Heterogeneous melting near the Thwaites Glacier grounding line.

Thwaites Glacier represents 15% of the ice discharge from the West Antarctic Ice Sheet and influences a wider catchment1-3. Because it is grounded below sea level4,5, Thwaites Glacier is thought to be susceptible to runaway retreat triggered at the grounding line (GL) at which the glacier reaches the ocean6,7. Recent ice-flow acceleration2,8 and retreat of the ice front8-10 and GL11,12 indicate that ice loss will continue. The relative impacts of mechanisms underlying recent retreat are however uncertain. Here we show sustained GL retreat from at least 2011 to 2020 and resolve mechanisms of ice-shelf melt at the submetre scale. Our conclusions are based on observations of the Thwaites Eastern Ice Shelf (TEIS) from an underwater vehicle, extending from the GL to 3 km oceanward and from the ice-ocean interface to the sea floor. These observations show a rough ice base above a sea floor sloping upward towards the GL and an ocean cavity in which the warmest water exceeds 2 °C above freezing. Data closest to the ice base show that enhanced melting occurs along sloped surfaces that initiate near the GL and evolve into steep-sided terraces. This pronounced melting along steep ice faces, including in crevasses, produces stratification that suppresses melt along flat interfaces. These data imply that slope-dependent melting sculpts the ice base and acts as an important response to ocean warming.

A human brain vascular atlas reveals diverse mediators of Alzheimer's risk.

The human brain vasculature is of great medical importance: its dysfunction causes disability and death1, and the specialized structure it forms-the blood-brain barrier-impedes the treatment of nearly all brain disorders2,3. Yet so far, we have no molecular map of the human brain vasculature. Here we develop vessel isolation and nuclei extraction for sequencing (VINE-seq) to profile the major vascular and perivascular cell types of the human brain through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 9 individuals with Alzheimer's disease and 8 individuals with no cognitive impairment. We identify brain-region- and species-enriched genes and pathways. We reveal molecular principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In Alzheimer's disease, we observe selective vulnerability of ECM-maintaining pericytes and gene expression patterns that implicate dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 genes that have been linked to Alzheimer's disease risk by genome-wide association studies (GWASs) are expressed in the human brain vasculature, and we confirm this by immunostaining. Vascular GWAS genes map to endothelial protein transport, adaptive immune and ECM pathways. Many are microglia-specific in mice, suggesting a partial evolutionary transfer of Alzheimer's disease risk. Our work uncovers the molecular basis of the human brain vasculature, which will inform our understanding of overall brain health, disease and therapy.

Dysregulation of brain and choroid plexus cell types in severe COVID-19.

Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms1-3. However, an unbiased understanding of the cellular and molecular processes that are affected in the brains of patients with COVID-19 is missing. Here we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control individuals (including 1 patient with terminal influenza) and 8 patients with COVID-19. Although our systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations indicating that barrier cells of the choroid plexus sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover microglia and astrocyte subpopulations associated with COVID-19 that share features with pathological cell states that have previously been reported in human neurodegenerative disease4-6. Synaptic signalling of upper-layer excitatory neurons-which are evolutionarily expanded in humans7 and linked to cognitive function8-is preferentially affected in COVID-19. Across cell types, perturbations associated with COVID-19 overlap with those found in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia and depression. Our findings and public dataset provide a molecular framework to understand current observations of COVID-19-related neurological disease, and any such disease that may emerge at a later date.

Ageing hallmarks exhibit organ-specific temporal signatures.

Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. Although major categories of ageing damage have been identified-such as altered intercellular communication, loss of proteostasis and eroded mitochondrial function1-these deleterious processes interact with extraordinary complexity within and between organs, and a comprehensive, whole-organism analysis of ageing dynamics has been lacking. Here we performed bulk RNA sequencing of 17 organs and plasma proteomics at 10 ages across the lifespan of Mus musculus, and integrated these findings with data from the accompanying Tabula Muris Senis2-or 'Mouse Ageing Cell Atlas'-which follows on from the original Tabula Muris3. We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions-including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue-including plasma cells that express immunoglobulin J-which also accrue concurrently across diverse organs. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of ageing, providing a foundation from which to track systemic sources of declining health at old age.

Physiological blood-brain transport is impaired with age by a shift in transcytosis.

