bluuebunny/crossref_metadata_2025 huggingface dataset:
TRMIntegrins CD103 and CD49a Differentially Support Adherence and Motility After Resolution of Influenza Virus Infection
Authors: Reilly Emma C , Emo Kris Lambert , Buckley Patrick M , Reilly Nicholas S , Chaves Francisco A , Yang Hongmei , Oakes Patrick W , Topham David J
Published: February 2020

Tissue resident memory CD8 T (TRM) cells are a unique immune memory subset that develops and remains in peripheral tissues at the site of infection, providing future host resistance upon re-exposure to that pathogen. In the pulmonary system, TRMare identified through S1P antagonist CD69 and expression of integrins CD103/β7 and CD49a/CD29(β1). Contrary to the established role of CD69 on CD8 T cells, the functions of CD103 and CD49a on this population are not well defined. This study examines the expression patterns and functions of CD103 and CD49a with a specific focus on their impact on T cell motility during influenza virus infection. We show that the TRMcell surface phenotype develops by two-weeks post-infection and that each integrin contributes a distinct function regulating CD8 T cell motility bothin vitroandin vivo, with CD49a facilitating migration and CD103 limiting motility through tethering. These results demonstrate for the first time how CD103 and CD49a differentially impact adherence and migration in the tissue, likely affecting overall retention, maintenance of TRM, and host protection.

Significance Statement

Current influenza vaccination strategies require annual immunizations, with fairly low efficacy rates. One technique to improve protection against a greater breadth of influenza viruses is to elicit broadly cross-reactive cell-mediated immunity and generate a local population of cytotoxic T cells to respond to conserved regions of circulating viruses. However, this approach requires improved understanding of how these cells migrate within and attach to the tissue, in order to persist and offer long-term immunity. This study investigates how receptors on the T cell surface impact the cell’s ability to interact with the tissue and provide evidence for which of these receptors are essential for protection. Furthermore, these studies reveal functionalin vivomechanisms of cellular markers used to characterize TRM.
ATRIP protects progenitor cells against DNA damagein vivo
Authors: Matos-Rodrigues Gabriel E. , Grigaravicius Paulius , Lopez Bernard S. , Hofmann Thomas , Frappart Pierre-Olivier , Martins Rodrigo A. P.
Published: February 2020

The maintenance of genomic stability during the cell cycle of progenitor cells is essential for the faithful transmission of genetic information. Mutations in genes that ensure genome stability lead to human developmental syndromes. Mutations in Ataxia Telangiectasia and Rad3-related (ATR) or in ATR-interacting protein (ATRIP) lead to Seckel syndrome, which is characterized by developmental malformations and short life expectancy. While the roles of ATR in replicative stress response and chromosomal segregation are well established, it is unknown how ATRIP contributes to maintaining genomic stability in progenitor cellsin vivo. Here, we generated the first mouse model to investigate ATRIP function. Conditional inactivation ofAtripin progenitor cells of the CNS and eye led to microcephaly, microphthalmia and postnatal lethality. To understand the mechanisms underlying these malformations, we used lens progenitor cells as a model and found that ATRIP loss promotes replicative stress and TP53-dependent cell death.Trp53inactivation inAtrip-deficient progenitor cells rescued apoptosis but increased mitotic DNA damage and mitotic defects. Our findings demonstrate an essential role of ATRIP in preventing DNA damage accumulation during unchallenged replication.
Abelson-induced phosphorylation of TACC3 modulates its interaction with microtubules and affects its impact on axon outgrowth and guidance
Authors: Erdogan Burcu , St. Clair Riley M. , Cammarata Garrett M. , Zaccaro Timothy , Ballif Bryan A. , Lowery Laura Anne
Published: February 2020

Axon guidance is a critical process in forming the connections between a neuron and its target. The growth cone steers the growing axon towards the appropriate direction by integrating extracellular guidance cues and initiating intracellular signal transduction pathways downstream of these cues. The growth cone generates these responses by remodeling its cytoskeletal components. Regulation of microtubule dynamics within the growth cone is important for making guidance decisions. TACC3, as a microtubule plus-end binding protein, modulates microtubule dynamics during axon outgrowth and guidance. We have previously shown that embryos depleted of TACC3 displayed spinal cord axon guidance defects, while TACC3-overexpressing spinal neurons showed increased resistance to Slit2-induced growth cone collapse. Here, in order to investigate the mechanism behind TACC3-mediated axon guidance, we studied the importance of tyrosine phosphorylation induced by Abelson tyrosine kinase. We find that the phosphorylatable tyrosines within the TACC domain are important for the microtubule plus-end tracking behavior of TACC3. Moreover, TACC domain phosphorylation impacts axon outgrowth and guidance, and it also regulates microtubule extension into the growth cone periphery. Together, our results suggest that phosphorylation of TACC3 is a key regulatory mechanism by which TACC3 controls axon outgrowth and pathfinding decisions of neurons during embryonic development.
Calcium homeostasis plays important roles in the internalisation and activities of the small synthetic antifungal peptide PAF26
Authors: Alexander Akira JT , Munoz Alberto , Marcos Jose F. , Read Nick D.
Published: February 2020

