bluuebunny/crossref_metadata_2025 huggingface dataset:
Negative controls to detect uncontrolled confounding in observational studies of mammographic screening comparing participants and non-participants
Authors: Lousdal Mette Lise , Lash Timothy L , Flanders W Dana , Brookhart M Alan , Kristiansen Ivar Sønbø , Kalager Mette , Støvring Henrik
Published: February 2020

Background

When comparing mammography-screening participants and non-participants, estimates of reduction in breast-cancer mortality may be biased by poor baseline comparability. We used negative controls to detect uncontrolled confounding.

Methods

We designed a closed cohort of Danish women invited to a mammography-screening programme at age 50–52 years in Copenhagen or Funen from 1991 through 2001. We included women with a normal screening result in their first-invitation round. Based on their second-invitation round, women were divided into participants and non-participants and followed until death, emigration or 31 December 2014, whichever came first. We estimated hazard ratios (HRs) of death from breast cancer, causes other than breast cancer and external causes. We added dental-care participation as an exposure to test for an independent association with breast-cancer mortality. We adjusted for civil status, parity, age at first birth, educational attainment, income and hormone use.

Results

Screening participants had a lower hazard of breast-cancer death [HR 0.47, 95% confidence interval (CI) 0.32, 0.69] compared with non-participants. Participants also had a lower hazard of death from other causes (HR 0.43, 95% CI 0.39, 0.46) and external causes (HR 0.35, 95% CI 0.23, 0.54). Reductions persisted after covariate adjustment. Dental-care participants had a lower hazard of breast-cancer death (HR 0.75, 95% CI 0.56, 1.01), irrespective of screening participation.

Conclusions

Negative-control associations indicated residual uncontrolled confounding when comparing breast-cancer mortality among screening participants and non-participants.
A multicentre outbreak of ST45 MRSA containing deletions in the spa gene in New South Wales, Australia
Authors: Beukers Alicia G , Newton Peter , Hudson Bernard , Ross Kimberly , Gottlieb Thomas , O’Sullivan Matthew , Daley Denise A , Pang Stanley , Coombs Geoffrey W , van Hal Sebastiaan J
Published: February 2020

Background

Early identification of MRSA by diagnostic medical microbiology laboratories enables improved antimicrobial choice and outcomes. The Cepheid Xpert® MRSA/SA BC test rapidly identifies Staphylococcus aureus bloodstream infections through spa gene detection and methicillin resistance via mecA gene detection. Recent emergence of S. aureus with deletions in the spa gene has resulted in false-negative results for this test, leading to misidentification of infections with this organism, particularly MRSA ST45.

Objectives

To investigate the emergence and prevalence of ST45 MRSA in New South Wales (NSW), Australia.

Methods

WGS read data from six NSW hospitals were collected for 131 ST45 MRSA isolates and analysed.

Results

Of the 131 ST45 MRSA investigated, 88.5% (116/131) contained a deletion in the spa gene that appeared to have arisen once in approximately 2010 followed by clonal expansion. Given the successful establishment of this ‘spa-deletion’ MRSA clone, the Cepheid Xpert® MRSA/SA BC test became unreliable for confirming S. aureus bacteraemia in NSW. Subsequently, the algorithm used by this test has been updated and evaluated to take into account the presence of S. aureus with either a spa deletion or SCCmec target variations.

Conclusions

This study highlighted the applied use of WGS for assessing diagnostic assays and informing necessary changes to ensure the viability of the Cepheid Xpert® MRSA/SA BC test in the context of the new ‘spa-deletion’ MRSA clone. It demonstrated how continued surveillance through WGS can reveal evolutionary events that may impact diagnostic assays, allowing corrective modifications to be made in real time.
An urban labor market with frictional housing markets: theory and an application to the Paris urban area
Authors: Chapelle Guillaume , Wasmer Etienne , Bono Pierre-Henri
Published: February 2020

We build a tractable model of frictional labor markets and segmented housing markets to study welfare effects of regulations, including spatial misallocation and deviation from competitive pricing of rents. The model is summarized by a labor demand curve depending on rents and wages, a wage curve reflecting labor market tightness and rents, and finally a rent curve reflecting employment. In this economy, the rent gradient in the flexible rent sector is higher than in a purely competitive housing market. This leads to spatial misallocation due to some employees commuting too much and some non-employed living inefficiently close to jobs. In turn, reducing generalized commuting costs reduces the rent gradient in the flexible rent sector and the cost of spatial misallocation of workers. The reduction in market rents is maximal when labor markets are less frictional and housing markets are more frictional, and welfare gains are larger when both are more efficient.
Conditional Survival, Cause-Specific Mortality, and Risk Factors of Late Mortality After Allogeneic Hematopoietic Cell Transplantation
Authors: Wong F Lennie , Teh Jennifer Berano , Atencio Liezl , Stiller Tracey , Kim Heeyoung , Chanson Dayana , Forman Stephen J , Nakamura Ryotaro , Armenian Saro H
Published: February 2020

Background

Long-term mortality after hematopoietic cell transplantation (HCT) is conventionally calculated from the time of HCT, ignoring temporal changes in survivors’ mortality risks. Conditional survival rates, accounting for time already survived, are relevant for optimal delivery of survivorship care but have not been widely quantified. We estimated conditional survival by elapsed survival time in allogeneic HCT patients and examined cause-specific mortality.

