bluuebunny/crossref_metadata_2025 huggingface dataset:
Subtropical Marine Low Stratiform Cloud Deck Spatial Errors in the E3SMv1 Atmosphere Model
Authors: Brunke Michael A. , Ma Po‐Lun , Reeves Eyre J. E. Jack , Rasch Philip J. , Sorooshian Armin , Zeng Xubin
Published: November 2019

Marine low‐level clouds continue to be poorly simulated in models despite many studies and field experiments devoted to their improvement. Here we focus on the spatial errors in the cloud decks in the Department of Energy Earth system model (the Energy Exascale Earth System Model [E3SM]) relative to the satellite climatology by calculating centroid distances, area ratios, and overlap ratios. Since model dynamics is better simulated than clouds, these errors are attributed primarily to the model physics. To gain additional insight, we performed a sensitivity run in which model winds were nudged to those of reanalysis. This results in a large change (but not necessarily an improvement) in the simulated cloud decks. These differences between simulations are mainly due to the interactions between model dynamics and physics. These results suggest that both model physics (widely recognized) and its interaction with dynamics (less recognized) are important to model improvement in simulating these low‐level clouds.
Atlantic Ocean Heat Transport Enabled by Indo‐Pacific Heat Uptake and Mixing
Authors: Holmes Ryan M. , Zika Jan D. , Ferrari Raffaele , Thompson Andrew F. , Newsom Emily R. , England Matthew H.
Published: November 2019

The ocean transports vast amounts of heat around the planet, helping to regulate regional climate. One important component of this heat transport is the movement of warm water from equatorial regions toward the poles, with colder water flowing in return. Here, we introduce a framework relating meridional heat transport to the diabatic processes of surface forcing and turbulent mixing that move heat across temperature classes. Applied to a (1/4)° global ocean model the framework highlights the role of the tropical Indo‐Pacific in the global ocean heat transport. A large fraction of the northward heat transport in the Atlantic is ultimately sourced from heat uptake in the eastern tropical Pacific. Turbulent mixing moves heat from the warm, shallow Indo‐Pacific circulation to the cold deeper‐reaching Atlantic circulation. Our results underscore a renewed focus on the tropical oceans and their role in global circulation pathways.
Intermittency in Wind‐Driven Surface Alteration on Mars Interpreted From Wind Streaks and Measurements by InSight
Authors: Day Mackenzie , Rebolledo Laura
Published: November 2019

Wind interacts with the surface of Mars to create the diverse landforms seen today. The morphology of wind streaks and related surface features has been used to interpret the winds on Mars in regions where actual wind measurement are lacking. Here we compare wind directions interpreted from bright wind streaks observed in orbitally‐acquired images with winds measured at the surface by the InSight lander in Elysium Planitia. The distribution of streak orientations is trimodal, dominantly reflecting winds from the southeast. The distribution of winds measured by InSight was highly variable with time of day but was dominantly characterized by winds from the northwest. The lack of coincidence between the two suggests that wind only intermittently deposits dust on the surface. The persistence of the streak orientations over five Mars years demonstrates that saltation in the region, if occurring, is not sustained long enough to rework these dust depositional surfaces.
Endocrine Complications of Cystic Fibrosis: A Multisystem Disease of the Endocrine Organs
Authors: Ode Katie Larson , Chan Christine L. , Granandos Andrea , Putman Melissa , Moheet Amir
Published: November 2019

Cystic fibrosis (CF) is one of the most common life-limiting genetic disorders. Although CF is typically considered primarily as a pulmonary disease, the CF conductance transmembrane regulator is present throughout the body. From an endocrine perspective, this multisystem disease manifests primarily in the pancreas as a unique form of diabetes (CF-related diabetes mellitus), as bone disease, and as reproductive health issues in people with CF. These complications have become ever more concerning to people with CF as treatment for pulmonary disease improves and lifespans lengthen, increasing the impact of nonpulmonary complications. Our understanding of the management of these concerns continues to evolve, and, although there are some effective treatments, there is great opportunity for continued investigation into the pathophysiology of the endocrine complications of CF and their treatment.
Trituration Proving of Australian Acacias (WA)
Authors: Moore Sally
Published: November 2019

To date, a few Australian plants have been proven and used as homoeopathic remedies.

We believe that the Australian native flora provides a yet untapped reservoir of healing potential.

Four Australian Acacia species were used in the trituration: Acacias dentifera, pulchella, floribunda and longifolia.

Potencies are available in the 3C, 4C and 5C range.
Implementation of the best practice guidelines on geriatric trauma care: a Canadian perspective
Authors: Bérubé Melanie , Pasquotti Theresa , Klassen Barbara , Brisson Angie , Tze Nancy , Moore Lynne
Published: November 2019

Background

traumatic injuries are increasingly affecting older patients who are prone to more complications and poorer recovery compared to younger patients. Practices of trauma health care providers therefore need to be adapted to meet the needs of geriatric trauma patients.

Objective

to assess the implementation of the American College of Surgeons best practice guidelines on geriatric trauma management across level I to III Canadian trauma centres.

Methods

69 decision-makers working in Canadian trauma centres were approached to complete a web-based practice survey. Percentages and means were calculated to describe the level of best practice guideline implementation.

