title: Visuo-tactile integration in texture perception: A replication and extension study

abstract: Employing a sensory conflict paradigm, previous research has found that vision and touch contribute, on average, equally to the visuo-tactile perception of surface texture. Our study aimed to, firstly, replicate the original findings using a comparable setup and stimulus set; secondly, examine whether equal modality contributions can also be observed on an individual basis (using a within-subject design); and thirdly, explore how visuo-tactile integration is affected by illumination angle (top vs. oblique). Participants explored a discrepant standard consisting of different abrasive papers by vision, touch, and using both modalities simultaneously, and subsequently had to find the closest visual, tactile, and visuo-tactile match from a set of matching stimuli. We replicated equal contribution from vision and touch across the whole sample in both illumination conditions. We also found considerable inter-individual variations in the modality contributions when the stimuli were illuminated from the top. Interestingly, this variation decreased under oblique illumination, with most participants showing an about-equal contribution from both modalities to the combined texture percept. These findings are consistent with the assumption that the perceived discrepancy between vision and touch was reduced under oblique illumination suggesting overall that visual and tactile information are only weighted equally within a certain range of experienced discrepancy. Outside this individual range, one of the modalities is weighted higher with no clear preference for either modality.


title: Cellular and Molecular Organization of the Rhesus Macaque Dorsal Horn with a Comparison to Mouse

abstract: The spinal dorsal horn transforms incoming somatosensory information and transmits it supraspinally to generate modality-specific sensory percepts. The lack of an established framework for the molecular and cellular organization of the dorsal horn across species has greatly hampered delineating precisely how this region processes somatosensory information, including pain. Furthermore, the translation potential of the rodent work is unclear without data from higher order species. To fill these gaps, we performed single nucleus RNA-sequencing of Rhesus macaque dorsal horn and compared the results to a recently reported meta-analysis of mouse. Because dorsal horn laminae serve as a key organizing principle for function, we also determined the laminar location of each identified cell type. The work provides a comprehensive cross-species cellular and molecular database that will be critical for decoding the logic of dorsal horn somatosensory circuits and validating preclinical targets.

category: neuroscience


title: Nonlinear Parameter and State Estimation Approach in End-stage Kidney Disease Patients

abstract:
ObjectiveThere are nearly 786,000 Americans with end-stage renal disease (ESKD), of which 71% rely on life-saving hemodialysis (HD) treatment. HD care costs Medicare annually in excess of $70 billion. One primary goal of HD treatment is to remove excess fluid via ultrafiltration. Intradialytic hypotension (IDH), a significant reduction in blood volume due to an imbalance between ultrafiltration and interstitial to intravascular fluid refilling rates, has severe implications for morbidity and mortality. However, fluid and blood volume are not accessible. It has been suggested that knowledge of extracellular fluid and absolute blood volume should improve HD outcomes.

MethodsThe new estimation approach combines a validated physiological-based fluid volume model during ultrafiltration, the nonlinear least squares method with an uncertainty quantification technique, and the unscented Kalman filter.

ResultsWe develop a novel estimation approach that estimates the underlying model parameters, bounds error estimation due to model uncertainty and measurement noise, reconstructs unmeasured fluid and blood volume, and predicts personalized outcomes (hematocrit), during HD treatment. Finally, we test the performance of our approach using actual HD data.

ConclusionThe extracellular (plasma, interstitial) fluid volume, absolute blood volume, and fluid shift/refill parameters can be estimated and bounded by the Fisher information matrix lower bounds. In addition, fluid volume corrections and personalized predictions for the blood volume evolution can be achieved during ultrafiltration by fitting the underlying parameters to a patients data.

SignificanceThis novel estimation algorithm, readily available for integration in current HD machines, could improve HD treatment outcomes.

category: bioengineering


title: Factors regulating translation coupled mRNA degradation in yeast

abstract: Codon optimality is a major factor governing translation speed and efficiency, mRNA expression, and stability. Presence of optimal codons maintains a steady translation time, while non-optimal codons can lead to slow peptidyl transfer, prolonged translation time and frequent halt. Owing to this, there are co-translational surveillance protein complexes which monitor this process meticulously and can trigger the release of the mRNA transcript after prolonged halt. The surveillance protein complexes are closely associated with various degradation enzymes which can break down these released transcripts. Degradation of the released transcripts will be ensured if they contain amenable regions for enzyme binding and action. Here, we have used sequence data to estimate the relative abundance of non-optimal codons within a transcript. We found that transcripts with high relative abundance of non-optimal codon show reduced stability and half-life compared to transcripts with lower relative abundance of non-optimal codon. We have further integrated the relative abundance of non-optimal codons with internal unstructured segments for the transcripts, to show that the former is responsible for transcript release and the latter provides susceptible platform for endonuclease cleavage, which together is capable of destabilising and reducing the transcripts half-life. Since this is a translational system, sequestration of mRNA into a dense forest of ribosomes is seen to prolong the transcripts half-life even in the presence of destabilising factors.

category: bioinformatics


title: GenMPI: Cluster Scalable Variant Calling forShort/Long Reads Sequencing Data

abstract: Rapid technological advancements in sequencing technologies allow producing cost effective and high volume sequencing data. Processing this data for real-time clinical diagnosis is potentially time-consuming if done on a single computing node. This work presents a complete variant calling workflow, implemented using the Message Passing Interface (MPI) to leverage the benefits of high bandwidth interconnects. This solution (GenMPI) is portable and flexible, meaning it can be deployed to any private or public cluster/cloud infrastructure. Any alignment or variant calling application can be used with minimal adaptation. To achieve high performance, compressed input data can be streamed in parallel to alignment applications while uncompressed data can use internal file seek functionality to eliminate the bottleneck of streaming input data from a single node. Alignment output can be directly stored in multiple chromosome-specific SAM files or a single SAM file. After alignment, a distributed queue using MPI RMA (Remote Memory Access) atomic operations is created for sorting, indexing, marking of duplicates (if necessary) and variant calling applications. We ensure the accuracy of variants as compared to the original single node methods. We also show that for 300x coverage data, alignment scales almost linearly up to 64 nodes (8192 CPU cores). Overall, this work outperforms existing big data based workflows by a factor of two and is almost 20% faster than other MPI-based implementations for alignment without any extra memory overheads. Sorting, indexing, duplicate removal and variant calling is also scalable up to 8 nodes cluster. For pair-end short-reads (Illumina) data, we integrated the BWA-MEM aligner and three variant callers (GATK HaplotypeCaller, DeepVariant and Octopus), while for long-reads data, we integrated the Minimap2 aligner and three different variant callers (DeepVariant, DeepVariant with WhatsHap for phasing (PacBio) and Clair3 (ONT)). All codes and scripts are available at: https://github.com/abs-tudelft/gen-mpi


title: LENS - Landscape of Effective Neoantigens Software

abstract: Elimination of cancer cells by T cells is a critical mechanism of antitumor immunity and cancer immunotherapy response. T cells recognize cancer cells via engagement of T cell receptors with peptide epitopes presented by major histocompatibility complex (MHC) molecules on the cancer cell surface. Peptide epitopes can be derived from antigen proteins coded for by multiple genomic sources. Bioinformatics tools used to identify tumor-specific epitopes via analysis of DNA and RNA sequencing data have largely focused on epitopes derived from somatic variants, though a smaller number have evaluated potential antigens from other genomic sources. We report here an open-source workflow utilizing the Nextflow DSL2 workflow manager, Landscape of Effective Neoantigen Software (LENS), which predicts tumor-specific and tumor-associated antigens from single nucleotide variants (SNVs), insertions and deletions (InDels), fusion events, splice variants, cancer testis antigens (CTAs), overexpressed self-antigens, viruses, and human endogenous retroviruses (hERVs). The main advantage of LENS is that it extends the breadth of genomic sources of tumor antigens that may be discovered using genomics data. Other advantages include modularity, extensibility, ease of use, incorporation of phasing and germline variant information in epitope identification, and harmonization of relative expression level and immunogenicity prediction across multiple genomic sources. Current limitations include lack of support for class II MHC epitope predictions and advanced visualization features. To demonstrate the utility of LENS, we present an analysis of predicted antigen landscape in 115 acute myeloid leukemia (AML) samples. We expect that LENS will be a valuable platform and resource for T cell epitope discovery bioinformatics, especially in cancers with few somatic variants and increased importance of tumor-specific epitopes from alternative genomic sources.

category: cancer biology


title: Tackling polypharmacology of kinase inhibitors by transcription factor activity profiling.

abstract: Protein kinase inhibitors (PKI) evolved as promising drugs for multiple diseases. However, PKIs promiscuity causes polypharmacological effects challenging therapeutic development. We show that the polypharmacology of PKIs can be inferred from their impact on transcription factors (TF) lying at the apexes of signaling pathways. Using a high-content reporter assay, we evaluated TF activity profiles (TFAP) in cells treated with Akt, CDK, Aurora, Raf, MEK, and ERK inhibitors. For each kinase family, we found kinase-specific consensus TFAP signatures signifying the on-target PKI activity. Remarkably, proximal kinases had the highest similarity of their PKIs consensus signatures. Furthermore, we show that individual PKIs exhibited the consensus, "on-target signatures" within certain "specificity windows" and distinct "off-target signatures" at other concentrations. We also show that the TFAP signatures permit pinpointing the off-target PKI activity at irrelevant kinases and non-kinase effectors. Therefore, the TFAP approach provides clear-cut quantitative metrics for assessing PKI activity and concentration ranges where the on-target activity dominates cell response. By illuminating PKI biology invisible to target-based techniques, this effect-based approach streamlines the selection of kinase chemical probes and PKI drug prioritization.

category: pharmacology and toxicology


title: Tackling polypharmacology of kinase inhibitors and selecting chemical kinase probes by transcription factor activity profiling.


title: Speed-dependent biomechanical changes vary across individual gait metrics post-stroke relative to neurotypical adults

abstract:
BackgroundGait training at fast speeds is recommended to reduce walking activity limitations post-stroke. Fast walking may also reduce gait kinematic impairments post-stroke. However, the magnitude of speed-dependent kinematic impairment reduction in people post-stroke relative to neurotypical adult walking patterns is unknown.

