bluuebunny/crossref_metadata_2025 huggingface dataset:
Fluid Responsiveness Predictability in Immediate Postoperative Pediatric Cardiac Surgery. Is the Old Slandered Central Venous Pressure Back Again?
Authors: Shostak Eran , Shochat Tzippy , Manor Orit , Nahum Elchanan , Dagan Ovadia , Schiller Ofer
Published: April 2021

Objective:

Acute low cardiac output (CO) is a frequent scenario in pediatric cardiac intensive care units (PCICU). While fluid responsiveness has been studied extensively, literature is scarce for the immediate postoperative congenital heart surgery population admitted to PCICUs. This study analyzed the utility of hemodynamic, bedside ultrasound, and Doppler parameters for prediction of fluid responsiveness in infants and neonates in the immediate postoperative cardiac surgery period.

Design:

A prospective observational study.

Setting:

University affiliated, tertiary care hospital, PCICU.

Participants:

Immediate postoperative pediatric patients displaying a presumed hypovolemic low CO state were included. A clinical, arterial derived, hemodynamic, sonographic, Doppler-based, and echocardiographic parameter assessment was performed, followed by a fluid bolus therapy.

Interventions:

Fifteen to 20 cc/kg crystalloid fluid bolus.

Main outcome measures:

Fluid responsiveness was defined as an increase in cardiac index >10% by echocardiography.

Results:

Of 52 patients, 34 (65%) were fluid responsive. Arterial systolic pressure variation, continuous-Doppler preload parameters, and inferior vena-cava distensibility index (IVCDI) by bedside ultrasound all failed to predict fluid responsiveness. Dynamic central venous pressure (CVP) change yielded a significant but modest fluid responsiveness predictability of area under the curve 0.654 (P = 0.0375).

Conclusions:

In a distinct population of mechanically ventilated, young, pediatric cardiac patients in the immediate postoperative period, SPV, USCOM preload parameters, as well as IVC-based parameters by bedside ultrasound failed to predict fluid responsiveness. Dynamic CVP change over several hours was the only parameter that yielded significant but modest fluid responsiveness predictability.
A Caveat to Using Wearable Sensor Data for COVID-19 Detection: The Role of Behavioral Change after Receipt of Test Results
Authors: Cleary Jennifer L. , Fang Yu , Sen Srijan , Wu Zhenke
Published: April 2021

Recent studies indicate that wearable sensors have the potential to capture subtle within-person changes that signal SARS-CoV-2 infection. However, it remains unclear the extent to which observed discriminative performance is attributable to behavioral change after receiving test results. We conducted a retrospective study in a sample of medical interns who received COVID-19 test results from March to December 2020. Our data confirmed that sensor data were able to differentiate between symptomatic COVID-19 positive and negative individuals with good accuracy (area under the curve (AUC) = 0.75). However, removing post-result data substantially reduced discriminative capacity (0.75 to 0.63; delta= −0.12, p=0.013). Removing data in the symptomatic period prior to receipt of test results did not produce similar reductions in discriminative capacity. These findings suggest a meaningful proportion of the discriminative capacity of wearable sensor data for SARS-CoV-2 infection may be due to behavior change after receiving test results.
Higher COVID-19 Vaccination Rates among Unemployed in the United States: State Level Study in the First 100 days of Vaccine Initiation
Authors: Roghani Ali , Panahi Samin
Published: April 2021

Background

Socioeconomic factors may impact the efficiency of COVID vaccine rollout; however, there are limited studies that examine how state socioeconomic status influences the speed of vaccine distribution. This study aimed to demonstrate how employment rates as one of the main socioeconomic factors affect vaccine coverage in 50 states of the United States.

Methods

This study has obtained vaccine data for the 50 states in the United States, available in the electronic online database ourworldindata.org. In addition to employment rates, other socioeconomic determinants including poverty level, uninsured rates, population density, homeownership, educational level, the percentage of the elderly population, and educational level were obtained from ourworldindata.org data platform. Data from these 50 states were used for regression analyses to examine the relationship between socioeconomic and vaccination rates.

Results

Our study revealed a positive linear association between unemployment and vaccine rates, and states with higher unemployment rates were more likely to have higher vaccination rates. However, other socioeconomic measures do not significantly associate with vaccine coverage.

Conclusion

Despite other studies showing that vulnerable populations had lower vaccine rates, this study shows that states with higher unemployment rates are more likely to be vaccinated. However, the finding suggests a need for more research for the states with higher than 5% unemployment rates, as they had a lower vaccine coverage than states with a range of 4% to 5% unemployment rates.
Von Meyenburg Complexes and Malignancy: A Systematic Review
Authors: Sheikh Abu Baker , Nguyen Anthony , Sheikh Abdul Ahad Ehsan , Javed Nismat , Leyba Katarina , Shekhar Rahul
Published: April 2021

