bluuebunny/crossref_metadata_2025 huggingface dataset:
Thromboelastometry, Thromboelastography, and Conventional Tests to Assess Anticoagulation During Extracorporeal Support: A Prospective Observational Study
Authors: Giani Marco , Russotto Vincenzo , Pozzi Matteo , Forlini Clarissa , Fornasari Chiara , Villa Silvia , Avalli Leonello , Rona Roberto , Foti Giuseppe
Published: June 2020

Optimal anticoagulation monitoring in patients with extracorporeal membrane oxygenation (ECMO) is fundamental to avoid hemorrhagic and thromboembolic complications. Besides conventional coagulation tests, there is growing interest in the use of viscoelastic hemostatic assays (VHA), in particular of tromboelastography (TEG). Evidence on the use of rotational thromboelastometry (ROTEM) is lacking in this setting. The aim of the study was to evaluate ROTEM as a tool for assessing hemostasis during ECMO, by comparing it to TEG and conventional coagulation assays. We conducted a prospective, observational, single-center study on adult patients on ECMO support anticoagulated with unfractioned heparin (UFH). Kaolin reaction time (R, min) for TEG and INTEM clotting time (CT, sec) for ROTEM were analyzed and compared with conventional coagulation tests. In the study period, we included 25 patients on ECMO support (14 V-A and 11 V-V); 84 data points were available for the analysis. Median UFH infusion rate was 15 [11–18] IU/min/kg. Median values for activated partial thromboplastin time (aPTT) ratio, Kaolin TEG R time, and INTEM CT were 1.44 [1.21–1.7], 22 [13–40] min, and 201 [183–225] sec, respectively. INTEM CT (ROTEM) showed a moderate correlation with standard coagulation tests (R
2 = 0.34 and 0.3 for aPTT and activated clotting time (ACT), respectively, p < 0.001). No significant correlation was found between INTEM CT and Kaolin R time (R
2 = 0.01). Further studies are needed to identify an appropriate anticoagulation target for ROTEM during ECMO.
In-hospital Outcomes of Left Ventricular Assist Devices (LVAD) Patients Undergoing Noncardiac Surgery
Authors: Briasoulis Alexandros , Chehab Omar , Alvarez Paulino
Published: June 2020

An increasing number of stage D heart failure patients are supported with left ventricular assist devices (LVADs), and the management of LVAD patients who require noncardiac surgery (NCS) presents unique challenges. Using the 2010–2014 National Inpatient Sample, we identified all adult cases of LVAD patients undergoing noncardiac surgeries using ICD-9-CM codes. We estimated inpatient mortality, bleeding complications, stroke, length of stay (LOS), and cost of hospitalization of the admissions related to NCS using mixed effects logistic and linear mixed regressions, respectively. A total of 30,323 patients with LVADs underwent 3,216 noncardiac surgeries (73.5% urgent) during the study period. LVAD recipients undergoing NCS had higher burden of certain comorbidities such as history of end-stage renal disease, pulmonary circulation disorders, peripheral vascular disease, and obesity. The most frequent NCS were general surgery, which included breast, endocrine, skin/burn, noncardiac transplantation, and abdominal surgeries (47.9%). In-hospital mortality was 7.7% with the highest rates observed among cases of neurologic surgeries. Vascular surgeries had the highest rates of ischemic stroke and gastrointestinal bleeding. Patients who underwent NCS had higher LOS and cost of hospitalization compared with LVAD recipients admitted to reasons other than NCS. Although bleeding complication trends have decreased, ischemic stroke and in-hospital mortality rates have increased overall during the study period. Urgent or emergency surgery was an independent predictor of mortality (OR 3.1, 95% CI 1.9–5). A significant burden of complications occurs after noncardiac surgeries in LVAD recipients.
Technical Report: Repeatability of Contrast Sensitivity Test in Children
Authors: Hernández-Andrés Rosa , Luque María Josefa , Serrano Miguel Ángel
Published: June 2020

SIGNIFICANCE

Contrast sensitivity (CS) in children is not routinely measured in the clinical setting, although CS losses have been found in amblyopic and premature children. Thus simple visual acuity measurements do not completely assess their quality of vision. To evaluate contrast sensitivity in children, a reliable and easy test, sampling the entire spatial frequency range, is necessary.

PURPOSE

This study aimed to evaluate the repeatability and normal range of the contrast sensitivity function measured using the Topcon CC-100 instrument, in children aged between 4 and 9 years, for use as a diagnostic tool.

METHODS

Contrast sensitivity was measured in 25 children, 11 boys and 14 girls, with normal or corrected-to-normal visual acuity, normal binocular function, and stereopsis. Two measurements were performed, 3 months apart, with a Topcon CC-100 device using achromatic sinusoidal gratings of 1.5, 3, 6, 12, and 18 cycles per degree (cpd) with random orientation in a circular window with sharp edges.

RESULTS

The normal range in the first visit is wider than in the second. Coefficients of variation are better for the middle-range spatial frequencies (6.6 and 7.8% at 3 and 6 cpd, respectively) and worst at 18 cpd (18.2%), with intermediate values at 1.5 cpd (11.3%) and 12 cpd (13.7%), and better for older than for younger children. No significant sex differences were found (P> .05, Mann-WhitneyUtest).

