bluuebunny/crossref_metadata_2025 huggingface dataset:
To buffer or to be labile? A framework to disentangle demographic patterns and evolutionary processes
Authors: Santos Gabriel Silva , Salguero-Gómez Roberto , Dias André Tavares Corrêa , Kajin Maja
Published: April 2021

Until recently, natural selection was assumed to reduce temporal fluctuation in vital rates due to its negative effects on population dynamics – the so-called Demographic Buffering Hypothesis (DBH). After several failures to support the DBH in the two decades since it was first posited, an alternative hypothesis was suggested; the Demographic Lability Hypothesis (DLH), where population vital rates should track rather than buffer the environmental conditions. Despite the huge contribution of both hypotheses to comprehend the demographic strategies to cope the environmental stochasticity, it remains unclear if they represent two competing patterns or the extreme ends of a continuum encompassing all demographic strategies. To solve this historical debate, we unify several methods with an integrative theoretical approach where: i) using the sum of stochastic elasticity with respect to mean and variance – a first-order derivative approach – we rank species on a Buffering-Lability (DB-DL) continuum and ii) using the second-order derivative, we examine how vital rates are shaped by natural selection. Our framework, applied to 40 populations of 34 mammals, successfully placed the species on the DB-DL continuum. We could also link the species' position on the DB-DL continuum to their generation time and time to recovery. Moreover, the second-order derivative unveiled that vital rates with lower temporal variation are not necessarily under a strong pressure of stabilizing selection, as predicted by DBH and DLH. Our framework provides an important step towards unifying the different perspectives of DBH and DLH with key evolutionary concepts.
Clustering single-cell RNA-seq data by rank constrained similarity learning
Authors: Mei Qinglin , Li Guojun , Su Zhengchang
Published: April 2021

Motivation

Recent breakthroughs of single-cell RNA sequencing (scRNA-seq) technologies offer an exciting opportunity to identify heterogeneous cell types in complex tissues. However, the unavoidable biological noise and technical artifacts in scRNA-seq data as well as the high dimensionality of expression vectors make the problem highly challenging. Consequently, although numerous tools have been developed, their accuracy remains to be improved.

Results

Here, we introduce a novel clustering algorithm and tool RCSL (Rank Constrained Similarity Learning) to accurately identify various cell types using scRNA-seq data from a complex tissue. RCSL considers both local similarity and global similarity among the cells to discern the subtle differences among cells of the same type as well as larger differences among cells of different types. RCSL uses Spearman’s rank correlations of a cell’s expression vector with those of other cells to measure its global similarity, and adaptively learns neighbour representation of a cell as its local similarity. The overall similarity of a cell to other cells is a linear combination of its global similarity and local similarity. RCSL automatically estimates the number of cell types defined in the similarity matrix, and identifies them by constructing a block-diagonal matrix, such that its distance to the similarity matrix is minimized. Each block-diagonal submatrix is a cell cluster/type, corresponding to a connected component in the cognate similarity graph. When tested on 16 benchmark scRNA-seq datasets in which the cell types are well-annotated, RCSL substantially outperformed six state-of-the-art methods in accuracy and robustness as measured by three metrics.

Availability

The RCSL algorithm is implemented in R and can be freely downloaded athttps://github.com/QinglinMei/RCSL.

Contact

guojunsdu@gmail.com,zcsu@uncc.edu

Supplementary information

Supplementary data are available atBioinformaticsonline.
Network dynamics scale with levels of awareness
Authors: Coppola Peter , Spindler Lennart R.B. , Luppi Andrea I. , Adapa Ram , Naci Lorina , Allanson Judith , Finoia Paola , Williams Guy B. , Pickard John D. , Owen Adrian M. , Menon David K. , Stamatakis Emmanuel A.
Published: April 2021

Small world topologies are thought to provide a valuable insight into human brain organisation and consciousness. However, functional magnetic resonance imaging studies in consciousness have not yielded consistent results. Given the importance of dynamics for both consciousness and cognition, here we investigate how the diversity of brain dynamics pertaining to small world topology (quantified by sample entropy; dSW-E) scales with decreasing levels of awareness (i.e., sedation and disorders of consciousness). Paying particular attention to result reproducibility, we show that dSW-E is a consistent predictor of levels of awareness even when controlling for the underlying functional connectivity dynamics. We find that dSW-E of subcortical and cortical areas are predictive, with the former showing higher and more robust effect sizes across analyses. Consequently, we propose that the dynamic reorganisation of the functional information architecture, in particular of the subcortex, is a characteristic that emerges with awareness and has explanatory power beyond that of the complexity of dynamic functional connectivity.
Sugar Signaling Induces Dynamic Changes during Meristem Development to Regulate Flowering in Arabidopsis
Authors: Musialak-Lange Magdalena , Fiddeke Katharina , Franke Annika , Kragler Friedrich , Abel Christin , Wahl Vanessa
Published: April 2021