Results

50 decision-makers completed the survey for a response rate of 72%. Specialised geriatric trauma resources were utilised in 37% of centres. Implementation of mechanisms to evaluate common geriatric issues (e.g. frailty, malnutrition and delirium) varied from 28 to 78% and protocols for the optimisation of geriatric care (e.g. Beers criteria to adjust medication, anticoagulant reversal and early mobilisation) from 8 to 56%. Guideline recommendations were more often implemented in level I and level II trauma centres. The adjustment of trauma team activation criteria to the geriatric population and transition of care protocols were more frequently used by level III centres.

Conclusion

despite the growing number of older patients admitted in Canadian trauma centres annually, the implementation of best practice guidelines on geriatric trauma management is still limited. Prospective multicentre studies are required to develop and evaluate interdisciplinary knowledge translation initiatives that will promote the uptake of guidelines by trauma centres.
Accuracy of computational pressure-fluid dynamics applied to coronary angiography to derive fractional flow reserve: FLASH FFR
Authors: Li Jianping , Gong Yanjun , Wang Weimin , Yang Qing , Liu Bin , Lu Yuan , Xu Yawei , Huo Yunlong , Yi Tieci , Liu Jian , Li Yongle , Xu Shaopeng , Zhao Lei , Ali Ziad A , Huo Yong
Published: November 2019

Aims

Conventional fractional flow reserve (FFR) is measured invasively using a coronary guidewire equipped with a pressure sensor. A non-invasive derived FFR would eliminate risk of coronary injury, minimize technical limitations, and potentially increase adoption. We aimed to evaluate the diagnostic performance of a computational pressure-flow dynamics derived FFR (caFFR), applied to coronary angiography, compared to invasive FFR.

Methods and results

The FLASH FFR study was a prospective, multicentre, single-arm study conducted at six centres in China. Eligible patients had native coronary artery target lesions with visually estimated diameter stenosis of 30–90% and diagnosis of stable or unstable angina pectoris. Using computational pressure-fluid dynamics, in conjunction with thrombolysis in myocardial infarction (TIMI) frame count, applied to coronary angiography, caFFR was measured online in real-time and compared blind to conventional invasive FFR by an independent core laboratory. The primary endpoint was the agreement between caFFR and FFR, with a pre-specified performance goal of 84%. Between June and December 2018, matched caFFR and FFR measurements were performed in 328 coronary arteries. Total operational time for caFFR was 4.54 ± 1.48 min. caFFR was highly correlated to FFR (R = 0.89, P = 0.76) with a mean bias of −0.002 ± 0.049 (95% limits of agreement −0.098 to 0.093). The diagnostic performance of caFFR vs. FFR was diagnostic accuracy 95.7%, sensitivity 90.4%, specificity 98.6%, positive predictive value 97.2%, negative predictive value 95.0%, and area under the receiver operating characteristic curve of 0.979.

Conclusions

Using wire-based FFR as the reference, caFFR has high accuracy, sensitivity, and specificity. caFFR could eliminate the need of a pressure wire, technical error and potentially increase adoption of physiological assessment of coronary artery stenosis severity.

Clinical Trial Registration

URL: http://www.chictr.org.cn Unique Identifier: ChiCTR1800019522.
Effects of Water Temperature Under Projected Climate Change on the Development and Survival of Enallagma civile (Odonata: Coenagrionidae)
Authors: Starr S M , McIntyre N E
Published: November 2019

Current climate projections for the Great Plains of North America indicate markedly increased air temperatures by the end of the current century. Because the Great Plains contains >80,000 intermittent wetlands that serve as irreplaceable wildlife habitat, this projected warming may have profound effects throughout a continental-scale trophic network. However, little research has been done to determine how projected warming may affect the growth, development, or survival of even common species in this region. We conducted laboratory warming experiments, using an abundant amphibious predatory insect, Enallagma civile (Hagen, 1861), as a model organism, to determine whether projected warming may affect development or survival. Eggs were collected and reared under four water temperature regimes representing current (26°C) and projected future conditions (32, 38, and 41°C). Nymph body size after each molt, development rate, and deaths were recorded. Elevated water temperatures were found to significantly affect the survivorship of E. civile eggs and nymphs as well as adult body size at emergence: an increase in temperature incurred a decrease in survival and size. Nymphs in the two hotter treatments were smaller and had low survivorship whereas individuals in the cooler temperatures generally survived to adulthood and were larger. Nymphs reared at 32°C experienced accelerated ontogenetic development compared with the other temperatures, going from egg to adult in 26 d. Projected elevated temperatures may, thus, be both advantageous and detrimental, causing concern for aquatic invertebrates in this region in the future.
Urban green space, tree canopy and prevention of cardiometabolic diseases: a multilevel longitudinal study of 46 786 Australians
Authors: Astell-Burt Thomas , Feng Xiaoqi
Published: November 2019

Background

Cross-sectional studies suggest that more green space may lower the odds of prevalent diabetes, hypertension and cardiovascular diseases (CVD) in cities. We assess if these results are replicable for tree canopy exposure and then extend the study longitudinally to examine incident cardiometabolic outcomes.

Methods

The study was set in the Australian cities of Sydney, Wollongong and Newcastle. Total green space and tree canopy as percentages of landcover within 1.6 km (1 mile) from home were linked to a residentially stable sample of 46 786 participants in the Sax Institute’s 45 and Up Study (baseline 2006–09; follow-up 2012–15). Separate multilevel models were used to investigate whether the odds of prevalent and incident doctor-diagnosed diabetes, hypertension and CVD were associated with total green space and tree canopy provision, adjusting for age, sex, income, education, employment and couple status.