ObjectiveTo determine the effect of faster walking speeds on gait kinematics post-stroke relative to neurotypical adults walking at similar speeds.

MethodsWe performed a secondary analysis with data from 28 people post-stroke and 50 neurotypical adults treadmill walking at multiple speeds. We evaluated the effects of speed and group on individual spatiotemporal and kinematic metrics and performed k-means clustering with all metrics at self-selected and fast speeds

ResultsPeople post-stroke decreased step length asymmetry and trailing limb angle impairment, reducing between-group differences at fast speeds. Speed-dependent changes in peak swing knee flexion, hip hiking, and temporal asymmetries exaggerated between-group differences. Our clustering analyses revealed two clusters. One represented neurotypical gait behavior, composed of neurotypical and post-stroke participants. The other characterized stroke gait behavior, comprised entirely of participants post-stroke. Cluster composition was largely consistent at both speeds, and the distance between clusters increased at fast speeds

ConclusionsThe biomechanical effect of fast walking post-stroke varied across individual gait metrics. For participants within the stroke gait behavior cluster, speed-dependent changes did not lead to an overall gait pattern more similar to neurotypical adults. This suggests that combining fast walking with an approach to strategically target gait metrics with smaller speed-dependent changes may potentiate the biomechanical benefits of fast walking.


title: Cue-driven motor planning facilitates express visuomotor responses in human arm muscles

abstract:
Humans can produce "express" ([~]100ms) arm muscle responses that are inflexibly locked in time and space to the presentation of a visual target, consistent with subcortical visuomotor transformations via the tecto-reticulo-spinal pathway. These express visuomotor responses are sensitive to explicit cue-driven expectations, but it is unclear at what stage of sensory-to-motor transformation such modulation occurs. Here, we recorded electromyographic activity from shoulder muscles as participants reached toward one of four virtual targets whose physical location was partially predictable from a symbolic cue. In an experiment in which targets could be veridically reached, express responses were inclusive of the biomechanical requirements for reaching the cued locations and not systematically modulated by cue validity. In a second experiment, movements were restricted to the horizontal plane so that the participants could perform only rightward or leftward reaches, irrespective of target position on the vertical axis. Express muscle responses were almost identical for targets that were validly cued in the horizontal direction, regardless of cue validity in the vertical dimension. Together, these findings suggest that the cue-induced enhancements of express responses are dominated by effects at the level of motor plans and not solely via facilitation of early visuospatial target processing. Notably, direct cortico-tectal and cortico-reticular projections exist that are well-placed to modulate pre-stimulus motor preparation state in subcortical circuits. Our results appear to reflect a neural mechanism by which contextually relevant motor plans can be stored within subcortical visuomotor nodes and rapidly released in response to compatible visual inputs.

NEW & NOTEWORTHYExpress arm muscle responses to suddenly appearing visual targets for reaching rapid have been attributed to the tecto-reticulo-spinal pathway in humans. We demonstrate that symbolic cues before target presentation can modulate such express arm muscle responses compatibly with the biomechanics of the cued reaching direction and the cue validity. This implies cortically mediated modulation of one or more sensorimotor transformation nodes of the subcortical express pathway.


title: An open-source, ready-to-use and validated ripple detector plugin for the Open Ephys GUI

abstract: Sharp wave-ripples (SWRs, 100-250 Hz) are oscillatory events extracellularly recorded in the CA1 subfield of the hippocampus during sleep and quiet wakefulness. SWRs are thought to be involved in the dialogue between the hippocampus and cortical regions to promote memory consolidation during sleep and memory-guided decision making. Many studies employed closed-loop strategies to either detect and abolish SWRs within the hippocampus or manipulate other relevant areas upon ripple detection. However, the code and schematics necessary to replicate the detection system are not always available, which hinders the reproducibility of experiments among different research groups. Furthermore, information about performance is not usually reported. Here, we present the development and validation of an open-source, real-time ripple detection plugin integrated into the Open Ephys GUI. It contains a built-in movement detector based on accelerometer or electromyogram data that prevents false ripple events (due to chewing, grooming, or moving, for instance) from triggering the stimulation/manipulation device. To determine the accuracy of the detection algorithm, we first carried out simulations in Matlab with synthetic and real ripple recordings. Using a specific combination of detection parameters (amplitude threshold of 5 standard deviations above the mean, time threshold of 10 ms, and RMS block size of 7 samples), we obtained a 97% true positive rate and 2.48 false positives per minute on the real data. Next, an Open Ephys plugin based on the same detection algorithm was developed, and a closed-loop system was set up to evaluate the round trip (ripple onset-to-stimulation) latency over synthetic data. The lowest latency obtained was 34.5 {+/-} 0.5 ms. Besides contributing to increased reproducibility, we anticipate that the developed ripple detector plugin will be helpful for many closed-loop applications in the field of systems neuroscience.


title: Functional Cell Types in the Mouse Superior Colliculus

abstract: The superior colliculus (SC) represents a major visual processing station in the mammalian brain that receives input from many types of retinal ganglion cells (RGCs). How many parallel channels exist in the SC, and what information does each encode? Here we recorded from mouse superficial SC neurons under a battery of visual stimuli including those used for classification of RGCs. An unsupervised clustering algorithm identified 24 functional types based on their visual responses. They fall into two groups: one that responds similarly to RGCs, and another with more diverse and specialized stimulus selectivity. The second group is dominant at greater depths, consistent with a vertical progression of signal processing in the SC. Cells of the same functional type tend to cluster near each other in anatomical space. Compared to the retina, the visual representation in the SC has lower dimensionality, consistent with a sifting process along the visual pathway.


title: Microstructural alterations in tract development in college football: a longitudinal diffusion MRI study

abstract:
Background and ObjectivesRepeated concussive and sub-concussive impacts in high-contact sports can affect the brains microstructure, which can be studied using diffusion MRI. Most prior imaging studies, however, employ a cross-sectional design, do not include low-contact players as controls, or use traditional diffusion tensor imaging without investigating novel tractspecific microstructural metrics.

MethodsWe examined brain microstructure in 63 high-contact (American football) and 34 low-contact (volleyball) collegiate athletes with up to 4 years of follow-up (315 total scans) using advanced diffusion MRI, a comprehensive set of multi-compartment models, and automated fiber quantification tools. We investigated diffusion metrics along the length of tracts using nested linear mixed-effects models to ascertain the acute and chronic effects of sub-concussive and concussive impacts, as well as associations between diffusion changes with clinical, behavioral, and sports-related measures.

ResultsSignificant longitudinal increases in fractional anisotropy and axonal water fraction were detected in volleyball players, but not in football players, along with decreases in radial and mean diffusivity as well as orientation dispersion index (all findings absolute T-statistic > 3.5, p < .0001). This pattern was present in the callosum forceps minor, left superior longitudinal fasciculus, left thalamic radiation, and right cingulum hippocampus. Longitudinal group differences were more prominent and observed in a larger number of tracts in concussed (previously or in-study) football players (p < .0001), while smaller effects were noted in un-concussed players. An analysis of immediate-post concussion scans in football players demonstrated a transient localized increase in axial diffusivity, mean and radial kurtosis in the left uncinate and right cingulum hippocampus (p < .0001). Finally, football players with high position-based sub-concussive risk demonstrated increased orientation dispersion index over time (p < .0001).

DiscussionThe observed longitudinal changes in our volleyball cohort likely reflect normal development in this age range, while the relative attenuation of these effects seen in football, and especially concussed athletes, could possibly reveal diminished myelination, altered axonal calibers, or depressed pruning processes leading to a static, non-decreasing axonal dispersion. This prospective longitudinal study demonstrates significantly divergent tract-specific trajectories of brain microstructure, possibly reflecting a concussive and/or repeated sub-concussive impact-related alteration of normal white matter development in football athletes.


title: Separation of NaV Subtypes in the Axon InitialSegment can Impede or Promote Backpropagation

abstract:
1In a variety of neurons, action potentials (APs) initiate at the proximal axon, within a region called the axon initial segment (AIS) which has favorable cable properties and a high density of voltage-gated ion channels. Pyramidal cells concentrate high-threshold sodium ion channels (NaV1.2) in the proximal AIS, and the distal AIS contains mostly lower threshold NaV1.6. It is widely believed that this separated NaV distribution favors backpropagation and lowers the AP threshold. We implemented a range of hypothetical NaV distributions in the AIS of a multicompartmental pyramidal cell model. Our simulations predict new effects on pyramidal neurons excitability and backpropagation threshold, caused directly by the naturally occurring spatial separation of NaV1.2 and NaV1.6 in the AIS. By controlling the distribution of NaVs, pyramidal cells create a lengthwise profile of gating properties in the AIS. Using a "shift-clamping" technique, we demonstrate that different gating properties drive the effect of proximal NaV1.2 on the backpropagation threshold when the neuron is stimulated somatically versus axonally. When stimulating current is injected at the soma, the intrinsic right-shift of NaV 1.2 activation causes these channels to raise the backpropagation threshold. However, with axonal stimulation, the right-shift of availability dominates, such that concentrating NaV1.2 in the proximal AIS facilitates backpropagation. The latter effect is dynamic: right-shifting steady-state availability is necessary but not sufficient to facilitate backpropagation; we show that the voltage-sensitive time constant of NaV1.2 availability must be right-shifted as well. Our results imply that regulation of NaV separation can sensitively control backpropagation, especially for somatodendritic stimulation.

