce as full-stack federated learning-to train and evaluate machine learning models across four UK hospital groups without centralising patient data. METHODS: We supplied a Raspberry Pi 4 Model B preloaded with our federated learning software pipeline to four National Health Service (NHS) hospital groups in the UK: Oxford University Hospitals NHS Foundation Trust (OUH; through the locally linked research University, University of Oxford), University Hospitals Birmingham NHS Foundation Trust (UHB), Bedfordshire Hospitals NHS Foundation Trust (BH), and Portsmouth Hospitals University NHS Trust (PUH). OUH, PUH, and UHB participated in federated training, training a deep neural network and logistic regressor over 150 rounds to form and calibrate a global model to predict COVID-19 status, using clinical data from patients admitted before the pandemic (COVID-19-negative) and testing positive for COVID-19 during the first wave of the pandemic. We conducted a federated evaluation of the global model for admissions during the second wave of the pandemic at OUH, PUH, and externally at BH. For OUH and PUH, we additionally performed local fine-tuning of the global model using the sites' individual training data, forming a site-tuned model, and evaluated the resultant model for admissions during the second wave of the pandemic. This study included data collected between Dec 1, 2018, and March 1, 2021; the exact date ranges used varied by site. The primary outcome was overall model performance, measured as the area under the receiver operating characteristic curve (AUROC). Removable micro secure digital (microSD) storage was destroyed on study completion. FINDINGS: Clinical data from 130 941 patients (1772 COVID-19-positive), routinely collected across three hospital groups (OUH, PUH, and UHB), were included in federated training. The evaluation step included data from 32 986 patients (3549 COVID-19-positive) attending OUH, PUH, or BH during the second wave of the pandemic. Federated training of a global deep neural network classifier improved upon performance of models trained locally in terms of AUROC by a mean of 27·6% (SD 2·2): AUROC increased from 0·574 (95% CI 0·560-0·589) at OUH and 0·622 (0·608-0·637) at PUH using the locally trained models to 0·872 (0·862-0·882) at OUH and 0·876 (0·865-0·886) at PUH using the federated global model. Performance improvement was smaller for a logistic regression model, with a mean increase in AUROC of 13·9% (0·5%). During federated external evaluation at BH, AUROC for the global deep neural network model was 0·917 (0·893-0·942), with 89·7% sensitivity (83·6-93·6) and 76·6% specificity (73·9-79·1). Site-specific tuning of the global model did not significantly improve performance (change in AUROC <0·01). INTERPRETATION: We developed an embedded system for federated learning, using microcomputing to optimise for ease of deployment. We deployed full-stack federated learning across four UK hospital groups to develop a COVID-19 screening test without centralising patient data. Federation improved model performance, and the resultant global models were generalisable. Full-stack federated learning could enable hospitals to contribute to AI development at low cost and without specialist technical expertise at each site. FUNDING: The Wellcome Trust, University of Oxford Medical and Life Sciences Translational Fund.

CRISPR-Cas9 base editing of pathogenic CaMKIIδ improves cardiac function in a humanized mouse model.

Cardiovascular diseases are the most common cause of worldwide morbidity and mortality, highlighting the necessity for advanced therapeutic strategies. Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) is a prominent inducer of various cardiac disorders, which is mediated by 2 oxidation-sensitive methionine residues within the regulatory domain. We have previously shown that ablation of CaMKIIδ oxidation by CRISPR-Cas9 base editing enables the heart to recover function from otherwise severe damage following ischemia/reperfusion (IR) injury. Here, we extended this therapeutic concept toward potential clinical translation. We generated a humanized CAMK2D knockin mouse model in which the genomic sequence encoding the entire regulatory domain was replaced with the human sequence. This enabled comparison and optimization of two different editing strategies for the human genome in mice. To edit CAMK2D in vivo, we packaged the optimized editing components into an engineered myotropic adeno-associated virus (MyoAAV 2A), which enabled efficient delivery at a very low AAV dose into the humanized mice at the time of IR injury. CAMK2D-edited mice recovered cardiac function, showed improved exercise performance, and were protected from myocardial fibrosis, which was otherwise observed in injured control mice after IR. Our findings identify a potentially effective strategy for cardioprotection in response to oxidative damage.