Results

Lower odds of prevalent diabetes were observed with 1% increases in total green space [odds ratio (OR) 0.993, 95% confidence interval (CI) 0.988 to 0.998] and tree canopy (0.984, 0.978 to 0.989). Lower odds of prevalent CVD were found with a 1% increase in tree canopy only (0.996, 0.993 to 0.999). Lower odds of incident diabetes (0.988, 0.981 to 0.994), hypertension (0.993, 0.989 to 0.997) and CVD (0.993, 0.988 to 0.998) were associated with a 1% increase in tree canopy, but not total green space. At ≥30% compared with 0–9% tree canopy, there were lower odds of incident diabetes (0.687, 0.547 to 0.855), hypertension (0.828, 0.719 to 0.952) and CVD (0.782, 0.652 to 0.935). However, ≥30% compared with 0–4% total green space was associated with lower odds of prevalent diabetes only (0.695, 0.512 to 0.962).

Conclusions

Restoring local tree canopy in neighbourhoods may help to prevent the incidence of cardiometabolic diseases.
The effect of openings ratio and wall thickness on energy performance in educational buildings
Authors: Hashem Alqahtani Laila Amer , Eldeen Elgizawi Lamis Saad
Published: November 2019

The building envelope is the boundary between the outer and inner spaces and it is considered as the most significant part in the process of preservation of internal spaces cooling energy consumption. In this context, it is argued that the weakest point in the envelope with the highest transmittance of thermal energy into and out of the internal spaces is the openings (windows and doors) which are affected by many factors such as their ratio, material thermal properties and construction. Therefore, this study sheds light on the alternatives of the envelope design generated with the help of a computer-based simulation tool, Design-Builder, as it has great possibilities for creating simulated scenarios for a specific building or space by linking these scenarios with specific changes in the building parameters. Thus, the study will focus on creating different scenarios for a selected classroom in the College of Arts and Design at Princess Nourah bint Abdulrahman University (Riyadh, KSA), with the aim of associating the openings ratios (20%, 30%, 50%, 100%) with wall thickness (12 cm, 25 cm solid brick, 25 cm hollow brick) and energy consumption. Optimum alternatives for the opening ratio and construction materials with the lowest cooling loads during working hours are proposed.
Rapid determination of the content of digestible energy and metabolizable energy in sorghum fed to growing pigs by near-infrared reflectance spectroscopy1
Authors: Hu Jie , Li Juntao , Pan Long , Piao Xiangshu , Sui Li , Xie Gengnan , Zhang Shuai , Zhang Liying , Wang Junjun
Published: November 2019

The object of this study was to establish a new method to predict the content of DE and ME in sorghum fed to growing pigs by using near-infrared reflectance spectroscopy (NIRS). A total of 33 sorghum samples from all over China were used in this study. The samples were scanned for their spectra in the range of 12,000 to 4,000 cm−1. Based on principal components analysis of the spectra, the samples were split into a calibration set (n = 24) and a validation set (n = 9) according to the ratio of 3:1. With animal experiment values as calibration reference, the calibration models of DE and ME were established using partial least squares regression algorithm. Different spectral pretreatments were applied on the spectra to reduce the noise level. The best wavenumber ranges were also investigated. Results showed that DE and ME content in sorghum fed to growing pigs ranged from 14.57 to 16.70 MJ/kg DM and 14.31 to 16.35 MJ/kg DM, respectively. The optimal spectral preprocessing method for DE and ME was the combination of first derivative and multiplicative scatter correction. The most informative near-infrared spectral regions were 9,403.9 to 6,094.4 cm−1 and 4,605.5 to 4,242.9 cm−1 for both DE and ME. The best performance for DE and ME calibration models was the coefficient of determination of calibration (R2c) of 0.94 and 0.93, coefficient of determination of cross-external validation (R2cv) of 0.88 and 0.86, residual predictive deviation of cross-external validation (RPDcv) of 2.86 and 2.64, coefficient of determination of external validation (R2v) of 0.90 and 0.81, and residual predictive deviation of external validation (RPDv) of 3.15 and 2.35, respectively. There were no significant differences between the measured and NIRS predicted values for DE and ME (P = 0.895 for DE and P = 0.644 for ME). As the number of calibration samples increased from 24 to 33, the calibration performance of DE and ME models was improved, indicated by increased R2c, R2cv, and RPDcv values. In conclusion, NIRS quantitative models of the available energy in sorghum were established in this study. The results demonstrated that the content of DE and ME in sorghum could be predicted with relatively high accuracy based on NIRS and NIRS showed the superiority of speediness and practicality when compared with previous research methods including animal experiments, regression equations, and computer-controlled simulated digestion system.
Effects of central and peripheral administration of an acute-phase protein, α-1-acid-glycoprotein, on feed intake and rectal temperature in sheep
Authors: Gregg Brittany A , Parker Paxton A , Waller Kathryn M , Schneider Liesel G , Garcia Miriam , Bradford Barry , Daniel Joseph A , Whitlock Brian K
Published: November 2019