2 Significance StatementNeurons use sodium ion currents, controlled by voltage-gated sodium channels (NaVs), to trigger electrical signals called action potentials (APs). APs propagate down the axon, and can backpropagate into the soma and dendrites where neurons receive synaptic input. Backpropagation is crucial for learning; neurons use this feedback to create and modify connections in the brain. The axon initial segment (AIS) triggers APs and backpropagation. In pyramidal neurons, the AIS contains two types of NaV: high-threshold channels clustered near the soma where the AIS begins, and low-threshold channels near the end of the AIS. Our modeling predicts how this natural spatial separation of NaV types can impede or promote backpropagation, and thus learning, depending on the site where the neuron is stimulated.


title: Brain-heart interactions are optimized across the respiratory cycle via interoceptive attention

abstract:
Respiration and heartbeat continuously interact within the living organism at many different levels, representing two of the main oscillatory rhythms of the body and providing major sources of interoceptive information to the brain. Despite the modulatory effect of respiration on exteroception and cognition has been recently established in humans, its role in shaping interoceptive perception has been scarcely investigated so far.

In two independent studies, we investigated the effect of spontaneous breathing on cardiac interoception by assessing the Heartbeat Evoked Potential (HEP) in healthy humans. In Study 1, we compared HEP activity for heartbeats occurred during inhalation and exhalation in 40 volunteers at rest. We found higher HEP amplitude during exhalation, compared to inhalation, over fronto-centro-parietal areas. This suggests increased brain-heart interactions and improved cortical processing of the heartbeats during exhalation. In Study 2, we tested the respiratory phase-dependent modulation of HEP activity in 20 volunteers during Exteroceptive and Interoceptive conditions of the Heartbeat Detection (HBD) task. In these conditions, participants were requested to tap at each heartbeat, either listened to or felt, respectively. Results showed higher HEP activity and higher detection accuracy at exhalation than inhalation in the Interoceptive condition only. These effects were positively correlated, suggesting a link between optimization of both cortical processing of cardiac signals and perception of heartbeats across the respiratory cycle. Direct comparisons of Interoceptive and Exteroceptive conditions confirmed stronger respiratory phase-dependent modulation of HEP and accuracy when attention was directed towards the interoceptive stimuli.

Overall, we provide data showing that respiration shapes cardiac interoception at the neurophysiological and behavioural levels. Specifically, exhalation may allow attentional shift towards the internal bodily states.


title: Stochastic analysis of frequency bandwidth and noise attenuation in neurotransmission

abstract: Action potential (AP)-triggered neurotransmitter release forms the key basis of inter-neuronal communication. We present a stochastic hybrid system model that captures the release of neurotransmitter-filled vesicles from a presynaptic neuron. More specifically, vesicles arrive as a Poisson process to attach at a given number of docking sites, and each docked vesicle has a certain probability of release when an AP is generated in the presynaptic neuron. The released neurotransmitters enhance the membrane potential of the postsynaptic neuron, and this increase is coupled to the continuous exponential decay of the membrane potential. The buildup of potential to a critical threshold level results in an AP firing in the postsynaptic neuron, with the potential subsequently resetting back to its resting level. Our model analysis develops formulas that quantify the fluctuations in the number of released vesicles and mechanistically connects them to fluctuations in both the postsynaptic membrane potential and the AP firing times. Increasing the frequency of APs in the presynaptic neuron leads to saturation effects on the postsynaptic side, resulting in a limiting frequency range of neurotransmission. Interestingly, AP firing in the postsynaptic neuron becomes more precise with increasing AP frequency in the presynaptic neuron. We also investigate how noise in AP timing varies with different parameters, such as the probability of releases, the number of docking sites, the voltage threshold for AP firing, and the timescale of voltage decay. In summary, our results provide a systematic understanding of how stochastic mechanisms in neurotransmission enhance or impinge the precision of AP fringing times.


title: Persistent pervasive transcription in RNA exosome depleted oocytes results in loss of female fertility

abstract: Maturing mammalian oocytes are transcriptionally inactive and attendant RNA degradation determines the maternal transcriptome for embryonic development1. Perturbing oocyte RNA degradation can result in failure of meiosis, fertilization, or zygotic gene activation1-5. We recently reported that conditional depletion of EXOSC10, an RNA exosome associated RNase, blocks oocyte growth-to-maturation transition by interfering with ribosomal RNA processing and meiotic checkpoint genes3. Here we have established oocyte-specific knockout mice of a second RNA exosome associated RNase, Dis3. Mutant females (Dis3cKO) exhibit significantly reduced fertility because oocytes arrest at early maturation. DIS3 depletion allows persistent pervasive transcription, which blocks transcription termination and sequesters RNA polymerase II in intergenic regions. In addition, Dis3cKO oocytes gain H3K27me3 at pre-defined loci6 due to insufficient demethylases KDM6A/B. Oocyte double knockout of Dis3 and Exosc10 causes much earlier growth defects for similar persistence of pervasive transcription, suggesting the RNA exosome complex plays a critical role to ensure transcriptome integrity during oocyte development.

category: developmental biology


title: Bird community structure in a mixed forest-production landscape in the northern Western Ghats, India

abstract: Production landscapes outside protected areas are important for the conservation of wildlife, especially in countries like India with high biodiversity and human densities. Production landscapes like plantations often occur in close proximity to biodiversity-rich areas. Rubber and cashew are lucrative plantation crops in India, which although grown under similar environmental conditions, vary in their management and productivity. These plantation crops are often found along the edges of forests, thereby creating a buffer between forested and urban landscapes. While these areas have the potential to be a refuge for species otherwise restricted to natural forests, they are poorly-studied. To address this knowledge gap, we studied how habitat type (cashew, rubber or forest) and habitat characteristics affect bird diversity and guild structure in the Tillari landscape of Western Ghats, Maharashtra. Additionally, we examined how these effects are mediated by distance of plantations to nearest forest edge. In each habitat type, in 2018, we sampled birds six times each in 30 locations using fixed radius point counts. We found that bird diversity in cashew plantations (14 species) was comparable to that of adjoining forests (15 species). Rubber plantations, on the other hand, had lower bird diversity (9 species) than that in cashew or forests. When bird diversity was analysed based on dietary guilds, rubber plantations had fewer bird species in all guilds and cashew plantations had higher abundance of nectivores and lower richness of insectivores than in forest. Distance from the forest did not affect bird diversity in rubber plantations, whereas cashew plantations had fewer nectivorous birds and higher insectivorous birds away from the forest edge. Our results show that cashew plantations can serve as an important surrogate habitat for forest birds in the northern Western Ghats. The findings indicate the unsuitability of rubber plantations for sustaining bird diversity. While there are many studies available on bird diversity in rubber plantations, this is among the first studies of bird community structure in cashew plantations. At a time when forests are rapidly being cleared for plantations, our findings provide valuable data to examine the differential impacts of plantation type on biodiversity.

category: ecology


title: Evolutionary responses of a reef-building coral to climate change at the end of the last glacial maximum

abstract: Climate change threatens the survival of coral reefs on a global scale, primarily through mass bleaching and mortality as a result of marine heatwaves. While these short-term effects are clear, predicting the fate of coral reefs over the coming century is a major challenge. One way to understand the longer-term effects of rapid climate change is to examine the response of coral populations to past climate shifts. Coastal and shallow-water marine ecosystems such as coral reefs have been reshaped many times by sea-level changes during the Pleistocene, yet, few studies have directly linked this with its consequences on population demographics, dispersal, and adaptation. Here we use powerful analytical techniques, afforded by haplotype phased whole-genomes, to establish such links for the reef-building coral, Acropora digitifera. We show that three genetically distinct populations are present in northwestern Australia, and that their rapid divergence since the last glacial maximum (LGM) can be explained by a combination of founder-effects and restricted gene flow. Signatures of selective sweeps, too strong to be explained by demographic history, are present in all three populations and overlap with genes that show different patterns of functional enrichment between inshore and offshore habitats. In contrast to rapid divergence in the host, we find that photosymbiont communities are largely undifferentiated between corals from all three locations, spanning almost 1000 km, indicating that selection on host genes and not acquisition of novel symbionts, has been the primary driver of adaptation for this species in northwestern Australia.

category: evolutionary biology


title: Behavioral dysregulation and monoaminergic deficits precede memory impairments in human tau-overexpressing (htau) mice

abstract: Alzheimers disease (AD) poses an ever-increasing public health concern as the population ages, affecting more than 6 million Americans. AD patients present with mood and sleep changes in the prodromal stages that may be partly driven by loss of monoaminergic neurons in brainstem, but a causal relationship has not been firmly established. The goal of the present study was to evaluate depressive and anxiety-like behaviors in a mouse model of human tauopathy (htau mice) at 4 and 6 months of age prior to the onset of cognitive impairments and correlate these behavior changes with tau pathology, neuroinflammation, and monoaminergic dysregulation in the DRN and LC. We observed depressive-like behaviors at 4 months of age in male and female htau mice and hyperlocomotion in male htau mice. At 6 months, male htau mice developed anxiety-like behavior in the EZM, whereas hyperlocomotion had resolved by this time point. Depressive-like behaviors in the social interaction test persisted at 6 months but were resolved in the sucrose preference test. There was also a significant reduction in number and density of 5-HT-immunoreactive neurons in the rostral DRN in htau mice at 4 months and 5-HT neuronal density was negatively correlated with the intensity of phosphorylated tau staining in this subregion. Additionally, we found evidence of microglial activation in the mid and caudal DRN and astrocytic activation in the rostral DRN. 5-HT neuronal activity was reduced in the DRN and accompanied by downregulation of Tph2 and Sert, whereas genes that promote neuroinflammation and tau phosphorylation were upregulated. Finally, there was enhanced ptau202/205 staining and microglial activity in the LC of htau mice and reduced TH optical density, although the number and density of TH+ neurons were not altered. In total, these results suggest that tau pathology in the DRN and the resulting loss of serotonergic neurotransmission may drive depressive-like behaviors in the early stages of AD, whereas anxiety-like behaviors develop later and may result from neurodegeneration in other regions.

category: animal behavior and cognition


title: Lumbar time-varying muscle synergies in trunk flexion and bending movements at different velocities

abstract:
PurposeAlthough the extent of which the central nervous system uses muscle synergies as a movement control strategy remains an open area of research, it is widely agreed that synergies facilitate the robustness of the neuromuscular system, allowing for effective postural control and flexible movement. This work aimed to investigate the muscle activation patterns of the trunk and time-varying muscle synergies using a novel 18-muscle 3-DOF, 3-D musculoskeletal model of the lumbar spine developed by the authors.