Von Meyenburg Complexes (VMC) are benign lesions secondary to ductal plate malformations. These are relatively rare in adults and are often asymptomatic, with many lesions being diagnosed on imaging. Despite these benign characteristics, VMC have the potential to undergo malignant changes leading to conditions such as cholangiocarcinoma and other cancers. The objective of the review is to report and analyze the cases of biliary hamartomas which were associated with malignancy. We performed a structured systematic review of literature and identified 31 cases of biliary duct hamartomas associated with malignancy. The mean age at onset was 61 years±13 (min 19 to max 88) with the majority of the patients being male (64.5%). Of all cases, 41.9% reported symptoms (13/31 cases) with the most common symptom being abdominal pain (32.3%). Biopsies reported malignancy in 77.4% of cases (24/31 cases) with the most common reported associated malignancy being cholangiocarcinoma 54.8% (17/31). 93.3% of the cases underwent surgical intervention (28/30 cases). VMC are an important entity with malignancy potential which is under-reported. Presence of ‘red flag’ symptoms such as weight loss and obstructive jaundice in patients with diagnosed biliary hamartomas should prompt an evaluation for malignancy.
Prolonged activation of nasal immune cell populations and development of tissue-resident SARS-CoV-2 specific CD8 T cell responses following COVID-19
Authors: Roukens Anna H.E. , König Marion , Dalebout Tim , Tak Tamar , Azimi Shohreh , Kruize Yvonne , Pothast Cilia R. , Hagedoorn Renate S. , Arbous Sesmu M. , Zhang Jaimie L. H. , Verheij Maaike , Prins Corine , van der Does Anne M. , Hiemstra Pieter S. , de Vries Jutte J.C. , Janse Jacqueline J. , Roestenberg Meta , Myeni Sebenzile K. , Kikkert Marjolein , Heemskerk Mirjam H.M. , Yazdanbakhsh Maria , Smits Hermelijn H. , Jochems Simon P. ,   BEAT-COVID group
Published: April 2021

The immune system plays a major role in Coronavirus Disease 2019 (COVID-19) pathogenesis, viral clearance and protection against re-infection. Immune cell dynamics during COVID-19 have been extensively documented in peripheral blood, but remain elusive in the respiratory tract. We performed minimally-invasive nasal curettage and mass cytometry to characterize nasal immune cells of COVID-19 patients during and 5-6 weeks after hospitalization. Contrary to observations in blood, no general T cell depletion at the nasal mucosa could be detected. Instead, we observed increased numbers of nasal granulocytes, monocytes, CD11c+ NK cells and exhausted CD4+ T effector memory cells during acute COVID-19 compared to age-matched healthy controls. These pro-inflammatory responses were found associated with viral load, while neutrophils also negatively correlated with oxygen saturation levels. Cell numbers mostly normalized following convalescence, except for persisting CD127+ granulocytes and activated T cells, including CD38+ CD8+ tissue-resident memory T cells. Moreover, we identified SARS-CoV-2 specific CD8+ T cells in the nasal mucosa in convalescent patients. Thus, COVID-19 has both transient and long-term effects on the immune system in the upper airway.
Live-cell micromanipulation of a genomic locus reveals interphase chromatin mechanics
Authors: Keizer Veer I. P. , Grosse-Holz Simon , Woringer Maxime , Zambon Laura , Aizel Koceila , Bongaerts Maud , Kolar-Znika Lorena , Scolari Vittore F. , Hoffmann Sebastian , Banigan Edward J. , Mirny Leonid A. , Dahan Maxime , Fachinetti Daniele , Coulon Antoine
Published: April 2021

Our understanding of the physical principles organizing the genome in the nucleus is limited by the lack of tools to directly exert and measure forces on interphase chromosomesin vivoand probe their material nature. Here, we present a novel approach to actively manipulate a genomic locus using controlled magnetic forces inside the nucleus of a living human cell. We observe viscoelastic displacements over microns within minutes in response to near-picoNewton forces, which are well captured by a Rouse polymer model. Our results highlight the fluidity of chromatin, with a moderate contribution of the surrounding material, revealing the minor role of crosslinks and topological effects and challenging the view that interphase chromatin is a gel-like material. Our new technology opens avenues for future research, from chromosome mechanics to genome functions.
Hot, unpredictable weather interacts with land use to restrict the distribution of the Yellow-tailed Black-Cockatoo
Authors: Amin Rahil J. , Buettel Jessie C. , Vaughan Peter M. , Fielding Matthew W. , Brook Barry W.
Published: April 2021

Conserving nomadic species is challenging due to the difficulty in monitoring their characteristically transient populations, and thereby detecting range-wide declines. An example is the Yellow-tailed Black-Cockatoo (YTBC;Zanda funerea), which disperses widely in search of food and is regularly—but sporadically—observed across eastern Australia. Under climate warming, a general southward shift in species distributions is expected in the southern hemisphere, with the extreme southern margins being truncated by an ocean barrier. Given these constraints, we ask whether sufficient refugia will exist for the YTBC in the future, by: (i) modelling habitat relationships within current geographic range of the YTBC based on weather, climate, vegetation, and land use, and (ii) using this framework, coupled with climate-model projections, to forecast 21stcentury impacts. Intensive land use and high variability in temperature and rainfall seem to most limit YTBC occurrence. In contrast, areas with a cooler, stable climate, and a network of old-growth forests, such as occurs in parts of south-eastern Australia and Tasmania, are most suitable for the species. As Australia becomes progressively hotter under climate change, the preferred bioclimatic envelope of the YTBC is forecast to contract poleward (as a general pattern) and to fragment within the existing range. However, despite an extensive loss of climatically suitable regions, the YTBC might find stable refugia at the southern margins of its geographic range, although continued loss of old-growth forests undermines their nesting potential. Therefore, beyond habitat conservation, creating nesting opportunities within plantation forests would likely be an effective conservation strategy to preserve habitat quality in climate refugia.
Species coexistence and temporal environmental fluctuations: a quantitative comparison between stochastic and seasonal variations
Authors: Meyer Immanuel , Steinmetz Bnaya , Shnerb Nadav M.
Published: April 2021