In rodents, an acute-phase protein, α-1-acid-glycoprotein (AGP), was shown to provide a link between inflammation and suppression of feed intake by acting as a leptin receptor agonist. The objective of this study was to determine the effects of AGP on feed intake and rectal temperature in sheep. Ewes were ovariectomized, implanted with a cannula into a lateral ventricle of the brain, and kept indoors in individual pens. Feed intake and rectal temperature were determined for sheep in all experiments. In the first experiment, ewes (n = 4) received 1 of 4 treatments [0 (control), 0.012 (low), 0.06 (medium), or 0.30 (high) mg/kg BW AGP] into the lateral ventricle (ICV). All sheep received all treatments in a Latin square design balanced for carryover effects with 10 d between treatments. In the second experiment, ewes (n = 10) received 1 of 2 treatments (0 and 3 mg/kg BW of AGP) intravenously (IV) in a completely randomized design. In the third experiment, ewes (n = 19) received peripheral treatments (IV) of an antipyretic [0 (control) or 2.2 mg/kg BW flunixin meglumine (FLU)] 30 min before receiving central AGP [0 (control) or 0.3 mg/kg BW of AGP] in a completely randomized design. All data were analyzed using a mixed model analysis of variance and tested for effects of treatment, time, and the interaction of treatment and time. Cumulative 48-h feed intake after administration of treatments was also determined. In the first experiment, there was no effect of ICV treatment (P = 0.37) on feed intake rate or on cumulative feed intake (P = 0.31). There was an effect of ICV treatment (P = 0.002) on rectal temperatures, which were greater (P < 0.05) after the high dose of centrally administered AGP. In the second experiment, there was no effect of AGP administration IV on feed intake rate (P = 0.98), on cumulative feed intake (P = 0.41) or on rectal temperature (P = 0.71). In the third experiment, there was an effect of central AGP treatment (P < 0.0001) and an interaction of central AGP and time (P < 0.0001) on rectal temperature, whereas FLU had no effect (P = 0.93), demonstrating that AGP increased rectal temperatures regardless of antipyretic treatment. These results indicate that central AGP increases rectal temperature in sheep by pathways that do not involve prostaglandins. Further research is needed to determine whether AGP may be an important integrator of energy balance and inflammation.
Prevention of peritoneal dialysis-related peritonitis by regular patient retraining via technique inspection or oral education: a randomized controlled trial
Authors: Xu Ying , Zhang Yuhui , Yang Bin , Luo Suping , Yang Zhikai , Johnson David W , Dong Jie
Published: November 2019

Background

There has been little research on strategies for prevention of peritoneal dialysis (PD)-related peritonitis. We explored whether regular retraining on bag exchanges (via two methods: technique inspection and oral education) every other month could help reduce the risk of peritonitis in PD patients through a randomized controlled trial (RCT).

Method

This is an RCT conducted at Peking University First Hospital. A total of 150 incident patients receiving PD at our centre were included between December 2010 and June 2016 and followed up until June 2018. Patients were randomly assigned 1:1:1 to receive retraining on bag exchange via technique inspection, oral education or usual care. The primary outcome was time to the first peritonitis episode. Secondary outcomes were time to organism-specific peritonitis, transfer to haemodialysis and all-cause death.

Results

Patients in the technique inspection group, oral education group and usual care group (n = 50 for each group) were followed up for 47.5 ± 22.9 months. Time to first peritonitis was comparable between the groups. The technique inspection group showed a lower risk of first non-enteric peritonitis than the usual care group, while the oral education group did not show a significant benefit. The incidence of first non-enteric peritonitis in the usual care group (0.07/patient-year) was significantly higher than that in the technique inspection group (0.02/patient-year; P < 0.01) but was comparable with that in the oral education group (0.06/patient-year). Transfer to haemodialysis and all-cause mortality were not significantly different between the groups.

Conclusions

Neither technique inspection nor oral education significantly altered the risk of all-cause peritonitis compared with usual care, despite technique inspection showing a trend towards reducing the risk of non-enteric PD-related peritonitis.

Trial registration

ClinicalTrials.gov (NCT01621997).
A 7-Year-Old Child With Headaches and Prolonged Fever Associated With Oral and Nail Lesions
Authors: Martin Sophie , Balligand Elise , Peeters Julie , Nassogne Marie-Cécile , Mondovits Bénédicte , Loop Michèle , de Selys Ariel , Vanclaire Jean , Vermylen Christiane , De Bruyckere Jean- Jacques , Chatzis Olga , Puel Anne , Gilliaux Olivier , Van Der Linden Dimitri
Published: November 2019

A 7-year-old child of Turkish origin presented with headache and vomiting in the context of prolonged fever of unknown source. At examination, oral candidiasis and chronic onychomycosis were noted. A Candida meningoencephalitis was diagnosed and intravenous Amphotericin B liposomal was given during 6 months relayed by oral Fluconazole after regression of CNS lesions was observed on MRI. A complete immune evaluation was performed, and genetic analysis detected homozygous CARD9 mutation. CARD9 deficiency have been associated with invasive candidiasis in otherwise healthy patients.

Culture of the cerebrospinal fluid grew for multisensitive Candida albicans. Brain magnetic resonance (MRI) showed the presence of focal lesions in the left caudate nucleus and in the right cerebellar hemisphere. Medullar MRI showed diffuse meningeal nodular lesions. Treatment with intravenous amphotericin B liposomal was given during 6 months relayed by oral fluconazole after regression of CNS lesions was observed on MRI.

