bluuebunny/crossref_metadata_2025 huggingface dataset:
Echolocation of Central Amazonian ‘whispering’ phyllostomid bats: call design and interspecific variation
Authors: Yoh Natalie , Syme Peter , Rocha Ricardo , Meyer Christoph F. J. , López-Baucells Adrià
Published: May 2020

Phyllostomids (New World leaf-nosed bats) are the ecologically most diverse bat family and have undergone the most extensive adaptive radiation of any mammalian family. However comprehensive, multi-species studies regarding phyllostomid echolocation are scarce in the literature despite abundant ecological research. In this study, we describe the call structure and interspecific variation in call design of 40 sympatric phyllostomid species from the Central Brazilian Amazon, focussing on general patterns within genera, subfamilies and between feeding guilds. All but one species utilized short, broadband FM calls consisting of multiple harmonics. As reported for other bat families, peak frequency was negatively correlated with body mass and forearm length. Twenty-five species alternated the harmonic of maximum energy, principally between the second and third harmonic. Based on PCA, we were unable to detect any significant differences in echolocation call parameters between genera, subfamilies or different feeding guilds, confirming that acoustic surveys cannot be used to reliably monitor these species. We presentAmetrida centurioas an exception to this generalized phyllostomid structure, as it is unique in producing a mono-harmonic call. Finally, we discuss several hypotheses regarding the evolutionary pressures influencing phyllostomid call structure.
Quality Decision-Making Practices in Pharmaceutical Companies and Regulatory Authorities: Current and Proposed Approaches to Its Documentation
Authors: Bujar Magdalena , McAuslane Neil , Connelly Patricia , Walker Stuart R.
Published: May 2020

Background

Pharmaceutical companies and regulatory agencies endeavor to relate their decision making with outcomes to improve future decision making and to ensure that gained knowledge is fed back into a learning system. Nevertheless, such a correlation can only be achieved by documenting the expected outcome of a decision at the time it is made, enabling comparison of the expected outcome with the actual result.

Methods

Participants at an international workshop discussed how the documentation of decisions could be evolved as companies and agencies look to improve their knowledge base. Discussions were informed by a pre-workshop survey of pharmaceutical companies and regulatory agencies.

Results

Most survey participants from 12 companies (55% response rate) and 11 agencies (73% response) have a system in place to enable documentation of major decisions, however, systems are used primarily to document outcomes rather than the process, while information from documentation is not always used, and feedback loops are not in place. The majority of participants indicated that their organization currently documents most decision-making practices included in the proposed template. Workshop participants agreed that all major past decisions should be referenceable and suggested incentives to enable decisions to be referenced, and confirmed elements and characteristics of a decision-documentation template.

Conclusions

This survey and workshop identified the current landscape and gaps in the documentation of decision making and suggested revisions for a proposed documentation template. The use of technology to enable information extraction with support from artificial intelligence and future decision making was a recommendation highlighted by participants.
Induced Hypothermia to 4.2°C with Neurologically Intact Survival: A Forgotten Case Series
Authors: Zafren Ken , Paal Peter , Brugger Hermann , Lechner Raimund
Published: May 2020

The lowest recorded core temperature from which a person with accidental hypothermia has survived neurologically intact is 11.8°C in a 2-y-old boy. The lowest recorded temperature from which an adult has been resuscitated neurologically intact is 13.7°C in a 29-y-old woman. The lowest core temperature with survival from induced hypothermia has been quoted as 9°C. We discovered a case series (n=50) from 1961 in which 5 patients with core temperatures below 11.8°C survived neurologically intact. The lowest core temperature in this group was 4.2°C. The authors also presented cardiovascular and other physiologic data at various core temperatures. The patients in the case series showed a wide variation in individual physiological responses to hypothermia. It is not known whether survival from accidental hypothermia is possible with a core temperature below 11.8°C, but this case series suggests that the lower limit for successful resuscitation may be far lower. We advise against using core temperature alone to decide whether a hypothermic patient in cardiac arrest has a chance of survival.
Effect of Calcium-Channel Blockade on the Cold-Induced Vasodilation Response
Authors: Milliner Brendan H.A. , Brant-Zawadzki Graham , McIntosh Scott E.
Published: May 2020

Introduction

Cold-induced vasodilation (CIVD) is seen in the extremities during exposure to cold. A strong vasodilation response has been associated with a decreased risk of cold injury. Increasing CIVD might further decrease this risk. The calcium-channel blocker nifedipine causes vasodilation and is used to treat Raynaud’s syndrome and chilblains. Nifedipine is also used for high altitude pulmonary edema and could potentially serve a dual purpose in preventing frostbite. The effects of nifedipine on CIVD have not been studied.

Methods

A double-blind crossover study comparing nifedipine (30 mg SR (sustained release) orally twice daily) to placebo was designed using 2 sessions of 4 finger immersion in 5°C water, with 24 h of medication pretreatment before each session. Finger temperatures were measured via nailbed thermocouples. The primary outcome was mean finger temperature; secondary outcomes were mean apex and nadir temperatures, first apex and nadir temperatures, subjective pain ranking, and time of vasodilation onset (all presented as mean±SD).

Results

Twelve volunteers (age 29±3 [24–34] y) completed the study. No significant difference in finger temperature (9.2±1.1°C nifedipine vs 9.0±0.7°C placebo, P=0.38) or any secondary outcome was found. Pain levels were similar (2.8±1.6 nifedipine vs 3.0±1.5 placebo, P=0.32). The most common adverse event was headache (32% of nifedipine trials vs 8% placebo).