Aerial parts of plants originate from pluripotent stem cells in the shoot apical meristem. Their population is maintained via the maintenance regulators WUSCHEL and CLAVATA3 in a negative feed-back loop. Meristem size is dynamic and undergoes a more than 2-fold expansion upon the transition to reproductive growth. The mechanism controlling this doming is largely unknown, but coinciding increased trehalose 6-phosphate and changed meristem size in overexpressing or knockdown lines of TREHALOSE PHOSPHATE SYNTHASE1 suggest a participation of sugar signaling. Here we show that TREHALOSE PHOSPHATE PHOSPHATASEJ is directly regulated by WUSCHEL. Plants with reduced levels of TREHALOSE PHOSPHATE PHOSPHATASEJ in the outer meristem layer are flowering early and its reduction in the late flowering clavata3 mutant, restores wild-type flowering. This is caused by a reduction of mature miR156 and increased expression of SQUAMOSA PROMOTER-BINDING PROTEIN-LIKE genes. We demonstrate that these are important for age pathway-induced flowering, in a negative feed-back loop with WUSCHEL downstream of the trehalose 6-phosphate pathway. In summary, our findings demonstrate a dynamic feed-back regulation between central maintenance and flowering time regulators with sugar signaling.
The reserve of joint torque determines movement coordination
Authors: Faity Germain , Mottet Denis , Pla Simon , Froger Jérôme
Published: April 2021

Humans coordinate biomechanical degrees of freedom to perform tasks at minimum cost. When reaching a target from a seated position, the trunk-arm-forearm coordination moves the hand to the well-defined spatial goal, while typically minimising hand jerk and trunk motion. However, due to fatigue or stroke, people visibly move the trunk more, and it is unclear what cost can account for this. Here we show that people recruit their trunk when the torque at the shoulder is too close to the maximum. We asked 26 healthy participants to reach a target while seated and we found that the trunk contribution to hand displacement increases from 11% to 27% when an additional load is handled. By flexing and rotating the trunk, participants spontaneously increase the reserve of anti-gravitational torque at the shoulder from 25% to 40% of maximal voluntary torque. Our findings provide hints on how to include the reserve of torque in the cost function of optimal control models of human coordination in healthy fatigued persons or in stroke victims.
Adaptive mossy cell circuit plasticity after status epilepticus
Authors: Butler Corwin R. , Westbrook Gary L. , Schnell Eric
Published: April 2021

Hilar mossy cells control network function in the hippocampus through both direct excitation and di-synaptic inhibition of dentate granule cells (DGCs). Substantial mossy cell loss occurs after epileptic seizures; however the contribution of surviving mossy cells to network activity in the reorganized dentate gyrus is unknown. To examine functional circuit changes after pilocarpine-induced status epilepticus, we optogenetically stimulated mossy cells in acute hippocampal slices. In control mice, activation of mossy cells produced monosynaptic excitatory and di-synaptic GABAergic currents in DGCs. In pilocarpine-treated mice, mossy cell density and excitation of DGCs were reduced in parallel, with only a minimal reduction in feedforward inhibition, enhancing the inhibition:excitation ratio. Surprisingly, mossy cell-driven excitation of parvalbumin-positive basket cells, the primary mediators of feed-forward inhibition, was maintained, indicating increased connectivity between surviving mossy cells and these targets. Our results suggest that mossy cell outputs reorganize following seizures, increasing their net inhibitory effect in the hippocampus.
Influence of Mpv17 on hair-cell mitochondrial homeostasis, synapse integrity, and vulnerability to damage in the zebrafish lateral line
Authors: Holmgren Melanie , Sheets Lavinia
Published: April 2021

Noise exposure is particularly stressful to hair-cell mitochondria, which must produce enough energy to meet high metabolic demands as well as regulate local intracellular Ca2+concentrations. Mitochondrial Inner Membrane Protein 17 (Mpv17) functions as a non-selective channel and plays a role in maintaining mitochondrial homeostasis. In zebrafish, hair cells inmpv17a9/a9mutants displayed elevated levels of reactive oxygen species (ROS), elevated mitochondrial calcium, hyperpolarized transmembrane potential, and greater vulnerability to neomycin, indicating impaired mitochondrial function. Using a strong water current to overstimulate hair cells in the zebrafish lateral line, we observedmpv17a9/a9mutant hair cells were more vulnerable to morphological disruption and hair-cell loss than wild type siblings simultaneously exposed to the same stimulus. To determine the role of mitochondrial homeostasis on hair-cell synapse integrity, we surveyed synapse number inmpv17a9/a9mutants and wild type siblings as well as the sizes of presynaptic dense bodies (ribbons) and postsynaptic densities immediately following stimulus exposure. We observed mechanically injuredmpv17a9/a9neuromasts, while they lost a greater number of hair cells, lost a similar number of synapses per hair cell relative to wild type. Additionally, we quantified the size of hair cell pre- and postsynaptic structures and observed significantly enlarged wild type postsynaptic densities, yet relatively little change in the size ofmpv17a9/a9postsynaptic densities following stimulation. These results suggest impaired hair-cell mitochondrial activity influences synaptic morphology and hair-cell survival but does not exacerbate synapse loss following mechanical injury.
Evidence provided by high-impact cell culture studies does not support authors’ claims
Authors: Özkaya Ali Burak , Geyik Caner
Published: April 2021

Background

Reliability of preclinical research is of critical concern. Previous studies demonstrate the low reproducibility in research and recommend raising standards to improve reproducibility and robustness. One understudied aspect of this quality issue is the harmony between the hypotheses and the experimental design in published work.

Methods and findings

In this study we focused on highly cited cell culture studies and investigated whether the claims of the study are backed with sufficient experimental evidence or not. We created an open access database containing all 282 claims asserted by 103 different high-impact articles as well as the results of this study. Our findings revealed that only 64% of all claims were sufficiently supported by evidence and there were concerning misinterpretations such as considering the results of tetrazolium salt reduction assays as indicators of cell death or apoptosis.