Methods

We calculated conditional survival rates and standardized mortality ratio for overall and cause-specific mortality in 4485 patients who underwent HCT for malignant hematologic diseases at a large transplant center during 1976–2014. Statistical tests were two-sided.

Results

The 5-year survival rate from HCT was 48.6%. After surviving 1, 2, 5, 10, and 15 years, the subsequent 5-year survival rates were 71.2%, 78.7%, 87.4%, 93.5%, and 86.2%, respectively. The standardized mortality ratio was 30.3 (95% confidence interval [CI] = 29.2 to 35.5). Although the standardized mortality ratio declined in longer surviving patients, it was still elevated by 3.6-fold in survivors of 15 years or more (95% CI = 3.0 to 4.1). Primary disease accounted for 50% of deaths in the overall cohort and only 10% in 15-year survivors; the leading causes of nondisease-related mortality were subsequent malignancy (26.1%) and cardiopulmonary diseases (20.2%). We also identified the risk factors for nondisease-related mortality in 1- and 5-year survivors.

Conclusion

Survival probability improves the longer patients survive after HCT. However, HCT recipients surviving 15 years or more remain at elevated mortality risk, largely because of health conditions other than their primary disease. Our study findings help inform preventive and interventional strategies to improve long-term outcomes after allogeneic HCT.
‘We can’t integrate in Europe. We will pay a high price if we go there’: Culture, Time and Migration Aspirations for Syrian Refugees in Istanbul
Authors: Rottmann Susan , Kaya Ayhan
Published: February 2020

In popular media, it is often assumed that Syrian refugees wish to reach Europe by any means necessary but, during field research in 2018, we found that many Syrians hoped to remain in Istanbul, despite their tenuous legal and social situation. The article examines how migrants established cultural intimacy and strong community social networks over time, and became increasingly sceptical about the life they imagined they would have in Europe. Addressing research on migration aspirations, we show that migration decisions are strongly affected by experiences in a transit country. Most research on aspirations stresses economic drivers and rational choices, but here we highlight the importance of emotions, the qualitative feeling of acceptance and safety, temporal effects and the growing feeling of being home over time. Prior research with Turkey’s Syrians has pointed to the significance of culture and social networks for creating a sense of being at home. This research explores these issues in more detail to show how culture, religion and gender are interlinked in migrant imaginings, how social networks evolve and how Europe is imagined.
Molecular and physiological characterization of the monosaccharide transporters gene family in Medicago truncatula
Authors: Komaitis Fotios , Kalliampakou Katerina , Botou Maria , Nikolaidis Marios , Kalloniati Chrysanthi , Skliros Dimitrios , Du Baoguo , Rennenberg Heinz , Amoutzias Grigoris D , Frillingos Stathis , Flemetakis Emmanouil
Published: February 2020

Monosaccharide transporters (MSTs) represent key components of the carbon transport and partitioning mechanisms in plants, mediating the cell-to-cell and long-distance distribution of a wide variety of monosaccharides. In this study, we performed a thorough structural, molecular, and physiological characterization of the monosaccharide transporter gene family in the model legume Medicago truncatula. The complete set of MST family members was identified with a novel bioinformatic approach. Prolonged darkness was used as a test condition to identify the relevant transcriptomic and metabolic responses combining MST transcript profiling and metabolomic analysis. Our results suggest that MSTs play a pivotal role in the efficient partitioning and utilization of sugars, and possibly in the mechanisms of carbon remobilization in nodules upon photosynthate-limiting conditions, as nodules are forced to acquire a new role as a source of both C and N.
Magnitude to luminance conversions and visual brightness of the night sky
Authors: Bará Salvador , Aubé Martin , Barentine John , Zamorano Jaime
Published: February 2020

The visual brightness of the night sky is not a single-valued function of its brightness in other photometric bands, because the transformations between photometric systems depend on the spectral power distribution of the skyglow. We analyse the transformation between the night sky brightness in the Johnson–Cousins V band (mV, measured in magnitudes per square arcsecond, mpsas) and its visual luminance (L, in SI units cd m−2) for observers with photopic and scotopic adaptation, in terms of the spectral power distribution of the incident light. We calculate the zero-point luminances for a set of skyglow spectra recorded at different places in the world, including strongly light-polluted locations and sites with nearly pristine natural dark skies. The photopic skyglow luminance corresponding to mV=0.00 mpsas is found to vary in the range 1.11–1.34 × 105 cd m−2 if mV is reported in the absolute (AB) magnitude scale, and in the range 1.18–1.43 × 105 cd m−2 if a Vega scale for mV is used instead. The photopic luminance for mV=22.0 mpsas is correspondingly comprised between 176 and 213 μcd m−2 (AB), or 187 and 227 μcd m−2 (Vega). These constants tend to decrease for increasing correlated colour temperature (CCT). The photopic zero-point luminances are generally higher than the ones expected for blackbody radiation of comparable CCT. The scotopic-to-photopic luminance (S/P) ratio for our spectral data set varies from 0.8 to 2.5. Under scotopic adaptation the dependence of the zero-point luminances with the CCT, and their values relative to blackbody radiation, is reversed with respect to photopic ones.
Trafficking of siRNA precursors by the dsRBD protein Blanks in Drosophila
Authors: Nitschko Volker , Kunzelmann Stefan , Fröhlich Thomas , Arnold Georg J , Förstemann Klaus
Published: February 2020