Temporal environmental variations may promote diversity in communities of competing populations. Here we compare the effect of environmental stochasticity with the effect of periodic (e.g., seasonal) cycles, using analytic solutions and individual-based Monte-Carlo simulations. Even when stochasticity facilitates coexistence it still allows for rare sequences of bad years that may drive a population to extinction, therefore the stabilizing effect of periodic variations is stronger. Correspondingly, the mean time to extinction grows exponentially with community size in periodic environment and switch to power-law dependence under stochastic fluctuations. On the other hand, the number of temporal niches in periodic environment is typically lower, so as diversity increases stochastic temporal variations may support higher species richness.
The memory of airway epithelium damage in smokers and COPD patients
Authors: Carlier François M. , Detry Bruno , Lecocq Marylène , Collin Amandine M. , Planté-Bordeneuve Thomas , Verleden Stijn E. , Delos Monique , Rondelet Benoît , Janssens Wim , Ambroise Jérôme , Vanaudenaerde Bart M. , Gohy Sophie , Pilette Charles
Published: April 2021

Rationale

Chronic obstructive pulmonary disease (COPD) is a devastating and mostly irreversible lung disease. In COPD, the bronchial epithelium displays several structural and functional abnormalities affecting barrier integrity, cell polarity, and differentiation, as well as epithelial-to-mesenchymal transition and inflammation. Although COPD displays mostly irreversible changes, the (ir)reversible nature of epithelium pathologyex vivoremains poorly known and was the aim of this study.

Methods

The persistence of COPD epithelium abnormalities was addressed in long-term (10 weeks) primary cultures of air/liquid interface-reconstituted airway epithelium from non-smoker controls, smoker controls, and COPD patients. Barrier function, epithelial polarity, cell commitment, epithelial-to-mesenchymal transition and inflammation were assessedin vitro, and certain features were comparedin situto the native epithelium. The role of inflammation was explored by stimulating cultures with a cytokine mix consisting of TNF-α, IL-6 and IL-1β.

Measurements and main results

Almost all epithelial defects (barrier dysfunction, impaired polarity, lineage abnormalities) observed in cells from smokers and COPD patients persistedin vitroup to week 10, except IL-8/CXCL-8 release and epithelial-to-mesenchymal transition which declined over time. Cell lineage and polarity impairments matched abnormalities observedin situin the surgical samples from which thein vitroepithelium was derived. Cytokine treatment induced COPD-like changes and, in COPD cells, reactivated epithelial-to-mesenchymal transition.

Conclusions

The airway epithelium from smokers and COPD patients displays a memory of its native state and previous injuries by cigarette smoking, which is multidimensional and sustained for extended periods of time.
The coiled-coil domain ofE. coliFtsLB is a structurally detuned element critical for modulating its activation in bacterial cell division
Authors: Craven Samuel J. , Condon Samson G.F. , Diaz-Vazquez Gladys , Cui Qiang , Senes Alessandro
Published: April 2021

The FtsLB complex is a key regulator of bacterial cell division, existing in either anofforonstate which supports the activation of septal peptidoglycan synthesis. InEscherichia coli, residues known to be critical for this activation are located in a region near the C-terminal end of the periplasmic coiled-coil domain of FtsLB, raising questions about the precise role of this conserved domain in the activation mechanism. Here, we investigate an unusual cluster of polar amino acids found within the core of the FtsLB coiled coil. We hypothesized that these amino acids likely reduce the structural stability of the domain and thus may be important for governing conformational changes. We found that mutating these positions to hydrophobic residues increased the thermal stability of FtsLB but caused cell division defects, suggesting that the coiled-coil domain is a “detuned” structural element. In addition, we identified suppressor mutations within the polar cluster, indicating that the precise identity of the polar amino acids is important for fine-tuning the structural balance between theoffandonstates. We propose a revised structural model of the tetrameric FtsLB (named the “Y-model”) in which the periplasmic domain splits into a pair of coiled-coil branches. In this configuration, the hydrophilic terminal moieties of the polar amino acids remain more favorably exposed to water than in the original four-helix bundle model (“I-model”). We propose that a shift in this architecture, dependent on its marginal stability, is involved in activating the FtsLB complex and triggering septal cell wall reconstruction.
Metabotropic group II glutamate receptors in the basolateral amygdala mediate cue-triggered increases in incentive motivation
Authors: Garceau Caroline , Samaha Anne-Noël , Cordahi Thomas , Servonnet Alice , Khoo Shaun Yon-Seng
Published: April 2021

Rationale

Reward-associated cues can trigger incentive motivation for reward and invigorate reward-seeking behaviour via Pavlovian-to-instrumental transfer (PIT). Glutamate signaling within the basolateral amygdala (BLA) modulates cue-triggered increases in incentive motivation. However, the role of BLA metabotropic group II glutamate (mGlu2/3) receptors is largely unknown.

Objectives

In Experiment 1, we characterized cue-triggered increases in incentive motivation for water reward using the PIT paradigm. In Experiment 2, we assessed the influence of intra-BLA microinjections of the mGlu2/3receptor agonist LY379268 on this effect.