Methods24 different biaxial trunk movements were simulated via the optimization of kinetic and kinematic measures towards obtaining the corresponding muscle activation patterns at 3 different velocities. These patterns were subsequently used to extract the principal (phasic and tonic) spatio-temporal synergies associated with the observed muscle activation patterns in the range of simulated movements.

ResultsFour dominant synergies were able to explain a considerable percent (about 75%) of the variance of the simulated muscle activities. The extracted synergies were spatially tuned in the direction of the main simulated movements (flexion/extension and right/left lateral bending). The temporal patterns demonstrated gradual monotonic shifts in tonic synergies and biphasic modulatory components in phasic synergies with spatially tuned time-delays. The increase in velocity resulted in an elevated amplitude coefficient and accelerated activation of phasic synergies.

ConclusionOur results suggest the plausibility of a time-varying synergies strategy in the dynamic control of trunk movement. Further work is needed to explore leveraging these concepts in various applications, such as rehabilitation and musculoskeletal biomechanics, towards providing more insight into the mechanisms underlying trunk stability and flexibility.


title: Machine Learning Classification Reveals Robust Morphometric Biomarker of Glial and Neuronal Arbors

abstract: Neurons and glia are the two main cell classes in the nervous systems of most animals. Although functionally distinct, neurons and glia are both characterized by multiple branching arbors stemming from the cell bodies. Glial processes are generally known to form smaller trees than neuronal dendrites. However, the full extent of morphological differences between neurons and glia in multiple species and brain regions has not yet been characterized, nor is it known whether these cells can be reliably distinguished based on geometric features alone. Here, we show that multiple supervised learning algorithms (K-nearest neighbor, random forest, and support vector machine) deployed on a large database of morphological reconstructions can systematically classify neuronal and glial arbors with nearly perfect accuracy and precision. Moreover, we report multiple morphometric properties, both size-related and size-independent, that differ substantially between these cell types. In particular, we newly identify an individual morphometric measurement, Average Branch Euclidean Length (ABEL) that can robustly separate neurons from glia across multiple animal models, a broad diversity of experimental conditions, and anatomical areas, with the notable exception of the cerebellum. We discuss the practical utility and physiological interpretation of this discovery.


title: A computational modeling of primary-microRNA expression

abstract: MicroRNAs (miRNAs) play crucial roles in gene regulation. Most studies so far focus on mature miRNAs, which leaves many gaps in our knowledge in primary miRNAs (pri-miRNA). To fill these gaps, we attempted to model the expression of pri-miRNAs in 1829 primary cell types and tissues in this study. We demonstrated that the expression of their associated mRNAs could model the expression of the pri-miRNAs well. These associated mRNAs are different from their corresponding target mRNAs and are enriched with specific functions. The majority of the associated mRNAs of a miRNA are shared across conditions, although a fraction of the associated mRNAs are condition-specific. Our study shed new light on the understanding of miRNA biogenesis and general gene transcriptional regulation.


title: Cellpose 2.0: how to train your own model

abstract: Generalist models for cellular segmentation, like Cellpose, provide good out-of-the-box results for many types of images. However, such models do not allow users to adapt the segmentation style to their specific needs and may perform sub-optimally for test images that are very different from the training images. Here we introduce Cellpose 2.0, a new package which includes an ensemble of diverse pretrained models as well as a human-in-the-loop pipeline for quickly prototyping new specialist models. We show that specialist models pretrained on the Cellpose dataset can achieve state-of-the-art segmentation on new image categories with very little user-provided training data. Models trained on 500-1000 segmented regions-of-interest (ROIs) performed nearly as well as models trained on entire datasets with up to 200,000 ROIs. A human-in-the-loop approach further reduced the required user annotations to 100-200 ROIs, while maintaining state-of-the-art segmentation performance. This approach enables a new generation of specialist segmentation models that can be trained on new image types with only 1-2 hours of user effort. We provide software tools including an annotation GUI, a model zoo and a human-in-the-loop pipeline to facilitate the adoption of Cellpose 2.0.


title: Motifizer: a tool for parsing high-throughput sequencing datasets and quantitative comparative analyses of transcription factor-binding sites

abstract:
BackgroundComparative analysis of Chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq), combined with transcriptomics data (RNA-seq), can provide critical insights into gene regulatory networks controlled by transcription factors in a given biological context. While multiple programs exist, which need to be individually installed and executed to generate such information, a user-friendly tool with low system requirements which combines the various computational processes into one package, using a docker container, is lacking.

ResultsIn this study, we present a user-interactive, infrastructure-independent computational pipeline, called Motifizer, which uses open source tools for processing ChIP-Seq and RNA-seq datasets. Motifizer performs extensive analysis of raw input data, performing peak calling, de-novo motif analysis and differential gene expression analysis on ChIP and RNA-seq datasets. Additionally, Motifizer can be used for analysis and quantitative comparison of transcription factor binding sites in user defined genomic regions. Motifizer also allows easy addition and/or changes of parameters, thereby adding to the versatility of the tool.

ConclusionThe Motifizer tool is an easy to use tool which uses a docker container system to install and execute ChIP-seq and RNA-seq data parsing. The Analysis module of Motifizer can be employed to identify putative targets involved in gene regulatory networks. Motifizer can be accessed by a large user base and does not require programming skill by the user. Motifizer can be locally installed from the repository (https://github.com/abhikbhattacharjee/Motifizer)


title: Single-cell multimodal modeling with deep parametric inference

abstract: The paired measurement of multiple modalities, known as the multimodal analysis, is an exciting frontier for connecting single-cell genomics with epitopes and functions. Mapping of transcriptomes in single-cells and the integration with cell phenotypes enable a better understanding of cellular states. However, assembling these paired omics into a unified representation of the cellular state remains challenging with the unique technical characteristics of each measurement. In this study, we built a deep parameter inference model (DPI) based on the properties of single-cell multimodal data. DPI is a complete single-cell multimodal omics analysis framework, which has built in multimodal data preprocessing, multimodal data integration, multimodal data reconstruction, reference and query, disturbance prediction and other analysis functions.


title: epiAneufinder: identifying copy number variations from single-cell ATAC-seq data

abstract: Single-cell open chromatin profiling via the single-cell Assay for Transposase-Accessible Chromatin using sequencing (scATAC-seq) assay has become a mainstream measurement of open chromatin in single-cells. Here we present a novel algorithm, epiAneufinder, that exploits the read count information from scATAC-seq data to extract genome-wide copy number variations (CNVs) for individual cells, allowing to explore the CNV heterogeneity present in a sample at the single-cell level. Using different cancer scATAC-seq datasets, we show how epiAneufinder can identify intratumor clonal heterogeneity in populations of single cells based on their CNV profiles. These profiles are concordant with the ones inferred from single-cell whole genome sequencing data for the same samples. epiAneufinder allows the addition of single-cell CNV information to scATAC-seq data, without the need of additional experiments, unlocking a layer of genomic variation which is otherwise unexplored.


title: Communication-Efficient Cluster Scalable Genomics Data Processing Using Apache Arrow Flight

abstract:
Current cluster scaled genomics data processing solutions rely on big data frameworks like Apache Spark, Hadoop and HDFS for data scheduling, processing and storage. These frameworks come with additional computation and memory overheads by default. It has been observed that scaling genomics dataset processing beyond 32 nodes is not efficient on such frameworks.

To overcome the inefficiencies of big data frameworks for processing genomics data on clusters, we introduce a low-overhead and highly scalable solution on a SLURM based HPC batch system. This solution uses Apache Arrow as in-memory columnar data format to store genomics data efficiently and Arrow Flight as a network protocol to move and schedule this data across the HPC nodes with low communication overhead.