Fungal diseases are responsible for the deaths of over 1.5 million people worldwide annually. Antifungal peptides represent a useful source of antifungals with novel mechanisms-of-action, and potentially provide new methods of overcoming resistance. Here we investigate the mode-of-action of the small, rationally designed synthetic antifungal peptide PAF26 using the model fungusNeurospora crassa. Here we show that the cell killing activity of PAF26 is dependent on extracellular Ca2+and the presence of fully functioning fungal Ca2+homeostatic/signalling machinery. In a screen of mutants with deletions in Ca2+-signalling machinery, we identified three mutants more tolerant to PAF26. The Ca2+ATPase NCA-2 was found to be involved in the initial interaction of PAF26 with the cell envelope. The vacuolar Ca2+channel YVC-1 was shown to be essential for its accumulation and concentration within the vacuolar system. The Ca2+channel CCH-1 was found to be required to prevent the translocation of PAF26 across the plasma membrane. In the wild type, Ca2+removal from the medium resulted in the peptide remaining trapped in small vesicles as in theΔyvc-1mutant. It is therefore apparent that cell killing by PAF26 is complex and unusually dependent on extracellular Ca2+and components of the Ca2+-regulatory machinery.

AUTHOR SUMMARY

Life threatening diseases can be caused when fungi invade human tissues. These invasions often occur when a person’s immune defences are down, often due to treatments for cancer or transplantation. These infections are commonly buried deep within the body and as such are difficult to access and treat. Current medications are often highly toxic to the patient. There is also a worrying rise in drug resistance seen in fungi sampled from patients, with infections effectively untreatable – a death sentence. Antifungal peptides such as PAF26 provide a possible solution by offering a cheap and rapidly produced alternative to conventional drugs. However, unlike antibacterial peptides, little is known about how these small molecules mostly exert their effects and cause death. Using live-cell imaging and deletion mutants, this study provides an analysis of the important roles that Ca2+-homeostasis and Ca2+-signalling, and possible accompanying vacuolar fusion, play during the dynamic internalization and interaction with and within the fungal cell following PAF26 treatment.
Motor training strengthens corticospinal suppression during movement preparation
Authors: Vassiliadis Pierre , Derosiere Gerard , Grandjean Julien , Duque Julie
Published: February 2020

Training can improve motor skills and modify neural activity at rest and during movement execution. Learning-related modulations may also concern motor preparation but the neural correlates and the potential behavioral relevance of such adjustments remain unclear. In humans, preparatory processes have been largely investigated using transcranial magnetic stimulation (TMS) with several studies reporting decreased corticospinal excitability (CSE) relative to a baseline measure; a phenomenon called preparatory suppression. Here, we investigated the effect of motor training on preparatory suppression of CSE in humans, as compared to modulatory changes at rest. We trained participants to initiate quick movements in an instructed-delay reaction time (RT) task and used TMS to investigate changes in CSE over the practice blocks. Training on the task speeded up RTs, with no repercussion on error rates. Training also increased baseline CSE at rest. Most interestingly, we found that motor activity during action preparation did not mirror the training-related rise in resting CSE. Rather, the degree of preparatory suppression from the rising baseline strengthened with practice. This training-related change in preparatory suppression predicted RT gains (but not the changes in baseline CSE): subjects showing a stronger expansion of preparatory suppression were also those exhibiting larger gains in RTs. Finally, such relationship between RTs and preparatory suppression was also evident at the single-trial level: RTs were generally faster in trials where preparatory suppression was deeper. These findings suggest that training induces changes in motor preparatory processes that are linked to an enhanced ability to initiate fast movements.

New and Noteworthy

Any movement is preceded by a period of preparation, which involves a broad suppression of the corticospinal pathway, a phenomenon called preparatory suppression. Here, we show that motor training strengthens preparatory suppression and that this strengthening is associated with an acceleration of movement initiation. Our findings yield an extension of former work, highlighting a key role of preparatory suppression in training-driven behavioral improvements.
The prospective sense of agency is rooted in local and global properties of intrinsic functional brain networks
Authors: Di Plinio Simone , Gianni Perrucci Mauro , Ebisch Sjoerd J.H.
Published: February 2020

The sense of agency (SoA) refers to a constitutional aspect of the self describing the extent to which individuals feel in control over their actions and consequences thereof. Although the SoA has been associated with mental health and well-being, it is still unknown how interindividual variability in the SoA is embedded in the intrinsic brain organization. We hypothesized that the prospective component of an implicit SoA is associated with brain networks related to SoA and sensorimotor predictions on multiple spatial scales. We replicated previous findings by showing a significant prospective SoA as indicated by intentional binding effects. Then, using task-free functional magnetic resonance imaging (fMRI) and graph analysis, we analyzed associations between intentional binding effects and the intrinsic brain organization at regional, modular, and whole-brain scales. The results showed that inter-modular connections of a fronto-parietal module including the premotor cortex, supramarginal gyrus, and dorsal precuneus are associated with individual differences in prospective intentional binding. Notably, prospective intentional binding effects were also related to global brain modularity within a specific structural resolution range. These findings suggest that an implicit SoA generated through sensorimotor predictions relies on the intrinsic organization of the brain connectome on both local and global scales.
Opposite effects of choice history and stimulus history resolve a paradox of sequential choice bias
Authors: Bosch Ella , Fritsche Matthias , Ehinger Benedikt V. , de Lange Floris P
Published: February 2020

