Intracellular lipid surveillance by small G protein geranylgeranylation.

Imbalances in lipid homeostasis can have deleterious effects on health1,2. Yet how cells sense metabolic demand due to lipid depletion and respond by increasing nutrient absorption remains unclear. Here we describe a mechanism for intracellular lipid surveillance in Caenorhabditis elegans that involves transcriptional inactivation of the nuclear hormone receptor NHR-49 through its cytosolic sequestration to endocytic vesicles via geranylgeranyl conjugation to the small G protein RAB-11.1. Defective de novo isoprenoid synthesis caused by lipid depletion limits RAB-11.1 geranylgeranylation, which promotes nuclear translocation of NHR-49 and activation of rab-11.2 transcription to enhance transporter residency at the plasma membrane. Thus, we identify a critical lipid sensed by the cell, its conjugated G protein, and the nuclear receptor whose dynamic interactions enable cells to sense metabolic demand due to lipid depletion and respond by increasing nutrient absorption and lipid metabolism.

MR Angiography Series: MR Angiography of the Extremities.

MR angiography (MRA) is a powerful tool for imaging of the extremities, allowing a thorough assessment of the arteries and veins in both the upper and lower limbs. Both contrast-enhanced and noncontrast MRA techniques are described in the online presentation, including practical tips and tricks to obtain all necessary information at every examination. This module is the sixth and final segment in a series created on behalf of the Society for Magnetic Resonance Angiography (SMRA), a group of researchers and clinicians who are passionate about the benefits of MRA but understand its challenges. The full digital presentation is available online. ©RSNA, 2022.

MR Angiography Series: Fundamentals of Contrast-enhanced MR Angiography.

The Society for Magnetic Resonance Angiography (SMRA) is a group of researchers and clinicians who are passionate about the benefits of MR angiography (MRA) but understand its challenges. Their mission is to study MRA, continually improve and innovate for the benefit of patients, and most important, educate the medical community so they can take full advantage of the benefits of MRA and overcome its challenges. In support of that mission, the authors have created a series of self-learning modules on behalf of the SMRA to demystify MRA protocols and help the reader perform patient-friendly high-quality MRA on a routine basis in clinical practice. The full digital presentation is available online. ©RSNA, 2021.

Singlet and Triplet State Properties and Singlet Oxygen Yield of an Amino-Acyl-Quinoxalinone Yellow Dye.

Amino-acyl-quinoxalinone yellow dyes are cyclised analogues of the yellow azomethine dyes developed for, and still used in, silver halide colour photography. Unlike image azomethine dyes, which are rapidly deactivated in their excited states by torsion about the azomethine bond, amino-acyl-quinoxalinone dyes have an interesting photophysics because torsion is not possible due to their cyclised structure. We report results from studies on singlet and triplet state properties, and singlet oxygen yields, of the yellow dye, 7-diethylamino-3-(2,2-dimethyl-propionyl)-5-methyl-1-phenyl-1H-quinoxalin-2-one, in polar and nonpolar solvents. The dye photophysics is characterised by a weak fluorescence, with a solvent dependent emission yield (ΦF ≈ 0.002-0.004), and short singlet state lifetime (τexpt ≈ 20-50 ps), both increasing by a factor of ≈2 in going from polar acetonitrile to non-polar dioxane as solvent. DFT ZINDO calculations show a transition involving significant electron transfer from the diethyl-amino group into the carbonyl region of the molecule. In solution, in the presence of oxygen, the triplet state decays almost exclusively by oxygen quenching, and singlet oxygen is produced in high yield (Φ∆ ≈ 0.5-0.55). The triplet state absorbs across the 450-750 nm region with maxima around 480 and 650 nm, and moderate molar absorption coefficients (ca. 6000-8000 M-1 cm-1). In a glass at 77 K, triplet decay gives a red phosphorescence, with λmax ≈ 640-650 nm, and a ≈ 0.25 s lifetime. If singlet oxygen yields are a good indication of triplet yields, then internal conversion and intersystem crossing occur with roughly equal efficiency.