Conclusions

Pretreatment with 30 mg of oral nifedipine twice daily does not affect the CIVD response in healthy individuals under cold stress.
Maternal intake of one-carbon metabolism-related B vitamins and anorectal malformations in the Japan Environment and Children’s Study
Authors: Michikawa Takehiro , Nitta Hiroshi , Sekiyama Makiko , Kuroda Tatsuo , Nakayama Shoji F. , Isobe Tomohiko , Kobayashi Yayoi , Iwai-Shimada Miyuki , Suda Eiko , Taniguchi Yu , Kawamoto Toshihiro , Yamazaki Shin ,   the Japan Environment and Children’s Study Group
Published: May 2020

The occurrence of anorectal malformations (ARM) is thought to be reduced with sufficient folate intake. However, there is no apparent evidence. We focused on enzyme cofactors for one-carbon metabolism, including folate (vitamin B9), vitamin B6and vitamin B12, and explored the association between maternal combined intake of these B vitamins and the risk of ARM. Using baseline data from a Japanese nationwide birth cohort study between 2011 and 2014, we analysed data of 89 235 women (mean age at delivery = 31·2 years) who delivered singleton live births without chromosomal anomalies. Information on dietary intake was obtained via a FFQ focused on early pregnancy and used to estimate B vitamin intake. We also collected information on the frequency of folic acid supplement use. ARM occurrence was ascertained from medical records. We identified forty-three cases of ARM diagnosed up to the first month after birth (4·8 per 10 000 live births). In terms of individual intake of the respective B vitamins, high vitamin B6intake was non-significantly associated with reduced odds of ARM. Compared with women in the low combined B vitamin intake group, the OR of having an infant with ARM was 0·4 (95 % CI 0·2, 1·0) in the high intake group (folate ≥400 μg/d, and upper half of vitamin B6and/or vitamin B12). In conclusion, our cohort analysis suggested an inverse association between the combined intake of one-carbon metabolism-related B vitamins in early pregnancy and ARM occurrence.
Challenges of the low FODMAP diet for managing irritable bowel syndrome and approaches to their minimisation and mitigation
Authors: Wilson Bridgette , Cox Selina R. , Whelan Kevin
Published: May 2020

Dietary restriction of fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) is clinically effective and a commonly utilised approach in the management of functional symptoms in irritable bowel syndrome. Despite this, the low FODMAP diet has a number of challenges: it can alter the gut microbiota; impact nutrient intake and diet quality; is complex to understand; requires the patient to be adequately supported to follow the diet accurately and safely; and lastly, not all patients respond to the diet. The current review highlights the evidence for the clinical effectiveness of the low FODMAP diet, but focusses on the challenges associated with the diet to the patient, health professionals and the wider healthcare service. Finally, the review discusses research findings and practical guidance for how these challenges can be minimised and mitigated. The low FODMAP diet is a useful management strategy for irritable bowel syndrome, with data from clinical trials suggesting a 50–80% response rate, and when administered appropriately, the challenges to implementing the diet can be overcome so that these outcomes can be realised effectively and safely in clinical practice.
Towards evaluating complex ontology alignments
Authors: Zhou Lu , Thiéblin Elodie , Cheatham Michelle , Faria Daniel , Pesquita Catia , Trojahn Cassia , Zamazal Ondřej
Published: May 2020

The development of semi-automated and automated ontology alignment techniques is an important part of realizing the potential of the Semantic Web. Until very recently, most existing work in this area was focused on finding simple (1:1) equivalence correspondences between two ontologies. However, many real-world ontology pairs involve correspondences that contain multiple entities from each ontology. These ‘complex’ alignments pose a challenge for existing evaluation approaches, which hinders the development of new systems capable of finding such correspondences. This position paper surveys and analyzes the requirements for effective evaluation of complex ontology alignments and assesses the degree to which these requirements are met by existing approaches. It also provides a roadmap for future work on this topic taking into consideration emerging community initiatives and major challenges that need to be addressed.
QRS fragmentation in children with suspected myocarditis: a possible additional diagnostic sign
Authors: Ferrero Paolo , Piazza Isabelle
Published: May 2020

Aims:

We aim to assess the diagnostic role of QRS fragmentation in children with suspected acute myocarditis.

Background:

Diagnosis of myocarditis in the paediatric population is challenging. Clinical suspicion, electrocardiogram, and laboratory tests are the main diagnostic features at presentation. However, electrocardiogram in patients with myocarditis is usually considered aspecific. We have previously described QRS fragmentation in adult patients with acute myocarditis.

Methods:

Patients aged less than 18 years, admitted between 2003 and 2019, and discharged with a diagnosis of acute myocarditis were included. Standard electrocardiogram, laboratory, and echocardiographic findings at admission and follow-up were reviewed. QRS fragmentation was defined by the presence of multiphasic R′ spikes. Cardiac magnetic resonance and biopsy were performed in selected patients.