The vascular interface of the brain, known as the blood-brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability1-3. Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins4,5. Thus, it is unclear whether permeability to individually injected exogenous tracers-as is standard in BBB studies-fully represents blood-to-brain transport. Here we label hundreds of proteins constituting the mouse blood plasma proteome, and upon their systemic administration, study the BBB with its physiological ligand. We find that plasma proteins readily permeate the healthy brain parenchyma, with transport maintained by BBB-specific transcriptional programmes. Unlike IgG antibody, plasma protein uptake diminishes in the aged brain, driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis. This age-related shift occurs alongside a specific loss of pericyte coverage. Pharmacological inhibition of the age-upregulated phosphatase ALPL, a predicted negative regulator of transport, enhances brain uptake of therapeutically relevant transferrin, transferrin receptor antibody and plasma. These findings reveal the extent of physiological protein transcytosis to the healthy brain, a mechanism of widespread BBB dysfunction with age and a strategy for enhanced drug delivery.

CD22 blockade restores homeostatic microglial phagocytosis in ageing brains.

Microglia maintain homeostasis in the central nervous system through phagocytic clearance of protein aggregates and cellular debris. This function deteriorates during ageing and neurodegenerative disease, concomitant with cognitive decline. However, the mechanisms of impaired microglial homeostatic function and the cognitive effects of restoring this function remain unknown. We combined CRISPR-Cas9 knockout screens with RNA sequencing analysis to discover age-related genetic modifiers of microglial phagocytosis. These screens identified CD22, a canonical B cell receptor, as a negative regulator of phagocytosis that is upregulated on aged microglia. CD22 mediates the anti-phagocytic effect of α2,6-linked sialic acid, and inhibition of CD22 promotes the clearance of myelin debris, amyloid-ß oligomers and α-synuclein fibrils in vivo. Long-term central nervous system delivery of an antibody that blocks CD22 function reprograms microglia towards a homeostatic transcriptional state and improves cognitive function in aged mice. These findings elucidate a mechanism of age-related microglial impairment and a strategy to restore homeostasis in the ageing brain.

One-year Thyroglobulin Levels as a Predictive Measure for Recurrence and Need for Continued Surveillance in Treated Differentiated Thyroid Cancer.

PURPOSE: Patients with differentiated thyroid cancer (DTC) undergo posttreatment surveillance for several years. We aim to better define an excellent response to therapy using thyroglobulin (TG) and thyroglobulin antibody (TGab) levels at 1-year to tailor appropriate length of surveillance. METHODS: Patients with DTC who underwent surgical treatment with or without adjuvant radioiodine therapy were followed with standard American Thyroid Association surveillance. TG and TGab levels at 1-year posttreatment were used to define 3 cohorts: undetectable TG (<0.5 ng/mL), detectable TG (≥0.5 ng/mL), and positive TGab (>1 IU/mL). The rates of structural recurrence and the trends of TG and TGab were compared. RESULTS: Of the 268 study patients at 1-year, 210 (78%) had undetectable TG, 29 (11%) had detectable TG, and 29 (11%) had positive TGab. The overall structural recurrence rate was 18/268 (7%): undetectable TG at 1 year, 3/210 (1%), detectable TG at 1-year, 11/29 (38%), and positive TGab at 1-year, 4/29 (13%). At the last follow-up, 196/210 (93%) patients with undetectable TG at 1-year continued to have undetectable TG levels. Regarding patients with detectable TG at 1-year, in 11/29 (38%), detectable TG was converted to undetectable TG at the last follow-up without additional treatments. Of those with positive TGab at 1 year, 6/29 (21%) had resolution of TGab and undetectable TG levels at the last follow-up without additional treatments. CONCLUSION: One year after treatment of DTC, TG levels <0.5 ng/mL, in the absence of TGab, are associated with an exceedingly low risk of recurrence suggesting that further surveillance may not be warranted.

Estimating the health-related quality of life of kidney stone patients: initial results from the Wisconsin Stone Quality of Life Machine-Learning Algorithm (WISQOL-MLA).