Perceptual decisions are biased towards previous decisions. Previous research suggests that this choice repetition bias is increased after previous decisions of high confidence, as inferred from response time measures (Urai et al., 2017), but also when previous decisions were based on weak sensory evidence (Akaishi et al., 2014). As weak sensory evidence is typically associated with low confidence, these previous findings appear conflicting. To resolve this conflict, we set out to investigate the effect of decision confidence on choice repetition more directly by measuring explicit confidence ratings in a motion coherence discrimination task. Moreover, we explored how choice and stimulus history jointly affect subsequent perceptual choices. We found that participants were more likely to repeat previous choices of high subjective confidence, as well as previous fast choices, confirming the boost of choice repetition with decision confidence. Furthermore, we discovered that current choices were biased away from the previous evidence direction, not previous choice, and that this effect grew with previous evidence strength. These findings point towards simultaneous biases of choice repetition, modulated by decision confidence, and adaptation, modulated by the strength of evidence, which bias current perceptual decisions in opposite directions.
Toward a comprehensive understanding of EEG and its analyses
Authors: Rocha A. F.
Published: February 2020

Background

EEG is the oldest tool for studying human cognitive function, but it is blamed to be useless because its poor spatial resolution despite it excellent temporal discrimination. Such comments arise from a reductionist point of view about the cerebral function. However, if the brain is assumed to be a distributed processing system recruiting different types of cells widely distribute over the cortex, then EEG temporal resolution and the many different tools available for its analysis, turn it the tool of choice to investigate human cognition.

Proposal

To better understand the different types of information encoded in the recorded cortical electrical activity, a clear model of the cortical structure and function of the different cortical column layers is presented and discussed. Taking this model into consideration, different available techniques for EEG analysis are discussed, under the assumption that tool combination is a necessity to provide a full comprehension of dynamics of the cortical activity supporting human cognition.

Methodology

The present approach combines many of the existing methods of analysis to extract better and richer information from the EEG, and proposes additional analysis to better characterize many of the EEG components identified by these different methods.

Analysis

Data on language understanding published elsewhere are used to illustrate how to use this combined and complex EEG analysis to disclose important details of cognitive cerebral dynamics, which reveal that cognitive neural circuits are scale free networks supporting entrainment of a large number of cortical column assemblies distributed all over the cortex.

Conclusions

Reasoning is then assumed to result from a well orchestrated large scale entrainment
Visual Attention Through Uncertainty Minimization in Recurrent Generative Models
Authors: Standvoss Kai , Quax Silvan C. , van Gerven Marcel A.J.
Published: February 2020

Allocating visual attention through saccadic eye movements is a key ability of intelligent agents. Attention is both influenced through bottom-up stimulus properties as well as top-down task demands. The interaction of these two attention mechanisms is not yet fully understood. A parsimonious reconciliation posits that both processes serve the minimization of predictive uncertainty. We propose a recurrent generative neural network model that predicts a visual scene based on foveated glimpses. The model shifts its attention in order to minimize the uncertainty in its predictions. We show that the proposed model produces naturalistic eye movements focusing on informative stimulus regions. Introducing additional tasks modulates the saccade patterns towards task-relevant stimulus regions. The model’s saccade characteristics correspond well with previous experimental data in humans, providing evidence that uncertainty minimization could be a fundamental mechanisms for the allocation of visual attention.
Bifurcation analysis of an impulsive system describing Partial Nitritation and Anammox in a hybrid reactor
Authors: Wade Matthew J. , Wolkowicz Gail S. K.
Published: February 2020

Abstract

Low-energy deammonification under mainstream conditions is a technology that has received significant attention in recent years as the water industry drives towards long-term sustainability goals. Simultaneous partial nitritation-Anammox (PN/A) is one process that can provide substantial energy reduction and lower sludge yields. Mathematical modelling of such a process offers engineers insights into the conditions for maximising the potential of PN/A. Laureniet al., Water Res. (2019) have recently published a reduced mechanistic model of the process in a sequencing batch reactor, which indicates the effect of three key operating parameters (Anammox biofilm activity, dissolved oxygen concentration and fraction of solids wasted) on performance. The analysis of the model is limited, however, to simulation with relatively few discrete parameter sets. Here, we demonstrate through the use of bifurcation theory applied to an impulsive system, that a phase space can be generated describing the continuous separation of system equilibria. Mapping process performance data onto these spaces allows engineers to target suitable operating regimes for specific objectives. Here, for example, we note that the nitrogen removal efficiency is maximised close to the trans-critical bifurcation curve denoting nitrite oxidising bacteria washout, but control of solids washout and Anammox biofilm activity can also reduce oxygen requirements whilst maintaining an appropriate Hydraulic Retention Time. The approach taken is significant given the possibility for using such a methodology for models of increasing complexity, which will enable engineers to probe the entire parameter space of systems of higher dimensionality and realism in a consistent manner.
Refinement of protein structure via contact based potentials in replica exchange simulations
Authors: Voronin Arthur , Weiel Marie , Schug Alexander
Published: February 2020