Conclusions

Our analysis revealed an alarming discordance between the actual experimental findings and the way that the manuscript is written to discuss them in highly cited cell culture studies. In order to improve quality of pre-clinical research, we require a clear nomenclature by which different cell culture claims are distinctively categorized, materials and methods sections to be written more meticulously and cell culture techniques to be selected and utilized more carefully.
fMRI Informed Montage Selection for Transcranial Electrical Stimulation: Frontoparietal Synchronization for Drug Cue Reactivity
Authors: Soleimani Ghazaleh , Kupliki Rayus , Bodurka Jerzy , Paulus Martin , Ekhtiari Hamed
Published: April 2021

Background

Frontoparietal network (FPN) with multiple cortical nodes is involved in executive functions. Transcranial electrical stimulation (tES) can potentially modulate interactions between these nodes using frontoparietal synchronization (FPS). Here we used fMRI and computational head models (CHMs) to inform electrode montage and dosage selection in FPS.

Methods

Sixty methamphetamine users completed an fMRI drug cue-reactivity task. Two sets of 4×1 HD electrodes with anode over F3 and F4 were simulated and spheres around maximum electric field in each hemisphere were defined as frontal seeds. Using frontal seeds, a task-based functional connectivity analysis was conducted based on a seed-to-whole brain generalized psychophysiological interaction (gPPI). Electrode placement for parietal sites was selected based on gPPI results. Task-based and resting-state connectivity were compared between fMRI-informed and classic F3-P3/F4-P4 montages.

Results

Whole-brain gPPI showed two significant clusters (left: 506 voxels P=0.006, right: 455 voxels P=0.016), located in the inferior parietal lobule under the CP5 and CP6 electrode location. Pair-wise ROI-based gPPI comparing informed (F3-CP5/F4-CP6) and classic (F3-P3/F4-P4) montages showed significant increased PPI and resting-state connectivity only in the informed montage. Cue-induced craving score was also correlated with left (F3-CP5) frontoparietal connectivity in the fMRI-informed montage.

Conclusion

This study proposes an analytic pipeline to select electrode montage and dosage in dual site tES using CHMs and task-based connectivity. Stimulating F3-F4 can tap into both FPN and saliency network (SN) based on the montage selection. Using CHM and fMRI will be essential to navigating ample parameter space in the stimulation protocols for future tES studies.

Highlights

We demonstrated a methodology for montage selection in network-based tES

Task-based functional connectivity can inform dual-site tES montage selection

Head models can help to induce balance tES dose in targeted brain regions

Targeting DLPFC with tES can tap into both saliency and frontoparietal networks

Lower resting-state frontoparietal connectivity before cue exposure followed by a greater craving
Ultra-fast insulin-pramlintide co-formulation for improved glucose management in diabetic rats
Authors: Maikawa Caitlin L. , Chen Peyton C. , Vuong Eric T. , Nguyen Leslee T. , Mann Joseph L. , d’Aquino Andrea I. , Lal Rayhan A. , Maahs David M. , Buckingham Bruce A. , Appel Eric A.
Published: April 2021

Dual-hormone replacement therapy with insulin and amylin in patients with type 1 diabetes has the potential to improve glucose management. Unfortunately, currently available formulations require burdensome separate injections at mealtimes and have disparate pharmacokinetics that do not mimic endogenous co-secretion. Here, we use amphiphilic acrylamide copolymers to create a stable co-formulation of monomeric insulin and amylin analogues (lispro and pramlintide) with synchronous pharmacokinetics and ultra-rapid action. The co-formulation is stable for over 16 hours under stressed aging conditions, whereas commercial insulin lispro (Humalog) aggregates in 8 hours. The faster pharmacokinetics of monomeric insulin in this co-formulation resulted in increased insulin-pramlintide overlap of 75 ± 6% compared to only 47 ± 7% for separate injections. The co-formulation resulted in similar delay in gastric emptying compared to pramlintide delivered separately. In a glucose challenge, in rats the co-formulation reduced deviation from baseline glucose compared to insulin only, or separate insulin and pramlintide administrations. Further, comparison of interspecies pharmacokinetics of monomeric pramlintide suggests that pharmacokinetics observed for the co-formulation will be well preserved in future translation to humans. Together these results suggest that the co-formulation has the potential to improve mealtime glucose management and reduce patient burden in the treatment of diabetes.
Plasma exosomal miRNA analysis of Alzheimer’s disease reveals the dysfunction of a neural network
Authors: Sun Yuzhe , Hefu Zhen , Lifang Wang , Li Benchao , Zhijie Song , Deng Yan , Zhili Liu , Ding Jiahong , Li Tao , Zhang Wenwei , Chao Nie , Rong Shuang
Published: April 2021