The impact of spatially varying wetland source signatures on the atmospheric variability of δD-CH4.

We present the first spatially resolved distribution of the [Formula: see text] signature of wetland methane emissions and assess its impact on atmospheric [Formula: see text]. The [Formula: see text] signature map is derived by relating [Formula: see text] of precipitation to measured [Formula: see text] of methane wetland emissions at a variety of wetland types and locations. This results in strong latitudinal variation in the wetland [Formula: see text] source signature. When [Formula: see text] is simulated in a global atmospheric model, little difference is found in global mean, inter-hemispheric difference and seasonal cycle if the spatially varying [Formula: see text] source signature distribution is used instead of a globally uniform value. This is because atmospheric [Formula: see text] is largely controlled by OH fractionation. However, we show that despite these small differences, using atmospheric records of [Formula: see text] to infer changes in the wetland emissions distribution requires the use of the more accurate spatially varying [Formula: see text] source signature. We find that models will only be sensitive to changes in emissions distribution if spatial information can be exploited through the spatially resolved source signatures. In addition, we also find that on a regional scale, at sites measuring excursions of [Formula: see text] from background levels, substantial differences are simulated in atmospheric [Formula: see text] if using spatially varying or uniform source signatures. This article is part of a discussion meeting issue 'Rising methane: is warming feeding warming? (part 1)'.

The homeodomain-interacting protein kinase HPK-1 preserves protein homeostasis and longevity through master regulatory control of the HSF-1 chaperone network and TORC1-restricted autophagy in Caenorhabditis elegans.

An extensive proteostatic network comprised of molecular chaperones and protein clearance mechanisms functions collectively to preserve the integrity and resiliency of the proteome. The efficacy of this network deteriorates during aging, coinciding with many clinical manifestations, including protein aggregation diseases of the nervous system. A decline in proteostasis can be delayed through the activation of cytoprotective transcriptional responses, which are sensitive to environmental stress and internal metabolic and physiological cues. The homeodomain-interacting protein kinase (hipk) family members are conserved transcriptional co-factors that have been implicated in both genotoxic and metabolic stress responses from yeast to mammals. We demonstrate that constitutive expression of the sole Caenorhabditis elegans Hipk homolog, hpk-1, is sufficient to delay aging, preserve proteostasis, and promote stress resistance, while loss of hpk-1 is deleterious to these phenotypes. We show that HPK-1 preserves proteostasis and extends longevity through distinct but complementary genetic pathways defined by the heat shock transcription factor (HSF-1), and the target of rapamycin complex 1 (TORC1). We demonstrate that HPK-1 antagonizes sumoylation of HSF-1, a post-translational modification associated with reduced transcriptional activity in mammals. We show that inhibition of sumoylation by RNAi enhances HSF-1-dependent transcriptional induction of chaperones in response to heat shock. We find that hpk-1 is required for HSF-1 to induce molecular chaperones after thermal stress and enhances hormetic extension of longevity. We also show that HPK-1 is required in conjunction with HSF-1 for maintenance of proteostasis in the absence of thermal stress, protecting against the formation of polyglutamine (Q35::YFP) protein aggregates and associated locomotory toxicity. These functions of HPK-1/HSF-1 undergo rapid down-regulation once animals reach reproductive maturity. We show that HPK-1 fortifies proteostasis and extends longevity by an additional independent mechanism: induction of autophagy. HPK-1 is necessary for induction of autophagosome formation and autophagy gene expression in response to dietary restriction (DR) or inactivation of TORC1. The autophagy-stimulating transcription factors pha-4/FoxA and mxl-2/Mlx, but not hlh-30/TFEB or the nuclear hormone receptor nhr-62, are necessary for extended longevity resulting from HPK-1 overexpression. HPK-1 expression is itself induced by transcriptional mechanisms after nutritional stress, and post-transcriptional mechanisms in response to thermal stress. Collectively our results position HPK-1 at a central regulatory node upstream of the greater proteostatic network, acting at the transcriptional level by promoting protein folding via chaperone expression, and protein turnover via expression of autophagy genes. HPK-1 therefore provides a promising intervention point for pharmacological agents targeting the protein homeostasis system as a means of preserving robust longevity.