Proteins are complex biomolecules which perform critical tasks in living organisms. Knowledge of a protein’s structure is essential for understanding its physiological function in detail. Despite the incredible progress in experimental techniques, protein structure determination is still expensive, time-consuming, and arduous. That is why computer simulations are often used to complement or interpret experimental data. Here, we explore howin silicoprotein structure determination based on replica exchange molecular dynamics can benefit from including contact information derived from theoretical and experimental sources, such as direct coupling analysis or NMR spectroscopy. To reflect the influence from erroneous and noisy data we probe how false-positive contacts influence the simulated ensemble. Specifically, we integrate varying numbers of randomly selected native and non-native contacts and explore how such a bias can guide simulations towards the native state. We investigate the number of contacts needed for a significant enrichment of native-like conformations and show the capabilities and limitations of this method. Adhering to a threshold of approximately 75% true-positive contacts within a simulation, we obtain an ensemble with native-like conformations of high quality. We find that contact-guided REX MD is capable of delivering physically reasonable models of a protein’s structure.

Author summary

Protein structure prediction, that is obtaining a protein structure starting from a sequence using any computational method, is a great challenge. Over the past years a broad variety of methods evolved, ranging from algorithms for “blind” orde novopredictions using Monte-Carlo or physics-based biomolecular simulation methods to algorithms transferring structure information obtained from known homologous proteins. Recently, purely data-driven approaches using neural networks have shown to be capable of predicting high-quality structures. However, some local structural motifs are only poorly resolved and need further refinement. Here, we explore to what extent contact information helps guiding replica exchange molecular dynamics towards the native fold. By adding a contact pair bias potential to the energy function, we effectively guide the search towards the target structure by narrowing the conformational space to be sampled. We find that such an energetic bias, even if containing false-positive contacts to a certain extent, greatly enhances the refinement process and improves the chance of finding the native state in a single run.
Buffering and total calcium levels determine the presence of oscillatory regimes in cardiac cells
Authors: Marchena M. , Echebarria Blas , Shiferaw Yohannes , Alvarez-Lacalle Enrique
Published: February 2020

Calcium oscillations and waves are often behind instances of extra depolarization in cardiac cells, eventually giving rise to life-threatening arrhythmias. In this work, we study the conditions for the appearance of calcium oscillations in both a detailed subcellular model of calcium dynamics and a minimal model that takes into account just the minimal ingredients of the calcium toolkit. To avoid the effects of homeostatic changes and the interaction with the action potential we consider the somewhat artificial condition of a cell without pacing and with no calcium exchange with the extracellular medium. This permits us to isolate the main reasons responsible for the oscillations by controlling externally the total calcium content of the cell. We find that as the calcium content is increased, the system transitions between two stationary states, corresponding to one with closed ryanodine receptors (RyR) and most calcium in the cell stored in the sarcoplasmic reticulum (SR), and another, with open RyRs and a depleted SR. In between these states, calcium oscillations may appear. This transition depends very sensitively in the amount of buffering in the cell. We find, for instance, that at high values of calsequestrin (CSQ) oscillations disappear, while they are present for a broad range of parameters at low values of CSQ. Using the minimal model, we can relate the stability of the oscillating state to the nullcline structure of the system, and find that its range of existence is bounded by a homoclinic and a Hopf bifurcation.

Author summary

In cardiac cells, calcium plays a very important role. An increase in calcium levels is the trigger used by the cell to initiate contraction. Besides, calcium modulates several transmembrane currents, affecting the cell transmembrane potential. Thus, dysregulations in calcium handling have been associated with the appearance of arrhythmias. Often, this dysregulation results in the appearance of periodic calcium waves or global oscillations, providing a pro-arrhythmic substrate. In this paper, we study the onset of calcium oscillations in cardiac cells using both a detailed subcellular model of calcium dynamics and a minimal model that takes into account just the minimal ingredients of the calcium toolkit. Both reproduce the main experimental results and link this behavior with the presence of different steady-state solutions and bifurcations that depend on the total amount of calcium in the cell and in the level of buffering present. We expect that this work will help to clarify the conditions under which calcium oscillations appear in cardiac myocytes and, therefore, will represent a step further in the understanding of the origin of cardiac arrhythmias.
Unstructured mRNAs form multivalent RNA-RNA interactions to generate TIS granule networks
Authors: Ma Weirui , Zhen Gang , Xie Wei , Mayr Christine
Published: February 2020