Results:

Twenty-one patients were analysed, 16 males (76%), median age 9.5 (2.5–16) years. At presentation, 12 patients (57%) displayed QRS fragmentation. Median ejection fraction was 40% (27–60). Nine patients (43%) underwent cardiac magnetic resonance and displayed late gadolinium enhancement. One patient underwent biopsy that showed borderline findings. Electrocardiogram leads showing QRS fragmentation correlated with distribution of late gadolinium enhancement. Median follow-up was 600 (190–2343) days. All patients were alive at last follow-up. Six patients (33%) patients displayed persistence of QRS fragmentation. Median ejection fraction was 60% (60–65%). In three patients (14%), ejection fraction remained depressed, two of which showed persistence of QRS fragmentation.

Conclusion:

In this cohort of children with suspected myocarditis, QRS fragmentation was confirmed as a new additional diagnostic finding to look for at admission and during follow-up.
Phonotactics, graphotactics and contrast: the history of Scots dental fricative spellings
Authors: MOLINEAUX BENJAMIN , KOPACZYK JOANNA , ALCORN RHONA , MAGUIRE WARREN , KARAISKOS VASILIS , LOS BETTELOU
Published: May 2020

The spelling conventions for dental fricatives in Anglic languages (Scots and English) have a rich and complex history. However, the various – often competing – graphemic representations (<þ>, <ð>,  and , among others) eventually settled on one digraph, , for all contemporary varieties, irrespective of the phonemic distinction between /ð/ and /θ/. This single representation is odd among the languages’ fricatives, which tend to use contrasting graphemes (cf.  vs  and
 vs ) to represent contrastive voicing, a sound pattern that emerged nearly a millennium ago. Close examinations of the scribal practices for English in the late medieval period, however, have shown that northern texts had begun to develop precisely this type of distinction for dental fricatives as well. Here /ð/ was predominantly represented by  and /θ/ by  (Jordan 1925; Benskin 1982). In the late fifteenth and early sixteenth centuries, this ‘Northern System’ collapsed, due to the northward spread of a London-based convention using exclusively  (Stenroos 2004). This article uses a rich body of corpus evidence for fifteenth-century Scots to show that, north of the North, the phonemic distinction was more clearly mirrored by spelling conventions than in any contemporary variety of English. Indeed, our data for Older Scots local documents (1375–1500) show a pattern where  progressively spreads into voiced contexts, while  recedes into voiceless ones. This system is traced back to the Old English positional preferences for <þ> and <ð> via subsequent changes in phonology, graphemic repertoire and letter shapes. An independent medieval Scots spelling norm is seen to emerge as part of a developing, proto-standard orthographic system, only to be cut short in the sixteenth century by top-down anglicisation processes.
Closing Time! Examining the Impact of Gender and Executive Branch Policy Makers on the Timing of Stay-at-Home Orders
Authors: Shay Laine P.
Published: May 2020

The 2019–20 coronavirus pandemic has significantly altered lives across the globe. In the United States, several states attempted to manage the pandemic by issuing stay-at-home orders. In this research note, I examine whether the gender of state policy makers in the executive branch might impact a state's adoption of a stay-at-home order. Using event history analysis, I find that the governor's gender has no impact on the likelihood of a state adopting a stay-at-home order. However, I find that gender plays a significant role for agency heads. Specifically, my analysis shows that states with a female-headed health agency tend to adopt stay-at-home orders earlier than states with a male administrator. These findings shed light on how female leadership in the executive branch may impact public policy regarding COVID-19.
A population-based case–control study of the association between weather-related extreme heat events and low birthweight
Authors: Lawrence Wayne R. , Soim Aida , Zhang Wangjian , Lin Ziqiang , Lu Yi , Lipton Emily A. , Xiao Jianpeng , Dong Guang-Hui , Lin Shao
Published: May 2020

Although prenatal exposure to high ambient temperatures were reported to be associated with preterm birth, limited research assessed the impact of weather-related extreme heat events (EHE) on birthweight, particularly by trimester. We, therefore, investigated the impact of prenatal EHE on birthweight among term babies (tLBW) by trimester and birthweight percentile. We conducted a population-based case–control study on singleton live births at 38–42 gestational weeks in New York State (NYS) by linking weather data with NYS birth certificates. A total of 22,615 cases were identified as birthweight <2500 gram, and a random sample of 139,168 normal birthweight controls was included. EHE was defined as three consecutive days with the maximum temperatures of ≥32.2 °C/90 °F (EHE90) and two consecutive days of temperatures ≥97th percentile (EHE97) based on the distribution of the maximum temperature for the season and region. We estimated odds ratios (ORs) and 95% confidence intervals (95% CI) with multivariable unconditional logistic regression, controlling for confounders. Overall exposure to EHE97 for 2 d was associated with tLBW (OR 1.05; 95% CI 1.02, 1.09); however, the strongest associations were only observed in the first trimester for both heat indicators, especially when exposure was ≥3 d (ORs ranged: 1.06–1.13). EHE in the first trimester was associated with significant reduction in mean birthweight from 26.78 gram (EHE90) to 36.25 gram (EHE97), which mainly affected the 40th and 60th birthweight percentiles. Findings revealed associations between multiple heat indicators and tLBW, where the impact was consistently strongest in the first trimester.
Higher dietary phytochemical index is associated with anthropometric	indices in children and adolescents: The weight disorders survey of the	CASPIAN-IV study
Authors: Azizi-Soleiman Fatemeh , Khoshhali Mehri , Heidari-Beni Motahar , Qorbani Mostafa , Ali Pourmirzaei Mohammad , Kelishadi Roya
Published: May 2020