OBJECTIVE: To build the Wisconsin Stone Quality of Life Machine-Learning Algorithm (WISQOL-MLA) to predict urolithiasis patients' health-related quality of life (HRQoL) based on demographic, symptomatic and clinical data collected for the validation of the Wisconsin Stone Quality-of-Life (WISQOL) questionnaire, an HRQoL measurement tool designed specifically for patients with kidney stones. MATERIAL AND METHODS: We used data from 3206 stone patients from 16 centres. We used gradient-boosting and deep-learning models to predict HRQoL scores. We also stratified HRQoL scores by quintile. The dataset was split using a standard 70%/10%/20% training/validation/testing ratio. Regression performance was evaluated using Pearson's correlation. Classification was evaluated with an area under the receiver-operating characteristic curve (AUROC). RESULTS: Gradient boosting obtained a test correlation of 0.62. Deep learning obtained a correlation of 0.59. Multivariate regression achieved a correlation of 0.44. Quintile stratification of all patients in the WISQOL dataset obtained an average test AUROC of 0.70 for the five classes. The model performed best in identifying the lowest (0.79) and highest quintiles (0.83) of HRQoL. Feature importance analysis showed that the model weighs in clinically relevant factors to estimate HRQoL, such as symptomatic status, body mass index and age. CONCLUSIONS: Harnessing the power of the WISQOL questionnaire, our initial results indicate that the WISQOL-MLA can adequately predict a stone patient's HRQoL from readily available clinical information. The algorithm adequately relies on relevant clinical factors to make its HRQoL predictions. Future improvements to the model are needed for direct clinical applications.

Association of Patient Age and Gender with Kidney Stone Related Quality of Life.

PURPOSE: Kidney stone formers have lower health related quality of life than nonstone formers. The North American Stone Quality of Life Consortium is a multicenter, longitudinal, prospective study of health related quality of life in patients with kidney stones using the WISQOL (Wisconsin Stone Quality of Life Questionnaire) with data on 2,052 patients from a total of 11 centers. This study is a subanalysis of cross-sectional data looking at the association of age, gender and race on health related quality of life of stone formers. MATERIALS AND METHODS: We performed multivariable analyses of ordinal logistic regression analyses to determine the impact of age, gender and race on health related quality of life, adjusting for other baseline covariates. The proportional odds assumption of ordinal logistic regression was checked. Total score and scores on 4 subdomains (social functioning, emotional functioning, stone related impact and vitality) were included. RESULTS: Median total score for all patients was 80.4. On multivariable analysis older patients had a significantly higher total health related quality of life score than younger patients (per 10-year increase OR 1.25, p <0.0001). Male patients had higher scores than females (OR 1.56, p = 0.0003) and nonCaucasian patients had lower health related quality of life than nonLatino Caucasian patients (OR 0.63, p = 0.0045). CONCLUSIONS: Younger and female patients with kidney stones have lower health related quality of life than older and male patients, respectively. NonCaucasian patients with stones also have lower health related quality of life. The clinical impact of these findings might include future implications for patient counseling, including dietary and medical management of stone disease, and potential changes to the paradigm of the surgical management of stones.

Low Income and Nonwhite Race are Strongly Associated with Worse Quality of Life in Patients with Nephrolithiasis.

PURPOSE: Kidney stones are a source of significant morbidity which have been shown to negatively impact health related quality of life. We sought to understand the association between health related quality of life, socioeconomic status and race among patients with kidney stones. MATERIALS AND METHODS: Patients with stones at a total of 11 stone centers across the United States completed the WISQOL (Wisconsin Stone Quality of Life questionnaire). The patient ZIP Code™ was used to estimate household income. A mixed effects regression model was constructed for analysis with ZIP Code as the random intercept. RESULTS: A total of 2,057 stone formers completed the WISQOL. Lower income was independently associated with significantly lower health related quality of life (ß = 0.372, p = 0.014), as were nonwhite race (ß = -0.299, p = 0.001), unemployed work status (ß = -0.291, p = 0.008), female gender (ß = -0.204, p <0.001), body mass index greater than 40 kg/m2 (ß = -0.380, p <0.001), 5 or more medical comorbidities (ß = -0.354, p = 0.001), severe recurrent stone formation (ß = -0.146, p = 0.045), enrollment at an acute care visit, or a preoperative or postoperative appointment (ß = -0.548, p <0.001) and recent stone symptoms (ß = -0.892, p <0.001). CONCLUSIONS: Lower income, nonwhite race and unemployed work status were independently associated with lower health related quality of life among patients with kidney stones. While clinical characteristics such as body mass and stone disease severity were also associated with health related quality of life, this study shows that socioeconomic factors are similarly important. Further research to understand the specific mechanisms by which socioeconomic status and race impact health may lend insight into methods to optimize clinical treatment of stone formers and patients with other chronic diseases.

Trial of magnetic resonance-guided putaminal gene therapy for advanced Parkinson's disease.

