Deuterium-enriched water ties planet-forming disks to comets and protostars.

Water is a fundamental molecule in the star and planet formation process, essential for catalysing the growth of solid material and the formation of planetesimals within disks1,2. However, the water snowline and the HDO:H2O ratio within proto-planetary disks have not been well characterized because water only sublimates at roughly 160 K (ref. 3), meaning that most water is frozen out onto dust grains and that the water snowline radii are less than 10 AU (astronomical units)4,5. The sun-like protostar V883 Ori (M* = 1.3 M⊙)6 is undergoing an accretion burst7, increasing its luminosity to roughly 200 L⊙ (ref. 8), and previous observations suggested that its water snowline is 40-120 AU in radius6,9,10. Here we report the direct detection of gas phase water (HDO and [Formula: see text]) from the disk of V883 Ori. We measure a midplane water snowline radius of approximately 80 AU, comparable to the scale of the Kuiper Belt, and detect water out to a radius of roughly 160 AU. We then measure the HDO:H2O ratio of the disk to be (2.26 ± 0.63) × 10-3. This ratio is comparable to those of protostellar envelopes and comets, and exceeds that of Earth's oceans by 3.1σ. We conclude that disks directly inherit water from the star-forming cloud and this water becomes incorporated into large icy bodies, such as comets, without substantial chemical alteration.

Circadian clock protein Rev-erbα regulates neuroinflammation.

Circadian dysfunction is a common attribute of many neurodegenerative diseases, most of which are associated with neuroinflammation. Circadian rhythm dysfunction has been associated with inflammation in the periphery, but the role of the core clock in neuroinflammation remains poorly understood. Here we demonstrate that Rev-erbα, a nuclear receptor and circadian clock component, is a mediator of microglial activation and neuroinflammation. We observed time-of-day oscillation in microglial immunoreactivity in the hippocampus, which was disrupted in Rev-erbα-/- mice. Rev-erbα deletion caused spontaneous microglial activation in the hippocampus and increased expression of proinflammatory transcripts, as well as secondary astrogliosis. Transcriptomic analysis of hippocampus from Rev-erbα-/- mice revealed a predominant inflammatory phenotype and suggested dysregulated NF-κB signaling. Primary Rev-erbα-/- microglia exhibited proinflammatory phenotypes and increased basal NF-κB activation. Chromatin immunoprecipitation revealed that Rev-erbα physically interacts with the promoter regions of several NF-κB-related genes in primary microglia. Loss of Rev-erbα in primary astrocytes had no effect on basal activation but did potentiate the inflammatory response to lipopolysaccharide (LPS). In vivo, Rev-erbα-/- mice exhibited enhanced hippocampal neuroinflammatory responses to peripheral LPS injection, while pharmacologic activation of Rev-erbs with the small molecule agonist SR9009 suppressed LPS-induced hippocampal neuroinflammation. Rev-erbα deletion influenced neuronal health, as conditioned media from Rev-erbα-deficient primary glial cultures exacerbated oxidative damage in cultured neurons. Rev-erbα-/- mice also exhibited significantly altered cortical resting-state functional connectivity, similar to that observed in neurodegenerative models. Our results reveal Rev-erbα as a pharmacologically accessible link between the circadian clock and neuroinflammation.

Functional Characterization of the MYO6 Variant p.E60Q in Non-Syndromic Hearing Loss Patients.

Hereditary hearing loss (HHL) is a common genetic disorder accounting for at least 60% of pre-lingual deafness in children, of which 70% is inherited in an autosomal recessive pattern. The long tradition of consanguinity among the Qatari population has increased the prevalence of HHL, which negatively impacts the quality of life. Here, we functionally validated the pathogenicity of the c.178G>C, p.E60Q mutation in the MYO6 gene, which was detected previously in a Qatari HHL family, using cellular and animal models. In vitro analysis was conducted in HeLa cells transiently transfected with plasmids carrying MYO6WT or MYO6p.E60Q, and a zebrafish model was generated to characterize the in vivo phenotype. Cells transfected with MYO6WT showed higher expression of MYO6 in the plasma membrane and increased ATPase activity. Modeling the human MYO6 variants in zebrafish resulted in severe otic defects. At 72 h post-injection, MYO6p.E60Q embryos demonstrated alterations in the sizes of the saccule and utricle. Additionally, zebrafish with MYO6p.E60Q displayed super-coiled and bent hair bundles in otic hair cells when compared to control and MYO6WT embryos. In conclusion, our cellular and animal models add support to the in silico prediction that the p.E60Q missense variant is pathogenic and damaging to the protein. Since the c.178G>C MYO6 variant has a 0.5% allele frequency in the Qatari population, about 400 times higher than in other populations, it could contribute to explaining the high prevalence of hearing impairment in Qatar.