Abstract. Objectives: The present study aimed to determine the association of total dietary phytochemical intake with generalized and abdominal obesity in children and adolescents. Material and methods: This nationwide cross-sectional study was conducted in 4296 students aged 6–18 years. Dietary phytochemical index (DPI) was calculated as a percentage of daily energy derived from phytochemical-rich foods divided by total daily energy intake. Results: The mean ± standard error of DPIs in the first, second, third and fourth quartiles were 12.70 ± 3.28, 20.36 ± 1.84, 27.52 ± 0.08 and 41.10 ± 0.26, respectively. Anthropometric measures including weight Z-score (−0.04 vs. 0.05, P = 0.023), body mass index (BMI) Z-score (−0.05 vs. 0.06, P = 0.013), waist circumference (WC) (65.80 cm vs. 66.95 cm P = 0.022), hip circumference (HC) (80.20 cm vs. 81.37 cm, P = 0.046), and neck circumference (NC) (30.06 cm vs. 30.45 cm, P = 0.031) were significantly lower among participants in the upper DPI quartile compared to those in the lower quartiles. In overweight and obese children, higher adjusted DPI scores had inverse correlation with BMI, WC, HC, wrist circumference, and NC (βs = −0.077, −0.10, −0.119, −0.01, and −0.032, respectively; P < 0.05). Comparison of the fourth quartile with the first quartile of DPI revealed beneficial effects of higher phytochemical intake on reducing the risk of obesity/overweight and abdominal obesity. However, these results were not statistically significant (P = 0.073). Conclusion: Higher DPI score was associated with lower risk of generalized and abdominal obesity in children and adolescents. However, the results were not statistically significant. Consuming phytochemical-rich foods can be encouraged to prevent childhood obesity.
Intraindividual Variability and Empathic Accuracy for Happiness in Older Couples
Authors: Michalowski Victoria I. , Gerstorf Denis , Hülür Gizem , Drewelies Johanna , Ashe Maureen C. , Madden Kenneth M. , Hoppmann Christiane A.
Published: May 2020

Abstract. Empathic accuracy involves identifying the emotions of others. Most evidence is based on younger samples, which is limiting because of well-established motivational shifts that occur in older adulthood. Here, we examine associations between fluctuations in happiness and empathic accuracy, using momentary assessments of happiness from 107 couples ( Mage = 75.2) in Berlin (Germany; up to 42 assessments) and 117 couples ( Mage = 71.1) in Vancouver (Canada; up to 28 assessments). Coordinated analyses show that perceivers are more accurate when they themselves have high happiness variability (Berlin, Vancouver). Target happiness variability did not moderate accuracy slopes. Follow-up analyses explore the role of partners sharing their feelings. Examining moderators of empathic pattern accuracy extends our understanding of positive socioemotional functioning in older couples.
Climate From the McMurdo Dry Valleys, Antarctica, 1986–2017: Surface Air Temperature Trends and Redefined Summer Season
Authors: Obryk M. K. , Doran P. T. , Fountain A. G. , Myers M. , McKay C. P.
Published: May 2020

The weather of the McMurdo Dry Valleys, Antarctica, the largest ice‐free region of the Antarctica, has been continuously monitored since 1985 with currently 14 operational meteorological stations distributed throughout the valleys. Because climate is based on a 30‐year record of weather, this is the first study to truly define the contemporary climate of the McMurdo Dry Valleys. Mean air temperature and solar radiation based on all stations were −20°C and 102 W m−2, respectively. Depending on the site location, the mean annual air temperatures on the valleys floors ranged between −15°C and −30°C, and mean annual solar radiation varied between 72 and 122 W m−2. Surface air temperature decreased by 0.7°C per decade from 1986 to 2006 at Lake Hoare station (longest continuous record), after which the record is highly variable with no trend. All stations with sufficiently long records showed similar trend shifts in 2005 ±1 year. Summer is defined as November through February, using a physically based process: up‐valley warming from the coast associated with a change in atmospheric stability.
Long‐Term Monitoring and Characterization of Soil Radon Emission in a Seismically Active Area
Authors: D'Alessandro Antonino , Scudero Salvatore , Siino Marianna , Alessandro Giuseppe , Mineo Rosario
Published: May 2020

Radon (222Rn) is a radioactive gas, which originates everywhere in rocks of Earth's crust through a process of natural decay of other radioactive elements. The monitoring of soil radon can be useful to address a multitude of geological and environmental issues. However, some difficulties arise when trying to use radon as earthquake precursor because the earthquake‐related anomaly cannot be easily and univocally discriminated from other anomalies of different origin. To explore the relationship between soil radon emission and seismicity, a local network is operating in southeastern Sicily (Italy). Its peculiarities are the uniform geological condition of the monitoring sites and the long data record with simultaneous measures of radon and the main climate variables. In this paper, we applied continuous wavelet transformation to a ≈ 3.5 years long soil radon time series to detect periodic variations. Results indicate the occurrence of cycles at annual, semiannual, and monthly periodicity, which are ascribable to the effects of the climatic‐environmental parameters. The periodic components have been modeled and the signal conveniently filtered. We show as the characterization of the long‐term behavior of radon signals is essential to recognize anomalies in radon emission, which can be related to geological/environmental phenomena. The methodology proposed in this work provides a reliable characterization of the radon time series and can be applied at various spatial/temporal scales, depending on the scientific objectives to be achieved. This approach can also represent the base for further analysis like the investigation of the modulation between the periodic components and short‐term forecasts.
Impact of Transmission Scheme of Visible Solar Radiation on Temperature and Mixing in the Upper Water Column With Inputs for Transmission Derived From Ocean Color Remote Sensing
Authors: Liu Tongtong , Lee Zhongping , Shang Shaoping , Xiu Peng , Chai Fei , Jiang Mingshun
Published: May 2020

