bluuebunny/crossref_metadata_2025 huggingface dataset:
Deletion of Autophagy geneATG1and F-box motif encoding geneYDR131Ctogether leads to Synthetic Growth Defects and Flocculation behaviour inSaccharomyces cerevisiae
Authors: Shoket Heena , Parvez Sadia , Sharma Meenu , Pandita Monika , Sharma Vishali , Kumar Prabhat , Bairwa Narendra K
Published: March 2020

F-box motif encodingYDR131Cis functionally uncharacterized gene which forms the complex with the SCF-E3 ligase. The F-box motif containing proteins are involved in substrate recruitment for the ubiquitination and subsequent degradation through 26S proteasome. Autophagy gene,ATG1 (ULK1in human) is a well conserved serine-threonine kinase, required for vesicle formation and cytoplasm to vacuole targeting pathway. Atg1p forms the complex with Atg13p and Atg17p during autophagy. The understanding of crosstalk between ubiquitin and autophagy pathways is crucial for synthetic lethality screen and drug targeting. Here we have conducted the study for genetic interaction between uncharacterizedYDR131CandATG1 gene representing both specific and non-specific protein degradation pathways. The single and double gene knockout strains ofYDR131CandATG1genes were constructed in the BY4741 genetic background and analysed for growth fitness. The strains were also evaluated for cellular growth response in presence of hydroxyurea (HU), methyl methane sulfonate (MMS), and hydrogen peroxide (H2O2) stress causing agents by spot assay. Theydr131cΔatg1Δshowed the synthetic growth defect phenotype with floc formation in rich medium which showed floc disruption in presence of EDTA. Theydr131cΔatg1Δcells showed the sensitivity to stress agents HU, MMS, and H2O2when compared withydr131cΔ, atg1Δ, and WT cells.. Based on the observations, we report thatYDR131CandATG1functions in parallel pathways for growth fitness and cellular growth response to stress agents. Interestingly this study also revealed the crosstalk between ubiquitination and autophagy pathways. The defects in both the pathways could lead to synthetic growth defects which may have implication for the precision medicine initiatives.
FastField: An Open-Source Toolbox for Efficient Approximation of Deep Brain Stimulation Electric Fields
Authors: Baniasadi Mehri , Proverbio Daniele , Gonçalves Jorge , Hertel Frank , Husch Andreas
Published: March 2020

Deep brain stimulation (DBS) is a surgical therapy to alleviate symptoms of certain brain disorders by electrically modulating neural tissues. Computational models predicting electric fields and volumes of tissue activated are key for efficient parameter tuning and network analysis. Currently, we lack efficient and flexible software implementations supporting complex electrode geometries and stimulation settings. Available tools are either too slow (e.g. finite element method–FEM), or too simple, with limited applicability to basic use-cases. This paper introduces FastField, an efficient open-source toolbox for DBS electric field and VTA approximations. It computes scalable e-field approximations based on the principle of superposition, and VTA activation models from pulse width and axon diameter. In benchmarks and case studies, FastField is solved in about 0.2s, ~ 1000 times faster than using FEM. Moreover, it is almost as accurate as using FEM: average Dice overlap of 92%, which is around typical noise levels found in clinical data. Hence, FastField has the potential to foster efficient optimization studies and to support clinical applications.
Quantifying flight aptitude variation in wildA. gambiaes.l. in order to identify long-distance migrants
Authors: Faiman Roy , Yaro Alpha S. , Diallo Moussa , Dao Adama , Djibril Samake , Sanogo Zana L. , Sullivan Margery , Krishna Asha , Krajacich Benjamin J. , Lehmann Tovi
Published: March 2020

Background

In the West African Sahel, during the 5-7 month-long dry season mosquito reproduction is halted due to the absence of surface waters required for larval development. Recent studies have suggested that bothAnopheles gambiaes.s andA. arabiensispersist in this region by migration from distant locations where larval sites are perennial, andA. coluzziiengages in long-distance migration, presumably within the Sahel, following shifting resources due to the ever-changing patterns of Sahelian rainfall. Understanding mosquito migration is key to malaria control, a disease that still kills >400,000 people, mostly children in Africa.

Methods

We used a new tethered-flight assay to characterize flight in the three primary malaria vectors mentioned above and evaluated seasonal differences in their flight activity. The flight of tethered wild mosquitoes was audio-recorded from 21:00h to 05:00h in the following morning and three flight aptitude indices were examined: total flight duration, longest flight bout, and the number of flight bouts during the assay. Based on recent studies, we predicted that(i)the distribution of the flight aptitude indices would exhibit bi-modality and/or marked skewness, indicating a subpopulation of high flight activity (HFA) associated with long-distance migrants, in contrast to low flight activity (LFA) in appetitive flyers. Additionally, flight aptitude would(ii)increase in the wet season, (iii) increase in gravid females, and(iv)vary among the vector species.

Results

The distributions of all flight indices departed sharply from a normal curve, and were strongly skewed to the right, consistent with the division of the population into a majority of LFAs and a minority of HFAs, e.g., the median total flight was 586 seconds, and its maximum value was 16,110 seconds (~4.5 h). As predicted, flight aptitude peaked in the wet season and was higher in gravid females than in non-bloodfed females. Flight aptitude was higher inA. coluzziithan inA. arabiensis, butA. gambiaes.s. was not statistically different from either. We evaluated differences in wing size and shape between LFAs and HFAs. During the wet season, wing size of HFAA. coluzziiwas larger than that of LFAs; it was wider than predicted by its length, indicating a shape change. However, no statistically significant differences were found in wings ofA. gambiaes.s. orA. arabiensis.