Exosomal microRNA (miRNA) is an emerging source for biomarkers of Alzheimer’s disease (AD). Here, we profiled miRNA expression in AD, mild cognitive impairment (MCI), and controls. The assessment and validation of differentially expressed miRNA represented their potential to be novel biomarkers for AD and MCI. We conducted 13 co-expression networks and a miRNA network module linked to neural function emerged as the most significantly associated with AD diagnosis. The conservation analysis revealed the M1 was highly preserved in controls but dysfunction in AD and MCI. The module pattern between MCI and NC was similar, but significantly differed from AD, suggesting that the neural network regulated by miRNA changed during the mild cognitive stage, and the total miRNA expression altered in AD stage. Additionally, 24 out of 26 M1 hub-miRNAs were derived from brain tissue, and 15 had been reported as AD biomarkers. We consequently proposed the other 11 miRNAs could play important roles in AD. Our study highlights that co-expression network analysis can provide a new path for finding novel biomarkers.
Host poly(A) polymerases PAPD5 and PAPD7 provide two layers of protection that ensure the integrity and stability of hepatitis B virus RNA
Authors: Liu Fei , Lee Amy C.H. , Guo Fang , Kondratowicz Andrew S. , Micolochick Steuer Holly M. , Miller Angela , Bailey Lauren D. , Wang Xiaohe , Chen Shuai , Kultgen Steven G. , Cuconati Andrea , Cole Andrew G. , Gotchev Dimitar , Dorsey Bruce D. , Rijnbrand Rene , Lam Angela M. , Sofia Michael J. , Gao Min
Published: April 2021

Noncanonical poly(A) polymerases PAPD5 and PAPD7 (PAPD5/7) stabilize HBV RNA via the interaction with the viral post-transcriptional regulatory element (PRE), representing new antiviral targets to control HBV RNA metabolism, HBsAg production and viral replication. Inhibitors targeting these proteins are being developed as antiviral therapies, therefore it is important to understand how PAPD5/7 coordinate to stabilize HBV RNA. Here, we utilized a potent small-molecule AB-452 as a chemical probe, along with genetic analyses to dissect the individual roles of PAPD5/7 in HBV RNA stability. AB-452 inhibits PAPD5/7 enzymatic activities and reduces HBsAg bothin vitro(EC50ranged from 1.4 to 6.8 nM) andin vivoby 0.93 log10. Our genetic studies demonstrate that the stem-loop alpha sequence within PRE is essential for both maintaining HBV poly(A) tail integrity and determining sensitivity towards the inhibitory effect of AB-452. Although neither single knock-out (KO) ofPAPD5norPAPD7reduces HBsAg RNA and protein production,PAPD5KO does impair poly(A) tail integrity and confers partial resistance to AB-452. In contrast,PAPD7KO could not result in any measurable phenotypic changes, but displays a similar antiviral effect as AB-452 treatment whenPAPD5is depleted simultaneously.PAPD5/7double KO confers complete resistance to AB-452 treatment. Our results thus indicate that PAPD5 plays a dominant role in stabilizing viral RNA by protecting the integrity of its poly(A) tail, while PAPD7 serves as a second line of protection. These findings inform PAPD5 targeted therapeutic strategies and open avenues for further investigating PAPD5/7 in HBV replication.

Importance

Chronic hepatitis B affects more than 250 million patients and is a major public health concern worldwide. HBsAg plays a central role in maintaining HBV persistence and as such, therapies reducing HBsAg have been extensively investigated. PAPD5/7 targeting inhibitors, with oral bioavailability, represent an opportunity to reduce both HBV RNA and HBsAg. Here we uncover that the SLα sequence is required for HBV poly(A) tail integrity and RNA stability, and that the antiviral activity of AB-452 mimics the SLα mutants. Although PAPD5 and PAPD7 regulate HBV RNA stability, it remains unclear how they coordinate in stabilizing HBV RNA. Based on our studies, PAPD5 plays a dominant role to stabilize viral RNA by protecting the integrity of its poly(A) tail, while PAPD7 serves as a backup protection mechanism. Our studies may point out a direction towards developing PAPD5-selective inhibitors that could be used effectively to treat chronic hepatitis B.
HspB8 prevents aberrant phase transitions of FUS by chaperoning its folded RNA binding domain
Authors: Boczek Edgar E. , Fürsch Julius , Jawerth Louise , Jahnel Marcus , Niedermeier Marie Laura , Ruer-Gruß Martine , Kammer Kai-Michael , Mediani Laura , Wang Jie , Yan Xiao , Pozniakovski Andrej , Poser Ina , Mateju Daniel , Carra Serena , Alberti Simon , Hyman Anthony A. , Stengel Florian
Published: April 2021

Aberrant liquid-to-solid phase transitions of biomolecular condensates have been linked to various neurodegenerative diseases. However, the underlying molecular interactions that drive aging remain enigmatic. Here, we develop quantitative time-resolved crosslinking mass spectrometry to monitor protein interactions and dynamics inside condensates formed by the protein fused in sarcoma (FUS). We identify misfolding of the RNA recognition motif (RRM) of FUS as a key driver of condensate ageing. We demonstrate that the small heat shock protein HspB8 partitions into FUS condensates via its intrinsically disordered domain and prevents condensate hardening via condensate-specific interactions that are mediated by its α-crystallin domain (αCD). These αCD-mediated interactions are altered in a disease-associated mutant of HspB8, which abrogates the ability of HspB8 to prevent condensate hardening. We propose that stabilizing aggregation-prone folded RNA-binding domains inside condensates by molecular chaperones may be a general mechanism to prevent aberrant phase transitions.
A simple model explains the cell cycle-dependent assembly of centromeric nucleosomes in holocentric species
Authors: Câmara Amanda Souza , Schubert Veit , Mascher Martin , Houben Andreas
Published: April 2021