The TIS granule network is a constitutively expressed membraneless organelle that concentrates mRNAs with AU-rich elements and interacts with the major site of protein synthesis, the rough endoplasmic reticulum. Most known biomolecular condensates are sphere-like, but TIS granules have a mesh-like morphology. Throughin vivoandin vitroreconstitution experiments we discovered that this shape is generated by extensive intermolecular RNA-RNA interactions. They are mostly accomplished by mRNAs with large unstructured regions in their 3′UTRs that we call intrinsically disordered regions (IDRs). As AU-rich RNA is a potent chaperone that suppresses protein aggregation and is overrepresented in mRNAs with IDRs, our data suggests that TIS granules concentrate mRNAs that assist protein folding. In addition, the proximity of translating mRNAs in TIS granule networks may enable co-translational protein complex formation.
Differentiating the Roles of UL16, UL21 and Us3 in the Nuclear Egress of Herpes Simplex Virus Capsids
Authors: Gao Jie , Finnen Renée L. , Sherry Maxwell R. , Le Sage Valerie , Banfield Bruce W.
Published: February 2020

Previous studies from our laboratory established that pUL16 and pUL21 are required for efficient nuclear egress of herpes simplex type 2 (HSV-2) capsids. To better understand the role of these proteins in nuclear egress, we wished to establish whether nuclear egress complex (NEC) localization and/or function was altered in the absence of either pUL16 or pUL21. We used antiserum raised against HSV-2 NEC components pUL31 and pUL34 to examine NEC localization by immunofluorescence microscopy. NEC localization in cells infected with pUL16 deficient viruses was indistinguishable from that observed in cells infected with wild type viruses. By contrast, NEC localization was found to be aberrant in cells infected with pUL21 deficient virus and, instead, showed some similarity to the aberrant NEC localization pattern observed in cells infected with pUs3 deficient virus. These results indicated that pUL16 plays a role in nuclear egress that is distinct from that of pUL21 and pUs3. Higher resolution examination of nuclear envelope ultrastructure in cells infected with pUL21 deficient viruses by transmission electron microscopy showed different types of nuclear envelope perturbations, including some that were not observed in cells infected with pUs3 deficient virus. The formation of the nuclear envelope perturbations observed in pUL21 deficient virus infections was found to be dependent on a functional NEC, revealing a novel role for pUL21 in regulating NEC activity. The results of comparisons of nuclear envelope ultrastructure in cells infected with viruses lacking pUs3, pUL16 or both pUs3 and pUL16 were consistent with a role for pUL16 upstream of primary capsid envelopment and shed new light on how pUs3 functions in nuclear egress.

Author summary

The membrane deformation activity of the herpesvirus nuclear egress complex (NEC), allows viral capsids to transit from their site of assembly in the nucleus through both nuclear membranes into the cytoplasm. The timing, extent and directionality of NEC activity must be precisely controlled during viral infection, yet our knowledge of how NEC activity is controlled is incomplete. To determine how pUL16 and pUL21, two viral proteins required for nuclear egress of herpes simplex virus type 2 (HSV-2) capsids, function to promote nuclear egress, we examined how the lack of each protein impacted NEC localization. These analyses revealed a function of pUL16 in nuclear egress that is distinct from that of pUL21, uncovered a novel role for pUL21 in regulating NEC activity and shed new light on how a viral kinase, pUs3, regulates nuclear egress. Nuclear egress of viral capsids is a common feature of the replicative cycle of all herpesviruses. A complete understanding of all aspects of nuclear egress, including how viral NEC activity is controlled, may yield strategies to disrupt this process that could be applied to the development of herpes-specific antiviral drugs.
Client processing is altered by novel myopathy-causing mutations in the HSP40 J domain
Authors: Pullen Melanie Y. , Weihl Conrad C. , True Heather L.
Published: February 2020

The misfolding and aggregation of proteins is often implicated in the development and progression of degenerative diseases. Heat shock proteins (HSPs), such as the ubiquitously expressed Type II Hsp40 molecular chaperone, DNAJB6, assist in protein folding and disaggregation. Historically, mutations within the DNAJB6 G/F domain have been associated with Limb-Girdle Muscular Dystrophy type 1D, now referred to as LGMDD1, a dominantly inherited degenerative disease. Recently, novel mutations within the J domain of DNAJB6 have been reported in patients with LGMDD1. Since novel myopathy-causing mutations in the Hsp40 J domain have yet to be characterized and both the function of DNAJB6 in skeletal muscle and the clients of this chaperone are unknown, we set out to assess the effect of these mutations on chaperone function using the genetically tractable yeast system. The essential yeast Type II Hsp40, Sis1, is homologous to DNAJB6 and is involved in the propagation of yeast prions. Using phenotypic, biochemical, and functional assays we found that homologous mutations in the Sis1 J domain differentially alter the processing of specific yeast prion strains, as well as a non-prion substrate. These data suggest that the newly-identified mutations in the J domain of DNAJB6 cause aberrant chaperone function that leads to the pathogenesis in LGMDD1.
Optimum Threshold Minimizes Noise in Timing of Intracellular Events
Authors: Kannoly Sherin , Gao Tianhui , Dey Supravat , Wang Ing-Nang , Singh Abhyudai , Dennehy John J.
Published: February 2020