Conclusions

The partial agreement between the assay results and predictions suggest a degree of discrimination between appetitive flyers and long-distance migrants. Wing size and shape seems to indicate higher flight activity inA. coluzziiduring the wet season.
Speech-evoked brain activity is more robust to competing speech when it is spoken by someone familiar
Authors: Holmes Emma , Johnsrude Ingrid S.
Published: March 2020

People are much better at understanding speech when it is spoken by a familiar talker—such as a friend or partner—than when the interlocutor is unfamiliar. This provides an opportunity to examine the substrates of intelligibility and familiarity, independent of acoustics. Is the familiarity effect evident as early as primary auditory cortex, or only at later processing stages? Here, we presented sentences spoken by naturally familiar talkers (the participant’s friend or partner) and unfamiliar talkers (the friends or partners of other participants). We compared multivariate activity in speech-sensitive regions of cortex between conditions in which target sentences were presented alone and conditions in which the same target sentences were presented at the same time as a competing sentence. Using representational similarity analysis (RSA), we demonstrate that the pattern of activity evoked by a spoken sentence is less degraded by the presence of a competing sentence when it is spoken by a friend or partner than by someone unfamiliar; the results cannot be explained by acoustic differences since familiar and unfamiliar talkers were nearly identical across the group. This familiar-voice advantage is most prominent in nonprimary auditory cortical areas, along the posterior superior and middle temporal gyri. Across participants, the magnitude of the familiar-unfamiliar RSA difference correlates with the familiar-voice benefit to intelligibility. Overall, our results demonstrate that experience-driven improvements in intelligibility are associated with enhanced patterns of neural activity in nonprimary auditory cortical areas.

Significance statement

Speech is a complex signal, and we do not yet fully understand how the content of a spoken sentence is encoded in cortex. Here, we used a novel approach based on analysing multivariate activity: we compared activity evoked by highly intelligible sentences presented alone and by the same sentences presented with a competing masker. The distributed pattern of activity in speech-sensitive regions of the brain was more similar between the alone and masker conditions when the target sentence was spoken by someone familiar—the participant’s friend or partner—than someone unfamiliar. This metric correlated with the intelligibility of the familiar voice. These results imply that the spatial pattern of activity in speech-sensitive regions reflects the intelligibility of a spoken sentence.
Significance of hydrophobic and charged sequence similarities in sodium-bile acid cotransporter and vitamin D-binding protein macrophage activating factor
Authors: Zunaid Ibne Raihan , Pacini Stefania , Ruggiero Marco
Published: March 2020

Sodium-bile acid cotransporter, also denominated sodium-taurocholate cotransporting polypeptide (NTCP) is an integral membrane protein with multiple hydrophobic transmembrane domains. The third extracellular domain of NTCP presents a stretch of nine aminoacids (KGIVISLVL) that is characterized by pronounced hydrophobicity and serves as receptor for a protein, preS1, showing the hydrophobic epta-peptide sequence NPLGFFP. Vitamin D-binding protein macrophage activating factor (DBP-MAF) is a multifunctional protein that is characterized by two hydrophobic regions able to bind fatty acids and vitamin D, respectively. Here we demonstrate that NTCP and DBP-MAF show significant sequence similarities as far as hydrophobic stretches of aminoacids are concerned. Alignment of the sequence of seven aminoacids preceding the 157-KGIVISLVL-165 stretch of NTCP shows four aminoacids that are identical to those of the corresponding sequence of DBP-MAF, and two that are conserved substitutions. In addition, in the sequence of DBP-MAF that is aligned with the sequence YKGIVISLVL of NTCP, there are two contiguous negatively charged aminoacids (ED) and, in the preceding epta-peptide sequence, there are three negatively charged aminoacids (D-ED), whereas in the corresponding sequence of NTCP there are only two (D--D) that are not contiguous. This concentration of negatively charged aminoacids may be involved in binding of protein inserts characterized by high density of positively charges residues. The alternating hydrophobic and electrostatic interactions described in this paper may help elucidating the biological roles of these proteins as far as protein-protein interactions are concerned.
Early maturational emergence of adult-like emotional reactivity and anxiety after brief exposure to an obesogenic diet
Authors: Vega-Torres Julio D. , Azadian Matine , Rios-Orsini Raul , Reyes-Rivera Arsenio L. , Ontiveros-Angel Perla , Figueroa Johnny D.
Published: March 2020

Background

Emerging evidence demonstrates that diet-induced obesity disrupts corticolimbic circuits underlying emotional regulation. Studies directed at understanding how obesity alters brain and behavior are easily confounded by a myriad of complications related to obesity. This study investigated the early neurobiological stress response triggered by an obesogenic diet. Furthermore, this study directly determined the combined impact of a short-term obesogenic diet and adolescence on critical behavioral and molecular substrates implicated in emotion regulation and stress.