CONCLUSIONS

Repeatability measured by the coefficient of variation is better for the middle frequency range (3 and 6 cpd) than for low (1.5 cpd) and high frequencies (12 and 18 cpd). The variability of the differences between the first and second measurements suggests that the participants were not able to maintain a stable response criterion. The test seems to be subject to a learning effect, and the standard normality range may not be adequate for children.
Spectrum of Binocular Vision Anomalies in Keratoconus Subjects
Authors: Dandapani Sushmitha Arcot , Padmanabhan Prema , Hussaindeen Jameel Rizwana
Published: June 2020

SIGNIFICANCE

Keratoconus (KC) is typically a bilateral asymmetric corneal condition associated with anisometropia. A detailed evaluation of binocular vision function is therefore a critical component of ocular examination in these patients for early detection and treatment of binocular vision anomalies.

PURPOSE

The purposes of this study were to measure the various parameters of binocular vision (BV) in patients with KC and to identify the factors that possibly influence them.

METHODS

This was a prospective, observational study of BV in patients with KC and with best-corrected visual acuity ≤0.4 logMAR in each eye. Age-matched, nonstrabismic normal patients served as controls. Binocular vision examination included motor assessment, accommodation parameters, and fusional vergence.

RESULTS

Binocular vision parameters of 84 KC patients were compared with those of 71 normal controls. The KC group showed statistically significant differences between fellow eyes in refractive cylinder (0.44 ± 2.1 D, P = .03), best-corrected visual acuity (0.06 ± 0.09 logMAR, P = .001), and maximum keratometry (6.64 ± 8.2D, P = .005). The control group showed no significant difference in any refractive or keratometric parameter between fellow eyes. Sixty-six (78.6%) of 84 KC patients had various combinations of BV anomalies: 48.8% had impaired stereopsis, 44% had abnormal fusional vergence, and 39.3% had accommodative infacility. Among individual parameters, all except accommodative amplitudes and negative distance fusional vergence showed statistically significant impairment compared with controls (P < .001). Median (interquartile range) stereoacuity was 70 (50 to 550) arc sec in the KC group and 40 (30 to 50) arc sec in control (P < .0001). There was a statistically significant but weak correlation between stereoacuity and positive fusional vergence for near (P = .008; Spearman coefficient, −0.28) and weak but significant negative correlation between phoria status and negative fusional vergence for near (P = .03; Spearman coefficient, −0.24).

CONCLUSIONS

A large proportion of KC patients have BV anomalies. Assessment of BV function should be included in the clinical examination of all KC patients.
Case Report: Cyclodialysis Cleft in a Case of Open-globe Injury and Role of Swept-source Anterior Segment Optical Coherence Tomography in Diagnosis
Authors: Selvan Harathy , Yadav Suresh , Gupta Viney , Gupta Shikha
Published: June 2020

SIGNIFICANCE

Cyclodialysis clefts can potentially develop secondary to open globe injury. The swept-source anterior segment optical coherence tomography (SS-AS-OCT) may be a valuable diagnostic tool for the identification and estimation of the circumferential extent of cyclodialysis clefts. It could be considered an alternative when ultrasound biomicroscopy cannot be performed successfully.

PURPOSE

The purpose of this study was to report a case of open-globe injury associated with cyclodialysis cleft and the utility of SS-AS-OCT in its diagnosis.

CASE REPORT

A 12-year-old boy presented to the clinic because of penetrating ocular trauma to his left eye with a projectile stone. He was diagnosed with limbal perforation with uveal tissue prolapse and cataract. He underwent limbal repair with cataract extraction and posterior chamber intraocular lens implantation. However, even at the 6 weeks' post-operative period, he did not gain vision and had persistent hypotony with hypotonic maculopathy. Gonioscopy showed a 2-clock-hour superonasal cyclodialysis cleft. However, on SS-AS-OCT, it was discovered that the cleft extended along 5 clock hours, involving both superonasal and inferonasal quadrants. Recognizing the large extent of the cleft, endocyclopexy by modified sewing-machine technique was planned and performed. An IOP spike and improvement in vision were noted on the next post-operative day. The SS-AS-OCT confirmed cleft closure.

CONCLUSIONS

Although rare, cyclodialysis can occur in cases of open globe injury. The SS-AS-OCT is a useful diagnostic tool to study the circumferential extent of cyclodialysis and may unravel detachments hidden behind intact anterior ciliary body face.
Cognitive Impairment among Veterans in Outpatient Vision Rehabilitation
Authors: Whitson Heather E. , Woolson Sandra , Olsen Maren , Massof Robert , Ferguson Stephanie M. , Muir Kelly W. , Dziadul John A. , McConnell Eleanor , Stelmack Joan A.
Published: June 2020

SIGNIFICANCE

Outpatient vision rehabilitation improves function in veterans with vision impairment, but the prevalence of cognitive impairment and the degree to which it may affect rehabilitation outcomes in the Veterans Affairs system are unknown.

PURPOSE

The purpose of this study was to determine the prevalence of cognitive impairment among veterans receiving outpatient vision rehabilitation in the Veterans Affairs system and compare the benefits of rehabilitation in veterans with and without cognitive impairment.

METHODS

We conducted cognitive assessments and a nested longitudinal cohort study in veterans with eye disorders at two outpatient rehabilitation sites. Cognition was assessed with the Modified Telephone Interview for Cognitive Status administered in person. Eligible veterans and their companions in the longitudinal study responded to questions about the veteran's function at baseline and 90 days later. Visual function was measured with the 48-item Low Vision Visual Function Questionnaire (LV-VFQ-48) and items from the Activity Inventory.