A complete immune evaluation was performed and genetic analysis detected a homozygous CARD9 mutation. CARD9 deficiency have been associated with invasive candidiasis in otherwise healthy patients.
Towards Genotype-Specific Care for Chronic Hepatitis B: The First 6 Years Follow Up From the CHARM Cohort Study
Authors: Davies Jane , Smith Emma L , Littlejohn Margaret , Edwards Rosalind , Sozzi Vitina , Jackson Kathy , Mcguire Katie , Binks Paula , Cowie Benjamin C , Locarnini Stephen , Davis Joshua S , Tong Steven Y C
Published: November 2019

Objective

There is increasing evidence to suggest that, among those with chronic hepatitis B virus infection, the natural history and rate of progression to cirrhosis and hepatocellular carcinoma is influenced by hepatitis B virus genotype. The unique hepatitis B virus genotype C4 circulates among Indigenous Australians. The aim of this work is to describe the process of establishing this cohort and review the first 6 years of available data in an effort to understand the real-world clinical care and natural history of this subgenotype.

Method

We followed a longitudinal cohort of Indigenous Australians from the Northern Territory of Australia with established subgenotype C4 infections. We assigned phases of disease according to Gastroenterological Society of Australia and Asian Pacific Association for the Study of the Liver criteria using clinical and laboratory information that had been collected for clinical management.

Results

Of 193 patients followed over a median of 38 months, 58 (30%) individuals transitioned from 1 disease phase to another, 10 (5%) cleared hepatitis B e antigen, and 6 cleared hepatitis B surface antigen (3%). In this relatively young cohort (median age 40.3 years), 26 (13%) had cirrhosis by the end of the follow up period, with the majority of these being in the immune control phase of disease.

Conclusions

In this cohort of hepatitis B subgenotype C4 patients, we report an aggressive and dynamic clinical phenotype. High rates of cirrhosis at a young age appear to occur in the early phases of disease.
Patient experiences with outpatient parenteral antibiotic therapy: results of a patient survey comparing skilled nursing facilities and home infusion
Authors: Mansour Omar , Arbaje Alicia I , Townsend Jennifer L
Published: November 2019

Background

Outpatient parenteral antibiotic therapy (OPAT) is prescribed for patients with serious infections requiring prolonged therapy. Most patients requiring OPAT are discharged either home with home healthcare companies (HHCs) or to skilled nursing facilities (SNFs). Few data are available regarding patient experiences in these different sites of care.

Objectives

(1) Compare overall patient satisfaction with OPAT care across the SNF and HHC settings; (2) Identify barriers to patient satisfaction in OPAT; and (3) Develop a model for OPAT patient satisfaction that can help programs improve the patient experience across both sites of care.

Methods

We developed and administered a patient experience survey to 100 patients returning to a single clinic for follow up. The survey consisted of 15 items (Likert scale, multiple choice, and free text responses). Patient characteristics and responses to the survey for patients who received care at home and at SNFs were analyzed and compared.

Results

Of the 100 patients surveyed, 98 completed the survey. Overall, HHC patients were more satisfied with their care than patients in SNFs, with a greater proportion stating they would recommend the site to others (71.7% for HHC and 32.7% for SNFs, p<0.01). Patients in SNFs had a larger number of complaints about lapses in medical care, infection prevention, and the physical environment than HHC patients.

Conclusion

OPAT patient satisfaction is higher for home infusion than SNFs. In order to improve the patient experience, OPAT programs need to engage stakeholders in HHCs and SNFs to improve communication and care delivery.
Effects of sleep on a high-heat capacity mattress on sleep stages, EEG power spectra, cardiac interbeat intervals and body temperatures in healthy middle-aged men‡
Authors: Herberger Sebastian , Kräuchi Kurt , Glos Martin , Lederer Katharina , Assmus Lisa , Hein Julia , Penzel Thomas , Fietze Ingo
Published: November 2019

Study Objectives

This study deals with the question whether a slow (non-disturbing) reduction of core body temperature (CBT) during sleep increases sleep stage N3 and EEG slow wave energy (SWE) and leads to a slowing of heart rate in humans.

Participants

Thirty-two healthy male subjects with a mean ± SD age 46 ± 4 years and body mass index 25.2 ± 1.8 kg/m2.

Methods

A high-heat capacity mattress (HM) was used to lower body temperatures in sleep and was compared to a conventional low-heat capacity mattress (LM) in a double-blinded fashion. Polysomnography was performed accompanied by measurements of skin-, core body- and mattress surface-temperatures, and heart rate. EEG power spectral analyses were carried out using Fast Fourier Transform. Interbeat intervals were derived from the electrocardiogram.

Results

The HM led to a larger decline in CBT, mediated through higher heat conduction from the core via the proximal back skin onto the mattress together with reduced heart rate. These effects occurred together with a significant increase in sleep stage N3 and standardized slow wave energy (sSWE, 0.791–4.297 Hz) accumulated in NREM sleep. In the 2nd half of the night sSWE increase was significantly correlated with body temperature changes, for example with CBT decline in the same phase.