The penetration of visible solar radiation (VSR) in the upper ocean contributes to heating in the upper water column, and this process is modulated by constituents in water such as phytoplankton. Various schemes have been developed to propagate surface VSR to deeper depths, which are incorporated in ocean circulation models to study basin‐scale impacts on ocean and atmosphere by phytoplankton. However, none of these studies evaluated sensitivity of the schemes of VSR transmission to upper‐water dynamics, especially when the required input is derived from ocean color remote sensing. We used an idealized one‐dimensional (1‐D) Regional Ocean Modeling System (ROMS) to simulate profiles of upper water column temperature at six locations with different ocean color characteristics (containing different water constituents). We incorporated and tested four different schemes of VSR transmission: the default water‐type scheme within the ROMS, two schemes based on concentrations of chlorophyll (Chl), and one scheme based on water's inherent optical properties (IOPs). The results showed that, although using the same ocean color information and the same circulation model, the IOPs‐ and Chl‐based schemes resulted in very different vertical temperature and upper‐water mixing compared to those using the default scheme, with differences in sea surface temperature up to 1.5–2°C. These results highlight the importance of developing and incorporating more appropriate VSR transmission schemes into large‐scale ocean circulation simulations, where the inputs for the transmission are inherently estimates from ocean color—the actual measurement from satellite remote sensing.
Impacts of TIPEX‐III Rawinsondes on the Dynamics and Thermodynamics Over the Eastern Tibetan Plateau in the Boreal Summer
Authors: Li Junjun , Chen Jinghua , Lu Chunsong , Wu Xiaoqing
Published: May 2020

Observations and simulations have shown that the Tibetan Plateau (TP) plays an important role in the climate and weather of East Asia. Uncertainties in reanalysis data sets have been documented by comparing them with independent rawinsonde data, but the impacts of incorporating this data into a reanalysis data set on the dynamical and thermodynamical features over the TP have not been assessed. Observations from the recent Third Tibetan Plateau Atmospheric Scientific Experiment (TIPEX‐III) can be used to evaluate the Eastern TP ERA‐Interim reanalysis data set (ERA). In this study, the Barnes objective analysis scheme is used to incorporate the rawinsonde data into the ERA to acquire the gridded data (OBJ) for examining heat and moisture budgets. It is shown that the OBJ budget‐estimated rainfall intensity is better correlated with the observations than the ERA budget‐estimated rainfall intensity. The ERA overestimates weak rainfall but underestimates heavy rainfall. The incorporation of special rawinsonde into the OBJ impacts the dynamical and thermodynamical characteristics both spatially and temporally. The downward motion and cooling are enhanced over the rainless regions/periods, while the upward motion and heating are enhanced over the rainy regions/periods. The rawinsonde effect is stronger with the increasing rainfall intensity. The differences of spatial distributions and temporal variations in heating between the OBJ and ERA are primarily determined by the vertical advection terms in heat and moisture budgets. The OBJ‐derived large‐scale forcing is essential for cloud‐resolving model simulations of TP cloud systems. The above conclusions can also be applied to the ERA5.
Ovarian BDNF promotes survival, migration, and attachment of tumor precursors originated from p53 mutant fallopian tube epithelial cells
Authors: Kang Min , Chong Kay Yi , Hartwich Tobias M. P. , Bi Fangfang , Witham Allyson K. , Patrick David , Morrisson Madeline J. , Cady Sarah L. , Cerchia Alexandra P. , Kelk Dawn , Liu Yifei , Nucci Jonah , Madarikan Oluwagbemisola , Ueno Daiki , Shuch Brian M. , Yang-Hartwich Yang
Published: May 2020

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecological malignancy. New evidence supports a hypothesis that HGSOC can originate from fallopian tube epithelium (FTE). It is unclear how genetic alterations and pathophysiological processes drive the progression of FTE tumor precursors into widespread HGSOCs. In this study, we uncovered that brain-derived neurotrophic factor (BDNF) in the follicular fluid stimulates the tropomyosin receptor kinase B (TrkB)-expressing FTE cells to promote their survival, migration, and attachment. Using in vitro and in vivo models, we further identified that the acquisition of common TP53 gain-of-function (GOF) mutations in FTE cells led to enhanced BDNF/TrkB signaling compared to that of FTE cells withTP53loss-of-function (LOF) mutations. Different mutant p53 proteins can either increase TrkB transcription or enhance TrkB endocytic recycling. Our findings have demonstrated possible interplays between genetic alterations in FTE tumor precursors (i.e., p53 GOF mutations) and pathophysiological processes (i.e., the release of follicular fluid upon ovulation) during the initiation of HGSOC from the fallopian tube. Our data revealed molecular events underlying the link between HGSOC tumorigenesis and ovulation, a physiological process that has been associated with risk factors of HGSOC.
Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2
Authors: Catanzaro Michele , Fagiani Francesca , Racchi Marco , Corsini Emanuela , Govoni Stefano , Lanni Cristina
Published: May 2020