Bacterial sepsis increases hippocampal fibrillar amyloid plaque load and neuroinflammation in a mouse model of Alzheimer's disease.

BACKGROUND: Sepsis, a leading cause for intensive care unit admissions, causes both an acute encephalopathy and chronic brain dysfunction in survivors. A history of sepsis is also a risk factor for future development of dementia symptoms. Similar neuropathologic changes are associated with the cognitive decline of sepsis and Alzheimer's disease (AD), including neuroinflammation, neuronal death, and synaptic loss. Amyloid plaque pathology is the earliest pathological hallmark of AD, appearing 10 to 20 years prior to cognitive decline, and is present in 30% of people over 65. As sepsis is also more common in older adults, we hypothesized that sepsis might exacerbate amyloid plaque deposition and plaque-related injury, promoting the progression of AD-related pathology. METHODS: We evaluated whether the brain's response to sepsis modulates AD-related neurodegenerative changes by driving amyloid deposition and neuroinflammation in mice. We induced polymicrobial sepsis by cecal ligation and puncture (CLP) in APP/PS1-21 mice, a model of AD-related ß-amyloidosis. We performed CLP or sham surgery at plaque onset (2 months of age) and examined pathology 2 months after CLP in surviving mice. RESULTS: Sepsis significantly increased fibrillar amyloid plaque formation in the hippocampus of APP/PS1-21 mice. Sepsis enhanced plaque-related astrocyte activation and complement C4b gene expression in the brain, both of which may play a role in modulating amyloid formation. CLP also caused large scale changes in the gut microbiome of APP/PS1 mice, which have been associated with a pro-amyloidogenic and neuroinflammatory state. CONCLUSIONS: Our results suggest that experimental sepsis can exacerbate amyloid plaque deposition and plaque-related inflammation, providing a potential mechanism for increased dementia in older sepsis survivors.

Development of a novel method for estimating dermal contact with hand-applied cleaning solutions.

Quantitatively characterizing dermal exposure for workers and consumers performing tasks with hand-applied cleaning solution is complex as many of the assessment variables are scenario specific. One of the key variables necessary for quantitatively estimating dermal exposure is the surface area of the hand contacted by the cleaning solution. However, no relevant data or methods are available in the literature. This study evaluated the feasibility of a novel simulation approach to measure skin contact area specific to hand cleaning with various types of liquid cleaning products to refine exposure and risk estimates for users of these products. This approach incorporates cotton rags wetted with pigmented cleaning solutions, volunteers wearing white cotton gloves during hand cleaning with those cotton rags, and digital imaging of the pigmented solution-contacted gloves post-simulation to quantify area of the hand contacted by the cleaning solution. When applied across three separate cleaning solutions, a denatured alcohol, an aqueous solution, and a lacquer thinner, this novel method performed well in estimating both palmer and dorsal surface areas of the hand contacted during simulated cleaning. The volume of cleaning solution applied to the rag and thickness of the rag were consistent predictors of contacted surface area. For the denatured alcohol, the time spent cleaning was additionally correlated with contacted surface area. This study suggests that this novel simulation approach could be an important tool for reducing an important source of uncertainty in dermal exposure assessments involving hand-applied cleaning solutions.

B Cells Produce Type 1 IFNs in Response to the TLR9 Agonist CpG-A Conjugated to Cationic Lipids.