As a use case, we use NGS short reads DNA sequencing data for pre-processing and variant calling applications. This solution outperforms existing Apache Spark based big data solutions in term of both computation time (2x) and lower communication overhead (more than 20-60% depending on cluster size). Our solution has similar performance to MPI-based HPC solutions, with the added advantage of easy programmability and transparent big data scalability. The whole solution is Python and shell script based, which makes it flexible to update and integrate alternative variant callers. Our solution is publicly available on GitHub at https://github.com/abs-tudelft/time-to-fly-high/genomics.


title: Elongated exons encoding disordered regions expedited eukaryotic evolution

abstract: Most prokaryotic proteins consist of one structural domain (SD), while a typical eukaryotic protein is comprised of multiple SDs and intrinsically disordered regions (IDRs) that by themselves do not adopt stable structures1-4. In eukaryotes IDRs are especially prevalent in transcription factors5 and are involved in condensates that regulate diverse cellular functions6. How eukaryotic proteins evolved to differ from prokaryotic proteins has not been fully elucidated. Here we find that the longer internal exons are, the more frequently they encode IDRs in general. Moreover, the boundaries of long internal exons tend to fall outside of structural domains. These findings are consistent with the idea that some internal exons whose boundaries were aligned outside of structural domains acquired sections encoding IDRs. Most of the internal exon segments that probably lengthened after the rat-mouse divergence encode IDRs, supporting the view. We surmise that many exons whose boundaries were not aligned to the inside of structural domains elongated to add IDRs to the encoded proteins, often conferring new functions. Some of the IDRs possibly served as spacers in acquiring structural domains through recombination. We propose that the  small bang that lengthened exons facilitated the evolution that led to the last common ancestor of eukaryotes.


title: A multiscale whole-cell theory for mechano-sensitive migration on viscoelastic substrates

abstract: Increasing experimental evidence validates that both the elastic stiffness and viscosity of the extracellular matrix regulate mesenchymal cell behavior, such as the rational switch between durotaxis (cell migration to stiffer regions), anti-durotaxis (migration to softer regions), and adurotaxis (stiffness-insensitive migration). To reveal the mechanisms underlying the crossover between these motility regimes, we have developed a multiscale chemo-mechanical whole-cell theory for mesenchymal migration. Our framework couples the sub-cellular focal adhesion dynamics at the cell-substrate interface with the cellular cytoskeletal mechanics and the chemical signaling pathways involving Rho GTPase proteins. Upon polarization by the Rho GTPase gradients, our simulated cell migrates by concerted peripheral protrusions and contractions, a hallmark of the mesenchymal mode. The resulting cell dynamics quantitatively reproduces the experimental migration speed as a function of the uniform substrate stiffness and explains the influence of viscosity on the migration efficiency. In the presence of stiffness gradients and absence of chemical polarization, our simulated cell can exhibit durotaxis, anti-durotaxis, and adurotaxis respectively with increasing substrate stiffness or viscosity. The cell moves toward an optimally stiff region from softer regions during durotaxis and from stiffer regions during anti-durotaxis. We show that cell polarization through steep Rho GTPase gradients can reverse the migration direction dictated by the mechanical cues. Overall, our theory demonstrates that opposing durotactic behaviors emerge via the interplay between intracellular signaling and cellmedium mechanical interactions in agreement with experiments, thereby elucidating complex mechano-sensing at the single-cell level.

category: biophysics


title: Drug addiction mutations unveil a methylation ceiling in EZH2-mutant lymphoma

abstract: Cancer mutations in Polycomb Repressive Complex 2 (PRC2) drive aberrant epigenetic states. Although therapies inhibiting the PRC2 enzymatic component EZH2 are FDA-approved, oncogene-specific dependencies remain to be discovered. Here, we identify mutations that confer both resistance and drug addiction to PRC2 inhibitors in EZH2-mutant lymphoma, resulting in cancer cells that paradoxically depend on drug for survival. Drug addiction is mediated by hypermorphic mutations in the CXC domain of EZH2, which maintain H3K27me3 levels even in the presence of PRC2 inhibitors. Drug removal leads to overspreading of H3K27me3, surpassing a repressive methylation ceiling compatible with lymphoma cell survival. Activating EZH2 cancer mutations establish an epigenetic state precariously close to this ceiling, which we show can be breached by inhibition of SETD2, a PRC2 antagonist, to block lymphoma growth. More broadly, we highlight how approaches to identify drug addiction mutations can be leveraged to discover cancer vulnerabilities.


title: A paracrine circuit of IL-1b/IL-1R1 between myeloid and tumor cells drives glioblastoma progression

abstract:
Monocytes and monocyte-derived macrophages (MDM) from blood circulation infiltrate and promote glioblastoma growth. Here we discover that glioma cells induce the expression of potent pro-inflammatory cytokine IL-1{beta} in MDM, which engages IL-1R1 in glioma cells, activates NF-{kappa}B pathway, and subsequently leads to the induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-1{beta}/IL-1R1 between the tumors and MDM creates an interdependence driving glioblastoma progression. Locally antagonizing IL-1{beta}/IL-1R1 leads to reduced MDM infiltration, diminished tumor growth, reduced exhausted CD8+ T cells, and thereby extends the survival of tumor-bearing mice. In contrast to IL-1{beta}, IL-1a exhibits anti-tumor effects. Genetic deletion of Il1a is associated with decreased recruitment of lymphoid cells and loss of interferon (IFN) signaling in various immune populations and subsets of malignant cells. IL-1{beta} antagonism of IL-1{beta} should be considered as an effective anti-glioblastoma therapy.

Graphical Abstract

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title: Laboratory evolution of synthetic electron transport system variants reveals a larger metabolic respiratory system and its plasticity

abstract: Respiration requires organisms to have an electron transport system (ETS) for the generation of proton motive force across the membrane that drives ATP synthase. Although the molecular details of the ETS are well studied and constitute textbook material, few studies have appeared to elucidate its systems biology. The most thermodynamically efficient ETS consists of two enzymes, an NADH: quinone oxidoreductase (NqRED) and a dioxygen reductase (O2RED), which facilitate the shuttling of electrons from NADH to oxygen. However, evolution has produced variations within ETS which modulate the overall energy efficiency of the system even within the same organism 1-3. The system-level impact of these variations and their individual physiological optimality remain poorly determined. To mimic varying ETS efficiency we generated four Escherichia coli deletion strains (named ETS-1H, 2H, 3H, and 4H) harboring unbranched ETS variants that pump 1, 2, 3, or 4 proton(s) per electron respectively. We then used a combination of synergistic methods (laboratory evolution, multi-omic analyses, and computation of proteome allocation) to characterize these ETS variants. We found that: (a) all four ETS variants evolved to a similar optimized growth rate, (b) the evolution of ETS variants was enabled by specific rewiring of major energy-generating pathways that couple to the ETS to optimize their ATP production capability, (c) proteome allocation per ATP generated was the same for all the variants, (d) the aero-type, that designates the overall ATP generation strategy 4 of a variant, remained conserved during its laboratory evolution, with the exception of the ETS-4H variant, and (e) integrated computational analysis of then data supported a proton-to-ATP ratio of 10 protons per 3 ATP for ATP synthase for all four ETS variants. We thus have defined the Aero-Type System (ATS) as a generalization of the aerobic bioenergetics, which is descriptive of the metabolic systems biology of respiration and demonstrates its plasticity.

category: systems biology


title: Chronic hM3Dq-DREADD mediated chemogenetic activation of parvalbumin-positive inhibitory interneurons in postnatal life alters anxiety and despair-like behavior in adulthood in a task and sex-dependent manner

abstract: Animal models of early adversity or neurodevelopmental disorders are associated with altered parvalbumin (PV)-positive inhibitory interneuron number and function, correlated with a dysregulated excitation-inhibition (E/I) balance that is implicated in the pathophysiology of neuropsychiatric disorders. We sought to address whether altering neuronal activity of PV-positive interneurons during the postnatal developmental window influences the emergence of anxio-depressive behaviors in adulthood, which are known to be perturbed in models of early adversity and neurodevelopmental disorders. We used a PV-Cre::hM3Dq-DREADD bigenic mouse line that selectively expresses the hM3Dq-DREADD receptor in PV-positive interneurons, and chemogenetically enhanced Gq signaling in PV-positive interneurons during the postnatal window via administration of the DREADD agonist, clozapine-N-oxide. Immunofluorescence studies indicated the selective expression of hM3Dq-DREADD in PV-positive interneurons in limbic circuits, and revealed a reduction in expression of the neuronal activity marker, c-Fos, in these circuits, following chemogenetic hM3Dq-DREADD mediated activation of PV-positive inhibitory interneurons. We noted no change in either growth or sensorimotor reflex milestones following chronic hM3Dq-DREADD mediated chemogenetic activation of PV-positive inhibitory interneurons in postnatal life. Adult male and female PV-Cre::hM3Dq-DREADD bigenic mice with a history of postnatal chemogenetic activation of PV-positive interneurons exhibited a reduction in anxiety and despair-like behavior in adulthood, which was noted in both a behavioral task and sex-dependent manner. These results indicate that altering neuronal activity within PV-positive interneurons during the critical postnatal developmental window can shape the emergence of anxio-depressive behaviors in adulthood, and suggest that interactions with sex as a variable play a key role in determining behavioral outcomes.


title: The Insulin receptor regulates the persistence of mechanical nociceptive sensitization in flies and mice

abstract: Early phase diabetes is often accompanied by pain sensitization. In the fruit fly Drosophila, the insulin receptor (InR) regulates the persistence of injury-induced thermal nociceptive sensitization. Whether Drosophila InR also regulates the persistence of mechanical nociceptive sensitization remains unclear. Mice with a sensory neuron deletion of the gene encoding the Insulin receptor (Insr) show normal nociceptive baselines, however, it is not known whether deletion of Insr in nociceptive sensory neurons leads to persistent nociceptive hypersensitivity in an inflammatory pain paradigm. In this study, we used fly and mouse nociceptive sensitization models to address these questions. In flies, InR mutants and larvae with sensory neuron-specific expression of RNAi transgenes targeting InR exhibited persistent mechanical hypersensitivity, as previously observed for the thermal sensory modality. Mice with a specific deletion of the Insr gene in NaV1.8+ nociceptive sensory neurons showed normal nociceptive thermal and mechanical baselines similar to controls. In an inflammatory paradigm, however, these mutant mice showed persistent mechanical (but not thermal) hypersensitivity, particularly in female mice. Mice with the NaV1.8+ sensory neuron specific deletion of Insr did not show metabolic abnormalities that would be typical of a systemic defect in insulin signaling. Our results show that some aspects of the regulation of nociceptive hypersensitivity by the Insulin receptor are shared between flies and mice and that this regulation is likely independent of metabolic effects.