To date, no vaccines or effective drugs have been approved to prevent or treat COVID-19 and the current standard care relies on supportive treatments. Therefore, based on the fast and global spread of the virus, urgent investigations are warranted in order to develop preventive and therapeutic drugs. In this regard, treatments addressing the immunopathology of SARS-CoV-2 infection have become a major focus. Notably, while a rapid and well-coordinated immune response represents the first line of defense against viral infection, excessive inflammatory innate response and impaired adaptive host immune defense may lead to tissue damage both at the site of virus entry and at systemic level. Several studies highlight relevant changes occurring both in innate and adaptive immune system in COVID-19 patients. In particular, the massive cytokine and chemokine release, the so-called “cytokine storm”, clearly reflects a widespread uncontrolled dysregulation of the host immune defense. Although the prospective of counteracting cytokine storm is compelling, a major limitation relies on the limited understanding of the immune signaling pathways triggered by SARS-CoV-2 infection. The identification of signaling pathways altered during viral infections may help to unravel the most relevant molecular cascades implicated in biological processes mediating viral infections and to unveil key molecular players that may be targeted. Thus, given the key role of the immune system in COVID-19, a deeper understanding of the mechanism behind the immune dysregulation might give us clues for the clinical management of the severe cases and for preventing the transition from mild to severe stages.
TGF-β1-mediated repression of SLC7A11 drives vulnerability to GPX4 inhibition in hepatocellular carcinoma cells
Authors: Kim Do Hyung , Kim Won Dong , Kim Sang Kyum , Moon Dae Hyuk , Lee Seung Jin
Published: May 2020

System xc− contributes to glutathione (GSH) synthesis and protects cells against ferroptosis by importing cystine and exchanging it with glutamate. Transforming growth factor β1 (TGF-β1) induces redox imbalance; however, its role in system xc− regulation remains poorly understood. The present study was the first to show that TGF-β1 repressed the protein and mRNA levels of xCT, a catalytic subunit of system xc−, in PLC/PRF/5, Huh7, Huh6, and HepG2 cells with an early TGF-β1 gene signature but not in SNU387, SNU449, SNU475, and SK-Hep1 cells with a late TGF-β1 gene signature. TGF-β1 treatment for 24 h reduced xCT expression in a dose-dependent manner but this TGF-β1-induced repression was blunted by pretreatment with a TGF-β1 receptor inhibitor. TGF-β1-mediated xCT repression was prevented by Smad3, but not Smad2 or Smad4, knockdown, whereas it was enhanced by Smad3 overexpression. TGF-β1 decreased GSH levels in control cells but not xCT-overexpressed cells. Furthermore, TGF-β1 increased reactive oxygen species (ROS) levels in PLC/PRF/5 cells and enhanced tert-butyl hydroperoxide-induced ROS levels in Huh7 cells; these changes were reversed by xCT overexpression. TGF-β1 treatment ultimately induced the ferrostatin-1- and deferoxamine-dependent lipid peroxidation after 2 days and 8 days in PLC/PRF/5 and Huh7 cells but not in SNU475 and SK-Hep1 cells. Pre-treatment of TGF-β1 for 2 days enhanced the reduction of cell viability induced by RSL3, a GSH peroxidase 4 (GPX4) inhibitor, in PLC/PRF/5 and Huh7 cells. In conclusion, TGF-β1 represses xCT expression via Smad3 activation and enhances lipid peroxidation in hepatocellular carcinoma cells with an early TGF-β1 signature, which would benefit from the targeting of GPX4.
Loss of Rictor in tubular cells exaggerates lipopolysaccharide induced renal inflammation and acute kidney injury via Yap/Taz-NF-κB axis
Authors: Gui Yuan , Hou Qing , Lu Qingmiao , Dai Chunsun , Li Jianzhong
Published: May 2020

Our previous study demonstrated that the mammalian target of rapamycin complex 2 (mTORC2) signaling alleviates renal inflammation and protects against cisplatin-induced AKI. However, the underlying mechanisms for mTORC2 in regulating renal inflammation in AKI remain to be determined. In this study, we found that lipopolysaccharide (LPS) could activate mTORC2 signaling in NRK-52E cells, and blockage of mTORC2 signaling led to Yap/Taz degradation, which in turn activated NF-κB signaling and induced inflammatory cytokines secretion. Overexpression of constitutively active Taz (Taz-S89A) could attenuate the inflammation-amplified role of mTORC2 blockage. In mouse models, tubule-specific deletion of Rictor had higher blood urea nitrogen level, severe morphological injury as well as more inflammatory cells accumulation compared with those in their littermate controls. Overall, these results demonstrate that mTORC2 signaling protects against renal inflammation and dictates the outcome of AKI by modulating Yap/Taz degradation.
SIRT1 directly activates autophagy in human chondrocytes
Authors: Sacitharan Pradeep K. , Bou-Gharios George , Edwards James R.
Published: May 2020