B cells express the innate receptor, TLR9, which signals in response to unmethylated CpG sequences in microbial DNA. Of the two major classes of CpG-containing oligonucleotides, CpG-A appears restricted to inducing type 1 IFN in innate immune cells and CpG-B to activating B cells to proliferate and produce Abs and inflammatory cytokines. Although CpGs are candidates for adjuvants to boost innate and adaptive immunity, our understanding of the effect of CpG-A and CpG-B on B cell responses is incomplete. In this study we show that both CpG-B and CpG-A activated B cells in vitro to proliferate, secrete Abs and IL-6, and that neither CpG-B nor CpG-A alone induced type 1 IFN production. However, when incorporated into the cationic lipid, DOTAP, CpG-A, but not CpG-B, induced a type 1 IFN response in B cells in vitro and in vivo. We provide evidence that differences in the function of CpG-A and CpG-B may be related to their intracellular trafficking in B cells. These findings fill an important gap in our understanding of the B cell response to CpGs, with implications for the use of CpG-A and CpG-B as immunomodulators.

T cell-dependent antigen adjuvanted with DOTAP-CpG-B but not DOTAP-CpG-A induces robust germinal center responses and high affinity antibodies in mice.

The development of vaccines for infectious diseases for which we currently have none, including HIV, will likely require the use of adjuvants that strongly promote germinal center responses and somatic hypermutation to produce broadly neutralizing antibodies. Here we compared the outcome of immunization with the T-cell dependent antigen, NP-conjugated to chicken gamma globulin (NP-CGG) adjuvanted with the toll-like receptor 9 (TLR9) ligands, CpG-A or CpG-B, alone or conjugated with the cationic lipid carrier, DOTAP. We provide evidence that only NP-CGG adjuvanted with DOTAP-CpG-B was an effective vaccine in mice resulting in robust germinal center responses, isotype switching and high affinity NP-specific antibodies. The effectiveness of DOTAP-CpG-B as an adjuvant was dependent on the expression of the TLR9 signaling adaptor MyD88 in immunized mice. These results indicate DOTAP-CpG-B but not DOTAP-CpG-A is an effective adjuvant for T cell-dependent protein antigen-based vaccines.

Potential Exposure and Cancer Risk from Formaldehyde Emissions from Installed Chinese Manufactured Laminate Flooring.

Lumber Liquidators (LL) Chinese-manufactured laminate flooring (CLF) has been installed in >400,000 U.S. homes over the last decade. To characterize potential associated formaldehyde exposures and cancer risks, chamber emissions data were collected from 399 new LL CLF, and from LL CLF installed in 899 homes in which measured aggregate indoor formaldehyde concentrations exceeded 100 µg/m3 from a total of 17,867 homes screened. Data from both sources were combined to characterize LL CLF flooring-associated formaldehyde emissions from new boards and installed boards. New flooring had an average (±SD) emission rate of 61.3 ± 52.1 µg/m2 -hour; >one-year installed boards had ∼threefold lower emission rates. Estimated emission rates for the 899 homes and corresponding data from questionnaires were used as inputs to a single-compartment, steady-state mass-balance model to estimate corresponding residence-specific TWA formaldehyde concentrations and potential resident exposures. Only ∼0.7% of those homes had estimated acute formaldehyde concentrations >100 µg/m3 immediately after LL CLF installation. The TWA daily formaldehyde inhalation exposure within the 899 homes was estimated to be 17 µg/day using California Proposition 65 default methods to extrapolate cancer risk (below the regulation "no significant risk level" of 40 µg/day). Using a U.S. Environmental Protection Agency linear cancer risk model, 50th and 95th percentile values of expected lifetime cancer risk for residents of these homes were estimated to be 0.33 and 1.2 per 100,000 exposed, respectively. Based on more recent data and verified nonlinear cancer risk assessment models, LL CLF formaldehyde emissions pose virtually no cancer risk to affected consumers.

Confluent Retropharyngeal, Lateral Pharyngeal, and Peritonsilar MRSA Abscess in an Infant.

Neck abscesses such as retropharyngeal, peritonsilar, and lateral pharyngeal are well described, typically cause a characteristic illness, and have a known epidemiology. We present a rare occurrence of case of confluent, mixed retropharyngeal, lateral pharyngeal, and peritonsilar abscess in a 9-month-old female infant. The symptoms at presentation were very mild and not expected in association with this extensive an abscess. The causative organism was methicillin-resistant Staphylococcus aureus.

Assessment of Health Risk from Historical Use of Cosmetic Talcum Powder.