Methods

Adolescent (postnatal day 31) or adult (postnatal day 81) Lewis rats were fed for one week with an experimental Western-like high-saturated fat diet (WD, 41% kcal from fat) or a matched control diet (CD, 13% kcal from fat). We used the acoustic fear-potentiated startle (FPS) paradigm to determine the effects of the WD on cued fear conditioning and fear extinction. We used c-Fos mapping to determine the functional influence of the diet and stress on corticolimbic circuits.

Results

We report that one-week WD consumption was sufficient to induce fear extinction deficits in adolescent rats, but not in adult rats. We identify fear-induced alterations in corticolimbic neuronal activation and demonstrate increased prefrontal cortex CRHR1 mRNA levels in the rats that consumed the WD.

Conclusions

Our findings demonstrate that short-term consumption of an obesogenic diet during adolescence heightens behavioral and molecular vulnerabilities associated with risk for anxiety and stress-related disorders. Given that fear extinction promotes resilience, and that fear extinction principles are the foundation of psychological treatments for PTSD, understanding how obesogenic environments interact with the adolescent period to affect the acquisition and expression of fear extinction memories is of tremendous clinical relevance.

HIGHLIGHTS

Short-term WD consumption during adolescence impairs cued fear extinction memory retention in a fear-potentiated startle paradigm.

Short-term WD consumption during adolescence attenuates neuronal activation to electric footshock stress in the basomedial nuclei of the amygdala.

Short-term WD consumption increases CRHR1 mRNA levels in the medial prefrontal cortex.

Adult LEW rats exhibit increased basal HPA axis tone and heightened emotional reactivity to footshock stress relative to adolescent rats.
Serological detection of 2019-nCoV respond to the epidemic: A useful complement to nucleic acid testing
Authors: Zhang Jin , Liu Jianhua , Li Na , Liu Yong , Ye Rui , Qin Xiaosong , Zheng Rui
Published: March 2020

Background

Pneumonia caused by 2019 novel coronavirus (2019-nCoV) was first reported in Wuhan, Hubei Province, China in December 2019. Then it has been reported in more than 20 countries and regions overseas rapidly. More than eighty thousand cases have been infected, resulting in more than three thousand deaths. Due to the limitation of nucleic acid detection, many clinical suspected cases cannot be diagnosed in time.

Methods

We used automated chemiluminescent immunoassay to detect serum IgM and IgG antibodies to 2019-nCoV of 736 subjects including confirmed Corona Virus Disease 2019 (COVID-19) patients, non-COVID-19 fever patients, other disease patients and medical staff as well as healthy people. The dynamic process of antibody production in COVID-19 disease progression were analyzed, and the value of antibody detection in the laboratory diagnosis of COVID-19 were evaluated.

Results

COVID-19 patients were becoming reactive(positive) for specific anti-2019-nCoV IgM antibodies from 7-12 days after the onset of morbidity, followed closely by the IgG. The levels of specific IgM and IgG antibodies increased with the progression of the disease. The trend of IgM and IgG changes in different cases is not exactly the same. The levels of IgM and IgG and their distributions in different groups were different with that of healthy people. The areas under the ROC curves for IgM and IgG to diagnose COVID-19 were 0.988 and 1.000, respectively.

Conclusions

Specific IgM or IgG antibody detection had good sensitivity and specificity for the diagnosis of suspected fever cases. Detection of specific antibodies in patients with fever can be a good distinction between COVID-19 and other diseases in low epidemic area.
Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection
Authors: Diao Bo , Wang Chenhui , Wang Rongshuai , Feng Zeqing , Tan Yingjun , Wang Huiming , Wang Changsong , Liu Liang , Liu Ying , Liu Yueping , Wang Gang , Yuan Zilin , Ren Liang , Wu Yuzhang , Chen Yongwen
Published: March 2020

BACKGROUND

The outbreak of a novel coronavirus (SARS-CoV-2, previously provisionally named 2019 novel coronavirus or 2019-nCoV) since December 2019 in Wuhan, China, has become an emergency of major international concern. Apart from the respiratory system, it is unclear whether SARS-CoV-2 can also directly infect other tissues such as the kidney or induce acute renal failure.

METHODS

We conducted a retrospective analysis of estimated glomerular filtration rate (eGFR) along with other clinical parameters from 85 patients with laboratory-confirmed COVID-19 admitted to a hospital in Wuhan from January 17, 2020 to March 3, 2020. Kidney tissues from six patients with postmortem examinations were analyzed by Hematoxylin and Eosin (H&E) andin situexpression of viral nucleocaspid protein (NP) antigen, immune cell markers (CD8, CD68 and CD56) and the complement C5b-9 was detected by immunohistochemistry. Moreover, the viral particles in kidneys were also investigated by transmission electronic microscope (EM).

RESULTS

27.06% (23/85) patients exhibited acute renal failure (ARF). The eldery patients and cases with comorbidities such as hypertension and heart failure more easily developed ARF (65.22%vs24.19%,p< 0.001; 69.57% vs 11.29%,p< 0.001, respectively). H&E staining demonstrated kidney tissues from postmortems have severe acute tubular necrosis and lymphocyte infiltration. Immunohistochemistry showed that SARS-CoV-2 NP antigen was accumulated in kidney tubules. EM observation also demonstrated that viruses-like particles are visible in the kidneys. Viral infection not only induces CD68+macrophages infiltrated into tubulointerstitium, but also enhances complement C5b-9 deposition on tubules.