RPN-6 determines C. elegans longevity under proteotoxic stress conditions.

Organisms that protect their germ-cell lineages from damage often do so at considerable cost: limited metabolic resources become partitioned away from maintenance of the soma, leaving the ageing somatic tissues to navigate survival amid an environment containing damaged and poorly functioning proteins. Historically, experimental paradigms that limit reproductive investment result in lifespan extension. We proposed that germline-deficient animals might exhibit heightened protection from proteotoxic stressors in somatic tissues. We find that the forced re-investment of resources from the germ line to the soma in Caenorhabditis elegans results in elevated somatic proteasome activity, clearance of damaged proteins and increased longevity. This activity is associated with increased expression of rpn-6, a subunit of the 19S proteasome, by the FOXO transcription factor DAF-16. Ectopic expression of rpn-6 is sufficient to confer proteotoxic stress resistance and extend lifespan, indicating that rpn-6 is a candidate to correct deficiencies in age-related protein homeostasis disorders.

Drought, agricultural adaptation, and sociopolitical collapse in the Maya Lowlands.

Paleoclimate records indicate a series of severe droughts was associated with societal collapse of the Classic Maya during the Terminal Classic period (∼800-950 C.E.). Evidence for drought largely derives from the drier, less populated northern Maya Lowlands but does not explain more pronounced and earlier societal disruption in the relatively humid southern Maya Lowlands. Here we apply hydrogen and carbon isotope compositions of plant wax lipids in two lake sediment cores to assess changes in water availability and land use in both the northern and southern Maya lowlands. We show that relatively more intense drying occurred in the southern lowlands than in the northern lowlands during the Terminal Classic period, consistent with earlier and more persistent societal decline in the south. Our results also indicate a period of substantial drying in the southern Maya Lowlands from ∼200 C.E. to 500 C.E., during the Terminal Preclassic and Early Classic periods. Plant wax carbon isotope records indicate a decline in C4 plants in both lake catchments during the Early Classic period, interpreted to reflect a shift from extensive agriculture to intensive, water-conservative maize cultivation that was motivated by a drying climate. Our results imply that agricultural adaptations developed in response to earlier droughts were initially successful, but failed under the more severe droughts of the Terminal Classic period.

Photoinduced charge transfer: from photography to solar energy.

To celebrate the centenary of Science Progress we offer a short survey of the progress made over the past one hundred years in the research and application of photoinduced charge transfer. After a brief historical overview and introduction to photoinduced charge transfer, we discuss developments in the theory and practice of photography, photovoltaics, photocatalysis, fluorescent probes and chemosensing.

Pronounced zonal heterogeneity in Eocene southern high-latitude sea surface temperatures.

Paleoclimate studies suggest that increased global warmth during the Eocene epoch was greatly amplified at high latitudes, a state that climate models cannot fully reproduce. However, proxy estimates of Eocene near-Antarctic sea surface temperatures (SSTs) have produced widely divergent results at similar latitudes, with SSTs above 20 °C in the southwest Pacific contrasting with SSTs between 5 and 15 °C in the South Atlantic. Validation of this zonal temperature difference has been impeded by uncertainties inherent to the individual paleotemperature proxies applied at these sites. Here, we present multiproxy data from Seymour Island, near the Antarctic Peninsula, that provides well-constrained evidence for annual SSTs of 10-17 °C (1σ SD) during the middle and late Eocene. Comparison of the same paleotemperature proxy at Seymour Island and at the East Tasman Plateau indicate the presence of a large and consistent middle-to-late Eocene SST gradient of ∼7 °C between these two sites located at similar paleolatitudes. Intermediate-complexity climate model simulations suggest that enhanced oceanic heat transport in the South Pacific, driven by deep-water formation in the Ross Sea, was largely responsible for the observed SST gradient. These results indicate that very warm SSTs, in excess of 18 °C, did not extend uniformly across the Eocene southern high latitudes, and suggest that thermohaline circulation may partially control the distribution of high-latitude ocean temperatures in greenhouse climates. The pronounced zonal SST heterogeneity evident in the Eocene cautions against inferring past meridional temperature gradients using spatially limited data within given latitudinal bands.