RESULTS

Of 291 veterans assessed (mean ± standard deviation age, 78.2 ± 12 years), 136 (46.7%) were cognitively intact (Modified Telephone Interview for Cognitive Status scores, ≥33), whereas 58 (19.9%) had borderline scores of 30 to 32, 82 (28.2%) had scores suggesting mild/moderate cognitive impairment (scores of 20 to 29), and 15 (5.2%) had scores suggesting severe cognitive impairment (score of <20). After 90 days, mean LV-VFQ-48 reading scores tended to improve in veterans with (n = 21) and without (n = 28) cognitive impairment. The magnitude of self-reported improvement in LV-VFQ-48 scores was greater among cognitively intact, compared with cognitively impaired, veterans (effect size, 0.56 for reading; 0.71 for visual motor). Veterans and companions reported similar 90-day reduction in difficulty with the veterans' top 3 Activity Inventory goals, regardless of cognitive status.

CONCLUSIONS

Approximately one in three veterans referred to outpatient vision rehabilitation has detectable cognitive impairment, yet many still experience functional improvements. Future research should determine best practices to accommodate challenges associated with cognitive impairment in vision rehabilitation and to track clinically meaningful outcomes.
The Effect of Cyclopentolate on Ocular Biometric Components
Authors: Hashemi Hassan , Asharlous Amir , Khabazkhoob Mehdi , Iribarren Rafael , Khosravi Ahmad , Yekta Abbasali , Emamian Mohammad Hassan , Fotouhi Akbar
Published: June 2020

SIGNIFICANCE

It is apparent that a variety of biometric changes are caused by different types of cycloplegic eye drops. However, these effects are inconsistent and have not been reported in different refractive groups.

PURPOSE

The purpose of this study was to determine the effect of cyclopentolate 1% on ocular biometric components in different types of refractive errors in children.

METHODS

This cross-sectional study was conducted on 226 eyes of 113 schoolchildren in Shahroud, northeast Iran, with a mean ± standard deviation age of 9.20 ± 1.65 years. All participants had noncycloplegic and cycloplegic objective refraction using an autorefractometer. Cycloplegia was induced using cyclopentolate 1% eye drops. Biometric measurements were made with Allegro Biograph (WaveLight AG, Erlangen, Germany) before and after administering cycloplegic drops. Mixed-effect model regression was used to analyze the data.

RESULTS

After cycloplegia, the vitreous chamber depth (VCD) (−0.043; 95% confidence interval [CI], −0.067 to −0.019 mm), lens thickness (−0.146; 95% CI, −0.175 to −0.117 mm), axial length (−0.009; 95% CI, −0.012 to −0.006 mm), and lens power (−0.335; 95% CI, −0.463 to −0.208 D) decreased significantly, whereas the anterior chamber depth (ACD) (0.183; 95% CI, 0.164 to 0.202 mm), anterior segment length (0.036; 95% CI, 0.014 to 0.058) mm), lens central point (0.109; 95% CI, 0.094 to 0.124 mm), and pupil diameter (1.599; 95% CI, 1.482 to 1.716 mm) increased (P value for all tests, <.001). For changes in VCD and ACD, a significant interaction was observed between different types of refractive errors and cycloplegia, such that the adjusted mean change for ACD was significantly lower and for VCD was significantly higher in hyperopes compared with emmetropes. Lens center moves backward in myopes (0.17 mm) and stays the same in hyperopes under cycloplegia.

CONCLUSIONS

According to the findings of this study, cycloplegia reduces the thickness of the crystalline lens and subsequently causes an increase in the ACD. Cycloplegia-related ocular biometric changes were different by type of refractive error.
Impact of Complications After Pancreatoduodenectomy on Mortality, Organ Failure, Hospital Stay, and Readmission
Authors: Smits F. Jasmijn , Verweij Maaike E. , Daamen Lois A. , van Werkhoven C. Henri , Goense Lucas , Besselink Marc G. , Bonsing Bert A. , Busch Olivier R. , van Dam Ronald M. , van Eijck Casper H. J. , Festen Sebastiaan , Koerkamp Bas Groot , van der Harst Erwin , de Hingh Ignace H. , Kazemier Geert , Klaase Joost M. , van der Kolk Marion , Liem Mike , Luyer Misha D. P. , Meerdink Mark , Mieog J. Sven D. , Nieuwenhuijs Vincent B. , Roos Daphne , Schreinemakers Jennifer M. , Stommel Martijn W. , Wit Fennie , Zonderhuis Babs M. , de Meijer Vincent E. , van Santvoort Hjalmar C. , Molenaar I. Quintus
Published: June 2020

Objective:

To quantify the impact of individual complications on mortality, organ failure, hospital stay, and readmission after pancreatoduodenectomy.

Summary of Background Data:

An initial complication may provoke a sequence of adverse events potentially leading to mortality after pancreatoduodenectomy. This study was conducted to aid prioritization of quality improvement initiatives.

Methods:

Data from consecutive patients undergoing pancreatoduodenectomy (2014–2017) were extracted from the Dutch Pancreatic Cancer Audit. Population attributable fractions (PAF) were calculated for the association of each complication (ie, postoperative pancreatic fistula, postpancreatectomy hemorrhage, bile leakage, delayed gastric emptying, wound infection, and pneumonia) with each unfavorable outcome [ie, in-hospital mortality, organ failure, prolonged hospital stay (>75th percentile), and unplanned readmission), whereas adjusting for confounders and other complications. The PAF represents the proportion of an outcome that could be prevented if a complication would be eliminated completely.