CONCLUSIONS

SARS-CoV-2 induces ARF in COVID-19 patients. Viruses directly infect human kidney tubules to induce acute tubular damage. The viruses not only have direct cytotoxicity, but also initiate CD68+macrophage together with complement C5b-9 deposition to mediate tubular pathogenesis.
Differential virulence contributions of the efflux transporter MexAB-OprM inPseudomonas syringaeinfecting a variety of host plants
Authors: Helmann Tyler C. , King Dana M. , Lindow Steven E.
Published: March 2020

Efflux transporters such as MexAB-OprM contribute to bacterial resistance to diverse antimicrobial compounds. Here, we show that MexB contributes to epiphytic and apoplastic growth ofPseudomonas syringaestrain B728a, as well as lesion formation in common bean (Phaseolus vulgaris). While amexBdeletion mutant formed fewer lesions after topical application to common bean, these lesions contain the same number of cells (105to 107cells) as those caused by the wild-type strain. The internalized population size of both the WT and the MexB mutant within small segments of surface-sterilized asymptomatic portions of the leaves varied from undetectably low to as high as 105cells/cm2. Localized populations of bacteria within the leaf must apparently exceed a threshold size of about 105cells/cm2in order for a visible lesion to form. Strain B728a was capable of moderate to extensive apoplastic growth in diverse host plants including lima bean (P. lunatus), fava bean (Vicia faba), pepper (Capsicum annuum),Nicotiana benthamiana, sunflower (Helianthus annuus), and tomato (Solanum lycopersicum). MexB was not required for growth in a subset of these plant species, and in which the duration of growth after inoculation was longer, indicating apparent variation in onset time or magnitude of plant chemical defenses among those hosts. The use of a hyper-susceptible efflux pump mutant strain is an informative strategy to explore the diversity of host chemical immune responses.
Computing and Optimizing Over All Fixed-Points of Discrete Systems on Large Networks
Authors: Riehl James R. , Zimmerman Maxwell I. , Singh Matthew F. , Bowman Gregory R. , Ching ShiNung
Published: March 2020

Equilibria, or fixed points, play an important role in dynamical systems across various domains, yet finding them can be computationally challenging. Here, we show how to efficiently compute all equilibrium points of discrete-valued, discrete-time systems on sparse networks. Using graph partitioning, we recursively decompose the original problem into a set of smaller, simpler problems that are easy to compute, and whose solutions combine to yield the full equilibrium set. This makes it possible to find the fixed points of systems on arbitrarily large networks meeting certain criteria. This approach can also be used without computing the full equilibrium set, which may grow very large in some cases. For example, one can use this method to check the existence and total number of equilibria, or to find equilibria that are optimal with respect to a given cost function. We demonstrate the potential capabilities of this approach with examples in two scientific domains: computing the number of fixed points in brain networks and finding the minimal energy conformations of lattice-based protein folding models.
Implementation of a pre- and in-scan system to minimize head motion in pediatric participants undergoing fMRI scans
Authors: Horien Corey , Fontenelle Scuddy , Joseph Kohrissa , Powell Nicole , Nutor Chaela , Fortes Diogo , Butler Maureen , Powell Kelly , Macris Deanna , Lee Kangjoo , McPartland James C. , Volkmar Fred R. , Scheinost Dustin , Chawarska Katarzyna , Constable R. Todd
Published: March 2020

Background

Performing fMRI scans of children can be a difficult task, as participants tend to move while being scanned. Head motion represents a significant confound in functional magnetic resonance imaging (fMRI) connectivity analyses, and methods to limit the impact of movement on data quality are needed. One approach has been to use shorter MRI protocols, though this potentially reduces the reliability of the results.

Objective

Here we describe steps we have taken to limit head motion in an ongoing fMRI study of children undergoing a 60 minute MRI scan protocol. Specifically, we have used a mock scan protocol that trains participants to lie still while being scanned. We provide a detailed protocol and describe other in-scanner measures we have implemented, including an incentive system and the use of a weighted blanket.

Materials and methods

Participants who received a formal mock scan (n = 12) were compared to participants who had an informal mock scan (n = 7). A replication group of participants (n = 16), including five with autism spectrum disorder, who received a formal mock scan were also compared to the informal mock scan group. The primary measure of interest was the mean frame-to-frame displacement across eight functional runs during the fMRI protocol.

Results

Participants in the formal mock scan and replication group tended to exhibit more low-motion functional scans than the informal mock scan group (P< 0.05). Across different functional scan conditions (i.e. while watching movie clips, performing an attention task, and during resting-state scans), effect sizes tended to be large (Hedge’sg> 0.8).