This study's objective is to assess the risk of asbestos-related disease being contracted by past users of cosmetic talcum powder.  To our knowledge, no risk assessment studies using exposure data from historical exposures or chamber simulations have been published. We conducted activity-based sampling with cosmetic talcum powder samples from five opened and previously used containers that are believed to have been first manufactured and sold in the 1960s and 1970s.  These samples had been subject to conflicting claims of asbestos content; samples with the highest claimed asbestos content were tested.  The tests were conducted in simulated-bathroom controlled chambers with volunteers who were talc users.  Air sampling filters were prepared by direct preparation techniques and analyzed by phase contrast microscopy (PCM), transmission electron microscopy (TEM) with energy-dispersive x-ray (EDX) spectra, and selective area diffraction (SAED).  TEM analysis for asbestos resulted in no confirmed asbestos fibers and only a single fiber classified as "ambiguous."  Hypothetical treatment of this fiber as if it were asbestos yields a risk of 9.6 × 10-7 (under one in one million) for a lifetime user of this cosmetic talcum powder.  The exposure levels associated with these results range from zero to levels far below those identified in the epidemiology literature as posing a risk for asbestos-related disease, and substantially below published historical environmental background levels.  The approaches used for this study have potential application to exposure evaluations of other talc or asbestos-containing materials and consumer products.

Early Disseminated Lyme Disease Masquerading as Mononucleosis: A Case Report.

BACKGROUND: Disseminated Lyme disease can be difficult to diagnose, as it begins with nonspecific signs and symptoms, which, if not treated correctly, can lead to atrioventricular conduction blocks and meningitis. In addition, the diagnosis can be further complicated by potentially false-positive test results. CASE REPORT: We report a case of early-disseminated Lyme disease presenting with Borrelia meningitis and concomitant Lyme carditis, which was misdiagnosed as mononucleosis. A young, previously healthy patient had been hiking in the woods of upstate New York and 4 weeks later developed fever, night sweats, and myalgias. He was diagnosed with mononucleosis via a positive rapid heterophile agglutination antibody test to the Epstein-Barr virus at a walk-in clinic and was started on medications, but then subsequently developed left hip pain, a facial droop, and a very long first-degree atrioventricular conduction block. He went to the Emergency Department, where he had testing that confirmed disseminated Lyme disease. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case highlights the difficulty in early diagnosis of disseminated Lyme disease and how a potentially false-positive laboratory test can lead to the complications of Borrelia meningitis and Lyme carditis in untreated young healthy patients. Emergency physicians need to consider Lyme disease in patients with nonspecific signs and symptoms, especially if they have been outdoors for prolonged periods of time in Lyme-endemic areas.

Disc space preparation in transforaminal lumbar interbody fusion: a comparison of minimally invasive and open approaches.

BACKGROUND: Minimally invasive surgical (MIS) approaches to transforaminal lumbar interbody fusion (TLIF) have been developed as an alternative to the open approach. However, concerns remain regarding the adequacy of disc space preparation that can be achieved through a minimally invasive approach to TLIF. QUESTIONS/PURPOSES: The purpose of this cadaver study is to compare the adequacy of disc space preparation through MIS and open approaches to TLIF. Specifically we sought to compare the two approaches with respect to (1) the time required to perform a discectomy and the number of endplate violations; (2) the percentage of disc removed; and (3) the anatomic location where residual disc would remain after discectomy. METHODS: Forty lumbar levels (ie, L1-2 to L5-S1 in eight fresh cadaver specimens) were randomly assigned to open and MIS groups. Both surgeons were fellowship-trained spine surgeons proficient in the assigned approach used. Time required for discectomy, endplate violations, and percentage of disc removed by volume and mass were recorded for each level. A digital imaging software program (ImageJ; US National Institutes of Health, Bethesda, MD, USA) was used to measure the percent disc removed by area for the total disc and for each quadrant of the endplate. RESULTS: The open approach was associated with a shorter discectomy time (9 versus 12 minutes, p = 0.01) and fewer endplate violations (one versus three, p = 0.04) when compared with an MIS approach, percent disc removed by volume (80% versus 77%, p = 0.41), percent disc removed by mass (77% versus 75%, p = 0.55), and percent total disc removed by area (73% versus 71%, p = 0.63) between the open and MIS approaches, respectively. The posterior contralateral quadrant was associated with the lowest percent of disc removed compared with the other three quadrants in both open and MIS groups (50% and 60%, respectively). CONCLUSIONS: When performed by a surgeon experienced with MIS TLIF, MIS and open approaches are similar in regard to the adequacy of disc space preparation. The least amount of disc by percentage is removed from the posterior contralateral quadrant regardless of the approach; surgeons should pay particular attention to this anatomic location during the discectomy portion of the procedure to minimize the likelihood of pseudarthrosis.