RNA interference targets aberrant transcripts with cognate small interfering RNAs, which derive from double-stranded RNA precursors. Several functional screens have identified Drosophila blanks/lump (CG10630) as a facilitator of RNAi, yet its molecular function has remained unknown. The protein carries two dsRNA binding domains (dsRBD) and blanks mutant males have a spermatogenesis defect. We demonstrate that blanks selectively boosts RNAi triggered by dsRNA of nuclear origin. Blanks binds dsRNA via its second dsRBD in vitro, shuttles between nucleus and cytoplasm and the abundance of siRNAs arising at many sites of convergent transcription is reduced in blanks mutants. Since features of nascent RNAs - such as introns and transcription beyond the polyA site – contribute to the small RNA pool, we propose that Blanks binds dsRNA formed by cognate nascent RNAs in the nucleus and fosters its export to the cytoplasm for dicing. We refer to the resulting small RNAs as blanks exported siRNAs (bepsiRNAs). While bepsiRNAs were fully dependent on RNA binding to the second dsRBD of blanks in transgenic flies, male fertility was not. This is consistent with a previous report that linked fertility to the first dsRBD of Blanks. The role of blanks in spermatogenesis appears thus unrelated to its role in dsRNA export.
HDAC3 functions as a positive regulator in Notch signal transduction
Authors: Ferrante Francesca , Giaimo Benedetto Daniele , Bartkuhn Marek , Zimmermann Tobias , Close Viola , Mertens Daniel , Nist Andrea , Stiewe Thorsten , Meier-Soelch Johanna , Kracht Michael , Just Steffen , Klöble Patricia , Oswald Franz , Borggrefe Tilman
Published: February 2020

Aberrant Notch signaling plays a pivotal role in T-cell acute lymphoblastic leukemia (T-ALL) and chronic lymphocytic leukemia (CLL). Amplitude and duration of the Notch response is controlled by ubiquitin-dependent proteasomal degradation of the Notch1 intracellular domain (NICD1), a hallmark of the leukemogenic process. Here, we show that HDAC3 controls NICD1 acetylation levels directly affecting NICD1 protein stability. Either genetic loss-of-function of HDAC3 or nanomolar concentrations of HDAC inhibitor apicidin lead to downregulation of Notch target genes accompanied by a local reduction of histone acetylation. Importantly, an HDAC3-insensitive NICD1 mutant is more stable but biologically less active. Collectively, these data show a new HDAC3- and acetylation-dependent mechanism that may be exploited to treat Notch1-dependent leukemias.
Looping of upstream cis-regulatory elements is required for CFTR expression in human airway epithelial cells
Authors: NandyMazumdar Monali , Yin Shiyi , Paranjapye Alekh , Kerschner Jenny L , Swahn Hannah , Ge Alex , Leir Shih-Hsing , Harris Ann
Published: February 2020

The CFTR gene lies within an invariant topologically associated domain (TAD) demarcated by CTCF and cohesin, but shows cell-type specific control mechanisms utilizing different cis-regulatory elements (CRE) within the TAD. Within the respiratory epithelium, more than one cell type expresses CFTR and the molecular mechanisms controlling its transcription are likely divergent between them. Here, we determine how two extragenic CREs that are prominent in epithelial cells in the lung, regulate expression of the gene. We showed earlier that these CREs, located at −44 and −35 kb upstream of the promoter, have strong cell-type-selective enhancer function. They are also responsive to inflammatory mediators and to oxidative stress, consistent with a key role in CF lung disease. Here, we use CRISPR/Cas9 technology to remove these CREs from the endogenous locus in human bronchial epithelial cells. Loss of either site extinguished CFTR expression and abolished long-range interactions between these sites and the gene promoter, suggesting non-redundant enhancers. The deletions also greatly reduced promoter interactions with the 5′ TAD boundary. We show substantial recruitment of RNAPII to the −35 kb element and identify CEBPβ as a key activator of airway expression of CFTR, likely through occupancy at this CRE and the gene promoter.
Serum magnesium, bone–mineral metabolism markers and their interactions with kidney function on subsequent risk of peripheral artery disease: the Atherosclerosis Risk in Communities Study
Authors: Menez Steven , Ding Ning , Grams Morgan E , Lutsey Pamela L , Heiss Gerardo , Folsom Aaron R , Selvin Elizabeth , Coresh Josef , Jaar Bernard G , Matsushita Kunihiro
Published: February 2020

Background

Few studies have investigated the association of magnesium levels with incident peripheral artery disease (PAD) despite emerging evidence of magnesium contributing to vascular calcification. Moreover, no data are available on whether the magnesium–PAD relationship is independent of or modified by kidney function.

Methods

A cohort of 11 839 participants free of PAD in the Atherosclerosis Risk in Communities Study at Visit 2 (1990–92) was studied. We investigated the association of serum magnesium and other bone–mineral metabolism markers [calcium, phosphorus, intact parathyroid hormone (iPTH) and intact fibroblast growth factor-23] with incident PAD using multivariable Cox proportional hazards regression.

Results

Over a median of 23 years, there were 471 cases of incident PAD. The hazard ratio for incident PAD in Quartile 1 (<1.5 mEq/L) versus Quartile 4 (>1.7 mEq/L) of magnesium was 1.96 (95% confidence interval 1.40–2.74) after adjustment for potential confounders. Lower magnesium levels were associated with greater incidence of PAD, particularly in those with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 (n = 11 606). In contrast, the association was largely flat in those with eGFR <60 mL/min/1.73 m2 (n = 233) with P-for-interaction 0.03. Among bone–mineral metabolism markers, only higher iPTH showed an interaction with kidney function (P-for-interaction 0.01) and iPTH >65 pg/mL was significantly related to PAD only in those with eGFR <60 mL/min/1.73 m2.