Centromeres are essential for chromosome movement. In independent taxa, species with holocentric chromosomes exist. In contrast to monocentric species, where no obvious dispersion of centromeres occurs during interphase, the organization of holocentromeres differs between condensed and decondensed chromosomes. During interphase, centromeres are dispersed into a large number of CENH3-positive nucleosome clusters in a number of holocentric species. With the onset of chromosome condensation, the centromeric nucleosomes join and form line-like holocentromeres. Using polymer simulations, we propose a mechanism, relying on the interaction between centromeric nucleosomes and Structural Maintenance of Chromosomes (SMC) proteins. All simulations represented a ~20 Mbp-long chromosome, corresponding to ~100,000 nucleosomes. Different sets of molecular dynamic simulations were evaluated by testing four parameters: 1) the concentration of Loop Extruders (LEs) corresponding to SMCs; 2) the distribution and number of centromeric nucleosomes; 3) the effect of centromeric nucleosomes on interacting LEs; and 4) the assembly of kinetochores bound to centromeric nucleosomes. We observed the formation of a line-like holocentromere, due to the aggregation of the centromeric nucleosomes when the chromosome was compacted into loops. A groove-like holocentromere structure formed after a kinetochore complex was simulated along the centromeric line. Similar mechanisms may also organize a monocentric chromosome constriction, and its regulation may cause different centromere types during evolution.
Optofluidic Fiber Component for Separation and counting of Micron-Sized Particles
Authors: Kumar T. , Harish A.V. , Etcheverry S. , Margulis W. , Laurell F. , Russom A.
Published: April 2021

An all-fiber separation component capable of sorting and counting micron-sized particles based on size is presented. A sequence of silica fiber capillaries with various diameters and longitudinal cavities were used to fabricate the component for separation and detection in an uninterrupted flow. Fluorescence microparticles of 1 μm and 10 μm sizes are mixed in a visco-elastic fluid and infused into the all-fiber separation component. Elasto-inertial forces focus the larger particle to the center of the silica capillary, while the smaller microparticles exit from a side capillary. Analysis of the separated particles at the output showed a separation efficiency of 100% for the 10 μm and 97% for the 1 μm particles. In addition, the counting of the larger particles is demonstrated in the same flow. The separated 10 μm particles are further routed through another all-fiber component for counting. A counting speed of ~1400 particles/min and with the variation in amplitude of 10% is achived. A combination of separation and counting can be powerful tool may find several applications in biology and medicine, such as separation and analysis of exosomes, bacteria, and blood cell sub-populations.
Computational modeling and quantitative physiology reveal central parameters for brassinosteroid-regulated early cell physiological processes linked to elongation growth of theArabidopsisroot
Authors: Großeholz Ruth , Wanke Friederike , Rohr Leander , Glöckner Nina , Rausch Luiselotte , Scholl Stefan , Scacchi Emanuele , Spazierer Amelie-Jette , Shabala Lana , Shabala Sergey , Schumacher Karin , Kummer Ursula , Harter Klaus
Published: April 2021

Brassinosteroids (BR) are key hormonal regulators of plant development. However, whereas the individual components of BR perception and signaling are well characterized experimentally, the question of how they can act and whether they are sufficient to carry out the critical function of cellular elongation remains open. Here, we combined computational modeling with quantitative cell physiology to understand the dynamics of the plasma membrane (PM)-localized BR response pathway during the initiation of cellular responses in the epidermis of theArabidopsisroot tip that are be linked to cell elongation. The model, consisting of ordinary differential equations, comprises the BR induced hyperpolarization of the PM, the acidification of the apoplast and subsequent cell wall swelling. We demonstrate that the competence of the root epidermal cells for the BR response predominantly depends on the amount and activity of H+-ATPases in the PM. The model further predicts that an influx of cations is required to compensate for the shift of positive charges caused by the apoplastic acidification. A potassium channel was subsequently identified and experimentally characterized, fulfilling this function. Thus, we established the landscape of components and parameters for physiological processes potentially linked to cell elongation, a central process in plant development.
Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells
Authors: Aaron Nicole , Kraakman Michael J. , Zhou Qiuzhong , Liu Qiongming , Yang Jing , Liu Longhua , Yu Lexiang , Wang Liheng , He Ying , Fan Lihong , Hirakawa Hiroyuki , Ding Lei , Lo James C , Wang Weidong , Zhao Baohong , Edward Guo X , Sun Lei , Rosen Clifford J. , Qiang Li
Published: April 2021

Background

Bone marrow (BM) adipose tissue (BMAT) has been shown to be vital for regulating metabolism and maintaining skeletal homeostasis in the marrow niche. As a reflection of BM remodeling, BMAT is highly responsive to nutrient fluctuations, hormonal changes and metabolic disturbances such as obesity and diabetes mellitus. Expansion of BMAT has also been strongly associated with bone loss in mice and humans. However, the regulation of BM plasticity remains poorly understood, as does the mechanism that links changes in marrow adiposity with bone remodeling.

Methods

Using C57BL/6 mice as a model, we employed the bone-protected PPARγ constitutive deacetylation (2KR), Adipsin, and its downstream effector, C3, knockout mice. These mice were challenged to thiazolidinedione treatment, calorie restriction, or aging in order to induce bone loss and MAT expansion. Analysis of bone density and marrow adiposity was performed using a μCT scanner and by RNA analysis to assess adipocyte and osteoblast markers. Forin vitrostudies, primary bone marrow stromal cells (BMSCs) were isolated and subjected to osteoblastogenic or adipogenic differentiation or chemical treatment followed by morphological and molecular analyses. Clinical data was obtained from samples of a previous clinical trial of fasting and high calorie diet in healthy human volunteers.