Methods

Water-restricted male Sprague-Dawley rats learned to press a lever for water. Separately, they learned to associate one of two auditory cues with free water. On test days, rats could lever press under extinction conditions (no water), with intermittent, non-contingent CS+ and CS- presentations. In Experiment 1, rats were tested under baseline conditions. In Experiment 2, rats received intra-BLA microinjections of LY379268 (0, 3 and 6 μg/hemisphere) before testing.

Results

Across experiments, CS+, but not CS- presentations increased water-associated lever pressing during testing, even though responding was reinforced neither by water nor the CS+. Intra-BLA LY379268 abolished both CS+ potentiated pressing on the water-associated lever and CS+ evoked conditioned approach to the site of water delivery. LY379268 did not influence locomotion or instrumental and Pavlovian response rates during intervals between CS presentations or during the CS-, indicating no motor effects.

Conclusions

mGlu2/3receptor activity in the BLA mediates CS-triggered potentiation of incentive motivation for reward, suppressing both CS-induced increases in instrumental pursuit of the reward and anticipatory approach behaviour.
Widespread multi-targeted therapy resistance via drug-induced secretome fucosylation
Authors: Aldonza Mark Borris D. , Cha Junghwa , Yong Insung , Ku Jayoung , Lee Dabin , Sinitcyn Pavel , Cho Ryeong-Eun , Delos Reyes Roben D. , Kim Dongwook , Sung Hye-Jin , Kim Soyeon , Kang Minjeong , Ku Yongsuk , Park Geonho , Ryu Han Suk , Cho Sukki , Kim Tae Min , Kim Pilnam , Cho Je-Yoel , Kim Yoosik
Published: April 2021

Cancer secretome is a reservoir for aberrant glycosylation. How therapies alter this post-translational cancer hallmark and the consequences thereof remain elusive. Here we show that an elevated secretome fucosylation is a pan-cancer signature of both response and resistance to multiple targeted therapies. Large-scale pharmacogenomics revealed that fucosylation genes display widespread association with resistance to these therapies. In both cancer cell cultures and patients, targeted kinase inhibitors distinctively induced core fucosylation of secreted proteins less than 60 kDa. Label-free proteomics of N-glycoproteomes revealed that fucosylation of the antioxidant PON1 is a critical component of the therapy-induced secretome. Core fucosylation in the Golgi impacts PON1 stability and folding prior to secretion, promoting a more degradation-resistant PON1. Non-specific and PON1-specific secretome de-N-glycosylation both limited the expansion of resistant clones in a tumor regression model. Our findings demonstrate that core fucosylation is a common modification indirectly induced by targeted therapies that paradoxically promotes resistance.
Suppression of Fatty Acid Oxidation by Thioesterase Superfamily Member 2 in Skeletal Muscle Promotes Hepatic Steatosis and Insulin Resistance
Authors: Imai Norihiro , Nicholls Hayley T. , Alves-Bezerra Michele , Li Yingxia , Ivanova Anna A. , Ortlund Eric A. , Cohen David E.
Published: April 2021

Thioesterase superfamily member 2 (Them2) is highly expressed in oxidative tissues where it hydrolyzes long chain fatty acyl-CoA esters to free fatty acids and CoA. Although mice globally lacking Them2 (Them2-/-) are protected against diet-induced obesity, insulin resistance and hepatic steatosis, liver-specificThem2-/-mice remain susceptible. To explore the contribution of Them2 in extrahepatic tissues, we created mice with Them2 deleted in skeletal muscle (S-Them2-/-), cardiac muscle (C-Them2-/-) or adipose tissue (A-Them2-/-). When fed a high-fat diet,S-Them2-/-but notC-Them2-/-orA-Them2-/-mice exhibited reduced weight gain. OnlyS-Them2-/-mice exhibited improved glucose homeostasis together with improved insulin sensitivity in skeletal muscle. Increased rates of fatty acid oxidation in skeletal muscle ofS-Them2-/-mice were reflected in alterations in skeletal muscle metabolites, including short chain fatty acids, branched chain amino acids and the pentose phosphate pathway. Protection from diet-induced hepatic steatosis inS-Them2-/-mice was attributable to increased VLDL triglyceride secretion rates in support of demands of increased muscle fatty acid utilization. These results reveal a key role for skeletal muscle Them2 in the pathogenesis of diet-induced obesity, insulin resistance and hepatic steatosis.
Single-molecule imaging of chromatin remodelers reveals role of ATPase in promoting fast kinetics of target search and dissociation from chromatin
Authors: Kim Jee Min , Visanpattanasin Pat , Jou Vivian , Liu Sheng , Tang Xiaona , Zheng Qinsi , Li Kai Yu , Snedeker Jonathan , Lavis Luke D. , Lionnet Timothée , Wu Carl
Published: April 2021

Conserved ATP-dependent chromatin remodelers establish and maintain genome-wide chromatin architectures of regulatory DNA during cellular lifespan, but the temporal interactions between remodelers and chromatin targets have been obscure. We performed live-cell single-molecule tracking for RSC, SWI/SNF, CHD1, ISW1, ISW2, and INO80 remodeling complexes in budding yeast and detected hyperkinetic behaviors for chromatin-bound molecules that frequently transition to the free state for all complexes. Chromatin-bound remodelers display notably higher diffusion than nucleosomal histones, and strikingly fast dissociation kinetics with 4-7 s mean residence times. These enhanced dynamics require ATP binding or hydrolysis by the catalytic ATPase, uncovering an additional function to its established role in nucleosome remodeling. Kinetic simulations show that multiple remodelers can repeatedly occupy the same promoter region on a timescale of minutes, implicating an unending ‘tug-of-war’ that controls a temporally shifting window of accessibility for the transcription initiation machinery.
Place Cells in the Claustrum Remap Under NMDA Receptor Control
Authors: Rizzello Emanuela , Martin Seán K. , Rouine Jennifer , Callaghan Charlotte K. , O’Mara Shane M.
Published: April 2021