OBJECTIVE: To investigate the safety and tolerability of convection-enhanced delivery of an adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor into the bilateral putamina of PD patients. METHODS: Thirteen adult patients with advanced PD underwent adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor and gadoteridol (surrogate MRI tracer) coinfusion (450 µL/hemisphere) at escalating doses: 9 × 1010 vg (n = 6); 3 × 1011 vg (n = 6); and 9 × 1011 vg (n = 1). Intraoperative MRI monitored infusion distribution. Patients underwent UPDRS assessment and [18 F]FDOPA-PET scanning preoperatively and 6 and 18 months postoperatively. RESULTS: Adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor was tolerated without clinical or radiographic toxicity. Average putaminal coverage was 26%. UPDRS scores remained stable. Ten of thirteen and 12 of 13 patients had increased [18 F]FDOPA Kis at 6 and 18 months postinfusion (increase range: 5-274% and 8-130%; median, 36% and 54%), respectively. Ki differences between baseline and 6- and 18-month follow-up were statistically significant (P < 0.0002). CONCLUSION: Adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor infusion was safe and well tolerated. Increased [18 F]FDOPA uptake suggests a neurotrophic effect on dopaminergic neurons. © 2019 International Parkinson and Movement Disorder Society.

Influence of machine-based puffing parameters on aerosol and smoke emissions from next generation nicotine inhalation products.

There is increasing diversity of nicotine inhalation products worldwide. Next Generation Products (NGP) such as e-cigarettes, have gained mass popularity, and there is increasing use of electrical and carbon-based Tobacco-Heating Products (e-THP and c-THP respectively). Recently, emission levels from these products have been compared to conventional cigarettes (CC); however, few formal laboratory testing standards exist, and inconsistent puffing parameters have been used. We investigated the impact of how a number of NGPs, including two e-cigarettes, a carbon-heated THP, and both pulse- and continuously-heated e-THPs, are puffed on the magnitude of their emissions, examining the influence of puff profile, volume, frequency and duration, in comparison to standard CCs. Our findings demonstrated that for each NGP choice of puffing parameters has a substantial impact on the magnitude of aerosol and smoke emissions, and that significant differences exist between different types of NGP. With e-cigarettes and pulse-heated e-THPs puff duration is the most important puffing parameter influencing yields. In contrast, for CCs, c-THPs and continuously-heated e-THPs, puff volume and puff frequency were the critical parameters. For e-cigarettes, there was no significant difference in emissions between rectangular and bell-shaped profiles. Our study has also shown that these different behaviours are a result of how heat-management within different NGPs, from heat-source to the nicotine- and aerosol-releasing substrates, is a vital mechanistic factor impacting aerosol generation. These findings point the need for detailed real-world e-cigarette and THP puffing topography data in order to identify the most appropriate puffing parameters for laboratory testing; our findings will help focus these studies on the most important parameters and can thereby support the future development of robust standardised NGP testing regimes.

Isovaleric acid and avicequinone-C are Chikungunya virus resistance principles in Glycosmis pentaphylla (Retz.) Correa.

BACKGROUND & OBJECTIVES: Oral administration of tender leaf extract of Glycosmis pentaphylla is traditionally known to prevent the chikungunya virus infection. Even with wide usage, the antiviral components in this plant are neither identified nor characterized. This study was carried out with the objectives of profiling the phytocompounds in this plant through LC-MS/MS and to identify the active antiviral constituents and their drug-likeliness through molecular docking. METHODS: Phytocompounds were extracted hydro-alcoholically from powdered plant parts and analyzed using LC-MS/MS. Based on mass-to-charge ratio from LC-MS/MS, compounds were identified and used as ligands for molecular docking against chikungunya target proteins. The active principles were subjected to ADME/T analysis to verify their drug-likeliness. RESULTS: The docking results and ADME/T evaluation showed that the compounds, isovaleric acid and avicequinone- C have good interaction with the protein targets and hence could be the antiviral principles of the selected plant. These compounds presented acceptable drug properties and hence could be carried forward to in vivo studies for drug development. INTERPRETATION & CONCLUSION: The antiviral properties of G. pentaphylla are known since time-immemorial. This study revealed the probable interactions after the oral administration of tender leaves of Glycosmis in preventing the chikungunya virus infection and paves the path for designing future plant-based drugs.