How the noisy expression of regulatory proteins affects timing of intracellular events is an intriguing fundamental problem that influences diverse cellular processes. Here we use the bacteriophage λ to study event timing in individual cells where cell lysis is the result of expression and accumulation of a single protein (holin) in theEscherchia colicell membrane up to a critical threshold level. Site-directed mutagenesis of the holin gene was used to generate phage variants that vary in their timing of lysis from 30 to 190 min. Observation of the lysis times of single cells reveals an intriguing finding – the noise in lysis timing first decreases with increasing lysis time to reach a minimum, and then sharply increases at longer longer lysis times. A mathematical model with stochastic expression of holin together with dilution from cell growth was sufficient to explain the non-monotonic noise profile, and identify holin accumulation thresholds that generate precision in lysis timing.
A novel function of sphingosine kinase 2 in the metabolism of sphinga-4,14-diene lipids
Authors: Couttas Timothy A , Rustam Yepy H , Song Huitong , Qi Yanfei , Teo Jonathan D , Chen Jinbiao , Reid Gavin E , Don Anthony S
Published: February 2020

The number, position, and configuration of double bonds in lipid acyl chains affects membrane packing, fluidity, and recruitment of signalling proteins. Studies on mammalian sphingolipids have focused on those with a saturated sphinganine or mono-unsaturated sphingosine long chain base. Sphingolipids with a diunsaturated sphingadiene base have been reported but are poorly characterised. Employing high-resolution untargeted mass spectrometry, we observed marked accumulation of lipids containing a sphingadiene base, but not those with a more common sphingosine backbone, in the hippocampus of mice lacking the metabolic enzyme sphingosine kinase 2 (SphK2). Applying ultraviolet photodissociation tandem mass spectrometry (UVPD-MS/MS) the double bonds were confidently assigned to the C4-C5 and C14-C15 positions of the sphingoid base. Sphingosine kinases are involved in lysosomal catabolism of all sphingolipids, producing sphingoid base phosphates that are irreversibly degraded by sphingosine 1-phosphate lyase. Both SphK1 and SphK2 phosphorylated sphinga-4,14-diene as efficiently as sphingosine, however deuterated tracer experiments demonstrated that ceramides with a sphingosine base are more rapidly metabolised in cultured cells than those with a sphingadiene base. SphK2 silencing significantly impeded the catabolism of both sphingosine- and sphingadiene-based sphingolipids. Since SphK2 is the dominant sphingosine kinase in brain, we propose that accumulation of sphingadiene lipids in SphK2-deficient brains results from the intrinsically slower catabolism of sphingadiene lipids, combined with a bottleneck in the catabolic pathway created by the absence of SphK2. We speculate that accumulation of these lipids in the absence of SphK2 function may affect the fluidity and signalling properties of cell membranes.
Maternal arterial blood values during delivery: effect of mode of delivery, maternal characteristics, obstetric interventions and correlation to fetal umbilical cord blood
Authors: Zaigham Mehreen , Helfer Sara , Kristensen Karl Heby , Isberg Per-Erik , Wiberg Nana
Published: February 2020

Objective

To determine a reference interval for maternal arterial blood values during vaginal delivery and to elucidate the effect of common maternal characteristics and obstetric interventions on maternal acid base values during vaginal and planned cesarean section (CS).

Design

Prospective, observational study of randomly selected women undergoing vaginal deliveries and planned CS at Skåne University Hospital, Malmö, Sweden.

Results

Two hundred and fifty women undergoing vaginal delivery (VD) and fifty-eight women undergoing planned CS were recruited. We found significant differences for gestational age, parity, artery pH, pCO2, pO2, sO2and cord venous pH, pCO2and lactate between the two study groups (P< 0.005). For women undergoing vaginal delivery, we found significant changes in base deficit, hemoglobin, bilirubin, potassium, glucose and lactate values as compared to women with planned CS (P< 0.02). Maternal characteristics did not significantly affect acid base parameters however, multiple regression showed significant associations for the use of epidural anesthesia on maternal pH (P< 0.05) and pO2(P< 0.01); and synthetic oxytocin on pCO2(P= 0.08), glucose (P< 0.00) and lactate (P< 0.02) in maternal blood. Maternal arterial pH, pCO2and lactate correlated significantly to values in venous umbilical cord blood (P< 0.000).

Conclusions

Reference values for maternal arterial blood gases in vaginal deliveries for term pregnancies were outlined and we found that most arterial blood gas parameters varied significantly according to mode of delivery. The use of different obstetrical interventions like epidural anesthesia or synthetic oxytocin, resulted in significant changes in blood gas values.
Similarity between deviant peers: Developmental trends in influence and selection*
Authors: Ragan Daniel T.
Published: February 2020