Osteoarthritis (OA) is the most common form of arthritis worldwide with no effective treatment. Ageing is the primary risk factor for OA. We sought to investigate if there is a distinct and functional convergence of ageing-related mechanisms SIRT1 and autophagy in chondrocytes. Our results show that, levels of SIRT1 are decreased in human normal aged and OA cartilage compared with young cartilage. Moreover, silencing SIRT1 in chondrocytes lead to decreased expression of chondrogenic markers but did not alter the expression of catabolic proteases. In contrast, activation of SIRT1 increased autophagy in chondrocytes by the deacetylation of lysine residues on crucial autophagy proteins (Beclin1, ATG5, ATG7, LC3). This activation was shown to be mTOR/ULK1 independent. Our results indicate that maintenance of autophagy in chondrocytes by SIRT1 is essential for preserving cartilage integrity throughout life and therefore is a target for drug intervention to protect against OA.
Evolution and structure of clinically relevant gene fusions in multiple myeloma
Authors: Foltz Steven M. , Gao Qingsong , Yoon Christopher J. , Sun Hua , Yao Lijun , Li Yize , Jayasinghe Reyka G. , Cao Song , King Justin , Kohnen Daniel R. , Fiala Mark A. , Ding Li , Vij Ravi
Published: May 2020

Multiple myeloma is a plasma cell blood cancer with frequent chromosomal translocations leading to gene fusions. To determine the clinical relevance of fusion events, we detect gene fusions from a cohort of 742 patients from the Multiple Myeloma Research Foundation CoMMpass Study. Patients with multiple clinic visits enable us to track tumor and fusion evolution, and cases with matching peripheral blood and bone marrow samples allow us to evaluate the concordance of fusion calls in patients with high tumor burden. We examine the joint upregulation ofWHSC1andFGFR3in samples with t(4;14)-related fusions, and we illustrate a method for detecting fusions from single cell RNA-seq. We report fusions atMYCand a neighboring gene,PVT1, which are related toMYCtranslocations and associated with divergent progression-free survival patterns. Finally, we find that 4% of patients may be eligible for targeted fusion therapies, including three with anNTRK1fusion.
The neuropeptide substance P regulates aldosterone secretion in human adrenals
Authors: Wils Julien , Duparc Céline , Cailleux Anne-Françoise , Lopez Antoine-Guy , Guiheneuf Caroline , Boutelet Isabelle , Boyer Hadrien-Gaël , Dubessy Christophe , Cherifi Saloua , Cauliez Bruno , Gobet Françoise , Defortescu Guillaume , Ménard Jean-François , Louiset Estelle , Lefebvre Hervé
Published: May 2020

Aldosterone, produced by the adrenals and under the control of plasma angiotensin and potassium levels, regulates hydromineral homeostasis and blood pressure. Here we report that the neuropeptide substance P (SP) released by intraadrenal nerve fibres, stimulates aldosterone secretion via binding to neurokinin type 1 receptors (NK1R) expressed by aldosterone-producing adrenocortical cells. The action of SP is mediated by the extracellular signal-regulated kinase pathway and involves upregulation of steroidogenic enzymes. We also conducted a prospective proof-of-concept, double blind, placebo-controlled clinical trial aimed to investigate the impact of the NK1R antagonist aprepitant on aldosterone secretion in healthy male volunteers (EudraCT: 2008-003367-40, ClinicalTrial.gov: NCT00977223). Participants received during two 7-day treatment periods aprepitant (125 mg on the 1st day and 80 mg during the following days) or placebo in a random order at a 2-week interval. The primary endpoint was plasma aldosterone levels during posture test. Secondary endpoints included basal aldosterone alterations, plasma aldosterone variation during metoclopramide and hypoglycaemia tests, and basal and stimulated alterations of renin, cortisol and ACTH during the three different stimulatory tests. The safety of the treatment was assessed on the basis of serum transaminase measurements on days 4 and 7. All pre-specified endpoints were achieved. Aprepitant decreases aldosterone production by around 30% but does not influence the aldosterone response to upright posture. These results indicate that the autonomic nervous system exerts a direct stimulatory tone on mineralocorticoid synthesis through SP, and thus plays a role in the maintenance of hydromineral homeostasis. This regulatory mechanism may be involved in aldosterone excess syndromes.
Efficient and stable tin perovskite solar cells enabled by amorphous-polycrystalline structure
Authors: Liu Xiao , Wang Yanbo , Wu Tianhao , He Xin , Meng Xiangyue , Barbaud Julien , Chen Han , Segawa Hiroshi , Yang Xudong , Han Liyuan
Published: May 2020

Tin perovskite solar cells (TPSCs) have triggered intensive research as a promising candidate for lead-free perovskite solar cells. However, it is still challenging to obtain efficient and stable TPSCs because of the low defects formation energy and the oxidation of bivalent tin; Here, we report a TPSC with a stable amorphous-polycrystalline structure, which is composed of a tin triple-halide amorphous layer and cesium-formamidinium tin iodide polycrystals. This structure effectively blocks the outside oxygen, moisture and also suppresses the ion diffusion inside the devices. In addition, its energy level benefits the charge extraction and transport in TPSCs. This design enabled us to obtain the certified quasi-steady-state efficiency over 10% for TPSCs from an accredited certification institute. The cell was stable, maintaining 95% of the initial PCE after operation at the maximum power point under AM 1.5 G simulated solar light (100 mWcm−2) for 1000 hours.
Detection of air and surface contamination by SARS-CoV-2 in hospital rooms of infected patients
Authors: Chia Po Ying , Coleman Kristen Kelli , Tan Yian Kim , Ong Sean Wei Xiang , Gum Marcus , Lau Sok Kiang , Lim Xiao Fang , Lim Ai Sim , Sutjipto Stephanie , Lee Pei Hua , Son Than The , Young Barnaby Edward , Milton Donald K. , Gray Gregory C. , Schuster Stephan , Barkham Timothy , De Partha Pratim , Vasoo Shawn , Chan Monica , Ang Brenda Sze Peng , Tan Boon Huan , Leo Yee-Sin , Ng Oon-Tek , Wong Michelle Su Yen , Marimuthu Kalisvar ,   for the Singapore 2019 Novel Coronavirus Outbreak Research Team, Lye David Chien , Lim Poh Lian , Lee Cheng Chuan , Ling Li Min , Lee Lawrence , Lee Tau Hong , Wong Chen Seong , Sadarangani Sapna , Lin Ray Junhao , Ng Deborah Hee Ling , Sadasiv Mucheli , Yeo Tsin Wen , Choy Chiaw Yee , Tan Glorijoy Shi En , Dimatatac Frederico , Santos Isais Florante , Go Chi Jong , Chan Yu Kit , Tay Jun Yang , Tan Jackie Yu-Ling , Pandit Nihar , Ho Benjamin Choon Heng , Mendis Shehara , Chen Yuan Yi Constance , Abdad Mohammad Yazid , Moses Daniela
Published: May 2020