Conclusions

A HM subtly decreases CBT, leading to an increased amount of sleep stage N3 and of sSWE, as well as a slowing of heart rate.
Single cell transcriptomic analysis revealed long-lasting adverse effects of prenatal tamoxifen administration on neurogenesis in prenatal and adult brains
Authors: Lee Chia-Ming , Zhou Liqiang , Liu Jiping , Shi Jiayu , Geng Yanan , Wang Jiaruo , Su Xinjie , Barad Nicholas , Wang Junbang , Sun Yi E. , Lin Quan
Published: November 2019

CreER/LoxP system has enabled precise gene manipulation in distinct cell subpopulations at any specific time point upon tamoxifen (TAM) administration. This system is widely accepted to track neural lineages and study gene functions. We have observed prenatal TAM treatment caused high rate of delayed delivery and mortality of pups. These substances could promote undesired results, leading to data misinterpretation. Here, we report that TAM administration during early stages of cortical neurogenesis promoted precocious neural differentiation, while inhibited neural progenitor cell (NPC) proliferation. The TAM-induced inhibition of NPC proliferation led to deficits in cortical neurogenesis, dendritic morphogenesis, and cortical patterning in neonatal and postnatal offspring. Mechanistically, single cell RNA sequencing (scRNA-seq) analysis combined with in vivo and in vitro assays showed TAM could exert these drastic effects mainly through dysregulating the expression of Dmrta2 and Wnt8b. In adult mice, administration of TAM significantly attenuated NPC proliferation in both the subventricular zone and the dentate gyrus. This study revealed the cellular and molecular mechanisms for the adverse effects of prenatal tamoxifen administration on corticogenesis, suggesting that tamoxifen-induced CreER/LoxP system may not be suitable for neural lineage tracing and genetic manipulation studies in both embryonic and adult brains.

Significant

For the first time, our study revealed the molecular mechanisms underlying tamoxifen activities on cortical development. This study also clearly showed that care must be taken when using tamoxifen-induced CreER/LoxP system for neural lineage tracing and genetic manipulation studies.
Global kinome silencing combined with 3D invasion screening of the tumor microenvironment identifies fibroblast-expressed PIK3Cδ involvement in triple-negative breast cancer progression
Authors: Gagliano Teresa , Shah Kalpit , Gargani Sofia , Lao Liyan , Alsaleem Mansour , Chen Jianing , Ntafis Vasileios , Huang Penghan , Ditsiou Angeliki , Vella Viviana , Yadav Kritika , Bienkowska Kamila , Bresciani Giulia , Kang Kai , Li Leping , Carter Philip , Benstead-Hum Graeme , O’Hanlon Timothy , Dean Michael , Pearl Frances M.G. , Lee Soo-Chin , Rakha Emad A , Green Andrew R , Kontoyiannis Dimitris L. , Song Erwei , Stebbing Justin , Giamas Georgios
Published: November 2019

As there is growing evidence for the tumor microenvironment’s (TME) role in tumorigenesis, we sought to investigate the role of fibroblast-expressed kinases in triple negative breast cancer (TNBC). Using a high-throughput kinome screen combined with 3D invasion assays, we identified fibroblast-expressed PIK3Cδ (f-PIK3Cδ) as a key regulator of progression. Although PIK3Cδ has been mainly described in leucocytes, we detected high expression in primary fibroblasts derived from TNBC patients, while PIK3Cδ was undetectable in cancer epithelial cell lines. Genetic and pharmacologic gain- and loss-of functions experiments verified the contribution of f-PIK3Cδ in TNBC cell invasion. By employing an integrated secretomics and transcriptomics analysis, we revealed a paracrine mechanism via which f-PIK3Cδ confers its pro-tumorigenic effects. Inhibition of f-PIK3Cδ promoted the secretion of factors, including PLGF and BDNF, which subsequently led to upregulation of NR4A1 in TNBC cells where it acts as a tumor suppressor. Inhibition of PIK3Cδ in an orthotopic BC mouse model reduced tumor growth only after inoculation with fibroblasts, indicating a role of f-PIK3Cδ in cancer progression. Similar results were observed in the MMTV-PyMT transgenic BC mouse model, in addition to a decrease on tumor metastasis emphasizing the potential immune-independent effects of PIK3Cδ inhibition. Finally, analysis of BC patient cohorts and TCGA datasets identified f-PIK3Cδ (protein and mRNA levels) as an independent prognostic factor for overall and disease free survival, highlighting it as a therapeutic target for TNBC.
MutateX: an automated pipeline forin-silicosaturation mutagenesis of protein structures and structural ensembles
Authors: Tiberti Matteo , Terkelsen Thilde , Cremers Tycho Canter , Di Marco Miriam , da Piedade Isabelle , Maiani Emiliano , Papaleo Elena
Published: November 2019

Mutations resulting in amino acid substitution influence the stability of proteins along with their binding to other biomolecules. A molecular understanding of the effects induced by protein mutations are both of biotechnological and medical relevance. The availability of empirical free energy functions that quickly estimate the free energy change upon mutation (ΔΔG) can be exploited for systematic screenings of proteins and protein complexes. Indeed,in silicosaturation mutagenesis can guide the design of new experiments or rationalize the consequences of already-known mutations at the atomic level. Often software such as FoldX, while fast and reliable, lack the necessary automation features to make them useful in high-throughput scenarios. Here we introduce MutateX, a software which aims to automate the prediction of ΔΔGs associated with the systematic mutation of each available residue within a protein or protein complex to all other possible residue types, by employing the FoldX energy function. MutateX also supports ΔΔG calculations over protein ensembles and the estimation of the changes in free energy upon post-translational modifications. At the heart of MutateX lies an automated pipeline engine that handles input preparation, performs parallel runs with FoldX and outputs publication-ready figures. We here illustrate the MutateX protocol applied to the study of the mutational landscape of cancer-related proteins, industrial enzymes and protein-protein interfaces. The results of the high-throughput scan provided by our tools could help in different applications, such as the analysis of disease-associated mutations, or in the design of protein variants for experimental studies or industrial applications. MutateX is a collection of Python tools that relies on Open Source libraries and requires the FoldX software to be installed beforehand. It is available free of charge and under the GNU General Public License fromhttps://github.com/ELELAB/mutatex.
Human NK cell deficiency as a result of biallelic mutations in MCM10
Authors: Mace Emily M. , Paust Silke , Conte Matilde I. , Baxley Ryan M. , Schmit Megan , Guilz Nicole C. , Mukherjee Malini , Pezzi Ashley E. , Chmielowiec Jolanta , Tatineni Swetha , Chinn Ivan K. , Akdemir Zeynep Coban , Jhangiani Shalini N. , Muzny Donna M. , Stray-Pedersen Asbjørg , Bradley Rachel E. , Moody Mo , Connor Philip P. , Heaps Adrian G. , Steward Colin , Banerjee Pinaki P. , Gibbs Richard A. , Borowiak Malgorziata , Lupski James R. , Jolles Stephen , Bielinsky Anja K. , Orange Jordan S.
Published: November 2019