Dermal versus total uptake of benzene from mineral spirits solvent during parts washing.

Quantitative approaches to assessing exposure to, and associated risk from, benzene in mineral spirits solvent (MSS), used widely in parts washing and degreasing operations, have focused primarily on the respiratory pathway. The dermal contribution to total benzene uptake from such operations remains uncertain because measuring in vivo experimental dermal uptake of this volatile human carcinogen is difficult. Unprotected dermal uptake involves simultaneous sustained immersion events and transient splash/wipe events, each yielding residues subject to evaporation as well as dermal uptake. A two-process dermal exposure framework to assess dermal uptake to normal and damaged skin was applied to estimate potential daily dermal benzene dose (Dskin ) to workers who used historical or current formulations of recycled MSS in manual parts washers. Measures of evaporation and absorption of MSS dermally applied to human subjects were modeled to estimate in vivo dermal uptake of benzene in MSS. Uncertainty and interindividual variability in Dskin was characterized by Monte Carlo simulation, conditioned on uncertainty and/or variability estimated for each model input. Dermal exposures are estimated to average 33% of total (inhalation + dermal) benzene parts washing dose, with approximately equal predicted portions of dermal dose due to splash/wipe and to continuous contact with MSS. The estimated median (95th percentile) dermal and total daily benzene doses from parts washing are: 0.0069 (0.024) and 0.025 (0.18) mg/day using current, and 0.027 (0.085) and 0.098 (0.69) mg/day using historical, MSS solvents, respectively.

Microglia phagocytic mechanisms: Development informing disease.

Microglia are tissue-resident macrophages and professional phagocytes of the central nervous system (CNS). In development, microglia-mediated phagocytosis is important for sculpting the cellular architecture. This includes the engulfment of dead/dying cells, pruning extranumerary synapses and axons, and phagocytosing fragments of myelin sheaths. Intriguingly, these developmental phagocytic mechanisms by which microglia sculpt the CNS are now appreciated as important for eliminating synapses, myelin, and proteins during neurodegeneration. Here, we discuss parallels between neurodevelopment and neurodegeneration, which highlights how development is informing disease. We further discuss recent advances and challenges towards therapeutically targeting these phagocytic pathways and how we can leverage development to overcome these challenges.

Kir6.2-K ATP channels alter glycolytic flux to modulate cortical activity, arousal, and sleep-wake homeostasis.

Metabolism plays an important role in the maintenance of vigilance states (e.g. wake, NREM, and REM). Brain lactate fluctuations are a biomarker of sleep. Increased interstitial fluid (ISF) lactate levels are necessary for arousal and wake-associated behaviors, while decreased ISF lactate is required for sleep. ATP-sensitive potassium (K ATP ) channels couple glucose-lactate metabolism with neuronal excitability. Therefore, we explored how deletion of neuronal K ATP channel activity (Kir6.2-/- mice) affected the relationship between glycolytic flux, neuronal activity, and sleep/wake homeostasis. Kir6.2-/- mice shunt glucose towards glycolysis, reduce neurotransmitter synthesis, dampen cortical EEG activity, and decrease arousal. Kir6.2-/- mice spent more time awake at the onset of the light period due to altered ISF lactate dynamics. Together, we show that Kir6.2-K ATP channels act as metabolic sensors to gate arousal by maintaining the metabolic stability of each vigilance state and providing the metabolic flexibility to transition between states. Highlights: Glycolytic flux is necessary for neurotransmitter synthesis. In its absence, neuronal activity is compromised causing changes in arousal and vigilance states despite sufficient energy availability. With Kir6.2-K ATP channel deficiency, the ability to both maintain and shift between different vigilance states is compromised due to changes in glucose utilization. Kir6.2-K ATP channels are metabolic sensors under circadian control that gate arousal and sleep/wake transitions.