Place cells are cells exhibiting location-dependent responses; they have mostly been studied in the hippocampus. Place cells have also been reported in the rat claustrum, an underexplored paracortical region with extensive corto-cortical connectivity. It has been hypothesised that claustral neuronal responses are anchored to cortical visual inputs. We show rat claustral place cells remap when visual inputs are eliminated from the environment and that this remapping is NMDA-receptor-dependent. Eliminating visual input enhances delta-band oscillatory activity in the claustrum, without affecting simultaneously-recorded visual cortical activity. We conclude that, like the hippocampus, claustral place field remapping might be mediated by NMDA receptor activity, and is modulated by visual cortical inputs. (106 words)
Costs, Benefits, Parasites and Mutualists: The Use and Abuse of the Mutualism–Parasitism Continuum Concept forEpichloëFungi
Authors: Newman Jonathan A. , Gillis Sierra , Hager Heather A.
Published: April 2021

The species comprising the fungal endophyte genusEpichloëare symbionts of cool season grasses. About half the species in this genus are strictly vertically transmitted, and evolutionary theory suggests that these species must be mutualists. Nevertheless, Faeth and Sullivan (e.g. 2003) have argued that such vertically transmitted endophytes are “usually parasitic,” and Müller and Krauss (2005) have argued that such vertically transmitted endophytes fall along a mutualism–parasitism continuum. These papers (and others) have caused confusion in the field. We used a systematic review to show that close to half of the published papers in this field incorrectly categorize the interaction. Here, we develop the argument that advantages and disadvantages are not the same things as mutualism and parasitism and that experimental evidence must be interpreted in the context of theory. We argue that,contraFaeth and Sullivan, it is highly unlikely that such strictly vertically transmitted endophytes can be parasites, and that,contraMüller and Krauss, it is inappropriate to apply the continuum concept to strictly vertically transmitted endophytes. We develop a mathematical model to support and illustrate our arguments. We use the model to clarify that parasitismrequiressome degree of horizontal transmission, and that while it is appropriate to use the continuum concept when referring to the genus as a whole, or to species that possess horizontal transmission, we argue that it is inappropriate to use the concept when referring to species that are strictly vertically transmitted.
Unperturbed dormancy recording reveals stochastic awakening strategies in endocrine treated breast cancer cells
Authors: Rosano Dalia , Sofyali Emre , Dhiman Heena , Ivanoiu Diana , Slaven Neil , Hong Sung Pil , Rocca Andrea , Bravaccini Sara , Ravaioli Sara , Noberini Roberta , Bonaldi Tiziana , Magnani Luca
Published: April 2021

Hormone dependent breast cancer (HDBC) is the most commonly diagnosed tumor type in women. Adjuvant endocrine therapies (ET) have been the cornerstone in the clinical management of HDBC patients for over forty years. A vast proportion of HDBC patients incur long periods of clinical dormancy following ET, with tumour awakening appearing at a steady pace for up to 25 years (Pan et al., 2017). Extensive genomic studies have demonstrated that 15-30% of clinical relapses develop recurrent genomic changes which contribute to drug resistance (i.e. ESR1 activating mutations) (Bertucci et al., 2019; Magnani et al., 2017; Razavi et al., 2018). However, even in these cases, there is no conclusive evidence around the pre-existence vs.de novonature of these events. We previously showed that ETs can trigger and select for dormancy in subpopulations of breast cancer (Hong et al., 2019). In this work we took two novel approaches to investigate the dormancy and awakening roadmap of HDBC cells at unprecedented detail. Firstly, we leveraged a rare cohort of n=5 patients which were treated with primary adjuvant ETs in the absence of surgery (TRACING-HT) to dissect the contribution of genomic aberrations to tumor awakening. Next, we developed a first of its kind evolutionary studyin vitroto systematically annotate cancer cells adaptive strategies at single cell level in unperturbed systems during a period of several months (TRADITIOM). Collectively our data suggest that ETs steer HDBC cells into an inherently unstable dormant state. Over time, routes to awakening emerge sporadically and spontaneously in single lineages. Each dormant cell retains an intrinsic awakening probability which we propose is a function of epigenetic decay. Awakening occurs without an external trigger and involves multiple apparent endpoint phenotypes that cannot be fully explained by conventional Darwinian genetic selection processes. Finally, our data show that common genetic hits associated with resistance happen downstream of awakening. Overall, our data have uncovered previously unsuspected roles for stochastic nongenetic events during dormancy with profound clinical implications.
A ‘Variant Viewer’ for investigating population-level variation inArabidopsis thaliana
Authors: Cumming Matthew , Esteban Eddi , Lau Vincent , Pasha Asher , Provart Nicholas J.
Published: April 2021