Conclusion

Results indicate that with appropriate measures, it is possible to achieve low-motion fMRI data in younger participants undergoing a long scan protocol.
Aberrant Sensory Encoding in Patients with Autism
Authors: Noel Jean-Paul , Zhang Ling-Qi , Stocker Alan A. , Angelaki Dora E.
Published: March 2020

Perceptual anomalies in patients with Autism Spectrum Disorder (ASD) have been attributed to irregularities in the Bayesian interpretation (i.e., decoding) of sensory information. Here we show that how sensory information is encoded and adapts to changing stimulus statistics also characteristically differs between healthy and ASD groups. In a visual estimation task, we extracted the accuracy of sensory encoding directly from psychophysical data, bypassing the decoding stage by using information theoretic measures. Initially, sensory representations in both groups reflected the statistics of visual orientations in natural scenes, but encoding capacity was overall lower in the ASD group. Exposure to an artificial statistical distribution of visual orientations altered the sensory representations of the control group toward the novel experimental statistics, while also increasing their total encoding resources. Neither total encoding resources nor their allocation changed significantly in the ASD group. Most interestingly, across both groups the adaptive re-allocation of encoding resources was correlated with subjects’ initial encoding capacity. These findings suggest that neural encoding resources are limited in ASD, and this limitation may explain their reduced perceptual flexibility.
LRP5 promotes adipose progenitor cell fitness and adipocyte insulin sensitivity
Authors: Loh Nellie Y. , Vasan Senthil K. , Verma Manu , Wesolowska-Andersen Agata , Neville Matt J. , Osmond Clive , Gregson Celia L. , Karpe Fredrik , Christodoulides Constantinos
Published: March 2020

WNT signalling is a developmental pathway which plays an important role in post-natal bone accrual. We have previously shown, that in addition to exhibiting extreme high bone mass, subjects with rare gain-of-function (GoF) mutations in the WNT co-receptor LRP5 also display increased lower-body fat mass. Here, we demonstrate using human physiological studies in GoF LRP5 mutation carriers and glucose uptake assays in LRP5 knockdown (KD) adipocytes that LRP5 promotes adipocyte insulin sensitivity. We also show that a low frequency missense variant in LRP5 shown to be associated with low heel bone mineral density in a genome wide association study meta-analysis, is associated with reduced leg fat mass. Finally, using genome wide transcriptomic analyses andin vitrofunctional studies in LRP5-KD adipose progenitors (APs) we demonstrate that LRP5 plays an essential role in maintaining AP fitness i.e. functional characteristics. Pharmacological activation of LRP5 signalling in adipose tissue provides a promising strategy to prevent the redistribution of adipose tissue and metabolic sequela associated with obesity and ageing.
Ankhd1enhances polycystic kidney disease development via promoting proliferation and fibrosis
Authors: Patera Foteini , Hautbergue Guillaume M , Wilson Patricia , Evans Paul C , Ong Albert CM , Fragiadaki Maria
Published: March 2020

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common genetic kidney disorder resulting in 10% of patients with renal failure. The molecular events responsible for the relentless growth of cysts are not defined. Thus, identification of novel drivers of ADPKD may lead to new therapies. Ankyrin Repeat and Single KH domain-1 (ANKHD1) controls cancer cell proliferation, yet its role in ADPKD is unexplored. Here, we present the first data that identify ANKHD1 as a driver of proliferative growth in cellular and mouse models of ADPKD. Using the firstAnkhd1-deficient mice, we demonstrate thatAnkhd1heterozygosity potently reduces cystic growth and fibrosis, in a genetically orthologous mouse model of ADPKD. We performed transcriptome-wide profiling of patient-derived ADPKD cells with and without ANKHD1 siRNA silencing, revealing a major role for ANKHD1 in the control of cell proliferation and matrix remodelling. We validated the role of ANKHD1 in enhancing proliferation in patient-derived cells. Mechanistically ANKHD1 promotes STAT5 signalling in ADPKD mice. Hence, ANKHD1 is a novel driver of ADPKD, and its inhibition may be of therapeutic benefit.
Fluoxetine treatment prevents cardiovascular changes in baroreflex and chemoreflex in rats subjected to chronic stress
Authors: Firmino Egidi Mayara Silva , Kuntze Luciana Bärg , Lagatta Davi Campos , Dias Daniel Penteado Martins , Resstel Leonardo Barbosa Moraes
Published: March 2020

Stress may influence the autonomic regulation, pathogenesis of cardiovascular disease and play an important role in animal behavior as depression. Depression is evidenced as a significant risk factor for cardiovascular changes. This is of great importance as some studies show an association between symptoms of depression and increased risk of cardiovascular disease (CVD) morbidity. Additionality, those alterations can be alleviated by use of antidepressants such as fluoxetine, which is a selective serotonin reuptake inhibitor (SSRIs). The link between depression and cardiovascular changes is known to be mediated in part by autonomic mechanisms that contribute to the regulation of cardiovascular function. However, studies on the effects of SSRIs on cardiovascular autonomic function are inconsistent. Thus, in the present study we investigated, in adult male rats, the effect of chronic and acute treatment with fluoxetine on changes in autonomic mechanisms of baroreflex and chemoreflex induced by the repeated restraint stress (RRS) or chronic variable stress (CVS) on baroreflex and chemoreflex in a protocol of 14 days of stress sessions. The results found demonstrated that exposure to chronic stress (RRS and CVS) promove changes on cardiovascular and ventilatory responses controlled by autonomic reflexes, such as baroreflex and chemoreflex. Additionality, that chronic fluoxetine treatment for 21 days was able to prevent not only anhedonic behavior, but also of autonomic changes cardiovascular induced by chronic stress. Taken together, our results show that pharmacological treatment with fluoxetine may be also helpful to prevent cardiovascular events on account of depressive states, by correcting alterations in autonomic function.
Effects of arousal and movement on secondary somatosensory and visual thalamus
Authors: Petty Gordon H. , Kinnischtzke Amanda K. , Hong Y. Kate , Bruno Randy M.
Published: March 2020