Results

We have shown that Adipsin is the most up-regulated adipokine during BMAT expansion in mice and humans, in a PPARγ acetylation-dependent manner. Ablation of Adipsin in mice specifically inhibited BMAT expansion but not peripheral adipose depots, and improved bone mass during calorie restriction, thiazolidinedione treatment, and aging. These effects were mediated through its downstream effector, complement component C3, to prime common progenitor cells toward adipogenesis rather than osteoblastogenesis through inhibiting Wnt/β- catenin signaling.

Conclusions

Adipsin promotes new adipocyte formation and affects skeletal remodeling in the BM niche. Our study reveals a novel mechanism whereby the BM sustains its own plasticity through paracrine and endocrine actions of a unique adipokine.

Funding

This work was supported by the National Institutes of Health T32DK007328 (NA), F31DK124926 (NA), R01DK121140 (JCL), R01AR068970 (BZ), R01AR071463 (BZ), R01DK112943 (LQ), and P01HL087123 (LQ).
Artificial selection of stable rhizosphere microbiota leads to heritable plant phenotype changes
Authors: Jacquiod Samuel , Spor Aymé , Wei Shaodong , Munkager Victoria , Bru David , Sørensen Søren J. , Salon Christophe , Philippot Laurent , Blouin Manuel
Published: April 2021

Research on artificial selection of microbial community has become popular due to perspectives in improving plant and animal health1-4. However, reported results still lack consistency5-8. We hypothesized that artificial selection may provide desired outcomes provided that microbial community structure has stabilized along the selection process. In a ten-generation artificial selection experiment involving 1,800 plants, we selected rhizosphere microbiota ofBrachypodium distachyonthat were associated with high or low levels of leaf greenness, a proxy for plant health9. Monitoring of the rhizosphere microbiota dynamics showed strong oscillations in community structure during an initial transitory phase of five generations, with no heritability in the selected property. In the last five generations, the structure of microbial communities displayed signs of stabilization, concomitantly to the appearance of heritability in leaf greenness. Selection pressure, initially ineffective, became successful in changing the greenness index in the intended direction, especially toward high greenness values. We showed a remarkable congruence between plant traits and selected microbial community structures, highlighting two phylogenetically distinct microbial sub-communities correlating with leaf greenness, whose abundance was significantly steered by directional artificial selection. Understanding microbial community structure stabilization can thus help improve the reliability of artificial microbiota selection.

Short Sentence

Stable microbiota selection enables trait heritability
Identifying planktonic foraminiferal morphospecies: which are the important images?
Authors: Scott George H.
Published: April 2021

Selection of imagery that promotes accurate identification of morphotaxa is viewed as a significant problem in the taxonomy of planktonic foraminifera. Currently, imagery of taxa is sparse, apparently selected by visual judgement, and presented without information about its typicality. What is required are impartially selected images which embrace population variation to serve as training sets for reliable identification of taxa. Outlined here is a simple morphometrically-based solution, applied to the shape of shells in two orientations, in which shape variation is resolved onto three principal component axes. On the premise that the best-adapted shells are the commonest, specimens within 1 standard deviation (sd) of the trivariate mean are recognized as population exemplars suitable for use as trainers. Specimens which project at ≥2 sd onto at least one axis are mapped as boundary specimens whose identity might be questioned. This procedure is trialled on samples ofTruncorotalia crassaformis. Exemplars from the Equatorial Atlantic and Caribbean compare closely; they partially overlap with those from a Holocene Southwest Pacific population provisionally interpreted as a subtaxon,Truncorotalia crassaformis hessi.
Interaction of the Causal Agent of Apricot bud gallAcalitus phloeocoptes(Nalepa) with Apricot: Implications in Infested Tissues
Authors: Li Shijuan , Khurshid Muhammad , Yao Junsheng , Dawuda Mohammed Mujitaba , Zhang Jin , Hassan Zeeshan , Ahmad Shahbaz , Xu Bingliang
Published: April 2021

Apricot bud gall mite,Acalitus phloeocoptes(Nalepa), is a destructive arthropod pest that causes significant economic losses to apricot trees worldwide. Infested bud examination revealed that the starch granules in the bud axon were extended at the onset of the attack. During the later stages of the attack, the cytoplasm was distributed in apricot. The results also demonstrated that the accumulation of large amounts of cytokinin (zeatin, ZT) and auxin (indoleacetic acid, IAA) led to rapid bud proliferation during the rapid growth period. Abscisic acid (ABA) controls the development of gall buds and plays a vital role in gall bud maturity. The reduction of gibberellic acid (GA3) content led to rapid lignification at the later phase of bud development. Our results reveal the mechanism underlying the interaction of apricot bud gall with its parasite and provide reliable information for designing valuable breeding programs. This study will be quite useful for pest management and will provide a comprehensive evaluation of ecology-based cost-effective control, life history and demographic parameters ofA. phloeocoptes.
Siderophore fromTalaromyces trachyspermus:augmentation and characterization
Authors: Sahu Sharda , Prakash Anil
Published: April 2021