High throughput sequencing has opened the doors for investigators to probe genetic variation present in large populations of organisms. In plants, the 1001 Genomes Project (1001genomes.org) is one such effort that sought to characterize the extant worldwide variation inArabidopsis thalianafor future analyses to compare and draw upon. We developed a web application that accesses the 1001 Genomes database called The Variant Viewer, for investigators to view variants in anyA. thalianagene and within gene families. These variants may be visualized in the context of alignments of queried genes, across splice isoforms of these genes and in relation to conserved domains.
Informational masking vs. crowding — A mid-level trade-off between auditory and visual processing
Authors: Zhang Min , Denison Rachel N , Pelli Denis G , Le Thuy Tien C , Ihlefeld Antje
Published: April 2021

In noisy or cluttered environments, sensory cortical mechanisms help combine auditory or visual features into perceived objects. Knowing that individuals vary greatly in their ability to suppress unwanted sensory information, and knowing that the sizes of auditory and visual cortical regions are correlated, we wondered whether there might be a corresponding relation between an individual’s ability to suppress auditory vs. visual interference. Inauditory masking, background sound makes spoken words unrecognizable. When masking arises due to interference at central auditory processing stages, beyond the cochlea, it is calledinformationalmasking (IM). A strikingly similar phenomenon in vision, calledvisual crowding, occurs when nearby clutter makes a target object unrecognizable, despite being resolved at the retina. We here compare susceptibilities to auditory IM and visual crowding in the same participants. Surprisingly, across participants, we find a negative correlation (R= −0.7) between IM susceptibility and crowding susceptibility: Participants who have low susceptibility to IM tend to have high susceptibility to crowding, and vice versa. This reveals a mid-level trade-off between auditory and visual processing.
Optical Probing of Local Membrane Potential with Fluorescent Polystyrene Beads
Authors: Shapira Zehavit , Degani-Katzav Nurit , Yudovich Shimon , Grupi Asaf , Weiss Shimon
Published: April 2021

Studying the electrical activity in single cells and in local circuits of excitable cells, like neurons, requires an easy to use and high throughput methodology that enables the measurement of membrane potential. Studying the electrical properties in particular sub-compartments of neurons, or in a specific type of neurons produces additional complexity. An optical voltage-imaging technique that allows high spatial and temporal resolution could be an ideal solution. However, most of the valid voltage imaging techniques are nonspecific; The ones that are more site-directed require much pre-work and specific adaptations in addition to other disadvantages. Here, a new technique for membrane voltage imaging, based on FRET between fluorescent polystyrene (FPS) beads and Dipicrylamine (DPA) is explored. Not only fluorescent intensity is demonstrated to be correlated with membrane potential, but more importantly, single particle voltage detection is demonstrated. Among other advantages, FPS beads can be synthesized with functional surface groups, and be further targeted to specific proteins via conjugation of recognition molecules. Therefore, FPS beads, in the presence of DPA, constitute single-particle detectors for membrane voltage, with a potential to be localized to specific membrane compartments. This new and accessible platform for targeted optical voltage imaging may further elucidate the mechanisms of neuronal electrical activity.
Point-localized and site-specific membrane potential optical recording by engineered single fluorescent nanodiscs
Authors: Grupi Asaf , Shapira Zehavit , Degani-Katzav Nurit , Yudovich Shimon , Weiss Shimon
Published: April 2021

Nanodisc technology was implemented as a platform for voltage nanosensors. A FRET-based voltage sensing scheme employing fluorescent nanodiscs and the hydrophobic ion dipicrylamine (DPA) was developed and utilized to optically record membrane potentials on the single nanodisc level. Ensemble- and single- nanosensor recordings were demonstrated for HEK293 cells and primary cortical neuron cells. Conjugation of nanodiscs to anti-GABA-A antibodies allowed for site specific membrane potential measurements from post synaptic sites.
A neural circuit for wind-guided olfactory navigation
Authors: Matheson Andrew M.M. , Lanz Aaron J. , Medina Ashley M. , Licata Al M. , Currier Timothy A. , Syed Mubarak H. , Nagel Katherine I.
Published: April 2021

To navigate towards a food source, animals must frequently combine odor cues that tell them what sources are useful with wind direction cues that tell them where the source can be found. Where and how these two cues are integrated to support navigation is unclear. Here we identify a pathway to the Drosophila fan-shaped body (FB) that encodes attractive odor and promotes upwind navigation. We show that neurons throughout this pathway encode odor, but not wind direction. Using connectomics, we identify FB local neurons called hΔC that receive input from this odor pathway and a previously described wind pathway. We show that hΔC neurons exhibit odor-gated, wind direction-tuned activity, that sparse activation of hΔC neurons promotes navigation in a reproducible direction, and that hΔC activity is required for persistent upwind orientation during odor. Based on connectome data, we develop a computational model showing how hΔC activity can promote navigation towards a goal such as an upwind odor source. Our results suggest that odor and wind cues are processed by separate pathways and integrated within the FB to support goal-directed navigation.
Pre-existing chromatin accessibility and gene expression differences among naïve CD4+T cells influence effector potential
Authors: Rogers Dakota , Sood Aditi , Wang HanChen , van Beek Jasper J. P. , Rademaker Thomas J. , Artusa Patricio , Schneider Caitlin , Shen Connie , Wong Dylan C. , Lebel Marie-Ève , Condotta Stephanie A. , Richer Martin J. , Martins Andrew J. , Tsang John S. , Barreiro Luis , Francois Paul , Langlais David , Melichar Heather J. , Textor Johannes , Mandl Judith N.
Published: April 2021