All neocortical sensory areas have an associated primary and secondary thalamic nucleus. While the primary nuclei encode sensory information for transmission to cortex, the nature of information encoded in secondary nuclei is poorly understood. We recorded juxtasomally from neurons in secondary somatosensory (POm) and visual (LP) thalamic nuclei of awake head-fixed mice with simultaneous whisker tracking and pupilometry. POm activity correlated with whether or not a mouse was whisking, but not precise whisking kinematics. This coarse movement modulation persisted after unilateral paralysis of the whisker pad and thus was not due to sensory reafference. POm continued to track whisking even during optogenetic silencing of primary somatosensory and motor cortex and after lesion of superior colliculus, indicating that motor efference copy cannot explain the correlation between movement and POm activity. Whisking and pupil dilation were strongly correlated, raising the possibility that POm may track arousal rather than movement. LP, being part of the visual system, is not expected to encode whisker movement. We discovered, however, that LP and POm track whisking equally well, suggesting a global effect of arousal on both nuclei. We conclude that secondary thalamus is a monitor of behavioral state, rather than movement, and may exist to alter cortical activity accordingly.
PhyloFold: Precise and Swift Prediction of RNA Secondary Structures to Incorporate Phylogeny among Homologs
Authors: Tagashira Masaki
Published: March 2020

Motivation

Thesimultaneous consideration of sequence alignment and RNA secondary structure, or structural alignment, is known to help predict more accurate secondary structures of homologs. However, the consideration is heavy and can be done only roughly to decompose structural alignments.

Results

The PhyloFold method, which predicts secondary structures of homologs considering likely pairwise structural alignments, was developed in this study. The method shows the best prediction accuracy while demanding comparable running time compared to conventional methods.

Availability

The source code of the programs implemented in this study is available on “https://github.com/heartsh/phylofold” and “https://github.com/heartsh/phyloalifold“.

Contact

“tagashira_masaki_17@stu-cbms.k.u-tokyo.ac.jp”.

Supplementary information

Supplementary data are available.
Space-time logic of liver gene expression at sublobular scale
Authors: Droin Colas , Kholtei Jakob El , Halpern Keren Bahar , Hurni Clémence , Rozenberg Milena , Muvkadi Sapir , Itzkovitz Shalev , Naef Felix
Published: March 2020

The mammalian liver performs key physiological functions for maintaining energy and metabolic homeostasis. Liver tissue is both spatially structured and temporally orchestrated. Hepatocytes operate in repeating anatomical units termed lobules and different lobule zones perform distinct functions. The liver is also subject to extensive temporal regulation, orchestrated by the interplay of the circadian clock, systemic signals and feeding rhythms. Liver zonation was previously analyzed as a static phenomenon and liver chronobiology at the tissue level. Here, we use single-cell RNA-seq to investigate the interplay between gene regulation in space and time. Categorizing mRNA expression profiles using mixed-effect models and smFISH validations, we find that many genes in the liver are both zonated and rhythmic, most of them showing multiplicative space-time effects. Such dually regulated genes cover key hepatic functions such as lipid, carbohydrate and amino acid metabolism, but also genes not previously associated with liver zonation such as chaperones. Our data also suggest that rhythmic and localized expression of Wnt targets could be explained by rhythmically expressed Wnt ligands from non-parenchymal cells near the central vein. Core circadian clock genes are expressed in a non-zonated manner, indicating that the liver clock is robust to zonation. Together, our comprehensive scRNA-seq analysis revealed how liver function is compartmentalized spatio-temporally at the sub-lobular scale.
ICELLNET: a transcriptome-based framework to dissect intercellular communication
Authors: Noël Floriane , Massenet-Regad Lucile , Carmi-Levy Irit , Cappuccio Antonio , Grandclaudon Maximilien , Trichot Coline , Kieffer Yann , Mechta-Grigoriou Fatima , Soumelis Vassili
Published: March 2020

Cell-to-cell communication can be inferred from ligand-receptor expression in cell transcriptomic datasets. However, important challenges remain: 1) global integration of cell-to-cell communication, 2) biological interpretation, and 3) application to individual cell population transcriptomic profiles. We developed ICELLNET, a transcriptomic-based framework integrating: 1) an original expert-curated database of ligand-receptor interactions accounting for multiple subunits expression, 2) quantification of communication scores, 3) the possibility to connect a cell population of interest with 31 reference human cell types (BioGPS), and 4) three visualization modes to facilitate biological interpretation. We applied ICELLNET to uncover different communication in breast cancer associated fibroblast (CAF) subsets. ICELLNET also revealed autocrine IL-10 as a switch to control human dendritic cell communication with up to 12 other cell types, four of which were experimentally validated. In summary, ICELLNET is a global, versatile, biologically validated, and easy-to-use framework to dissect cell communication from single or multiple cell-based transcriptomic profile(s).
redPATH: Reconstructing the Pseudo Development Time of Cell Lineages in Single-Cell RNA-Seq Data and Applications in Cancer
Authors: Xie Kaikun , Liu Zehua , Chen Ning , Chen Ting
Published: March 2020