title: Bidirectional modulation of neuronal excitability via ionic actuation of potassium

abstract:
Potassium K+ is a fundamental actor in the shaping of action potentials, and its concentration in the extracellular microenvironment represents a crucial modulator of neural excitability. Yet, its employment as a neuromodulation modality is still in its infancy. Recent advances in the technology of ionic actuators are enabling the control of ionic concentrations at the spatiotemporal scales of micrometers and milliseconds, thereby holding the promise of making the control of K+ concentration a key enabling technology for the next generation of neural interfaces. In this regard, a theoretical framework to understand the possibilities and limits offered by such technology is pivotal. To this aim, we exploit the Hodgkin-Huxley modeling framework, augmented to account for the perturbation of extracellular K+ concentration. We leverage methods of bifurcation analysis to investigate which regimes of electrical activity arise in the space of the input variables, namely the extent of ionic actuation and the synaptic current. We show that, depending on the type of target neuron, switchings of the class of excitability may occur in such space. These effects could rule out the possibility of eliciting tonic spiking when the extracellular K+ concentration is assumed as a sole control input. Building upon these findings, we show in simulations how to address the problem of neuromodulation via ionic actuation in a principled fashion. In this respect, we account for a bidirectional scenario, namely from the perspective of both inhibiting and stimulating electrical activity. We then provide a first-order motivation for the switchings of neural excitability in terms of the conductances of the K+-selective channels. Finally, we introduce a Pinsky-Rinzel-like model to investigate the effects of performing the ionic actuation locally at the neural membrane.

Author summaryNeural interfaces rely on technologies to sense and perturb the electrical activity of neurons. For the latter aim, many strategies have been established to date, each one targeting a different actor involved in the electrophysiology of neurons. Examples include electrical, chemical, and optogenetic techniques. However, the main actors that shape neuronal signals, namely ions such as potassium K+, are still not directly targeted. Recent advances in bioelectronic technologies are enabling the manipulation of ionic concentrations as a viable strategy for neuromodulation, which we refer to as ionic actuation. These findings come mainly from the experimental literature, and the theoretical understanding of how ionic actuation can be used to shape neural activity is still lacking. This paper aims to help fill this gap, adopting the ionic actuation of K+ as a case study. Our results could guide the design and control of novel neural interfaces targeting the ionic composition of cellular fluids. Moreover, they may suggest novel therapies for pathologies related to impairments in the regulation of ionic homeostasis, such as drug-resistant epilepsy.


title: The influence of stereopsis on visual saliency in a proto-object based model of selective attention

abstract: Some animals including humans use stereoscopic vision which reconstructs spatial information about the environment from the disparity between images captured by eyes in two separate adjacent locations. Like other sensory information, such stereoscopic information is expected to influence attentional selection. We develop a biologically plausible model of binocular vision to study its effect on bottom-up visual attention, i.e., visual saliency. In our model, the scene is organized in terms of proto-objects on which attention acts, rather than on unbound sets of elementary features. We show that taking into account the stereoscopic information improves the performance of the model in the prediction of human eye movements with statistically significant differences.


title: Information theory characteristics improve the prediction of lithium response in bipolar disorder patients using an SVM classifier

abstract: Bipolar disorder (BD) is a mood disorder with a high morbidity and death rate. Lithium (Li), a prominent mood stabilizer, is fully effective in roughly 30% of BD patients. The remaining patients respond partially or do not respond at all. Another drug used to treat BD patients is valproate (VPA). Plenty of efforts has been made to understand how these drugs affect the patients neurons. We have performed electrophysiological recordings in patient-derived dentate gyrus (DG) granule neurons for three groups: control individuals, BD patients who respond to Li treatment (LR), and BD patients who do not respond to Li treatment (NR). The recordings were analyzed by the statistical tools of modern information theory, which enabled us to recognize new relationships between the electrophysiological features. These added features included the entropy of several electrophysiological measurements and the mutual information between different types of electrophysiological measurements. Information theory features provided further knowledge about the distribution of the electrophysiological entities, which improved basic classification schemes. These newly added features enabled a significant improvement in our ability to distinguish the BD patients from the control individuals (an improvement from 60% accuracy to 74% accuracy) and the Li responders from the non-responders in the BD population using Support Vector Machine (SVM) classification algorithms (an improvement from 81% accuracy to 99% accuracy). These new tools showed that LR neurons are less distinguishable from control neurons after Li treatment but not after VPA treatment, whereas NR neurons become more distinguishable from control neurons after Li treatment.


title: DomeVR: A setup for experimental control of an immersive dome virtual environment created with Unreal Engine 4

abstract: 1Immersive virtual reality (VR) environments are a powerful tool to explore cognitive processes ranging from memory and navigation to visual processing and decision making - and to do so in a naturalistic yet controlled setting. As such, they have been employed across different species, and by a diverse range of research groups. Unfortunately, designing and implementing behavioural tasks in such environments often proves complicated. To tackle this challenge, we created DomeVR, an immersive VR environment built using Unreal Engine 4 (UE4). UE4 is a powerful game engine with photo-realistic graphics containing a visual scripting language designed for use by non-programmers. As a result, virtual environments are easily created using drag-and-drop elements. DomeVR aims to make these features accessible to neuroscience experiments. This includes a logging and synchronization system to solve timing uncertainties inherent in UE4; an interactive GUI for scientists to observe subjects during experiments and adjust task parameters on the fly, and a dome projection system for full task immersion in non-human subjects. These key features are modular and can easily be added individually into other UE4 projects. Finally, we present proof-of-principle data highlighting the functionality of DomeVR in three different species: human, macaque and mouse.


title: Functional coupling of the mesencephalic locomotor region and V2a reticulospinal neurons driving forward locomotion

abstract: Locomotion in vertebrates relies on high brain centers converging onto the mesencephalic locomotor region (MLR). How the MLR recruits brainstem reticulospinal neurons (RSNs) to initiate locomotion is incompletely understood due to the challenge of recording these cells in vivo. To tackle this question, we leveraged the transparency and genetic accessibility of larval zebrafish. In this model organism, we uncovered the locus of the MLR as a small region dorsal to the locus coeruleus containing glutamatergic and cholinergic neurons. MLR stimulations reliably elicited forward bouts of controlled duration and speed. We find that the MLR elicits forward locomotion by recruiting V2a RSNs in the pontine and retropontine regions, and gradually in the medulla. Remarkably, recruited V2a RSNs in the medulla act as maintain cells encoding speed of forward locomotion. Altogether, our study reveals that the MLR recruits genetically-identified reticulospinal neurons in the medulla to control the kinematics of exploration.


title: Firing behavior of single motor neurons of the tibialis anterior in human walking as non-invasively revealed by HDsEMG decomposition

abstract: Investigation of the firing behavior of spinal motor neurons (MNs) provides essential neuromuscular control information because MNs form the "final common pathway" in motor control. The MNs activated during human infants leg movements and rodent locomotion, mainly controlled by the spinal central pattern generator (CPG), show highly synchronous firing. In addition to spinal CPGs, the cerebral cortex is involved in neuromuscular control during walking in human adults. Thus, MN firing behavior during adult walking is expected to be similar to that of infants and rodents and has some unique features. Recent technical advances allow non-invasive investigation of MN firing by high-density surface electromyogram (HDsEMG) decomposition. Therefore, we investigated the MN firing behavior of the tibialis anterior muscle during walking by HDsEMG decomposition. We found motor unit recruitment modulation compared with steady isometric contractions, doublet firings, and gait phase-specific firings during walking. We also found high MN synchronization during walking over a wide range of frequencies, probably including cortical and spinal CPG-related components. The amount of MN synchronization was modulated between the gait phases and motor tasks. These results suggest that the central nervous system, including the spinal CPG and cerebral cortex, flexibly controls MN firing to generate appropriate muscle force during human walking. In addition to revealing the neural control mechanisms of walking, our data demonstrate the feasibility of non-invasive investigation of MNs during walking, which will open new frontiers for the study of neuromuscular function in medical and exercise sciences.


title: Kidins220 regulates the development of B cells bearing the {lambda} light chain

abstract:
The ratio between Ig{kappa} and Ig{lambda} light chain (LC)-expressing B cells varies considerably between species. We recently identified Kinase D-interacting substrate of 220 kDa (Kidins220) as an interaction partner of the BCR. In vivo ablation of Kidins220 in B cells resulted in a marked reduction of {lambda}LC-expressing B cells. Kidins220 knockout B cells fail to open and recombine the genes of the{lambda} LC locus, even in genetic scenarios where the{kappa} LC genes cannot be rearranged or where the {kappa}LC confers autoreactivity.{kappa} LC gene recombination and expression in Kidins220-deficient B cells is normal. Kidins220 regulates the development of {lambda}LC B cells by enhancing the survival of developing B cells and thereby extending the time-window in which the{lambda} LC locus opens and the genes are rearranged and transcribed. Further, our data suggest that Kidins220 guarantees optimal pre-BCR and BCR signaling to induce{lambda} LC locus opening and gene recombination during B cell development and receptor editing.