Results:

Overall, 2620 patients were analyzed. In-hospital mortality occurred in 95 patients (3.6%), organ failure in 198 patients (7.6%), and readmission in 427 patients (16.2%). Postoperative pancreatic fistula and postpancreatectomy hemorrhage had the greatest independent impact on mortality [PAF 25.7% (95% CI 13.4–37.9) and 32.8% (21.9–43.8), respectively] and organ failure [PAF 21.8% (95% CI 12.9–30.6) and 22.1% (15.0–29.1), respectively]. Delayed gastric emptying had the greatest independent impact on prolonged hospital stay [PAF 27.6% (95% CI 23.5–31.8)]. The impact of individual complications on unplanned readmission was smaller than 11%.

Conclusion:

Interventions focusing on postoperative pancreatic fistula and postpancreatectomy hemorrhage may have the greatest impact on in-hospital mortality and organ failure. To prevent prolonged hospital stay, initiatives should in addition focus on delayed gastric emptying.
Application of the Muse portable EEG system to aid in rapid diagnosis of stroke
Authors: Wilkinson Cassandra M. , Burrell Jennifer I. , Kuziek Jonathan W. P. , Thirunavukkarasu Sibi , Buck Brian H. , Mathewson Kyle E.
Published: June 2020

Objective

In this pilot study, we investigated using portable electroencephalography (EEG) as a potential prehospital stroke diagnostic method.

Methods

We used a portable EEG system to record data from 25 participants, 16 had acute ischemic stroke events, and compared the results of age-matched controls that included stroke mimics. Delta/alpha ratio (DAR), (delta+theta)/(alpha+beta) ratio (DBATR) and pairwise-derived Brain Symmetry Index (pdBSI) were investigated, as well as accelerometer and gyroscope trends. We then made classification trees using TreeBagger to distinguish between different subgroups.

Results

DAR and DBATR showed an increase in ischemic stroke patients that correlates with stroke severity (p<0.01, partial η2 = 0.293; p<0.01, partial η2 = 0.234). pdBSI decreased in low frequencies and increased in high frequencies in patients who had a stroke (p<0.05, partial η2 = 0. 177). All quantitative EEG measures were significant between stroke patients and controls. Using classification trees, we were able to distinguish between subgroups of stroke patients and controls.

Conclusions

There are significant differences in DAR, DBATR, and pdBSI between patients with ischemic stroke when compared to controls; results relate to severity.

Significance

With significant differences between patients with strokes and controls, we have shown the feasibility and utility for the Muse™ EEG system to aid in patient triage and diagnosis as an early detection tool.
Predator morphology affects prey consumption: evidence from an anuran population in subtropical wetlands
Authors: da Silva Camila Maria Mendonça , Dalmolin Diego Anderson , Schuck Laura Kauer , Moser Camila Fernanda , Tozetti Alexandro Marques
Published: June 2020

Morphology and diet are key factors in the ecology of organisms, determining aspects of natural history and evolution of the species. In this work, we evaluated the diet-morphology relationship in an anuran population, measuring the influence of morphological traits on the variation in the diet of individuals ofLeptodactylus latrans. For this purpose, we collected individuals from a natural grassland habitat in southern Brazil. We analyzed the stomach content of individuals and consumed food items were classified up to the level of order. We also measured four morphological traits per individual ofL. latrans: snout-vent length, relative limb length, distance between eyes and relative mouth width. We applied Linear Mixed Effect Models to evaluate the relationship of anuran morphological traits, number of prey taxa and volume of consumed prey. We tested the hypothesis that the configuration of predator morphological traits determines both the number of taxa and the volume of consumed prey. Our results indicate that individuals ofL. latranswith larger body size consume a larger volume of prey and mouth width is directly and positively associated with the number of consumed taxa. In the same way that body size seems to define the capacity to ingest a large number of prey items, mouth width could be a limiting factor in prey selection. The capacity to consume a large prey volume could be an advantage in unpredictable environments, especially those with great daily thermal amplitudes such as the subtropical Brazilian grasslands.
C. elegansREMO-1, a glial GPCR, regulates stress-induced nervous system remodeling and behavior
Authors: Lee In Hae , Procko Carl , Lu Yun , Shaham Shai
Published: June 2020

Animal nervous systems remodel following stress. Although global stress-dependent changes are well documented, contributions of individual neuron remodeling events to animal behavior modification are challenging to study. In response to environmental insults,C. elegansbecome stress-resistant dauers. Dauer entry induces amphid sensory-organ remodeling, in which bilateral AMsh glial cells expand and fuse, allowing embedded AWC chemosensory neurons to extend sensory receptive endings. We show that amphid remodeling accelerates dauer exit upon exposure to favorable conditions, and identify a G protein-coupled receptor, REMO-1, driving AMsh glia fusion, AWC neuron remodeling, and dauer exit. REMO-1 is expressed in and localizes to AMsh glia tips, is dispensable for other remodeling events, and promotes stress-induced expression of the remodeling receptor tyrosine kinase VER-1. Our results demonstrate how single-neuron structural changes affect animal behavior, identify key glial roles in stress-induced nervous system shape changes, and demonstrate that remodeling primes animals to respond to favorable conditions.
Biases in demographic modelling affect our understanding of recent divergence
Authors: Momigliano Paolo , Florin Ann-Britt , Merilä Juha
Published: June 2020