Understanding the particle size distribution in the air and patterns of environmental contamination of SARS-CoV-2 is essential for infection prevention policies. Here we screen surface and air samples from hospital rooms of COVID-19 patients for SARS-CoV-2 RNA. Environmental sampling is conducted in three airborne infection isolation rooms (AIIRs) in the ICU and 27 AIIRs in the general ward. 245 surface samples are collected. 56.7% of rooms have at least one environmental surface contaminated. High touch surface contamination is shown in ten (66.7%) out of 15 patients in the first week of illness, and three (20%) beyond the first week of illness (p = 0.01, χ2 test). Air sampling is performed in three of the 27 AIIRs in the general ward, and detects SARS-CoV-2 PCR-positive particles of sizes >4 µm and 1–4 µm in two rooms, despite these rooms having 12 air changes per hour. This warrants further study of the airborne transmission potential of SARS-CoV-2.
Computational framework for a systematic investigation of anionic redox process in Li-rich compounds
Authors: Tygesen Alexander Sougaard , Chang Jin Hyun , Vegge Tejs , García-Lastra Juan Maria
Published: May 2020

Anionic redox processes play a key role in determining the accessible capacity and cycle life of Li-rich cathode materials for batteries. We present a framework for investigating the anionic redox processes based on data readily available from standard DFT calculations. Our recipe includes a method of classifying different anionic species, counting the number of species present in the structure and a preconditioning scheme to promote anionic redox. The method is applied to a set of LixMnO3 (1 ≤ x ≤2) structures, with cationic disorder, to identify the evolution of anionic redox processes during cycling. Additionally, we investigate how different choices of exchange-correlation functionals affect the formation of anionic redox species. The preconditioning of the structures is shown to promote the formation of peroxo-like species. Furthermore, the choice of exchange-correlation functional has a large impact on the type of anionic redox species present, and thus care must be taken when considering localization in anionic species.
dbPSP 2.0, an updated database of protein phosphorylation sites in prokaryotes
Authors: Shi Ying , Zhang Ying , Lin Shaofeng , Wang Chenwei , Zhou Jiaqi , Peng Di , Xue Yu
Published: May 2020

In prokaryotes, protein phosphorylation plays a critical role in regulating a broad spectrum of biological processes and occurs mainly on various amino acids, including serine (S), threonine (T), tyrosine (Y), arginine (R), aspartic acid (D), histidine (H) and cysteine (C) residues of protein substrates. Through literature curation and public database integration, here we reported an updated database of phosphorylation sites (p-sites) in prokaryotes (dbPSP 2.0) that contains 19,296 experimentally identified p-sites in 8,586 proteins from 200 prokaryotic organisms, which belong to 12 phyla of two kingdoms, bacteria and archaea. To carefully annotate these phosphoproteins and p-sites, we integrated the knowledge from 88 publicly available resources that covers 9 aspects, namely, taxonomy annotation, genome annotation, function annotation, transcriptional regulation, sequence and structure information, family and domain annotation, interaction, orthologous information and biological pathway. In contrast to version 1.0 (~30 MB), dbPSP 2.0 contains ~9 GB of data, with a 300-fold increased volume. We anticipate that dbPSP 2.0 can serve as a useful data resource for further investigating phosphorylation events in prokaryotes. dbPSP 2.0 is free for all users to access at: http://dbpsp.biocuckoo.cn.
First-passage times and normal tissue complication probabilities in the limit of large populations
Authors: Hufton Peter G. , Buckingham-Jeffery Elizabeth , Galla Tobias
Published: May 2020

The time of a stochastic process first passing through a boundary is important to many diverse applications. However, we can rarely compute the analytical distribution of these first-passage times. We develop an approximation to the first and second moments of a general first-passage time problem in the limit of large, but finite, populations using Kramers–Moyal expansion techniques. We demonstrate these results by application to a stochastic birth-death model for a population of cells in order to develop several approximations to the normal tissue complication probability (NTCP): a problem arising in the radiation treatment of cancers. We specifically allow for interaction between cells, via a nonlinear logistic growth model, and our approximations capture the effects of intrinsic noise on NTCP. We consider examples of NTCP in both a simple model of normal cells and in a model of normal and damaged cells. Our analytical approximation of NTCP could help optimise radiotherapy planning, for example by estimating the probability of complication-free tumour under different treatment protocols.