One Sentence SummaryWe demonstrate that the scaffold protein Kidins220 regulates the development of {lambda}LC B cells by supporting B cell precursor survival and optimizing pre-BCR and BCR signaling to open, recombine, and transcribe the genes of the{lambda} LC locus.

category: immunology


title: Breast cancer stem cell-derived tumors escape from γδ T cell immunosurveillance in vivo by modulating γδ T cell ligands

abstract: Triple negative breast cancer (TNBC) lacks targeted therapy options. TNBC is enriched in breast cancer stem cells (BCSCs), which play a key role in metastasis, chemoresistance, relapse and mortality. {gamma}{delta} T cells hold great potential in immunotherapy against cancer, and might be an alternative to target TNBC. {gamma}{delta} T cells are commonly observed to infiltrate solid tumors and have an extensive repertoire of tumor sensing, recognizing stress-induced molecules and phosphoantigens (pAgs) on transformed cells. We show that patient-derived triple negative BCSCs are efficiently recognized and killed by ex vivo expanded {gamma}{delta} T cells from healthy donors. Orthotopically xenografted BCSCs, however, were refractory to {gamma}{delta} T cell immunotherapy. Mechanistically, we unraveled concerted differentiation and immune escape: xenografted BCSCs lost stemness, expression of {gamma}{delta} T cell ligands, adhesion molecules and pAgs, thereby evading immune recognition by {gamma}{delta} T cells. Indeed, neither pro-migratory engineered {gamma}{delta} T cells, nor anti-PD-1 checkpoint blockade significantly prolonged overall survival of tumor-bearing mice. BCSC immune escape was independent of the immune pressure exerted by the {gamma}{delta} T cells, and could be pharmacologically reverted by Zoledronate or IFN- treatment. These results pave the way for novel combinatorial immunotherapies for TNBC.


title: T cell-mediated development of stromal fibroblasts with an immune-enhancing chemokine profile

abstract:
Stromal fibroblasts reside in inflammatory tissues that are characterized by either immune suppression or immune activation, but whether these cells adapt to these contrasting microenvironments is not known. Cancer-associated fibroblasts (CAFs) mediate immune quiescence by producing the chemokine CXCL12 that coats cancer cells to suppress T cell infiltration. We examined whether CAFs can adopt an immune-promoting chemokine profile. Single-cell RNA-sequencing of CAFs from mouse pancreatic adenocarcinomas identified a sub-population with decreased expression of CXCL12 and increased expression of the T cell-attracting chemokine, CXCL9, that was expanded when tumors were infiltrated with T cells. Conditioned media from activated CD8+ T cells containing TNF and IFN{gamma} converted the chemokine profile of stromal fibroblasts from a CXCL12+/CXCL9- immune suppressive phenotype into a CXCL12-/CXCL9+ immune-activating phenotype. Studies with recombinant cytokines showed that TNF acted synergistically with IFN{gamma} to induce CXCL9 expression, and alone was mainly responsible for suppressing CXCL12 expression. This coordinated chemokine switch demonstrates that stromal fibroblasts have a phenotypic plasticity that allow their adaptation to contrasting immune tissue microenvironments.

SummaryIt is unclear whether and how stromal fibroblasts adapt and contribute to varying tissue microenvironments. This study shows immune-suppressive cancer-associated fibroblasts (CAFs) have the capacity to develop an immune-promoting chemokine profile in response to cytokines from infiltrating T cells.


title: Climate change will redefine taxonomic, functional, and phylogenetic diversity patterns of Odonata in space and time

abstract: Climate change is rearranging the mosaic of biodiversity on our planet. These broad-scale species re-distributions will affect the structure of communities across multiple biodiversity facets (taxonomic, phylogenetic, and functional diversity). The current challenges to understand such effects involve focusing on organisms other than vertebrates and considering the signature of species redistribution on phylogenetic and functional diversity in addition to species composition. Using European dragonflies and damselflies (Odonata), we asked: i) how climate change will redefine taxonomic, phylogenetic, and functional diversity at continental scales; ii) which traits will mediate species response to global change; and iii) whether this response will be conserved across the phylogeny. First, we constructed stacked species distribution models for 107 species of Odonata under current and future climate conditions. Then, we quantified the temporal variation of taxonomic, functional and phylogenetic components, forecasting alpha and beta diversity changes through our geographical grid. Lastly, we used phylogenetic comparative models to test the influence of phylogeny and traits on range shifts. We observed broad latitudinal and altitudinal rearrangements in community composition driven by climate change. Given the high dispersal ability of Odonata, changes are predicted to be rapid, especially in areas experiencing faster climate change rates. According to our predictions, changes in species composition cascade to affect functional and phylogenetic diversity, determining broad turnovers in traits and evolutionary lineages. There was no clear phylogenetic signal in the range-shift response of European Odonata to climate change. According to our phylogenetic regression models, only body size and flight period can be partly correlated with observed range shifts. By considering all three primary facets of biodiversity, our results support the design of inclusive management and conservation strategies, accounting not only for the diversity of species, but also the services they provide and the phylogenetic heritage they carry in a targeted ecosystem.


title: Prey resources are more important than climatic conditions for predicting the distribution of a broad-ranged apex predator

abstract: A current biogeographic paradigm states that climate regulates species distributions at continental scales and that biotic interactions are undetectable at coarse-grain extents. However, recent advances in spatial modelling show that incorporating food resource distributions are important for improving model predictions at large distribution scales. This is particularly relevant to understand the factors limiting distribution of widespread apex predators whose diets are likely to vary across their range. The harpy eagle (Harpia harpyja) is a large raptor, whose diet is largely comprised of arboreal mammals, such as sloths and primates, all with broad distributions across Neotropical lowland forest. Here, we used a hierarchical modelling approach to determine the relative importance of abiotic factors and prey resource distribution on harpy eagle range limits. Our hierarchical approach consisted of the following modelling sequence of explanatory variables: (a) abiotic covariates, (b) prey resource distributions predicted by an equivalent modelling for each prey, (c) the combination of (a) and (b), and (d) as in (c) but with prey resources considered as a single prediction equivalent to prey species richness. Incorporating prey distributions improved model predictions but using solely these biotic covariates still resulted in a high performing model. In the Abiotic model, Climatic Moisture Index (CMI) was the most important predictor, contributing 80 % to model prediction. Three-toed sloth (Bradypus spp.) was the most important prey resource, contributing 57 % in a combined Abiotic-Biotic model, followed by CMI contributing 29 %. Harpy eagle distribution had moderate to high environmental overlap across all prey distributions in geographic space when measured individually, but overlap was substantially lower in environmental space when prey distributions were combined. With strong reliance on prey distributions across its range, harpy eagle conservation programs must therefore consider its most important food resources as a key element in the protection of this threatened raptor.


title: Systematic identification of unannotated ORFs in Drosophila reveals evolutionary heterogeneity

abstract: De novo gene origination, where a previously non-genic genomic sequence becomes genic through evolution, has been increasingly recognized as an important source of evolutionary novelty across diverse taxa. Many de novo genes have been proposed to be protein-coding, and in several cases have been experimentally shown to yield protein products. However, the systematic study of de novo proteins has been hampered by doubts regarding the translation of their transcripts without the experimental observation of protein products. Using a systematic, ORF-focused mass-spectrometry-first computational approach, we identify almost 1000 unannotated open reading frames with evidence of translation (utORFs) in the model organism Drosophila melanogaster, 371 of which have canonical start codons. To quantify the comparative genomic similarity of these utORFs across Drosophila and to infer phylostratigraphic age, we further develop a synteny-based protein similarity approach. Combining these results with reference datasets on tissue- and life-stage-specific transcription and conservation, we identify heterogeneity amongst these utORFs. Contrary to expectations, the fastest-evolving utORFs are not the youngest evolutionarily. We observed more utORFs in the brain than in the testis. Most of the identified utORFs may be of de novo origin, even accounting for the possibility of false-negative similarity detection. Finally, sequence divergence after an inferred de novo origin event remains substantial, raising the possibility that de novo proteins turn over frequently. Our results suggest that there is substantial unappreciated diversity in de novo protein evolution: many more may exist than have been previously appreciated; there may be divergent evolutionary trajectories; and de novo proteins may be gained and lost frequently. All in all, there may not exist a single characteristic model of de novo protein evolution, but rather complex origins and evolutionary trajectories for de novo proteins.


title: The genetic architectures of vine and skin maturity in tetraploid potato

abstract: As with most crops, maturity is a critical trait for potato production and therefore breeding. In this study, both vine and skin maturity, which refer to foliar senescence and adherence of the tuber periderm, respectively, were measured in breeding populations (N = 586) over a two-year period. It is well established that S. tuberosum Cyclin DOF Factor 1 (CDF1) affects vine maturity, but this is the first study to quantify its effect on skin maturity, using linked markers discovered through genome-wide association studies (GWAS). Skin maturity had slightly less genomic heritability than vine maturity (0.41 vs. 0.47), and the importance of CDF1 was considerably less for skin maturity, accounting for only 39% of the additive variance vs. 70% for vine maturity. Using path analysis, the additive genetic correlation between the two maturity traits was estimated at 0.65, of which 0.51 was attributed to CDF1. Within the GWAS panel was a half-diallel population derived from three parents, which was analyzed by joint linkage mapping. Based on the estimated effects of the parental haplotypes and prior knowledge of the allelic series for CDF1, the CDF1 allele for each haplotype was predicted and ultimately confirmed through whole-genome sequencing. The ability to connect statistical alleles from QTL models with biological alleles based on DNA sequencing represents a new milestone in genomics-assisted breeding for tetraploid species.