Conclusions

Lower magnesium was independently associated with incident PAD, but this association was significantly weaker in those with reduced kidney function. In contrast, higher iPTH levels were particularly related to PAD risk in this clinical population.
Gamma-ray spectra from thermal neutron capture on gadolinium-155 and natural gadolinium
Authors: Tanaka Tomoyuki , Hagiwara Kaito , Gazzola Enrico , Ali Ajmi , Ou Iwa , Sudo Takashi , Kumar Das Pretam , Singh Reen Mandeep , Dhir Rohit , Koshio Yusuke , Sakuda Makoto , Kimura Atsushi , Nakamura Shoji , Iwamoto Nobuyuki , Harada Hideo , Collazuol Gianmaria , Lorenz Sebastian , Wurm Michael , Focillon William , Gonin Michel , Yano Takatomi
Published: February 2020

Natural gadolinium is widely used for its excellent thermal neutron capture cross section, because of its two major isotopes: $^{\rm 155}$Gd and $^{\rm 157}$Gd. We measured the $\gamma$-ray spectra produced from the thermal neutron capture on targets comprising a natural gadolinium film and enriched $^{\rm 155}$Gd (in Gd$_{2}$O$_{3}$ powder) in the energy range from 0.11 MeV to 8.0 MeV, using the ANNRI germanium spectrometer at MLF, J-PARC. The freshly analyzed data of the $^{\rm 155}$Gd($n, \gamma$) reaction are used to improve our previously developed model (ANNRI-Gd model) for the $^{\rm 157}$Gd($n, \gamma$) reaction [K. Hagiwara et al. [ANNRI-Gd Collaboration], Prog. Theor. Exp. Phys. 2019, 023D01 (2019)], and its performance confirmed with the independent data from the $^{\rm nat}$Gd($n, \gamma$) reaction. This article completes the development of an efficient Monte Carlo model required to simulate and analyze particle interactions involving the thermal neutron captures on gadolinium in any relevant future experiments.
A Sharp Lorentz-Invariant Strichartz Norm Expansion for the Cubic Wave Equation in ℝ1+3
Authors: Negro Giuseppe
Published: February 2020

We provide an asymptotic formula for the maximal Strichartz norm of small solutions to the cubic wave equation in Minkowski space. The leading coefficient is given by Foschi’s sharp constant for the linear Strichartz estimate. We calculate the constant in the second term, which differs depending on whether the equation is focussing or defocussing. The sign of this coefficient also changes accordingly.
Bovine or Porcine: Does the Type of Surfactant Matter?
Authors: Boshoff Coyles Lize , Joolay Yaseen , Tooke Lloyd
Published: February 2020

Background

Hyaline membrane disease contributes majorly to preterm mortality, particularly in the developing world. There are two animal-derived surfactants available in South Africa: poractant-alfa (120 mg/1.5 ml) and beractant (100 mg/4 ml). At equivalent doses, studies have shown no difference in mortality or morbidity, although there are limited data from the developing world. Both surfactants have been available for use at Groote Schuur Hospital in Cape Town but due to policy change, poractant-alfa was no longer available from November 2014. Due to weight-based dosing charts, infants who were given poractant-alfa received 20% higher dosages of phospholipid.

Methods

A before-and-after policy change non-experimental study was performed including infants from 2013 to 2015. Infants weighing <1500 g were recruited by identifying them from the surfactant register and further data were obtained from patient records. Data fields included infant weight, gestation, respiratory support and outcomes.

Results

Two hundred and eight infants were included. One hundred and eight received beractant and 100 received poractant-alfa. The mean birth weight was 1031 g and gestational age 28.8 weeks. Seventy-nine percent of the infants received surfactant via the INSURE (intubation, surfactant and extubation) method. The combined outcome for death or bronchopulmonary dysplasia was 35.3% in the beractant group and 36% in the poractant-alfa group (p = 0.902). All secondary outcomes including neonatal morbidities, oxygen at 28 days or length of ventilation were not statistically significant.

Conclusion

There were no significant differences in outcomes between the two groups of infants who received different surfactants at the dosages used in our unit. This is one of the few studies of this type performed in a low- and middle-income countries.
Preventative Root-Collar Excavation Reduces Peach Tree Mortality Caused By Armillaria Root Rot On Replant Sites
Authors: Miller Sarah. B. , Gasic Ksenija , Reighard Gregory L. , Henderson William G. , Rollins Phillip A. , Vassalos Michael , Schnabel Guido
Published: February 2020