Human natural killer cell deficiency (NKD) arises from inborn errors of immunity that lead to impaired NK cell development, function or both. Through the understanding of the biological perturbations in individuals with NKD, requirements for the generation of terminally mature functional innate effector cells can be elucidated. Here we report a novel cause of NKD resulting from compound heterozygous mutations in MCM10 that impaired NK cell maturation in a child with fatal susceptibility to CMV. MCM10 has not been previously associated with monogenic disease and plays a critical role in the activation and function of the eukaryotic DNA replisome. By modeling MCM10 deficiency in human NK cell lines and primary NK cell precursors, we demonstrate that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function.
A novel microRNA-based strategy to expand the differentiation potency of stem cells
Authors: Salazar-Roa María , Trakala Marianna , Álvarez-Fernández Mónica , Valdés-Mora Fátima , Zhong Cuiqing , Muñoz Jaime , Yu Yang , Peters Timothy J. , Graña Osvaldo , Serrano Rosa , Zapatero-Solana Elisabet , Abad María , Bueno María José , de Cedrón Marta Gómez , Fernández-Piqueras José , Serrano Manuel , Blasco María A. , Wang Da-Zhi , Clark Susan J. , Izpisua-Belmonte Juan Carlos , Ortega Sagrario , Malumbres Marcos
Published: November 2019

Full differentiation potential along with self-renewal capacity is a major property of pluripotent stem cells (PSCs). However, the differentiation capacity frequently decreases during expansion of PSCs in vitro. We show here that transient exposure to a single microRNA, expressed at early stages during normal development, improves the differentiation capacity of already-established murine and human PSCs. Short exposure to miR-203 in PSCs (miPSCs) results in expanded differentiation potency as well as improved efficiency in stringent assays such as tetraploid complementation and human-mouse interspecies chimerism. Mechanistically, these effects are mediated by direct repression ofde novoDNA methyltransferases Dnmt3a and Dnmt3b, leading to transient and reversible erasing of DNA methylation. As a proof of concept, miR-203 improves differentiation and maturation of PSCs into cardiomyocytes in vitro as well as cardiac regeneration in vivo, after cardiac injury. These data support the use of transient exposure to miR-203 as a general and single method to reset the epigenetic memory in PSCs, and improve their use in regenerative medicine.
Leveraging correlations between polygenic risk score predictors to detect heterogeneity in GWAS cohorts
Authors: Yuan Jie , Xing Henry , Lamy Alexandre ,   The Schizophrenia Working Group of the Psychiatric Genomics Consortium, Lencz Todd , Pe’er Itsik
Published: November 2019

Evidence from both GWAS and clinical observation has suggested that certain psychiatric, metabolic, and autoimmune diseases are heterogeneous, comprising multiple subtypes with distinct genomic etiologies and Polygenic Risk Scores (PRS). However, the presence of subtypes within many phenotypes is frequently unknown. We present CLiP (Correlated Liability Predictors), a method to detect heterogeneity in single GWAS cohorts. CLiP calculates a weighted sum of correlations between SNPs contributing to a PRS on the case/control liability scale. We demonstrate mathematically and through simulation that among i.i.d. homogeneous cases, significant anti-correlations are expected between otherwise independent predictors due to ascertainment on the hidden liability score. In the presence of heterogeneity from distinct etiologies, confounding by covariates, or mislabeling, these correlation patterns are altered predictably. We further extend our method to two additional association study designs: CLiP-X for quantitative predictors in applications such as transcriptome-wide association, and CLiP-Y for quantitative phenotypes, where there is no clear distinction between cases and controls. Through simulations, we demonstrate that CLiP and its extensions reliably distinguish between homogeneous and heterogeneous cohorts when the PRS explains as low as 5% of variance on the liability scale and cohorts comprise 50, 000 − 100, 000 samples, an increasingly practical size for modern GWAS. We apply CLiP to heterogeneity detection in schizophrenia cohorts totaling > 50, 000 cases and controls collected by the Psychiatric Genomics Consortium. We observe significant heterogeneity in mega-analysis of the combined PGC data (p-value 8.54e-4), as well as in individual cohorts meta-analyzed using Fisher’s method (p-value 0.03), based on significantly associated variants.
Lipid Specificity of the Fusion of Bacterial Extracellular Vesicles with the Host Membrane
Authors: Prince Ashutosh , Tiwari Anuj , Mandal Titas , Koiri Debraj , Meher Geetanjali , Sinha Deepak Kumar , Saleem Mohammed
Published: November 2019