Oxygen Therapy in Ireland: A Nationwide Review of Delivery, Monitoring and Cost Implications

Aims Our aim was to establish which hospitals in Ireland are running oxygen clinics and to compare oxygen prescription in hospitals to a guideline standard. Long term oxygen therapy is known to be of benefit to a specific cohort of patients but is not without risk. Methods We sent an online questionnaire and followed up by phone to representatives in Irish hospitals in which domiciliary oxygen is prescribed. We obtained responses from 32 hospitals. Results Twelve hospitals (38%) had a dedicated oxygen assessment clinic while twenty (62%) did not. Centres without oxygen clinics generally prescribed oxygen following an in-patient stay 18/23 centres (78%) and were unable to provide follow up for patients on oxygen in 6/23 centres (26%). Centres with oxygen clinics generally met criteria for initial assessment and oxygen prescription, however titration of oxygen and general follow up did not meet guideline recommendations. Conclusion Due to a lack of dedicated oxygen assessment and review services, many Irish patients are not optimally treated with domiciliary oxygen.

The Effect of Thiazide and Potassium Citrate Use on the Health Related Quality of Life of Patients with Urolithiasis.

PURPOSE: To our knowledge it is unknown whether the benefits of medical management of urolithiasis outweigh the potential side effects of the medications used, including potassium citrate and thiazide diuretics. Therefore, we evaluated the relationship between potassium citrate or thiazides and overall stone related health related quality of life. MATERIALS AND METHODS: Cross-sectional data were obtained on stone forming enrollees in the North American Stone Quality of Life Consortium. We used the WISQOL (Wisconsin Stone Quality of Life) questionnaire to compare health related quality of life between patients treated and not treated with potassium citrate or thiazide type diuretics. Additionally, the likelihood of gastrointestinal complaints was compared between those prescribed and not prescribed potassium citrate. The likelihood of fatigue and sexual complaints was also compared in those prescribed and not prescribed thiazides. RESULTS: Of the 1,511 subjects, including 787 males and 724 females, 279 were on potassium citrate and 238 were on thiazides at study enrollment. Patients prescribed potassium citrate had higher health related quality of life in each domain vs those not prescribed potassium citrate (p <0.001). Patients prescribed thiazides had higher health related quality of life in each domain compared to those not prescribed thiazide (all p <0.01). Those prescribed potassium citrate were less likely than those not prescribed potassium citrate to report nausea, stomach upset or cramps (OR 0.57, p <0.001). Patients prescribed thiazides were less likely than those not prescribed thiazides to report fatigue (OR 0.63, p = 0.004) or reduced sexual interest and/or activity (OR 0.64, p = 0.005). CONCLUSIONS: Among stone formers the use of potassium citrate and thiazides was associated with better health related quality of life across all WISQOL domains without an increased likelihood of gastrointestinal complaints and fatigue or sexual complaints, respectively. These findings may be useful when counseling patients regarding the initiation of potassium citrate or thiazides for medical management of nephrolithiasis.

Timing resolution studies of the optical part of the AFP Time-of-flight detector.

We present results of the timing performance studies of the optical part and front-end electronics of the time-of-flight subdetector prototype for the ATLAS Forward Proton (AFP) detector obtained during the test campaigns at the CERN-SPS test-beam facility (120 GeV π+ particles) in July 2016 and October 2016. The time-of-flight (ToF) detector in conjunction with a 3D silicon pixel tracker will tag and measure protons originating in central exclusive interactions p + p → p + X + p, where the two outgoing protons are scattered in the very forward directions. The ToF is required to reduce so-called pileup backgrounds that arise from multiple proton interactions in the same bunch crossing at high luminosity. The background can fake the signal of interest, and the extra rejection from the ToF allows the proton tagger to operate at the high luminosity required for the measurement of the processes. The prototype detector uses fused silica bars emitting Cherenkov radiation as a relativistic particle passes through them. The emitted Cherenkov photons are detected by a multi-anode micro-channel plate photomultiplier tube (MCP-PMT) and processed by fast electronics.

Correction: Visible light-promoted alkylation of imines using potassium organotrifluoroborates.

Correction for 'Visible light-promoted alkylation of imines using potassium organotrifluoroborates' by Davis P. Plasko et al., Photochem. Photobiol. Sci., 2018, 17, 534-538.

Visible light-promoted alkylation of imines using potassium organotrifluoroborates.

A mild, redox-neutral, alkylation of imines with potassium alkyltrifluoroborates is described. The reaction proceeds under photoredox conditions at ∼30 °C with primary, secondary, and tertiary alkyltrifluoroborates, leading to alkylation products in moderate to good yield in most cases. Aryl-, vinyl-, and cyclopropyltrifluoroborates failed to react under the reported conditions.