Recent advancement of single-cell RNA-seq technology facilitates the study of cell lineages in developmental processes as well as cancer. In this manuscript, we developed a computational method, called redPATH, to reconstruct the pseudo developmental time of cell lineages using a consensus asymmetric Hamiltonian path algorithm. Besides, we implemented a novel approach to visualize the trajectory development of cells and visualization methods to provide biological insights. We validated the performance of redPATH by segmenting different stages of cell development on multiple neural stem cell and cancerous datasets, as well as other single-cell transcriptome data. In particular, we identified a subpopulation of malignant glioma cells, which are stem cell-like. These cells express known proliferative markers such asGFAP(also identifiedATP1A2,IGFBPL1,ALDOC) and remain silenced in quiescent markers such asID3. Furthermore,MCL1is identified as a significant gene that regulates cell apoptosis, andCSF1Rconfirms previous studies for re-programming macrophages to control tumor growth. In conclusion, redPATH is a comprehensive tool for analyzing single-cell RNA-Seq datasets along a pseudo developmental time. The software is available viahttp://github.com/tinglab/redPATH.
Exploring the upper pH limits of nitrite oxidation: diversity, ecophysiology, and adaptive traits of haloalkalitolerantNitrospira
Authors: Daebeler Anne , Kitzinger Katharina , Koch Hanna , Herbold Craig W. , Steinfeder Michaela , Schwarz Jasmin , Zechmeister Thomas , Karst Søren M. , Albertsen Mads , Nielsen Per H. , Wagner Michael , Daims Holger
Published: March 2020

Nitrite-oxidizing bacteria of the genusNitrospiraare key players of the biogeochemical nitrogen cycle. However, little is known about their occurrence and survival strategies in extreme pH environments. Here, we report on the discovery of physiologically versatile, haloalkalitolerantNitrospirathat drive nitrite oxidation at exceptionally high pH.Nitrospiradistribution, diversity, and ecophysiology were studied in hypo- and subsaline (1.3-12.8 g salt/l), highly alkaline (pH 8.9-10.3) lakes by amplicon sequencing, metagenomics, and cultivation-based approaches. Surprisingly, not only wereNitrospirapopulations detected, but they were also considerably diverse with presence of members ofNitrospiralineages I, II and IV. Furthermore, the ability ofNitrospiraenrichment cultures to oxidize nitrite at neutral to highly alkaline pH of 10.5 was demonstrated. Metagenomic analysis of a newly enrichedNitrospiralineage IV species, “CandidatusNitrospira alkalitolerans”, revealed numerous adaptive features of this organism to its extreme environment. Among them were a sodium-dependent N-type ATPase and NADH:quinone oxidoreductase next to the proton-driven forms usually found inNitrospira. Other functions aid in pH and cation homeostasis and osmotic stress defense. “Ca.Nitrospira alkalitolerans” also possesses group 2a and 3b [NiFe] hydrogenases, suggesting it can use hydrogen as alternative energy source. These results reveal howNitrospiracope with strongly fluctuating pH and salinity conditions and expand our knowledge of nitrogen cycling in extreme habitats.
Pex24 and Pex32 tether peroxisomes to the ER for organelle biogenesis, positioning and segregation
Authors: Wu Fei , de Boer Rinse , Krikken Arjen M. , Akşit Arman , Bordin Nicola , Devos Damien P. , van der Klei Ida J.
Published: March 2020

We analyzed all four Pex23 family proteins of the yeastHansenula polymorpha, which localize to the ER. Of these Pex24 and Pex32, but not Pex23 and Pex29, accumulate at peroxisome-ER contacts, where they are important for normal peroxisome biogenesis and proliferation and contribute to organelle positioning and segregation.

Upon deletion ofPEX24andPEX32- and to a lesser extent ofPEX23andPEX29- peroxisome-ER contacts are disrupted, concomitant with peroxisomal defects. These defects are suppressed upon introduction of an artificial peroxisome-ER tether.

Accumulation of Pex32 at peroxisomes-ER contacts is lost in the absence of the peroxisomal membrane protein Pex11. At the same time peroxisome-ER contacts are disrupted, indicating that Pex11 contributes to Pex32-dependent peroxisome-ER contact formation.

Summarizing, our data indicate thatH. polymorphaPex24 and Pex32 are tethers at peroxisome-ER contacts that are important for normal peroxisome biogenesis and dynamics.

TwoHansenula polymorphaER proteins, Pex24 and Pex32, are tethers at peroxisome-ER contacts and function together with the peroxisomal protein Pex11. Their absence disturbs these contacts leading to multiple peroxisomal defects, which can be restored by an artificial tether.
Isoform cell type specificity in the mouse primary motor cortex
Authors: Booeshaghi A. Sina , Yao Zizhen , van Velthoven Cindy , Smith Kimberly , Tasic Bosiljka , Zeng Hongkui , Pachter Lior
Published: March 2020

Full-length SMART-Seq single-cell RNA-seq can be used to measure gene expression at isoform resolution, making possible the identification of isoform markers for cell types and for an isoform atlas. In a comprehensive analysis of 6,160 mouse primary motor cortex cells assayed with SMART-Seq, we find numerous examples of isoform specificity in cell types, including isoform shifts between cell types that are masked in gene-level analysis. These findings can be used to refine spatial gene expression information to isoform resolution. Our results highlight the utility of full-length single-cell RNA-seq when used in conjunction with other single-cell RNA-seq technologies.
Mapping the principal gradient onto the corpus callosum
Authors: Friedrich Patrick , Forkel Stephanie J. , de Schotten Michel Thiebaut
Published: March 2020