Testing among competing demographic models of divergence has become an important component of evolutionary research in model and non-model organisms. However, the effect of unaccounted demographic events on model choice and parameter estimation remains largely unexplored. Using extensive simulations, we demonstrate that under realistic divergence scenarios, failure to account for population size (Ne) changes in daughter and ancestral populations leads to strong biases in divergence time estimates as well as model choice. We illustrate these issues reconstructing the recent demographic history of North Sea and Baltic Sea turbots (Schopthalmus maximus) by testing 16 Isolation with Migration (IM) and 16 Secondary Contact (SC) scenarios, modelling changes inNeas well as the effects of linked selection and barrier loci. Failure to account for changes inNeresulted in selecting SC models with long periods of isolation and divergence times preceding the formation of the Baltic Sea. In contrast, models accounting forNechanges suggest recent (<6 kya) divergence with constant gene flow. We further show how interpreting genomic landscapes of differentiation can help discerning among competing models. For example, in the turbots data islands of differentiation show signatures of recent selective sweeps, rather than old divergence resisting secondary introgression. The results have broad implications for the study of population divergence by high-lighting the potential effects of unmodeleld changes inNeon demographic inference. Tested models should aim at representing realistic divergence scenarios for the target taxa, and extreme caution should always be exercised when interpreting results of demographic modelling.
ACUTE VISION LOSS IN A PATIENT WITH COVID-19
Authors: Selvaraj Vijairam , Sacchetti Daniel , Finn Arkadiy , Dapaah-Afriyie Kwame
Published: June 2020

To date, there have been reports of neurologic manifestations in Covid-19 patients including ischemic strokes, Guillain-Barre Syndrome and anosmia. In this case report, we describe a patient who presented with dysosmia, dysgeusia along with monocular peripheral vision loss after being diagnosed with Covid-19.
Evolutionary conservation and divergence of human brain co-expression networks
Authors: Pembroke WG , Hartl CL , Geschwind DH
Published: June 2020

Mouse models have allowed for the direct interrogation of genetic effects on molecular, physiological and behavioral brain phenotypes. However, it is unknown to what extent neurological or psychiatric traits may be human or primate-specific and therefore, which components can be faithfully recapitulated in mouse models. We identify robust co-expression modules reflecting whole brain and regional patterns of gene expression and compare conservation of co-expression in 116 independent data sets derived from human, mouse and non-human primate representing more than 15,000 total samples. We observe greater co-expression changes occurring on the human lineage than mouse, and substantial regional variation that highlights cerebral cortex as the most diverged region. Cell type specific modules are the most divergent across the brain, compared with those that represent basic metabolic processes. Among these, glia are the most divergent, three times that of neurons. We show that regulatory sequence divergence explains a significant fraction of co-expression divergence. Similarly, protein coding sequence constraint parallels co-expression conservation, such that genes with loss of function intolerance are enriched in neuronal, rather than glial modules. We also identify dozens of human disease risk genes, such as COMT, PSEN-1, LRRK2, and SNCA, with highly divergent co-expression between mouse and primates or human. We show that 3D human brain organoids recapitulate in vivo co-expression modules representing several human cell types, which along with our analysis of human-mouse disease gene divergence, serve as a foundational resource to guide disease modeling and its interpretation.
Natural killer activation for bladder cancer elimination can be achievedin vitroby heat-killed BCG
Authors: Esteso Gloria , Aguiló Nacho , Julián Esther , Ashiru Omodele , Ho Mei. M. , Martín Carlos , Valés-Gómez Mar
Published: June 2020

Immunotherapy, via intravesical instillations ofBacillus Calmette-Guérin(BCG) is the therapy of choice for patients with high risk non-muscle invasive bladder cancer. The subsequent recruitment of lymphocytes and myeloid cells, as well as the release of cytokines and chemokines, induces a local immune response that contributes to eliminate these tumours. The history of BCG development resulted in a large number of genetically diverse BCG substrains which could stimulate the immune system in different ways. Here, while investigating the capacity of different BCG substrains to promote the activation of NK cells, we confirmed that all the evaluated substrains could activate a cytotoxic CD56brightNK cell population which efficiently degranulated against bladder cancer cells; Tice, Connaught and Moreau were the substrains having a stronger effect. Dead mycobacteria also stimulated PBMC cultures and we demonstrate that subcellular fractions of BCG-Tice could contribute to the induction of this NK cell response. Lipids from BCG-Tice, but not fromMycobacterium bovis, stimulated NK cell activation and degranulation, however the aqueous fraction of either bacteria did not activate lymphocytes. Delipidated BCG-Tice activated effector cells (CD3+CD56+and NK). These data suggest that different immune subpopulations could be stimulated using different fractions of mycobacteria for cancer elimination.
Adverse neurological effects of short-term sleep deprivation in aging mice are prevented by SS31 peptide
Authors: Wu Jinzi , Dou Yan , Ladiges Warren C.
Published: June 2020