Bacterial membrane vesicles (MVs) facilitate long-distance delivery of virulence factors crucial for pathogenicity. The entry and trafficking mechanisms of virulence factors inside host cells are recently emerging, however, if bacterial MVs can fuse and modulate the physicochemical properties of the host lipid membrane and membrane lipid parameter for fusion remains unknown. Here we reconstitute the interaction of bacterial MV with host cell lipid membranes and quantitatively show that bacterial MV interaction increases the fluidity, dipole potential, and Compressibility of a biologically relevant multi-component host membrane upon fusion. The presence of cylindrical lipids such as phosphatidylcholine and a moderate acyl chain length of C16 helps the MV interaction. While significant binding of bacterial MVs to the raft-like lipid membranes with phase-separated regions of the membrane was observed, however, MVs prefer binding to the liquid-disordered regions of the membrane. Further, the elevated levels of cholesterol tend to hinder the interaction of bacterial MVs as evident from the favorable excess Gibbs free energy of mixing of bacterial MVs with host lipid membranes. The findings provide new insights that might have implications for the regulation of host machinery by bacterial pathogens through the manipulation of host membrane properties.
Disruption of the HIV-1 Envelope allosteric network blocks CD4-induced rearrangements
Authors: Henderson Rory , Lu Maolin , Zhou Ye , Mu Zekun , Parks Robert , Han Qifeng , Hsu Allen L. , Carter Elizabeth , Blanchard Scott C. , Edwards RJ , Wiehe Kevin , Saunders Kevin O. , Borgnia Mario J. , Bartesaghi Alberto , Mothes Walther , Haynes Barton F. , Acharya Priyamvada , Alam S. Munir
Published: November 2019

The trimeric HIV-1 Envelope protein (Env) mediates viral-host cell fusionviaa network of conformational transitions, with allosteric elements in each protomer orchestrating host receptor-induced exposure of the co-receptor binding site and fusion elements. To understand the molecular details of this allostery, we introduced Env mutations aimed to prevent CD4-induced rearrangements in the HIV-1 BG505 Env trimer. Binding analysis performed on the soluble ectodomain BG505 SOSIP Env trimers, cell-surface expressed BG505 full-length trimers and single-molecule Förster Resonance Energy Transfer (smFRET) performed on the full-length virion-bound Env confirmed that these mutations prevented CD4-induced transitions of the HIV-1 Env. Structural analysis by single-particle cryo-electron microscopy performed on the BG505 SOSIP mutant Env proteins revealed rearrangements in the gp120 topological layer contacts with gp41. Specifically, a conserved tryptophan at position 571 (W571) was displaced from its typical pocket at the interface of gp120 topological layers 1 and 2 by lysine 567, disrupting key gp120-gp41 contacts and rendering the Env insensitive to CD4 binding. Vector based analysis of closed Env SOSIP structures revealed the newly designed trimers exhibited a quaternary structure distinct from that typical of SOSIPs and residing near a cluster of Env trimers bound to vaccine-induced fusion peptide-directed antibodies (vFP Mabs). These results reveal the critical function of W571 as a conformational switch in Env allostery and receptor-mediated viral entry and provide insights on Env conformation that are relevant for vaccine design.
qPaLM: quantifying occult microarchitectural relationships in histopathological landscapes
Authors: Kendall Timothy J , Duff Catherine M , Thomson Andrew M , Iredale John P
Published: November 2019

Optimal tissue imaging methods should be easy to apply, not require use-specific algorithmic training, and should leverage feature relationships central to subjective gold-standard assessment. We reinterpret histological images as landscapes to describe quantitative pathological landscape metrics (qPaLM), a generalisable framework defining topographic relationships in tissue using geoscience approaches. qPaLM requires no user-dependent training to operate on all image datasets in a classifier-agnostic manner to quantify occult abnormalities, derive mechanistic insights, and define a new feature class for machine-learning diagnostic classification.
Mapping the micro-proteome of the nuclear lamina and lamin associated domains
Authors: Cutler Jevon A. , Wong Xianrong , Hoskins Victoria E. , Gordon Molly , Madugundu Anil K. , Pandey Akhilesh , Reddy Karen L.
Published: November 2019

The nuclear lamina is a proteinaceous network of filaments that provide both structural and gene regulatory functions by tethering proteins and large domains of DNA, so-called lamin associated domains (LADs), to the periphery of the nucleus. LADs are a large fraction of the mammalian genome that are repressed, in part, by their association to the nuclear periphery. The genesis and maintenance of LADs is poorly understood as are the proteins that participate in these functions. In an effort to identify proteins that reside at the nuclear periphery and potentially interact with LADs, we have taken a two-pronged approach. First, we have undertaken an interactome analysis of the inner nuclear membrane bound LAP2β to further characterize the nuclear lamina proteome. To accomplish this, we have leveraged the BioID system, which previously has been successfully used to characterize the nuclear lamina proteome. Second, we have established a system to identify proteins that bind to LADs by developing a chromatin directed BioID system. We combined the BioID system with the m6A-tracer system which binds to LADs in live cells to identify both LAD proximal and nuclear lamina proteins. In combining these datasets, we have further characterized the protein network at the nuclear lamina, identified putative LAD proximal proteins and found several proteins that appear to interface with both micro-proteomes. Importantly, several proteins essential for LAD function, including heterochromatin regulating proteins related to H3K9 methylation, were identified in this study.