In the southeastern United States, Armillaria root rot (ARR) is caused by Desarmillaria tabescens and has become the primary cause of premature mortality in peach orchards. Most rootstocks used in commercial orchards are susceptible and management options are limited. A postinfection practice known as root-collar excavation (RCE), which involves permanent removal of the soil from the base of the trunk, has been shown to improve yields and prolong the productive life of symptomatic trees. However, symptomatic trees already have an advanced infection at the base of the trunk. This study evaluated the efficacy of preventative RCE on the progression of tree mortality in two orchards that were planted in infested replant sites. To provide convincing data for growers, the study was carried out in a commercial orchard and an experimental orchard for 8 years. Furthermore, representative enterprise budgets and net present value (NPV) analysis were utilized to compare the profitability of the two approaches. Trees were planted shallow on berms (45 by 90 cm) to facilitate RCE with hoes and AirSpade 2 years later. Tree mortality in the RCE treatment of the experimental orchard was first observed in year 6 and increased 8% on average per year thereafter. In contrast, tree mortality in the “Grower Standard” treatment was first observed in year 4 and increased 12.7% on average per year thereafter. At the commercial orchard, tree mortality in the RCE treatment was first observed in year 7 and increased 1.9% on average thereafter, while tree mortality in the Grower Standard treatment first appeared in year 5 and increased 4.3% on average thereafter. The delayed onset of ARR-associated tree mortality and the lower annual tree mortality rate in the RCE treatment led to higher NPVs in both locations. There were no negative effects on yield or fruit quality. However, the new planting system can create horticultural challenges, including the formation of a proper berm, uneven ground around the tree interfering with tree care and harvest, increased erosion due to channeling of rainwater, and increased rootstock suckering. The RCE is a valid option for southeastern growers needing to manage high ARR disease pressure on replant sites or on sites only recently cleared from ARR-infected forest land.
Enhanced Serologically Based Detection of Liberibacters Associated with Citrus Huanglongbing
Authors: Ding Fang , Peng Shu-ang , Hartung John S.
Published: February 2020

‘Candidatus Liberibacter spp.’ are associated with the most devastating disease of citrus Huanglongbing (HLB). In previous work, we established an in situ tissue print method for the detection of ‘Ca. L. asiaticus’ (CLas) in sweet orange. We optimized the protocol by preincubation of the anti-Omp antibody with 5% (w/v) extract of healthy rough lemon. This simple process eliminated cross reactions between citrus and the antibody. The optimized protocol enhanced the application of the polyclonal antibody, and we demonstrate detection of CLas from all parts of the world, including isolates from Japan, Thailand, Vietnam, Pakistan, Saudi Arabia, Brazil, the United States, and a selection of strains from China representative of the diversity extant there. The assay also was used to detect four isolates of ‘Ca. L. africanus’ (CLaf) representative of the diversity present in South Africa. The corresponding outer membrane genes of representative isolates were cloned and sequenced. The coding sequences were highly conserved, and isolates of CLas and CLaf shared 53.8 to 55.9% identity between species at the amino acid level. The optimized protocol is efficient for recognition of both CLas and CLaf in phloem cells of different citrus tissues regardless of geographic origin of the HLB samples. The method is simple and scales well to match the urgent need for accurate, sensitive, and high-throughput screening of HLB bacteria, and may play an important role especially for plant inspection and quarantine programs.
Using Low-Cost Models for Training First-Year Pediatric Residents on 4 Accreditation Council for Graduate Medical Education–Required Procedures
Authors: Petroski Tara , Lawrence Lynn , Qiao Haiping , Wrotniak Brian H.
Published: February 2020

Objectives

The aims of the study were to assess the feasibility of using low-cost models to train first-year pediatric residents and to examine whether residents who receive such training will be as competent as their experienced colleagues in performing 4 American College of Graduate Education–required procedures, including suturing, splinting, lumbar puncture, and venipuncture.

Methods

We performed a pilot study with postgraduate year (PGY) 1 to 3 residents. Postgraduate year 1 residents completed a self-assessment questionnaire before the onset of training. A lecture was given to all PGY levels residents about procedural techniques. The PGY-1 residents practiced these techniques on low-fidelity models immediately after the lecture. One and 9 months after the initial lecture, all residents were assessed on these models using a 10-point checklist for each skill.

Results

Thirteen PGY-1 residents, 10 PGY-2 residents, and 10 PGY-3 residents completed the study. There was no statistically significant difference in performance of PGY-1 residents when compared with PGY-2 and PGY-3 residents in performing lumbar puncture, venipuncture, and suturing on models in the initial assessment that was performed 1 month after the lecture. Postgraduate year 1 residents performed equally well to PGY-3 residents and significantly (P < 0.05) better than PGY-2 residents, in splinting.

There was no statistically significant difference between groups at final follow-up, supporting that training on models could help enhance proficiency among residents.

Conclusions

This pilot study supports the feasibility of using low-cost models to train residents on invasive and painful procedures. Furthermore, residents trained on models showed maintenance of skills for a 9-month period.
Molecular identification of microsporidian species in patients with epithelial keratitis
Authors: Sanpool Oranuch , Thanathanee Onsiri , Laummuanwai Porntip , Maleewong Wanchai , Intapan Pewpan M.
Published: February 2020

Introduction. Ocular microsporidiosis is a significant emerging infectious disease reported in immunocompromised patients and immunocompetent persons throughout the world.

Aim. To identify the pathogens responsible for human keratitis, via corneal scrapings.

Methodology. Thirty-three hospitalized patients with epithelial keratitis were examined using staining and DNA sequencing. DNA was extracted from corneal samples and the small-subunit ribosomal RNA gene was amplified by polymerase chain reaction (PCR) and sequenced.

Results. Twenty-one samples were positive by staining while PCR generated amplicons in 18 cases. Of the 18 sequences, 16 were identical with, or very similar to, those of Vittaforma corneae (99–100 % similarity) and the remaining two sequences were similar to that of unidentified Microsporidium species deposited in the GenBank.