In the present study, a siderophore compound produced by an endophytic fungus,Talaromyces trachyspermuswas optimized for maximum production, 88.9 % SU by applying Plackett-Burman design and Response Surface Methodology through Central Composite Design that showed the succinic acid (1.141 g/L), sucrose (31.028 g/L) and temperature (27.475 °C) as significant factors. On scale up, a further increase in siderophore yield was obtained (by 3%) The compound was extracted, purified and detected chemically as catecholate siderophore showing max. λ absorbance at 279nm. Contained of hydroxy benzene as shown by GC-MS analysis and further identified as berberine by HRLC-MS studies. The compound berberine is clinically a very important drug with several ethnobotanical properties. This is rare to report fungal catecholate and first to report the production of berberine fromTalaromyces species.
PhosIDP: a web tool to visualize the location of phosphorylation sites in disordered regions
Authors: Nicolaou Sonia T. , Hebditch Max , Jonathan Owen J. , Verma Chandra S. , Warwicker Jim
Published: April 2021

Charge is a key determinant of intrinsically disordered protein (IDP) and intrinsically disordered region (IDR) properties. IDPs and IDRs are enriched in sites of phosphorylation, which alters charge. Visualizing the degree to which phosphorylation modulates the charge profile of a sequence would assist in the functional interpretation of IDPs and IDRs. PhosIDP is a web tool that shows variation of charge and fold propensity upon phosphorylation. In combination with the displayed location of protein domains, the information provided by the web tool can lead to functional inferences for the consequences of phosphorylation. IDRs are components of many proteins that form biological condensates. It is shown that IDR charge, and its modulation by phosphorylation, is more tightly controlled for proteins that are essential for condensate formation than for those present in condensates but inessential.
The Effects of Unilateral Transcranial Direct Current Stimulation on Unimanual Laparoscopic Peg-Transfer Task
Authors: Hadi Zaeem , Umbreen Aysha , Anwar Muhammad Nabeel , Navid Muhammad Samran
Published: April 2021

Introduction

Efficient training methods are required for laparoscopic surgical skills training to reduce the time needed for proficiency. Transcranial direct current stimulation (tDCS) is widely used to enhance motor skill acquisition and can be used to supplement the training of laparoscopic surgical skill acquisition. The aim of this study was to investigate the effect of anodal tDCS over the primary motor cortex (M1) on the performance of a unimanual variant of the laparoscopic peg-transfer task.

Methods

Fifteen healthy subjects participated in this randomized, double-blinded crossover study involving an anodal tDCS and a sham tDCS intervention separated by 48 hours. On each intervention day, subjects performed a unimanual variant of laparoscopic peg-transfer task in three sessions (baseline, tDCS, post-tDCS). The tDCS session consisted of 10 minutes of offline tDCS followed by 10 minutes of online tDCS. The scores based on the task completion time and the number of errors in each session were used as a primary outcome measure. A linear mixed-effects model was used for the analysis.

Results

We found that the scores increased over sessions (p<0.001). However, we found no effects of stimulation (anodal tDCS vs. sham tDCS) and no interaction of stimulation and sessions.

Conclusion

This study suggests that irrespective of the type of current stimulation (anodal and sham) over M1, there was an improvement in the performance of the unimanual peg-transfer task, implying that there was motor learning over time. The results would be useful in designing efficient training paradigms and further investigating the effects of tDCS on laparoscopic peg-transfer tasks.
Systematic benchmark of state-of-the-art variant calling pipelines identifies major factors affecting accuracy of coding sequence variant discovery
Authors: Abasov Ruslan , Tvorogova Varvara E. , Glotov Andrey S. , Predeus Alexander V. , Barbitoff Yury A.
Published: April 2021

Accurate variant detection in the coding regions of the human genome is a key requirement for molecular diagnostics of Mendelian disorders. Efficiency of variant discovery from nextgeneration sequencing (NGS) data depends on multiple factors, including reproducible coverage biases of NGS methods and the performance of read alignment and variant calling software. In this work, we systematically evaluated the performance of 4 popular short read aligners (Bowtie2, BWA, Isaac, and Novoalign) and 6 variant calling and filtering methods (based on DeepVariant, Genome Analysis ToolKit (GATK), FreeBayes, and Strelka2) using a set of 10 “gold standard” WES and WGS datasets. Our results suggest that Bowtie2 performs significantly worse than other aligners and should not be used for medical variant calling. When other aligners were used, the accuracy of variant discovery mostly depended on the variant caller and not the read aligner. Among the tested variant callers, DeepVariant consistently showed the best performance and the highest robustness, with other state-of-the-art tools, i.e. Strelka2 and GATK with 1D convolutional neural network variant scoring, also showing high performance on both WES and WGS data. The results show surprisingly large differences in the performance of cutting-edge tools even on high confidence regions of the coding genome. This highlights the importance of regular benchmarking of quickly evolving tools and pipelines. Finally, we discuss the need for a more diverse set of gold standard genomes (e.g. of African, Hispanic, or mixed ancestry) that would allow to control for deep learning model overfitting. For similar reasons there is a need for better variant caller assessment in the repetitive regions of the coding genome.
TNFα increases Tyrosine Hydroxylase expression in human monocytes
Authors: Gopinath Adithya , Badova Martin , Francisa Madison , Shaw Gerry , Collins Anthony , Miller Douglas R. , Hansen Carissa A. , Mackie Phillip , Tansey Malú Gámez , Dagra Abeer , Madorsky Irina , Ramirez-Zamora Adolfo , Okun Michael S. , Streit Wolfgang J. , Khoshbouei Habibeh
Published: April 2021