Perkin's and Caro's mauveine in Queen Victoria's lilac postage stamps: a chemical analysis.

Mauveine, a chemical icon, is no longer commercially available. If nowadays one wanted to have a sample of the original Perkin, or Caro, mauveine, and see its colour, where would one find it? The answer is on UK Victorian 6d postage stamps from 1867-1880. This was found from a comparison with historical samples of mauveine, from both William Perkin and a Heinrich Caro sample (here analysed for the first time). These have distinctly different compositions and this was used to identify the origin of mauveine in the postage stamps, with evidence found for mauveine made by both Perkin's and Caro's synthesis.

Polypeptide transfer from Hsp40 to Hsp70 molecular chaperones.

Heat shock protein 40 (Hsp40) co-chaperones assist in cellular protein folding and degradation through the binding and delivery of non-native proteins to heat shock protein 70 (Hsp70). The mechanism for substrate transfer from Hsp40s to Hsp70 is unknown. Two recent studies provide new details that shed light on novel mechanisms for substrate recognition by Hsp40s and a common mechanism for polypeptide transfer to Hsp70.

Personalization above anonymization? A role for considering the humanity and spirituality of the dead in anatomical education.

Clinical anatomy education is meant to prepare students for caring for the living, often by working with the dead. By their nature many clinical anatomy education programs privilege topographical form  over the donor's humanity. This inbalance between the living and the dead generates tensions between the tangible and the spiritual insofar as semblances of the humanity of donors endure even in depictions and derivatives. This article argues that considering the relevance of spirituality, and what endures of a donor's humanity after death, would enhance contemporary anatomy education and the ethical treatment of human body donors (and derivatives). In developing this argument, we (the authors) address the historical connection between spirituality and anatomy, including the anatomical locations of the soul. This serves as a basis for examining the role of the mimetic-or imitative-potential of deceased human donors as representations of the living. We deliberate on the ways in which the depersonalization and anonymization of those donating challenge the mimetic purpose of human body donors and the extent to which such practices are misaligned with the health care shift  from a biomedical to a biopsychosocial model. Weighing up the risks and opportunities of anonymization versus personalization of human body donors, we propose curricula that could serve to enhance the personalization of human donors to support students learning topographical form. In doing so, we argue that the personalization of human donors and depictions could prevent the ill effects of digital representations going "viral," and enhance opportunities for donors to help the general public learn more about the human form.

Blood Markers in Relation to a History of Traumatic Brain Injury Across Stages of Cognitive Impairment in a Diverse Cohort.