Gradients capture some of the variance of the resting-state functional magnetic resonance imaging (rsfMRI) signal. Amongst these, the principal gradient depicts a functional processing hierarchy that spans from sensory-motor cortices to regions of the default-mode network. While the cortex has been well characterised in terms of gradients little is known about its underlying white matter. For instance, comprehensive mapping of the principal gradient on the largest white matter tract, the corpus callosum, is still missing. We hence mapped the principal gradient onto the callosal midsection using the 7T human connectome project dataset. We further explored how quantitative measures and variability in callosal midsection connectivity relate to the principal gradient values. In so doing, we demonstrated that the extreme values of the principal gradient are located within the callosal genu and the posterior body, have lower connectivity variability but a larger spatial extent along the midsection of the corpus callosum than mid-range values. Our results shed light on the relationship between the brain’s functional hierarchy and the corpus callosum. We further speculate about how these results may bridge the gap between functional hierarchy, brain asymmetries, and evolution.
Approximate k-nearest neighbors graph for single-cell Hi-C dimensional reduction with MinHash
Authors: Wolff Joachim , Backofen Rolf , Grüning Björn
Published: March 2020

Single-cell Hi-C interaction matrices are high dimensional and very sparse. To cluster thousands of single-cell Hi-C interaction matrices they are flattened and compiled into one matrix. This matrix can, depending on the resolution, have a few millions or even billions of features and any computation with it is therefore memory demanding. A common approach to reduce the number of features is to compute a nearest neighbors graph. However, the exact euclidean distance computation is inO(n2) and therefore we present an implementation of an approximate nearest neighbors method based on local sensitive hashing running inO(n). The presented method is able to process a 10kb single-cell Hi-C data set with 2500 cells and needs 53 GB of memory while the exact k-nearest neighbors approach is not computable with 1 TB of memory.
An inducible CRISPR-interference library for genetic interrogation of Saccharomyces cerevisiae biology
Authors: Momen-Roknabadi Amir , Oikonomou Panos , Zegans Maxwell , Tavazoie Saeed
Published: March 2020

Genome-scale CRISPR interference (CRISPRi) is widely utilized to study cellular processes in a variety of organisms. Despite its dominance as a model eukaryote, a genome-wide CRISPRi library, optimized for targeting the Saccharomyces cerevisiae genome, has not been presented to date. We have generated a comprehensive, inducible CRISPRi library, based on spacer design rules optimized for yeast. We have validated this library for genome-wide interrogation of gene function across a variety of applications, including accurate discovery of haploinsufficient genes and identification of enzymatic and regulatory genes involved in adenine and arginine biosynthesis. The comprehensive nature of the library also revealed parameters for optimal transcriptional repression, including upstream distance, nucleosomal occupancy, and strand bias. CRISPRi screens, using this library can identify genes and pathways with high precision and low false discovery rate across a variety of experimental conditions, enabling rapid and reliable genome-wide assessment of gene function and genetic interactions in S.cerevisiae.
Transitioning from global to local computational strategies during brain-machine interface learning
Authors: Bridges Nathaniel , Stickle Matthew , Moxon Karen
Published: March 2020

When learning to use a brain-machine interface (BMI), the brain modulates neuronal activity patterns, exploring and exploiting the state space defined by their neural manifold. Neurons directly involved in BMI control can display marked changes in their firing patterns during BMI learning. However, whether these changes extend to neurons not directly involved in BMI control remains unclear. To clarify this issue, we studied BMI learning in animals that were required to control the position of a platform with their neural signals. Animals that learned to control the platform and improved their performance in the task shifted from a global strategy, where both direct and indirect neurons modified their firing patterns, to a local strategy, where only direct neurons modified their firing rate, as animals became expert in the task. These results provide important insights into what differentiates successful and unsuccessful BMI learning and the computational mechanisms adopted by the neurons.
Practical Fluorescence Reconstruction Microscopy for Large Samples and Low-Magnification Imaging
Authors: LaChance Julienne , Cohen Daniel J.
Published: March 2020

Fluorescence reconstruction microscopy (FRM) describes a class of techniques where transmitted light images are passed into a convolutional neural network that then outputs predicted epifluorescence images. This approach enables many benefits including reduced phototoxicity, freeing up of fluorescence channels, simplified sample preparation, and the ability to re-process legacy data for new insights. However, FRM can be complex to implement, and current FRM benchmarks are abstractions that are difficult to relate to how valuable or trustworthy a reconstruction is. Here, we relate the conventional benchmarks and demonstrations to practical and familiar cell biology analyses to demonstrate that FRM should be judged in context. We further demonstrate that it performs remarkably well even with lower-magnification microscopy data, as are often collected in screening and high content imaging. Specifically, we present promising results for nuclei, cell-cell junctions, and fine feature reconstruction; provide data-driven experimental design guidelines; and provide researcher-friendly code, complete sample data, and a researcher manual to enable more widespread adoption of FRM.