Most, if not all, peripheral immune cells in humans and animals express tyrosine hydroxylase (TH), the rate limiting enzyme in catecholamine synthesis. Since TH is typically studied in the context of brain catecholamine signaling, little is known about changes in TH production and function in peripheral immune cells. This knowledge gap is due, in part, to the lack of an adequately sensitive assay to measure TH in immune cells expressing lower TH levels compared to other TH expressing cells. Here, we report the development of a highly sensitive and reproducible Bio-ELISA to quantify picogram levels of TH in multiple model systems. We have applied this assay to monocytes isolated from blood of persons with Parkinson’s disease (PD) and to age-matched, healthy controls. Our study unexpectedly revealed that PD patients’ monocytes express significantly higher levels of TH protein in peripheral monocytes relative to healthy controls. Tumor necrosis factor (TNFδ), a pro-inflammatory cytokine, has also been shown to be increased in the brains and peripheral circulation in human PD, as well as in animal models of PD. Therefore, we investigated a possible connection between higher levels of TH protein and the known increase in circulating TNFδ in PD. Monocytes isolated from healthy donors were treated with TNFδ or with TNFδ in the presence of an inhibitor. Tissue plasminogen activator (TPA) was used as a positive control. We observed that TNFδ stimulation increased both the number of TH+ monocytes and the quantity of TH per monocyte, without increasing the total numbers of monocytes. These results revealed that TNFδ could potentially modify monocytic TH production and serve a regulatory role in peripheral immune function. The development and application of a highly sensitive assay to quantify TH in both human and animal cells will provide a novel tool for further investigating possible PD immune regulatory pathways between brain and periphery.
Variant calling from scRNA-seq data allows the assessment of cellular identity in patient-derived cell lines
Authors: Ramazzotti Daniele , Angaroni Fabrizio , Maspero Davide , Ascolani Gianluca , Castiglioni Isabella , Piazza Rocco , Antoniotti Marco , Graudenzi Alex
Published: April 2021

Abstract

Matters Arising from:Sharma, A., Cao, E.Y., Kumar, V. et al. Longitudinal single-cell RNA sequencing of patient-derived primary cells reveals drug-induced infidelity in stem cell hierarchy.Nat Commun9, 4931 (2018).https://doi.org/10.1038/s41467-018-07261-3.

In Sharma, A. et al.Nat Commun9, 4931 (2018) the authors employ longitudinal single-cell transcriptomic data from patient-derived primary and metastatic oral squamous cell carcinomas cell lines, to investigate possible divergent modes of chemo-resistance in tumor cell subpopulations. We integrated the analyses presented in the manuscript, by performing variant calling from scRNA-seq data via GATK Best Practices. As a main result, we show that an extremely high number of singlenucleotide variants representative of the identity of a specific patient is unexpectedly found in the scRNA-seq data of the cell line derived from a second patient, and vice versa. This finding likely suggests the existence of a sample swap, thus jeopardizing some of the translational conclusions of the article. Our results prove the efficacy of a joint analysis of the genotypic and transcriptomic identity of single-cells.
pUL21 is a viral phosphatase adaptor that promotes herpes simplex virus replication and spread
Authors: Benedyk Tomasz H. , Muenzner Julia , Connor Viv , Han Yue , Brown Katherine , Wijesinghe Kaveesha J. , Zhuang Yunhui , Colaco Susanna , Stoll Guido A. , Tutt Owen S. , Svobodova Stanislava , Svergun Dmitri I. , Bryant Neil A. , Deane Janet E. , Firth Andrew E. , Jeffries Cy M. , Crump Colin M. , Graham Stephen C.
Published: April 2021

The herpes simplex virus (HSV)-1 protein pUL21 is essential for efficient virus replication and dissemination. While pUL21 has been shown to promote multiple steps of virus assembly and spread, the molecular basis of its function remained unclear. Here we identify that pUL21 is a virus-encoded adaptor of protein phosphatase 1 (PP1). pUL21 directs the dephosphorylation of cellular and virus proteins, including components of the viral nuclear egress complex, and we define a conserved non-canonical linear motif in pUL21 that is essential for PP1 recruitment.In vitroevolution experiments reveal that pUL21 directly antagonises the activity of the virus-encoded kinase pUS3, with growth and spread of pUL21 PP1-binding mutant viruses being restored when pUS3 activity is disrupted. This study shows that virus-directed phosphatase activity is essential for efficient herpesvirus assembly and spread, highlighting the fine balance between kinase and phosphatase activity required for optimal virus replication.
Emergence and function of cortical offset responses in sound termination detection
Authors: Sołyga Magdalena , Barkat Tania Rinaldi
Published: April 2021

Offset responses in auditory processing appear after a sound terminates. They arise in neuronal circuits within the peripheral auditory system, but their role in the central auditory system remains unknown. Here we ask what the behavioural relevance of cortical offset responses is and what circuit mechanisms drive them. At the perceptual level, our results reveal that experimentally minimizing auditory cortical offset responses decreases the mouse performance to detect sound termination, assigning a behavioural role to offset responses. By combiningin vivoelectrophysiology in the auditory cortex and thalamus of awake mice, we also demonstrate that cortical offset responses are not only inherited from the periphery but also amplified and generatedde novo. Finally, we show that offset responses code more than silence, including relevant changes in sound trajectories. Together, our results reveal the importance of cortical offset responses in encoding sound termination and detecting changes within temporally discontinuous sounds crucial for speech and vocalization.