CD4+T cells have a remarkable potential to differentiate into diverse effector lineages following activation. Here, we probed the heterogeneity present among naïve CD4+T cells before encountering their cognate antigen to ask whether their effector potential is modulated by pre-existing transcriptional and epigenetic differences. Using single-cell RNA sequencing, we showed that key drivers of variability are genes involved in T cell receptor (TCR) signaling. Using CD5 expression as a read-out of the strength of tonic TCR interactions with self-peptide MHC, and sorting on the ends of this self-reactivity spectrum, we find that pre-existing transcriptional differences among naïve CD4+T cells impact follicular helper cell (TFH) versus non-TFHeffector lineage choice. Moreover, our data implicate TCR signal strength during thymic development in establishing differences in naïve CD4 T cell chromatin landscapes that ultimately shape their effector potential.
Nrf2 modulates the hybrid epithelial/mesenchymal phenotype and Notch signaling during collective cancer migration
Authors: Vilchez Mercedes Samuel A , Bocci Federico , Zhu Ninghao , Levine Herbert , Onuchic José N , Jolly Mohit Kumar , Wong Pak Kin
Published: April 2021

Hybrid epithelial/mesenchymal cells (E/M) are key players in aggressive cancer metastasis. It remains a challenge to understand how these cell states, which are mostly non-existent in healthy tissue, become stable phenotypes participating in collective cancer migration. The transcription factor Nrf2, which is associated with tumor progression and resistance to therapy, appears to be central to this process. Here, using a combination of single cell biosensors, immunocytochemistry, and computational modeling, we show that Nrf2 functions as a phenotypic stability factor for hybrid E/M cells by inhibiting a complete epithelial-mesenchymal transition (EMT) during collective cancer migration. We also demonstrate that Nrf2 and EMT signaling are spatially coordinated near the migrating front. In particular, computational analysis of an Nrf2-EMT-Notch network and experimental modulation of Nrf2 by pharmacological treatment or CRISPR/Cas9 gene editing reveal that Nrf2 stabilizes a hybrid E/M phenotype which is maximally observed in the interior region immediately behind the leading edge. We further demonstrate that the Nrf2-EMT-Notch network enhances Dll4 and Jagged1 expression near the leading edge, which correlates with the formation of leader cells and protruding tips. Altogether, our results provide direct evidence that Nrf2 acts as a phenotypic stability factor in restricting complete EMT and plays an important role in coordinating collective cancer migration.
Multi-state structure determination and dynamics analysis reveals a new ubiquitin-recognition mechanism in yeast ubiquitin C-terminal hydrolase
Authors: Okada Mayu , Tateishi Yutaka , Nojiri Eri , Mikawa Tsutomu , Rajesh Sundaresan , Ogasa Hiroki , Ueda Takumi , Yagi Hiromasa , Kohno Toshiyuki , Kigawa Takanori , Shimada Ichio , Güntert Peter , Ito Yutaka , Ikeya Teppei
Published: April 2021

Despite accumulating evidence that protein dynamics is indispensable for understanding the structural basis of biological activities, it remains challenging to visualize the spatial description of the dynamics and to associate transient conformations with their molecular functions. We have developed a new NMR protein structure determination method for the inference of multi-state conformations using multiple types of NMR data, including paramagnetic NMR and residual dipolar couplings, as well as conventional NOEs. Integration of these data in the structure calculation permits delineating accurate ensemble structures of biomacromolecules. Applying the method to the protein yeast ubiquitin hydrolase 1 (YUH1), we find large dynamics of its N-terminus and crossover loop surrounding the active site for ubiquitin-recognition and proteolysis. The N-terminus gets into and out of the crossover loop, suggesting their underlying functional significance. Our results, including those from biochemical analysis, show that large motion surrounding the active site contributes strongly to the efficiency of the enzymatic activity.
Establishing and maintaining fertility: the importance of cell cycle arrest
Authors: Frost Emily R. , Taylor Güneş , Baker Mark A. , Lovell-Badge Robin , Sutherland Jessie M.
Published: April 2021

Development of the ovary or testis is required to establish reproductive competence. Gonad development relies on key cell fate decisions that occur early in embryonic development and are actively maintained. During gonad development, both germ cells and somatic cells proliferate extensively, a process facilitated by cell cycle regulation. This review focuses on the Cip/Kip family of cyclin-dependent kinase inhibitors (CKIs) in mouse gonad development. We particularly highlight recent single-cell RNA sequencing studies that show the heterogeneity of cyclin-dependent kinase inhibitors. This diversity highlights new roles for cell cycle inhibitors in controlling and maintaining female fertility.
Essential histone chaperones collaborate to regulate transcription and chromatin integrity
Authors: Viktorovskaya Olga , Chuang James , Jain Dhawal , Reim Natalia I. , López-Rivera Francheska , Murawska Magdalena , Spatt Dan , Churchman L. Stirling , Park Peter J. , Winston Fred
Published: April 2021