Conclusion. This study has reconfirmed that V. corneae causes epithelial keratitis in humans and that a newly detected Microsporidium species is also involved in microsporidial keratitis as one of the emerging pathogens in Thailand. Ophthalomologists should be aware of microsporidial keratitis in people from Thailand and those from neighbouring countries.
Hemodynamic modeling of aspirin effects on BOLD responses at 7T
Authors: Do Cao-Tri , Manjaly Zina-Mary , Heinzle Jakob , Schöbi Dario , Kasper Lars , Pruessmann Klaas P. , Stephan Klaas Enno , Frässle Stefan
Published: February 2020

Aspirin is considered a potential confound for functional magnetic resonance imaging (fMRI) studies. This is because aspirin affects the synthesis of prostaglandin, a vasoactive mediator centrally involved in neurovascular coupling, a process that underlies the blood oxygenated level dependent (BOLD) response. Aspirin-induced changes in BOLD signal are a potential confound for fMRI studies of patients (e.g. with cardiovascular conditions or stroke) who receive low-dose aspirin prophylactically and are compared to healthy controls that do not take aspirin. To examine the severity of this potential confound, we combined high field (7 Tesla) MRI during a simple hand movement task with a biophysically informed hemodynamic model. Comparing elderly volunteers with vs. without aspirin medication, we tested for putative effects of low-dose chronic aspirin on the BOLD response. Specifically, we fitted hemodynamic models to BOLD signal time courses from 14 regions of the human motor system and examined whether model parameter estimates were significantly altered by aspirin. While our analyses indicate that hemodynamics differed across regions, consistent with the known regional variability of the BOLD response, we neither found a significant main effect of aspirin (i.e., an average effect across brain regions) nor an expected drug×region interaction. While our sample size is not sufficiently large to rule out small-to-medium global effects of aspirin, we had adequate statistical power for detecting the expected interaction. Altogether, our analysis suggests that low-dose aspirin, as used for prophylactic purposes, does not strongly affect BOLD signals and may not represent a critical confound for fMRI studies.
Dysregulated lipid metabolism precedes onset of psychosis in people at clinical high risk
Authors: Dickens Alex M. , Sen Partho , Kempton Matthew J , Barrantes-Vidal Neus , Iyegbe Conrad , Nordentoft Merete , Pollak Thomas , Riecher-Rössler Anita , Ruhrmann Stephan , Sachs Gabriele , Bressan Rodrigo , Krebs Marie-Odile , de Haan Lieuwe , van der Gaag Mark , Valmaggia Lucia , Hyötyläinen Tuulia , Orešič Matej , McGuire Philip ,   the EU-GEI High Risk Study
Published: February 2020

A key clinical challenge in the management of individuals at clinical high risk for psychosis (CHR) is that it is difficult to predict their future clinical outcomes. Here, we investigated if the levels of circulating molecular lipids are related to adverse clinical outcomes in this group. Serum lipidomic analysis was performed in 263 CHR individuals and 51 healthy controls (HC), who were then clinically monitored for up to five years. Machine learning was used to identify lipid profiles that discriminated between CHR subjects and HC, and between subgroups of CHR subjects with distinct clinical outcomes. At baseline, compared to HC, CHR subjects (independent of outcome) had higher levels of triacylglycerols (TGs) with a low acyl carbon number and a double bond count, as well as higher levels of lipids in general. CHR subjects who subsequently developed psychosis (n=50) were distinguished from those that did not (n=213) on the basis of lipid profile at baseline, using a model with an AUC = 0.81 (95% CI = 0.69-0.93). CHR subjects who became psychotic had lower levels of ether phospholipids than CHR individuals who did not (p<0.01). Collectively, these data suggest that lipidomic abnormalities predate the onset of psychosis, and that blood lipidomic measures may be useful in predicting which CHR individuals are most likely to develop psychosis.
FLAME: Macroscopic imaging with microscopic resolution. Optical biopsy of human skin
Authors: Fast Alexander , Lal Akarsh , Durkin Amanda F. , Zachary Christopher B. , Ganesan Anand K. , Balu Mihaela
Published: February 2020

We introduce a compact, fast large area multiphoton exoscope (FLAME) system with enhanced molecular contrast for macroscopic imaging of human skin with microscopic resolution. A versatile imaging platform with multiple modes of operation for comprehensive analysis of live or resected thick human skin tissue, it produces 3D images that encompass sub-mm2to cm2scale areas of tissue within minutes. The FLAME imaging platform, which expands on a design recently introduced by our group, features deep learning, additional scanning hardware elements and time-resolved single photon counting detection to uniquely allow fast discrimination and 3D virtual staining of melanin. We demonstrate its performance and utility by fastex vivoandin vivoimaging of human skin. With the ability to provide rapid access to depth resolved images of skin over cm2area and to generate 3D distribution maps of key sub-cellular skin components such as melanocytic dendrites and melanin, FLAME represents a promising imaging tool for enhancing diagnosis accuracy, guiding therapy and understanding skin biology.
Arabidopsis AZG2, an auxin induced putative cytokinin transporter, regulates lateral root emergence
Authors: Tessi Tomás M. , Brumm Sabine , Winklbauer Eva , Schumacher Benjamin , Lescano Carlos I. , González Claudio A. , Wanke Dierk , Maurino Verónica G. , Harter Klaus , Desimone Marcelo
Published: February 2020