Sleep deprivation is a potent stress factor that disrupts regulatory pathways in the brain resulting in cognitive dysfunction and increased risk of neurodegenerative disease with increasing age. Prevention of the adverse effects of sleep deprivation could be beneficial in older individuals by restoring healthy brain function. We report here on the ability of SS31, a mitochondrial specific peptide, to attenuate the negative neurological effects of short-term sleep deprivation in aging mice. C57BL/6 female mice, 20 months old, were subcutaneously injected with SS31 (3mg/kg) or saline daily for 4 days. Sleep deprivation was 4 hours daily for the last 2 days of SS31 treatment. Mice were immediately tested for learning ability followed by collection of brain and other tissues. In sleep deprived mice treated with SS31, learning impairment was prevented, brain mitochondrial ATP levels and synaptic plasticity regulatory proteins were restored, and ROS and inflammatory cytokines levels were decreased in the hippocampus. The observations suggest possible therapeutic benefits of SS31 for alleviating adverse neurological effects of acute sleep loss.
Alteration of ribosome function upon 5-fluorouracil treatment favours cancer cell drug-tolerance
Authors: Therizols Gabriel , Bash-Imam Zeina , Panthu Baptiste , Machon Christelle , Vincent Anne , Nait-Slimane Sophie , Garcia Maxime , Chalabi-Dchar Mounira , Lafôrets Florian , Marcel Virginie , Boubaker-Vitre Jihane , Souahlia Guillaume , Albaret Marie-Alexandra , Mertani Hichem C. , Prudhomme Michel , Bertrand Martin , Saurin Jean-Christophe , Bouvet Philippe , Ohlmann Théophile , Guitton Jérôme , Dalla-Venezia Nicole , Pannequin Julie , Catez Frédéric , Diaz Jean-Jacques
Published: June 2020

Partial response to chemotherapy leads to disease resurgence. Upon treatment, a subpopulation of cancer cells, called drug-tolerant persistent cells, display a transitory drug tolerance that lead to treatment resistance1,2. Though drug-tolerance mechanisms remain poorly known, they have been linked to non-genomic processes, including epigenetics, stemness and dormancy2–4. 5-fluorouracil (5-FU), the most widely used chemotherapy in cancer treatment, is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways5–9. Here, we show that 5-FU treatment leads to the unexpected production of fluorinated ribosomes, exhibiting altered mRNA translation. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts and human tumours. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs according to the nature of their 5’-untranslated region. As a result, we found that sustained translation ofIGF-1RmRNA, which codes for one of the most potent cell survival effectors, promoted the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that “man-made” fluorinated ribosomes favour the drug-tolerant cellular phenotype by promoting translation of survival genes. This could be exploited for developing novel combined therapies. By unraveling translation regulation as a novel gene expression mechanism helping cells to survive a drug-challenge, our study extends the spectrum of molecular mechanisms driving drug-tolerance.
Lessons learned from bugs in models of human history
Authors: Ragsdale Aaron P. , Nelson Dominic , Gravel Simon , Kelleher Jerome
Published: June 2020

Simulation plays a central role in population genomics studies. Recent years have seen rapid improvements in software efficiency that make it possible to simulate large genomic regions for many individuals sampled from large numbers of populations. As the complexity of the demographic models we study grows, however, there is an ever-increasing opportunity to introduce bugs in their implementation. Here we describe two errors made in defining population genetic models using the msprime coalescent simulator that have found their way into the published record. We discuss how these errors have affected downstream analyses and give recommendations for software developers and users to reduce the risk of such errors.
Predicting substitutions to modulate disorder and stability in coiled-coils
Authors: Karami Yasaman , Saighi Paul , Vanderhaegen Rémy , Gerlier Denis , Longhi Sonia , Laine Elodie , Carbone Alessandra
Published: June 2020

Coiled-coils are described as stable structural motifs, where two or more helices wind around each other. However, coiled-coils are associated with local mobility and intrinsic disorder. Intrinsically disordered regions (IDRs) in proteins are characterized by lack of stable secondary and tertiary structure under physiological conditionsin vitro. They are increasingly recognized as important for protein function. However, characterizing their behaviour in solution and determining precisely the extent of disorder of a protein region remains challenging, both experimentally and computationally. In this work, we propose a computational framework to quantify the extent of disorder within a coiled-coil in solution and to help design substitutions modulating such disorder. Our method relies on the analysis of conformational ensembles generated by relatively short all-atom Molecular Dynamics (MD) simulations. We apply it to the phosphoprotein multimerisation domains (PMD) of Measles virus (MeV) and Nipah virus (NiV), both forming tetrameric left-handed coiled-coils. We show that our method can help quantify the extent of disorder of the C-terminus region of MeV and NiV PMDs, without requiring the input MD trajectory to actually sample the unfolded states of these regions. Moreover, this study provided a conceptual framework for the rational design of substitutions aimed at modulating the stability of the coiled-coils. By assessing the impact of four substitutions known to destabilize coiled-coils, we derive a set of rules to control MeV PMD structural stability and cohesiveness. We therefore design two contrasting substitutions, one increasing the stability of the tetramer and the other increasing its flexibility. Consequently, our method can be considered as a platform to reason about how to design substitutions aimed at regulating flexibility and stability.
A burning question: Can savannah fire management generate enough carbon revenue to help save the lion from extinction?
Authors: Tear Timothy H. , Wolff Nicholas H. , Lipsett-Moore Geoffrey J. , Ritchie Mark E. , Ribeiro Natasha S. , Petracca Lisanne S. , Lindsey Peter A. , Hunter Luke , Loveridge Andrew J. , Steinbruch Franziska
Published: June 2020

Lions (Panthera leo) in Africa have lost nearly half their population in just the last two decades, and effective management of the protected areas (PAs) where lions live will cost an estimated USD >$1 B/year in new funding. We explore the potential for launching a fire management and habitat restoration carbon-financing program to help fill this PA management funding gap. We demonstrate how introducing early dry season fire management programs could produce potential carbon revenues (PCR) from either a single carbon-financing method (avoided emissions) or from multiple sequestration methods of USD $59.6-$655.9 M/year (at USD $5/ton) or USD $155.0 M–$1.7 B/year (at USD $13/ton). We highlight variable but significant PCR for PAs with the greatest potential for restoring lion numbers between USD $1.5–$44.4 M per PA. We suggest investing in lion-centric fire management programs to jump-start the United Nations Decade of Ecological Restoration and help preserve African lions across their range.