Histone chaperones are critical for controlling chromatin integrity during transcription, DNA replication, and DNA repair. Three conserved and essential chaperones, Spt6, Spn1/Iws1, and FACT, associate with elongating RNA polymerase II and interact with each other physically and/or functionally; however, there is little understanding of their individual functions or their relationships with each other. In this study, we selected for suppressors of a temperature-sensitive spt6 mutation that disrupts the Spt6-Spn1 physical interaction and that also causes both transcription and chromatin defects. This selection identified novel mutations in FACT. Surprisingly, suppression by FACT did not restore the Spt6-Spn1 interaction, based on coimmunoprecipitation, ChIP, and mass spectrometry experiments. Furthermore, suppression by FACT bypassed the complete loss of Spn1. Interestingly, the FACT suppressor mutations cluster along the FACT-nucleosome interface, suggesting that they alter FACT-nucleosome interactions. In agreement with this observation, we showed that the spt6 mutation that disrupts the Spt6-Spn1 interaction caused an elevated level of FACT association with chromatin, while the FACT suppressors reduced the level of FACT-chromatin association, thereby restoring a normal Spt6-FACT balance on chromatin. Taken together, these studies reveal previously unknown regulation between histone chaperones that is critical for their essential in vivo functions.
A facilitation between large herbivores and ants accelerates litter decomposition by modifying soil microenvironmental conditions
Authors: Li Xiaofei , Risch Anita C. , Sanders Dirk , Liu Guofang , Prather Chelse , Wang Zhongnan , Hassan Nazim , Gao Qiang , Wang Deli , Zhong Zhiwei
Published: April 2021

Large herbivores and insects commonly coexist and play important functional roles in grassland ecosystems. The interactive effects of these two animal groups in shaping ecosystem processes and functioning are poorly understood. In a semi‐arid grassland of northeastern China, we previously found a reciprocal facilitation between large herbivores (cattle;Bos tarurs) and ants: cattle grazing led to a twofold increase in ant mound abundance compared with ungrazed sites, while the presence of ant mounds, in turn, increased the foraging of cattle during the peak of the growing season.

Here, by using a large‐scale, 4‐year (2010–2013) manipulative experiment, we further investigated how such a facilitation between large herbivores and ants can affect a key ecosystem process, litter decomposition. Using a set of small‐scale reciprocal translocation litterbag experiments, we separated the effects of litter quality and soil microenvironmental factors altered by cattle and ants on litter decomposition rates.

A significant interaction between the experimental factors, cattle grazing and ant presence, showed that litter decomposition rate was at the highest levels when both cattle and ants were present, with only a small impact when each was present on its own. Mechanistically, cattle and ants exerted limited effects on litter quality (litter C:N ratio). However, these animals greatly altered soil microenvironments by increasing soil N availability, which in turn increased soil microbial biomass and accelerated decomposition process.

Synthesis. Our results demonstrate how positive interactions between two groups of animals, large herbivores and ants, can affect decomposition rates, with important consequences for ecosystem carbon and nutrient cycling. Large herbivores, either domestic or wild, often coexist and interact frequently with a diverse of other fauna in terrestrial ecosystems. Assessing their interactive effects will help us to better understand their role in shaping ecosystem processes and functioning with important management implications.

A freePlain Language Summarycan be found within the Supporting Information of this article.
Respiratory temperature responses of tropical conifers differ with leaf morphology
Authors: Schmiege Stephanie C. , Buckley Brendan M. , Stevenson Dennis W. , Heskel Mary A. , Cuong Truong Quang , Nam Le Canh , Griffin Kevin L.
Published: April 2021

Photosynthetic traits suggest that shade tolerance may explain the contrasting success of two conifer taxa, Podocarpaceae and Pinaceae, in tropical forests. Needle‐leaved species from Pinus (Pinaceae) are generally absent from tropical forests, whereas Pinus krempfii, a flat‐leaved pine, and numerous flat‐leaved Podocarpaceae are abundant. Respiration (R) traits may provide additional insight into the drivers of the contrasting success of needle‐ and flat‐leaved conifers in tropical forests.

We measured the short‐term respiratory temperature (RT) response between 10 and 50°C and foliar morphological traits of three needle‐ and seven flat‐leaved conifer species coexisting in a tropical montane forest in the Central Highlands of Vietnam containing notable conifer diversity. We fit a lognormal polynomial model to each RT curve and extracted the following three parameters: a (basal R), and b and c (together describing the shape of the response).

Needle‐leaved species (Pinus kesiya, Pinus dalatensis and Dacrydium elatum) had higher rates of area‐based R at 25°C (R25‐area) as well as higher area‐based modelled basal respiration (a) than flat‐leaved species (P. krempfii, Podocarpus neriifolius, Dacrycarpus imbricatus, Nageia nana, Taxus wallichiana, Keteeleria evelyniana and Fokienia hodginsii). No significant differences were found between needle‐ and flat‐leaved species in mass‐based R25 (R25‐mass) or in the shape of the RT response (b and c); however, interspecific differences in R25‐mass, R at nighttime temperature extremes (R4.1 and R20.6) and leaf traits were apparent.

Differences in R25‐area and a suggest that needle‐leaved foliage may be more energetically costly to maintain than flat‐leaved foliage, providing new insight and additional support for the hypothesis that shade tolerance is an important driver of Podocarpaceae success and Pinaceae absence in the majority of tropical forests.

Interspecific differences in R25‐mass and leaf traits highlight that varying ecological strategies are employed by conifers to coexist and survive in the Central Highlands of Vietnam. Ultimately, these data further our understanding of current conifer biogeographical distributions and underscore the need for additional studies to elucidate the effects of extreme temperature events on the continued survival of conifers in this unique forest.

A free Plain Language Summary can be found within the Supporting Information of this article.