The phytohormones cytokinin (CK) and auxin are key regulators of plant growth and development. During the last decade specialised transport mechanisms turned out to be the key for the control of local and long distance hormone distributions. In contrast to auxin, CK transport is poorly understood. Here we show thatArabidopsis thalianaAZG2, a member of the AZG purine transporter family, acts as CK transporter involved in the determination of the root system architecture. The expression ofAtAZG2is primarily auxin dependent and restricted to a small group of cells surrounding the lateral root primordia. Compared to wild type, mutants carrying loss-of-function alleles ofAtazg2have higher density of lateral roots, suggesting AZG2 as being part of a regulatory pathway in lateral root emergence. Moreover,azg2mutants are partially insensitive to exogenously applied CK, which is consistent with the observation that the CK reporter geneTCSnpro:GFPshowed lower fluorescence signal in the roots ofazg2mutants compared to those of wild type. These results indicate a defective CK signalling pathway in the region of lateral root primordia. By the integration of AtAZG2 subcellular localization and CK transport capacity data, our results allowed us to propose a local Auxin/CK signalling model for the regulation of lateral root emergence.
Retrograde induction of phyB orchestrates ethylene-auxin hierarchy to regulate growth
Authors: Jiang Jishan , Xiao Yanmei , Hu Wei , Chen Hao , Zeng Liping , Ke Haiyan , Ditengou Franck A. , Devisetty Upendra , Palme Klaus , Maloof Julin , Dehesh Katayoon
Published: February 2020

Exquisitely regulated plastid-to-nucleus communication by retrograde signaling pathways is essential for fine-tuning of responses to the prevailing environmental conditions. The plastidial retrograde signaling metabolite methylerythritol cyclodiphosphate (MEcPP) has emerged as a stress signal transduced into a diverse ensemble of response outputs. Here we demonstrate enhanced phytochrome B protein abundance in red-light grown MEcPP-accumulating mutant (ceh1) plant relative to wild-type seedlings. We further establish MEcPP-mediated coordination of phytochrome B with auxin and ethylene signaling pathways, and uncover differential hypocotyl growth of red-light grown seedlings in response to these phytohormones. Genetic and pharmacological interference with ethylene and auxin pathways outline the hierarchy of responses, placing auxin epistatic to the ethylene signaling pathway. Collectively, our finding establishes the key role of a plastidial retrograde metabolite in orchestrating the transduction of a repertoire of signaling cascades, and positions plastids at the zenith of relaying information coordinating external signals and internal regulatory circuitry to secure organismal integrity.

Two sentence summary

The plastidial retrograde metabolite, MEcPP, orchestrates coordination of light and hormonal signaling cascade through induction of phytochrome B abundance and modulation of auxin and ethylene levels for optimal adaptive responses to light environment.
Impact of prior and projected climate change on US Lyme disease incidence
Authors: Couper Lisa I. , MacDonald Andrew J. , Mordecai Erin A.
Published: February 2020

Lyme disease is the most common vector-borne disease in temperate zones and a growing public health threat in the United States (US). The life cycles of the tick vectors and spirochete pathogen are highly sensitive to climate, but determining the impact of climate change on Lyme disease burden has been challenging due to the complex ecology of the disease and the presence of multiple, interacting drivers of transmission. Here we incorporated 18 years of annual, county-level Lyme disease case data in a panel data statistical model to investigate prior effects of climate variation on disease incidence while controlling for other putative drivers. We then used these climate-disease relationships to project Lyme disease cases using CMIP5 global climate models and two potential climate scenarios (RCP4.5 and RCP8.5). We find that interannual variation in Lyme disease incidence is associated with climate variation in all US regions encompassing the range of the primary vector species. In all regions, the climate predictors explained less of the variation in Lyme disease incidence than unobserved county-level heterogeneity, but the strongest climate-disease association detected was between warming annual temperatures and increasing incidence in the Northeast. Lyme disease projections indicate that cases in the Northeast will increase significantly by 2050 (23,619 ± 21,607 additional cases), but only under RCP8.5, and with large uncertainty around this projected increase. Significant case changes are not projected for any other region under either climate scenario. The results demonstrate a regionally variable and nuanced relationship between climate change and Lyme disease, indicating possible nonlinear responses of vector ticks and transmission dynamics to projected climate change. Moreover, our results highlight the need for improved preparedness and public health interventions in endemic regions to minimize the impact of further climate change-induced increases in Lyme disease burden.
Inferring the Spiking Rate of a Population of Neurons from Wide-Field Calcium Imaging
Authors: Stern Merav , Shea-Brown Eric , Witten Daniela
Published: February 2020

Wide-field calcium imaging techniques allow recordings of high-resolution neuronal activity across one or more brain regions. However, since the recordings capture light emission generated by the fluorescence of the calcium indicator, the neural activity that drives the calcium changes is masked by the calcium indicator dynamics. Here we develop and evaluate new methods to deconvolve the calcium traces and estimate the underlying neural spiking rate. Our methods take into account both the noise in the recordings and the temporal dynamics of the calcium indicator response. Our first proposal estimates firing rates that are constant over discrete time bins. The size of each time bin depends on the data and is determined dynamically. Our second proposal estimates the rate as a continuous function and is meant for studies that look for slow rate fluctuations rather than abrupt changes. We compare our results with those of two alternative approaches: direct deconvolution using a ‘first differences’ approach, and the ‘Lucy-Richardson’ image recovery method, adapted to recover temporal dynamics. We show that our methods outperform competitors on synthetic data as well as on wide-field calcium recordings in which the spikes were recorded in parallel using multi-channel silicon probe.
Godanti Bhasma (anhydrous CaSO4) induces massive cytoplasmic vacuolation and cell survival response through stimulation of LC3 Associated Phagocytosis (LAP)
Authors: Das Subrata K. , Joshi Alpana , Bisht Laxmi , Das Neeladrisingha , Balkrishna Achariya , Dhara Santanu
Published: February 2020