SCIENCE FOR SOCIETY

The United Nation’s recently launched the Decade of Ecological Restoration in response to planet-wide land degradation. This study analyses the potential for savanna fire management programs to restore fire regimes that can generate new sources of revenue from carbon financing for chronically under-funded protected areas in Africa with lions, as lions are a key indicator of savanna ecosystem health. We estimated the amount of carbon saved by shifting fires that normally burn in the late dry season (and emit more carbon) to the early dry season (that accrue more carbon in the soil and woody vegetation). Based on current carbon market values we found substantial potential to eliminate or significantly reduce the $>1B annual funding gap needed to save the lion from extinction. Given additional benefits for nature and people from new savanna fire programs, we recommend integrated conservation and development projects direct more funding to some of the least developed countries with high biodiversity and support fire management programs in Africa.
scNym: Semi-supervised adversarial neural networks for single cell classification
Authors: Kimmel Jacob C. , Kelley David R.
Published: June 2020

Annotating cell identities is a common bottleneck in the analysis of single cell genomics experiments. Here, we present scNym, a semi-supervised, adversarial neural network that learns to transfer cell identity annotations from one experiment to another. scNym takes advantage of information in both labeled datasets and new, unlabeled datasets to learn rich representations of cell identity that enable effective annotation transfer. We show that scNym effectively transfers annotations across experiments despite biological and technical differences, achieving performance superior to existing methods. We also show that scNym models can synthesize information from multiple training and target datasets to improve performance. In addition to high performance, we show that scNym models are well-calibrated and interpretable with saliency methods.
Rewiring PBMC responses to prevent CHIKV infection-specific monocyte subset redistribution and cytokine responses
Authors: Aguilar-Briseño José Alberto , Silva Mariana Ruiz , Moser Jill , Pauzuolis Mindaugas , Smit Jolanda M. , Rodenhuis-Zybert Izabela A.
Published: June 2020

Infection with the mosquito-borne Chikungunya virus (CHIKV) causes acute or chronic arthritis in humans. Inflammatory responses mediated by monocytes, the primary target cells of CHIKV infection in the blood, are considered to play an important role in CHIKV pathogenesis. A recent study revealed that the acute phase of CHIKV infection is characterized by a monocyte-driven response, with an expansion of the intermediate monocyte (IM) subset. In this study, we adopted a previously established in vitro model of CHIKV infection in peripheral blood mononuclear cells, to elucidate the mechanism and relevance of IM expansion in CHIKV replication and associated inflammatory responses. Our data show that infectious but not replication-incompetent CHIKV increases the frequency of IM and to a lesser extent, non-classical (NM) monocytes while reducing the number of classical monocytes (CM). The increase of IM or NM frequency coincided with the activation of inflammatory response and occurred in the absence of lymphocytes implying that monocyte-derived cues are sufficient to drive this effect. Importantly, priming of monocytes with LPS prevented expansion of IM and NM but had no effect on viral replication. It did however alter CHIKV-induced cytokine signature. Taken together, our data delineate the role of IM in CHIKV infection-specific innate immune responses and provide insight for the development of therapeutic strategies that may focus on rewiring monocyte immune responses to prevent CHIKV-mediated arthralgia and arthritis.
Altered Huntingtin-Chromatin Interactions Predict Transcriptional and Epigenetic Changes in Huntington’s Disease Mouse Models
Authors: Pearl Jocelynn R , Shetty Amol C , Cantle Jeffrey P , Bergey Dani E , Bragg Robert M. , Coffey Sydney R. , Kordasiewicz Holly B. , Hood Leroy E , Price Nathan D , Ament Seth A , Carroll Jeffrey B
Published: June 2020

Progressive striatal gene expression changes and epigenetic alterations are a prominent feature of Huntington’s disease (HD), but the mechanistic basis remains poorly understood. Using chromatin immunoprecipitation and sequencing (ChIP-seq), we show that the huntingtin protein (HTT) reproducibly occupies specific locations in the mouse genome. Moreover, many genomic loci were differentially occupied by HTT in striatal tissue from a homozygous knock-in mouse model of HD (B6.HttQ111/Q111) when compared to wildtype controls. Huntingtin ChIP-seq peaks were enriched in the coding regions of cell identity genes important for striatal function, with many of these genes found to have reduced expression in the striata of HD patients and mouse models, as well as reduced HTT occupancy inHttQ111/Q111mice compared to controls. Conversely, HTT ChIP-seq peaks were depleted near genes that are up-regulated in HD. ChIP-seq of bulk striatal histone modifications, generated in parallel, revealed genotype-specific colocalization of HTT with active chromatin marks (H3K4me3 and H3K27ac), and with enhancer of zeste homolog 2 (EZH2), a key enzymatic component of the PRC2 complex. Near genes that are differentially regulated in HD, greater HTT occupancy inHttQ111/Q111vs. wildtype mice was associated with increased EZH2 binding, increased histone H3 lysine 4 (H3K4me3), and decreased histone H3 lysine 27 (H3K27me3). Our study suggests that huntingtin-chromatin interactions may play a direct role in organizing chromatin and promoting cell type-specific gene expression, with loss of HTT occupancy predicting decreased gene expression in HD.
A Tumbling Magnetic Microrobot System for Biomedical Applications
Authors: Niedert Elizabeth E. , Bi Chenghao , Adam Georges , Lambert Elly , Solorio Luis , Goergen Craig J. , Cappelleri David J.
Published: June 2020