BACKGROUND: Traumatic brain injury (TBI) has been linked to multiple pathophysiological processes that could increase risk for Alzheimer's disease and related dementias (ADRD). However, the impact of prior TBI on blood biomarkers for ADRD remains unknown. OBJECTIVE: Using cross-sectional data, we assessed whether a history of TBI influences serum biomarkers in a diverse cohort (approximately 50% Hispanic) with normal cognition, mild cognitive impairment, or dementia. METHODS: Levels of glial fibrillary acidic protein (GFAP), neurofilament light (NFL), total tau (T-tau), and ubiquitin carboxy-terminal hydrolase-L1 (UCHL1) were measured for participants across the cognitive spectrum. Participants were categorized based on presence and absence of a history of TBI with loss of consciousness, and study samples were derived through case-control matching. Multivariable general linear models compared concentrations of biomarkers in relation to a history of TBI and smoothing splines modelled biomarkers non-linearly in the cognitively impaired groups as a function of time since symptom onset. RESULTS: Each biomarker was higher across stages of cognitive impairment, characterized by clinical diagnosis and Mini-Mental State Examination performance, but these associations were not influenced by a history of TBI. However, modelling biomarkers in relation to duration of cognitive symptoms for ADRD showed differences by history of TBI, with only GFAP and UCHL1 being elevated. CONCLUSIONS: Serum GFAP, NFL, T-tau, and UCHL1 were higher across stages of cognitive impairment in this diverse clinical cohort, regardless of TBI history, though longitudinal investigation of the timing, order, and trajectory of the biomarkers in relation to prior TBI is warranted.

Cytosolic dopamine determines hypersensitivity to blunt force trauma.

The selective vulnerability of dopaminergic neurons to trauma-induced neurodegeneration is conserved across species, from nematodes to humans. However, the molecular mechanisms underlying this hypersensitivity to blunt force trauma remain elusive. We find that extravesicular dopamine, a key driver of Parkinson's disease, extends its toxic role to the acute challenges associated with injury. Ectopic dopamine synthesis in serotonergic neurons sensitizes this resilient neuronal subtype to trauma-induced degeneration. While dopaminergic neurons normally maintain dopamine in a functional and benign state, trauma-induced subcellular redox imbalances elicit dopamine-dependent cytotoxicity. Cytosolic dopamine accumulation, through perturbations to its synthesis, metabolism, or packaging, is necessary and sufficient to drive neurodegeneration upon injury and during aging. Additionally, degeneration is further exacerbated by rapid upregulation of the rate-limiting enzyme in dopamine synthesis, cat-2, via the FOS-1 transcription factor. Fundamentally, our study in C. elegans unravels the molecular intricacies rendering dopaminergic neurons uniquely prone to physical perturbation across evolutionary lines.

Fluorescence quenching of protonated ß-carbolines in water and microemulsions: evidence for heavy-atom and electron-transfer mechanisms.

The fluorescence quenching of protonated ß-carbolines has been investigated in acidic aqueous solutions and in w/o microemulsions using I(-), Br(-), Cu(2+), SCN(-), and Pb(2+) as quenchers. It was found that fluorescence quenching by these compounds is much more efficient in water than in microemulsions since quenching in microemulsions depends on the simultaneous occupancy of the water droplets by both fluorophore and quencher. Linear Stern-Volmer plots were obtained in all cases, leading to quenching rate constants of ca. 10(8)-10(10) M(-1) s(-1) in water and ca. 10(7)-10(8) M(-1) s(-1) in microemulsions. In the case of quenching by SCN(-), ns flash photolysis studies indicate formation of (SCN)2(˙-) showing that at least part of the quenching process involves an electron transfer mechanism. This indicates that the singlet excited states of the protonated ß-carbolines can act as relatively strong oxidants (E° > 1.6 V), capable of oxidizing many species, including the biologically relevant DNA base guanine. The observation of the (SCN)2(˙-) transient in microemulsions demonstrates that it is possible to have the protonated ß-carboline and at least two thiocyanate ions in the same water pool.

Use of bevacizumab in a patient with Whipple's disease: managing diagnostic uncertainty.