The association between an adolescent's own behavior and that of his or her peers remains a key empirical finding in the study of delinquency, and this similarity is often explained in criminology by invoking processes of social influence and homophily. Adolescence is a period of rapid change for both individuals and their surroundings, however, and influence and homophily are often discussed without attending to their development over time. In the current study, I employ longitudinal social network models to estimate social influence and homophily related to alcohol and cigarette use and to determine whether there is change in the strength of these processes. Furthermore, I test whether the broader social environment conditions these processes and their observed changes. The results from this study indicate that although influence from peers decreases from early to mid‐adolescence, homophily on drinking and smoking increases. There is also evidence that school‐level opportunities and expectations affect social influence and homophily but do not account for the average changes observed in these processes.
genodive version 3.0: Easy‐to‐use software for the analysis of genetic data of diploids and polyploids
Authors: Meirmans Patrick G.
Published: February 2020

genodive version 3.0 is a user‐friendly program for the analysis of population genetic data. This version presents a major update from the previous version and now offers a wide spectrum of different types of analyses. genodive has an intuitive graphical user interface that allows direct manipulation of the data through transformation, imputation of missing data, and exclusion and inclusion of individuals, population and/or loci. Furthermore, genodive seamlessly supports 15 different file formats for importing or exporting data from or to other programs. One major feature of genodive is that it supports both diploid and polyploid data, up to octaploidy (2n = 8x) for some analyses, but up to hexadecaploidy (2n = 16x) for other analyses. The different types of analyses offered by genodive include multiple statistics for estimating population differentiation (φST, FST, FʹST, GST, GʹST, GʹʹST, Dest, RST, ρ), analysis of molecular variance‐based K‐means clustering, Hardy–Weinberg equilibrium, hybrid index, population assignment, clone assignment, Mantel test, Spatial Autocorrelation, 23 ways of calculating genetic distances, and both principal components and principal coordinates analyses. A unique feature of genodive is that it can also open data sets with nongenetic variables, for example environmental data or geographical coordinates that can be included in the analysis. In addition, genodive makes it possible to run several external programs (lfmm, structure, instruct and vegan) directly from its own user interface, avoiding the need for data reformatting and use of the command line. genodive is available for computers running Mac OS X 10.7 or higher and can be downloaded freely from: http://www.patrickmeirmans.com/software.
The preoperative platelet distribution width: A predictive factor of the prognosis in patients with non‐small cell lung cancer
Authors: Liu Chang , Zhang Hua , Qi Qi , Zhang Bin , Yue Dongsheng , Wang Changli
Published: February 2020

Background

The prognostic value of platelet distribution width (PDW) is different in various malignancies. The purpose of this study was to identify the relationship between preoperative PDW and survival in patients with non‐small cell lung cancer (NSCLC).

Methods

Optimal cutoff values of PDW were confirmed using a receiver operating characteristic (ROC) curve. The Kaplan‐Meier method and log‐rank test were used to estimate disease‐free survival (DFS) and overall survival (OS). Univariate and multivariate Cox regression models were used for prognostic analysis. The likelihood ratio test (LRT) and Akaike information criterion (AIC) were used to compare two models of the TNM staging system and the PDW‐TNM staging system (combination of PDW and the TNM staging system).

Results

Survival analysis indicated that the disease‐free survival (DFS) and overall survival (OS) of patients with PDW > 12.65 were both significantly longer than those of patients with PDW ≤ 12.65. Multivariate analysis showed that PDW was an independent prognostic factor for DFS and OS. After the two prediction models were established, further LRT analysis showed that the PDW‐TNM model had a better ability to assess patient prognosis.

Conclusions

PDW might act as an independent risk factor to predict progression and prognosis. Preoperative PDW combined with the TNM staging system showed a better ability to assess the prognosis of NSCLC patients.

Key points

Our study focused on the prognostic value of preoperative PDW in 750 patients with NSCLC. We also analyzed preoperative PDW in different stages and histological subtypes systematically.

A model built by preoperative PDW combined with the TNM staging system had a better prognostic ability. LRT was used to calculate values of the goodness of fit between the model and the TNM staging system.
The safety and feasibility of intraoperative near‐infrared fluorescence imaging with indocyanine green in thoracoscopic sympathectomy for primary palmar hyperhidrosis
Authors: Pei Guotian , Liu Yanguo , Liu Qiang , Min Xianjun , Yang Yingshun , Wang Shuai , Liu Jun , Wang Jun , Huang Yuqing
Published: February 2020

Background

We investigated the safety and feasibility of intraoperative near‐infrared (NIR) imaging using indocyanine green (ICG) during sympathectomy in the management of primary palmar hyperhidrosis (PPH).

Methods

We performed a retrospective review of 142 patients (ICG group) who underwent endoscopic thoracic sympathectomy (ETS) between February 2018 and April 2019. All patients received a 5 mg/kg infusion of ICG 24 hours preoperatively. The vital signs before and after ICG injection and adverse reactions were recorded. Meanwhile, 498 patients (Non‐ICG group) who underwent ETS by normal thoracoscopy during August 2017 to April 2019 were also reviewed to compare the abnormal white blood cell (WBC) counts, alanine transaminase (ALT), aspartate transaminase (AST), blood urea nitrogen (BUN), and creatinine (Cr) levels before and after operation between two groups.

Results

For ICG group, the vital signs including body temperature, heart rate and blood pressure before and after ICG injection were stable. There was no significant difference in the abnormal WBC counts, ALT, AST, BUN, and Cr levels before and after operation between two groups. Only one patient had mild adverse reaction (0.7%) after ICG injection. The visibility rate of all sympathetic ganglions was 96.7% (1369/1415). The visibility rate from T1 to T5 was 98.23% (278/283), 98.23% (278/283), 97.17% (275/283), 95.76% (271/283), and 94.35% (267/283), respectively. There was no significant difference in the visibility rate with regard to age, gender, height, weight, body mass index, and PPH grade.