A microrobot system comprised of an untethered tumbling magnetic microrobot, a two degree of freedom rotating permanent magnet, and an ultrasound imaging system has been developed forin vitroandin vivobiomedical applications. The microrobot tumbles end-over-end in a net forward motion due to applied magnetic torque from the rotating magnet. By turning the rotational axis of the magnet, two-dimensional directional control is possible and the microrobot was steered along various trajectories, including a circular path and P-shaped path. The microrobot is capable of moving over the unstructured terrain within a murine colon inin vitro,in situ, andin vivoconditions, as well as a porcine colon inex vivoconditions. High frequency ultrasound imaging allows for real-time determination of the microrobot’s position while it is optically occluded by animal tissue. When coated with a fluorescein payload, the microrobot was shown to release the majority of the payload over a one hour time period in phosphate-buffered saline. Cytotoxicity tests demonstrated that the microrobot’s constituent materials, SU-8 and polydimethylsiloxane (PDMS), did not show a statistically significant difference in toxicity to murine fibroblasts from the negative control, even when the materials were doped with magnetic neodymium microparticles. The microrobot system’s capabilities make it promising for targeted drug delivery and otherin vivobiomedical applications.
Induction of intracellular wild-type p53 amyloids leading to cellular transformation and tumor formation in mice
Authors: Navalkar Ambuja , Pandey Satyaprakash , Singh Namrata , Dey Amit Kumar , Saha Sandhini , Patel Komal , Mohanty Bhabani , Jadhav Sachin , Chaudhari Pradip , Maiti Tushar K. , Maji Samir K.
Published: June 2020

Tumor suppressor p53 mutations, with subsequent loss-of-tumor suppressive function and gain-of oncogenic functions, are associated with more than 50% of human cancers. Aggregation and amyloid formation are also mechanisms by which wild type and mutant p53 might be involved in cancer, but the direct evidence of how aggregated p53 acts as an oncogene is lacking. In this study, we directly demonstrate that wild-type p53 amyloid formation imparts oncogenic properties to normal cells. Cells with p53 amyloids show enhanced survival, apoptotic resistance with increased proliferation and migration rates. The tumorigenic potential of p53 amyloid transformed cells is further confirmed in a mice xenograft model, wherein the tumor showed p53 amyloid aggregates. Gene-expression analysis and proteomic profiling suggest that p53 amyloid formation triggers aberrant expression of pro-oncogenes while downregulating the tumor-suppressive genes. Interestingly, disaggregating p53 rescues the cellular transformation and also inhibits tumor development in mice. We propose that wild-type p53 amyloid formation can potentially contribute to the initiation of tumor development.
A simple and effective F0 knockout method for rapid screening of behaviour and other complex phenotypes
Authors: Kroll François , Powell Gareth T , Ghosh Marcus , Antinucci Paride , Hearn Timothy J , Tunbak Hande , Lim Sumi , Dennis Harvey W , Fernandez Joseph M , Whitmore David , Dreosti Elena , Wilson Stephen W , Hoffman Ellen J , Rihel Jason
Published: June 2020

Hundreds of human genes are associated with neurological diseases, but translation into tractable biological mechanisms is lagging. Larval zebrafish are an attractive model to investigate genetic contributions to neurological diseases. However, current CRISPR-Cas9 methods are difficult to apply to large genetic screens studying behavioural phenotypes. To facilitate rapid genetic screening, we developed a simple sequencing-free tool to validate gRNAs and a highly effective CRISPR-Cas9 method capable of converting >90% of injected embryos directly into F0 biallelic knockouts. We demonstrate that F0 knockouts reliably recapitulate complex mutant phenotypes, such as altered molecular rhythms of the circadian clock, escape responses to irritants, and multi-parameter day-night locomotor behaviours. The technique is sufficiently robust to knockout multiple genes in the same animal, for example to create the transparent triple knockoutcrystalfish for imaging. Our F0 knockout method cuts the experimental time from gene to behavioural phenotype in zebrafish from months to one week.
Structural insight into outer membrane asymmetry maintenance of Gram-negative bacteria by the phospholipid transporter MlaFEDB
Authors: Tang Xiaodi , Chang Shenghai , Qiao Wen , Luo Qinghua , Chen Yuejia , Jia Zhiying , Coleman James , Zhang Ke , Wang Ting , Zhang Zhibo , Zhang Changbin , Zhu Xiaofeng , Wei Xiawei , Dong Changjiang , Zhang Xing , Dong Haohao
Published: June 2020

The asymmetric phospholipid outer membrane (OM) of Gram-negative bacteria serves as the first line of defense against cytotoxic substances such as antibiotics. The Mla pathway is known to maintain the lipid asymmetry of the OM by transporting phospholipids between the inner and outer membranes. Six Mla proteins MlaFEDBCA are involved, with the ABC transporter MlaFEDB acts through a mechanism yet to be elucidated. Here we determine cryo-EM structures of MlaFEDB in apo, phospholipid-, ADP- or AMP-PNP-bound state to 3.3-3.75 Å resolution and establish a proteoliposome-based transport system containing MlaFEDB, MlaC and MlaA/OmpF to reveal the transport direction of phospholipids. Mutagenetic in vitro transport assays and in vivo sensitivity assays reveal functional residues which recognize and transport phospholipids as well as regulate the activity and structural stability of the MlaFEDB complex. Our work provides molecular basis for understanding the mechanism of the Mla pathway which could be targeted for antimicrobial drug development.