A man in his 30s with intellectual disability presented with 1 month of diarrhoea, weight loss and dyspnoea. Investigations were hampered due to significant anxiety. Laboratory tests detected microcytic anaemia and hypoalbuminaemia. CT demonstrated a fat-containing infiltrate in the mediastinum, mesentery and axillae, and pulmonary ground-glass infiltrates. Biopsy of the axilla showed cystic lymphatic malformations involving adipose tissue and lymph nodes, leading to a provisional diagnosis of generalised lymphatic anomaly. Over the subsequent 4 months, the patient's respiratory status deteriorated, leading to type 1 respiratory failure necessitating intubation. After multidisciplinary discussion, a decision was made to trial bevacizumab, an anti-VEGF agent, with subsequent improvement in respiratory status. While intubated, gastroscopy was performed; duodenal biopsies revealed pathognomonic changes of Whipple's disease, confirmed on PCR of duodenal and axillae biopsies. This was deemed the most likely unifying diagnosis; antibiotic treatment was commenced, bevacizumab was ceased, and the patient has remained well after 18 months.

Artificial intelligence and clinical anatomical education: Promises and perils.

Anatomy educators are often at the forefront of adopting innovative and advanced technologies for teaching, such as artificial intelligence (AI). While AI offers potential new opportunities for anatomical education, hard lessons learned from the deployment of AI tools in other domains (e.g., criminal justice, healthcare, and finance) suggest that these opportunities are likely to be tempered by disadvantages for at least some learners and within certain educational contexts. From the perspectives of an anatomy educator, public health researcher, medical ethicist, and an educational technology expert, this article examines five tensions between the promises and the perils of integrating AI into anatomy education. These tensions highlight the ways in which AI is currently ill-suited for incorporating the uncertainties intrinsic to anatomy education in the areas of (1) human variations, (2) healthcare practice, (3) diversity and social justice, (4) student support, and (5) student learning. Practical recommendations for a considered approach to working alongside AI in the contemporary (and future) anatomy education learning environment are provided, including enhanced transparency about how AI is integrated, AI developer diversity, inclusion of uncertainty and anatomical variations within deployed AI, provisions made for educator awareness of AI benefits and limitations, building in curricular "AI-free" time, and engaging AI to extend human capacities. These recommendations serve as a guiding framework for how the clinical anatomy discipline, and anatomy educators, can work alongside AI, and develop a more nuanced and considered approach to the role of AI in healthcare education.

Comparison of Pediatric Dentistry Under General Anesthesia in a Surgery Center vs a Hospital.

OBJECTIVE: Pediatric patients who undergo general anesthesia (GA) for dentistry may be treated in different venues. This retrospective study compared patients treated in an ambulatory surgery center (ASC) to those treated in a hospital operating room (H-OR). The 2-venue model was also compared with a historical hospital-only model. METHODS: Twelve months of data were collected via records review: patient demographics, American Society of Anesthesiology (ASA) classification, and medical comorbidities. Data from patients treated at the H-OR 10 years prior were referenced for comparison. RESULTS: Between July 2017 and June 2018, 1148 patients were treated: 635 at the ASC and 513 at the H-OR. The most common age range for both venues was 3 to 8 years. Of all the ASC patients, 78% were ASA I, while 48% of H-OR patients were ASA III (P < .001). The number of patients treated with the 2-venue model represented a 240% annual increase compared with those treated historically using the hospital-only model. CONCLUSION: Because of differences in patient medical comorbidities, both the ASC and H-OR are needed to adequately address the needs of pediatric dental patients who require GA. Treating healthy patients in an ASC also creates increased capacity in the H-OR to better accommodate those with higher medical acuity.

Mild Traumatic Brain Injury Is Related to Elevated Cerebrospinal Fluid Tau in Alzheimer's Disease Dementia.

Few studies have examined an association between mild traumatic brain injury (mTBI) and Alzheimer's disease (AD). For this reason, we compared an AD dementia group with an mTBI history (n = 10) to a matched AD control group (n = 20) on measures of cognitive function, cerebral glucose metabolism, and markers of amyloid and tau deposition. Only a trend and medium-to-large effect size for higher phosphorylated and total tau was identified for the mTBI group. A history of mTBI may be associated with greater tau in AD, indicating a potential pathway for increasing risk for AD, though further evaluation with larger samples is needed.