Conclusions

NIR fluorescence imaging with ICG for identifying sympathetic ganglions is relatively safe and feasible.

Key points

• Significant findings of the study.

NIR fluorescence imaging with ICG for identifying sympathetic ganglions is relatively safe and feasible.

• What this study adds.

This technology may take the place of the rib‐oriented method as standard practice for the precise localization of sympathetic ganglions, and may improve the effect of sympathectomies.
Predictive value of CD73 expression for the efficacy of immune checkpoint inhibitors in NSCLC
Authors: Ishii Hidenobu , Azuma Koichi , Kawahara Akihiko , Kinoshita Takashi , Matsuo Norikazu , Naito Yoshiko , Tokito Takaaki , Yamada Kazuhiko , Akiba Jun , Hoshino Tomoaki
Published: February 2020

Background

CD73 induces the dephosphorylation of adenosine monophosphate converting it to adenosine, enabling malignancies to escape from immune surveillance. Although CD73 overexpression has been reported to be a poor prognostic factor in several malignancies including non‐small cell lung cancer (NSCLC), its predictive relevance in NSCLC patients receiving immune checkpoint inhibitors is unknown. The present research was conducted to investigate the prognostic significance of CD73 expression in NSCLC patients receiving immune checkpoint inhibitors (ICIs).

Methods

We screened 91 patients with advanced or recurrent NSCLC who received immune checkpoint inhibitors. CD73 expression was evaluated immunohistochemically using tissue specimens obtained just before treatment with ICIs.

Results

Analysis of progression‐free survival (PFS) and overall survival (OS) in relation to several levels of CD73 expression (1%, 10%, 30%, and 50%) showed that both tended to be more favorable as expression of CD73 increased. PFS and OS were longer for patients in whom at least 50% of the tumor cells expressed CD73 than for those in whom <50% of the tumor cells did so. In patients who were positive for EGFR mutation, immune checkpoint inhibitors were significantly more effective in those with high CD73 expression, whereas CD73 expression did not significantly affect the efficacy in patients with EGFR mutation‐negative NSCLC. Furthermore, CD73 expression was predictive factor for the PFS independent of PD‐L1 expression in patients with EGFR mutation.

Conclusions

High CD73 expression may predict a favorable response to ICIs in NSCLC patients, especially those harboring EGFR mutations.

Key points

Significant findings of the study: In patients who were positive for EGFR mutation, immune checkpoint inhibitors (ICIs) were significantly more effective in those with high CD73 expression, whereas CD73 expression did not significantly affect the efficacy in patients with EGFR mutation‐negative NSCLC.

What this study adds: High CD73 expression may predict a favorable response to immune checkpoint inhibitors in NSCLC patients, especially those harboring EGFR mutations.
Cone‐beam CT radiomics features might improve the prediction of lung toxicity after SBRT in stage I NSCLC patients
Authors: Qin Qingjin , Shi Anhui , Zhang Ran , Wen Qiang , Niu Tianye , Chen Jinhu , Qiu Qingtao , Wan Yidong , Sun Xiaorong , Xing Ligang
Published: February 2020

Background

Stereotactic body radiotherapy (SBRT) is the standard care for inoperable early stage non‐small cell lung cancer (NSCLC). The purpose of our study was to investigate whether a prediction model based on cone‐beam CT (CBCT) plus pretreatment CT radiomics features could improve the prediction of tumor control and lung toxicity after SBRT in comparison to a model based on pretreatment CT radiomics features alone.

Methods

A total of 34 cases of stage I NSCLC patients who received SBRT were included in the study. The pretreatment planning CT and serial CBCT radiomics features were analyzed using the imaging biomarker explorer (IBEX) software platform. Multivariate logistic regression was conducted for the association between progression‐free survival (PFS), lung toxicity and features. The predictive capabilities of the models based on CBCT and CT features were compared using receiver operating characteristic (ROC) curves.

Results

Five CBCT features and two planning CT features were correlated with disease progression. Six CBCT features and two planning CT features were related to lung injury. The ROC curves indicated that the model based on the CBCT plus planning CT features might be better than the model based on the planning CT features in predicting lung injury. The other ROC curves indicated that the model based on the planning CT features was similar to the model based on the CBCT plus planning CT features in predicting disease progression.

Conclusions

Both pretreatment CT and CBCT radiomics features could predict disease progression and lung injury. A model with CBCT plus pretreatment CT radiomics features might improve the prediction of lung toxicity in comparison with a model with pretreatment CT features alone.

Key points

Significant findings of the study: A model with cone‐beam CT radiomics features plus pre‐treatment CT radiomics features might improve the prediction of lung toxicity after SBRT in stage I NSCLC patients.

What this study adds: In the prediction of PFS and lung toxicity in early‐stage NSCLC patients treated with SBRT, CBCT radiomics could be another effective method.