Bhasmas are Ayurvedic herbo-mineral formulations that have been used since ancient times for therapeutic benefits. Godanti Bhasma (GB) is an anhydrous calcium sulfate preparation processed by heating of gypsum powder with herbal extracts. Thermo-transformation of gypsum into the anhydrous GB was confirmed by Raman and FT-IR spectroscopy. GB particle showed size range of 0.5-5 µm and neutral surface charge. Exposure to mammalian cells with GB particles showed massive vacuolation in their cytoplasm. Interestingly, no vacuolation was observed with parent gypsum particle. The result indicated that the cytoplasmic vacuolation by GB was due to its unique physicochemical property obtained during the thermo-transformation of gypsum. Using lysosomal inhibitors Bafilomycin A1 (BFA1) and Chloroquine (CQ), the process of vacuole formation was suppressed indicating GB induced vacuolation require acidic environment. The GB induced vacuolation was also found to follow dose and time dependent manner. Vacuolation often accompany with the sign of cell death whereas, in our study, massive vacuolation by GB did not induce any cell death. Moreover, GB treated cells survive with massive vacuolar process, which was reversed following post-treatment with vacuole inhibitors in GB treated cells, suggesting normal vacuolar function is essential for cell survival. Treatment of cells with GB was also found to induce translocation of LC3 protein from the nucleus to vacuolar membrane, indicating LC3 associated phagocytosis (LAP) is involved in the vacuolar process. Interestingly, the LAP function was found to be reversed in the cells treated with vacuole inhibitors. Our results provide a mechanistic correlation with GB induced vacuolation and associated LAP function, essential for cell survival.

Abstract Figure
The cation diffusion facilitator protein MamM’s cytoplasmic domain exhibits metal-type dependent binding modes and discriminates against Mn2+
Authors: Barber-Zucker Shiran , Hall Jenny , Froes Afonso , Kolusheva Sofiya , MacMillan Fraser , Zarivach Raz
Published: February 2020

Cation diffusion facilitator (CDF) proteins are a conserved family of divalent transition metal cation transporters. CDF proteins are usually composed of two domains: the transmembrane domain (TMD), in which the metal cations are transported through, and a regulatory cytoplasmic C-terminal domain (CTD). Each CDF protein transports either one specific metal, or multiple metals, from the cytoplasm. Here, the model CDF protein MamM, from magnetotactic bacteria, was used to probe the role of the CTD in metal selectivity. Using a combination of biophysical and structural approaches, the binding of different metals to MamM CTD was characterized. Results reveal that different metals bind distinctively to MamM CTD in terms of; their binding sites, thermodynamics and binding-dependent conformation, both in crystal form and in solution. Furthermore, the results indicate that the CTD discriminates against Mn2+and provides the first direct evidence that CDF CTD’s play a role in metal selectivity.
Detection of hypermucoviscousKlebsiella pneumoniaesequence type 86 capsular type K2 in South America as an unexpected cause of a fatal outbreak in captivity marmosets
Authors: Guerra Juliana M. , de A. Fernandes Natália. C.C. , Santos Alessandra Loureiro Morales dos , de Souza Pereira Barrel Joana , Petri Bruno Simões Sergio , Milanelo Liliane , Tiba-Casas Monique Ribeiro , Liserre Alcina Maria , Gonçalves Cláudia Regina , Sacchi Cláudio Tavares , Catão-Dias José Luiz , Camargo Carlos Henrique
Published: February 2020

After the sudden death of eleven captives marmosets in a rehabilitation center of wildlife in São Paulo, Brazil, histological and microbiological study was conducted. Liver, spleen, intestine, central nervous system, lung, thymus, stomach, testicle tissues were analyzed by light microscopy and microbial cultures were conducted. Environmental cultures were also performed. Prophylactic antimicrobial therapy, restricted access to marmosets’ cages with dedicated staff, and additional sanitization of animals’ fruits were implemented. Histological findings were compatible with hyperacute septicemia, and microbiological cultures and molecular tests identified the etiologic agent as hypermucoviscous sequence type 86 capsular type K2K. pneumoniaefor the first time in South America. Implementation of prompt containment measures led to successful control of this outbreak. Detection of a hypervirulent and zoonotic pathogen, such as hypermucoviscousK. pneumoniaeST86 K2, in an unexpected and human interface reservoir underscores its potential threat in public health settings.
CLOCK-induced upregulated HMGB1 resulting in circadian rhythms disruption of inflammatory microglia contributes to non-dipper hypertension in stressed rats
Authors: Zhang Shutian , Hu Li , Xia Chunmei
Published: February 2020

The authors have withdrawn their manuscript as they have discovered some potential inconsistencies in their results after further experimentation. Therefore, the authors do not wish this work to be cited as reference for the project.