A glial circadian gene expression atlas reveals cell type and disease-specific reprogramming in response to amyloid pathology or aging.

While circadian rhythm disruption may promote neurodegenerative disease, how aging and neurodegenerative pathology impact circadian gene expression patterns in different brain cell types is unknown. Here, we used translating ribosome affinity purification methods to define the circadian translatomes of astrocytes, microglia, and bulk cerebral cortex, in healthy mouse brain and in the settings of amyloid-beta plaque pathology or aging. Our data reveal that glial circadian translatomes are highly cell type-specific and exhibit profound, context-dependent reprogramming of rhythmic transcripts in response to amyloid pathology or aging. Transcripts involved in glial activation, immunometabolism, and proteostasis, as well as nearly half of all Alzheimer Disease (AD)-associated risk genes, displayed circadian oscillations, many of which were altered by pathology. Amyloid-related differential gene expression was also dependent on time of day. Thus, circadian rhythms in gene expression are cell- and context dependent and provide important insights into glial gene regulation in health, AD, and aging.

Neuronal deletion of the circadian clock gene Bmal1 induces cell-autonomous dopaminergic neurodegeneration.

Circadian rhythm dysfunction is a hallmark of Parkinson disease (PD), and diminished expression of the core clock gene Bmal1 has been described in patients with PD. BMAL1 is required for core circadian clock function but also serves nonrhythmic functions. Germline Bmal1 deletion can cause brain oxidative stress and synapse loss in mice, and it can exacerbate dopaminergic neurodegeneration in response to the toxin MPTP. Here we examined the effect of cell type-specific Bmal1 deletion on dopaminergic neuron viability in vivo. We observed that global, postnatal deletion of Bmal1 caused spontaneous loss of tyrosine hydroxylase+ (TH+) dopaminergic neurons in the substantia nigra pars compacta (SNpc). This was not replicated by light-induced disruption of behavioral circadian rhythms and was not induced by astrocyte- or microglia-specific Bmal1 deletion. However, either pan-neuronal or TH neuron-specific Bmal1 deletion caused cell-autonomous loss of TH+ neurons in the SNpc. Bmal1 deletion did not change the percentage of TH neuron loss after α-synuclein fibril injection, though Bmal1-KO mice had fewer TH neurons at baseline. Transcriptomics analysis revealed dysregulation of pathways involved in oxidative phosphorylation and Parkinson disease. These findings demonstrate a cell-autonomous role for BMAL1 in regulating dopaminergic neuronal survival and may have important implications for neuroprotection in PD.

Maternal Caffeine Consumption and Its Impact on the Fetus: A Review.

Maintaining a healthy diet is essential for pregnant women and their developing fetuses, including being mindful of caffeine consumption. While consuming caffeine during pregnancy is generally safe, there is a concern among healthcare practitioners about whether it can adversely impact pregnancy. There is a lack of accurate information about the effects of caffeine on fetal development and inadequate education on the risks of excessive caffeine intake during pregnancy. Therefore, to address this gap, our review provides an overview of the current literature on the impact of caffeine consumption during pregnancy on fetal development. We thoroughly searched databases, including PubMed and Clinicatrial.gov, from September 2022 to January 2023, focusing on relevant clinical studies with a level of clinical evidence II or higher. Our findings reveal that caffeine intake during pregnancy has notable effects on human fetal development. It increases fetal breathing and heart rates but can lead to reduced growth and a lower birth weight. Although it does not affect gestational length or cause hypertension, caffeine increases uterine contractions, potentially resulting in spontaneous abortion. In some cases, it even contributes to the development of pre-eclampsia in the later stages of pregnancy. However, the data on the association between caffeine consumption and the risk of congenital disabilities remains inconclusive. Based on these findings, it is clear that more extensive research is needed to fully understand the impact of caffeine consumption on the development of congenital disabilities in infants born to caffeine-consuming pregnant women. Furthermore, gaining a deeper understanding of how caffeine affects fetal development and pregnancy mechanisms is crucial.