category: genetics


title: Remodeling of gene regulatory networks underlying thermogenic stimuli-induced adipose beiging

abstract: Beige adipocytes are induced by cold temperatures or {beta}3-adrenergic receptor (Adrb3) agonists. They create heat through glucose and fatty acid (FA) oxidation, conferring metabolic benefits. The distinct and shared mechanisms by which these treatments induce beiging are unknown. Here, we performed single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq) on adipose tissue from mice exposed to cold or an Adrb3 agonist to identify cellular and chromatin accessibility dynamics during beiging. Both stimuli induce chromatin remodeling that influence vascularization and inflammation in adipose. Beige adipocytes from cold-exposed mice have increased accessibility at genes regulating glycolytic processes, whereas Adrb3 activation increases cAMP responses. While both thermogenic stimuli increase accessibility at genes regulating thermogenesis, lipogenesis, and beige adipocyte development, the kinetics and magnitudes of the changes are distinct for the two stimuli. Accessibility changes at lipogenic genes are linked to functional changes in lipid composition of adipose. Both stimuli tend to decrease the proportion of palmitic acids, a saturated FA in adipose. However, Adrb3 activation increases the proportion of monounsaturated FAs, whereas cold increases the proportion of polyunsaturated FAs. These findings reveal common and distinct mechanisms of cold and Adrb3 induced beige adipocyte biogenesis, and identify the unique functional consequences of manipulating these pathways in vivo.

category: genomics


title: A Self-Purifying Microfluidic System for Identifying Drugs Acting Against Adult Schistosomes

abstract: The discovery of novel antihelminthic molecules to combat the development and spread of schistosomiasis, a disease caused by several Schistosoma flatworm species, mobilizes significant research efforts worldwide. In the absence of reliable and practical biochemical assays for measuring the viability of adult worms, the antischistosomicidal activity of molecules is usually evaluated by a detailed microscopic observation of worm mobility and/or integrity upon drug exposure. These assays have the disadvantage of being inacurate, subjective, biased by the limited in vitro worm viability and difficult to integrate at high density. We describe here a self-purifiying microfluidic system enabling the selection of healthy adult worms and the identification of molecules acting on the parasite. The worms are assayed in a dynamic environment that eliminates unhealthy worms that cannot attach firmly to the chip walls prior to being exposed to the drug. The detachment of the worms is also used as second step readout for identifying active compounds. We have validated this new fluidic screening approach using the two major antihelmintic drugs, Praziquantel and Artemisinin. The reported dynamic system is simple to produce and to parallelize. Importantly, it enables a quick, sensitive and reliable detection of antischistosomal compounds in no more than one day. This system can potentially be modified in the future to better mimic the natural habitat of the parasite.


title: Engineering Proprioceptive Implants via Surgical and Regenerative Approaches: Preliminary Interpretations

abstract: The periodontal ligaments are a group of specialized connective tissue fibres with vascular and neural elements that essentially attach a tooth to the alveolar bone. Endosseous dental implant replacing a lost tooth, gets ankylosed to the alveolar bone without intervening periodontal fibres (osseointegration). Hence, proprioception, one of the most important function of periodontal ligament is not elicited by commercial dental implants currently in use. To salvage the flaw, in our proof-of-principle trial in rabbits, biodegradable nanofibres were coiled around the additive manufactured (AM) customized titanium implants. Further, human dental pulp stem cells (DPSCs), adult mesenchymal stem cells of neuro-ectodermal origin, were seeded on the nanofibrous coated, orthotopically placed 3D-printed titanium implants and were induced to differentiate into neural cell lineages. The invivo anchoring mechanism of these biodegradable neuro-supportive scaffold coated implants could probably be "proprioceptive osseointegration" instead of defaults events leading to normal "osseointegration" and could exhibit features similar to periodontium, having possible anastomosis between the severed nerve terminals present in the wall of the extraction socket relaying to/from brain and newly differentiated neural cells present in the regenerated neo-tissue complex, gradually replacing the biodegradable scaffold and may eventually results in the development of proprioceptive osseointegrated root-form endosseous dental implants in near future.


title: Noncoding RNA's competing endogenous gene pair as motif in serous ovarian cancer

abstract: The non-coding RNA (ncRNA) regulation apprears to be associated to the diagnosis and targeted therapy of complex diseases. Motifs of non-coding RNAs and genes in the competing endogenous RNA (ceRNA) network would probably contribute to the accurate prediction of serous ovarian carcinoma (SOC). Hence, we profiled a whole transcriptome of eight human SOCs and eight controls and constructed a ceRNA network including mRNAs, long ncRNAs, and circular RNAs (circRNAs). We identified the mRNA-ncRNA-mRNA motifs in the ceRNA network named the non-coding RNAs competing endogenous gene pairs (ceGPs), through the denoised individualized pair analysis of gene expression (deiPAGE) proposed in this study. 18 cricRNAs ceGPs (cceGPs) were identified from multiple cohorts and were fused as an indicator (SOC index) for SOC discrimination, which carried a high predictive capacity in independent cohorts. It was found that the index was negatively correlated with the CD8+/CD4+ ratio in tumour-infiltration, reflecting the migration and growth of tumour cells in ovarian cancer progression.


title: Circular RNA's competing endogenous gene pair as motif in serous ovarian cancer


title: Principal component analysis- and tensor decomposition-based unsupervised feature extraction to select more reasonable differentially methylated cytosines: Optimization of standard deviation versus state-of-the-art methods

abstract:
MotivationIn contrast to RNA-seq analysis, which has various standard methods, no standard methods for identifying differentially methylated cytosines (DMCs) exist. To identify DMCs, we tested principal component analysis and tensor decomposition based on unsupervised feature extraction with optimized standard deviation whose effectiveness toward differentially expressed gene (DEG) identification was recently recognized.

ResultsThe proposed methods can outperform some conventional methods, including those that must assume beta-binomial distribution for methylation that the proposed methods do not have to assume especially when applied to methylation profiles measured using high throughput sequencing. DMCs identified by the proposed method are also significantly overlapped with various functional sites, including known differentially methylated regions, enhancers, and DNase I hypersensitive sites. This suggests that the proposed method is a promising candidate for standard methods for identifying DMCs..

AvailabilitySample R source code is available at https://github.com/tagtag/PCAUFEOPSD

Contacttag@granular.com


title: DeepToA: An Ensemble Deep-Learning Approach to Predicting the Theater of Activity of a Microbiome

abstract:
MotivationMetagenomics is the study of microbiomes using DNA sequencing. A microbiome consists of an assemblage of microbes that is associated with a "theater of activity" (ToA). To what degree does the taxonomic and functional content of the former depend on the (details of the) latter? More technically, given a taxonomic and/or functional profile estimated from metagenomic sequencing data, how to predict the associated ToA? Here we present a deep learning approach to this question. We use both taxonomic and functional profiles as input. We apply node2vec to embed hierarchical taxonomic profiles into numerical vectors. We then perform dimension reduction using clustering, to address the sparseness of the taxonomic data and thus make it more amenable to deep learning algorithms. Functional features are combined with textual descriptions of protein families or domains. We present an ensemble deep-learning framework DeepToA for predicting the  theater of activity" of microbial community, based on taxonomic and functional profiles. We use SHAP (SHapley Additive exPlanations) values to determine which taxonomic and functional features are important for the prediction.

ResultsBased on 7,560 metagenomic profiles downloaded from MGnify, classified into ten different theaters of activity, we demonstrate that DeepToA has an accuracy of 98.61%. We show that adding textual information to functional features increases the accuracy.

AvailabilityOur approach is available at http://ab.inf.uni-tuebingen.de/software/deeptoa.

Contactdaniel.huson@uni-tuebingen.de

Supplementary informationSupplementary data are available at Bioinformatics online.


title: Talin-drug interaction reveals a key molecular determinant for biphasic mechanical effect: studied under single-molecule resolution

abstract: Talin as an adhesion protein, exhibits a strong force-dependent structure-function dynamics. Being a mechanosensitive focal adhesion (FA) protein, talin might interact to several FA targeting drugs; however, the molecular mechanism of talin-drug interactions remains elusive. Here we combined magnetic tweezers and molecular dynamics (MD) simulation to explore mechanical stability of talin with three drugs based on their talin specificity. Interestingly, our study revealed that talin displays a bimodal force distribution with a low and high unfolding force population. We observed that talin nonspecific drugs (tamoxifen and letrozole) display biphasic effect: increase talin mechanical stability upto optimum concentration, followed by a decrease in stability with further concentration increase. By contrast, talin-specific cyanidin 3-O-glucoside promotes a steady increase to talin mechanical stability with its concentration. We reconciled our observation from the simulation study: tamoxifen enters into talin hydrophobic core, eventually destabilizing the protein; whereas cyanidin 3-O-glucoside stabilizes the protein core by maintaining the inter-helix distance. Finally, we observed a strong correlation among hydrophobicity and cavity analysis, illustrating a detailed mechanistic analysis of drug effect on the mechanosensitive protein. Overall this study presents a novel perspective for drug designing against mechanosensitive proteins and studying off-target effects of already known drugs.


title: Tumor spheroids accelerate persistently invading cancer cells

abstract: Glioblastoma brain tumors form in brains white matter and remains one of the most lethal cancers despite intensive therapy and surgery. The complex morphology of these tumors includes infiltrative growth and gain of cell motility. Therefore, various brain-mimetic model systems have been developed to investigate invasion dynamics. Despite this, exactly how gradients of cell density, chemical signals and metabolites influence individual cells migratory behavior remains elusive. Here we show that the gradient field - induced by the spheroid - accelerates cells invasion of the extracellular matrix. We show that cells are pushed away from the spheroid along a radial gradient, as predicted by a biased persistent random walk (BPRW). Thus, our results grasp in a simple model the complex behavior of metastasizing cells. We anticipate that this well-defined and quantitative assay could be instrumental in the development of new anti-cancer strategies.


title: Loss of HOXA10 causes endometrial hyperplasia progressing to endometrial cancer

abstract: Endometrial cancer is the fourth most common malignancy in women and the precursor lesion is endometrial hyperplasia. HOXA10 is a transcription factor that plays key roles in endometrial functions such as the endowment of receptivity, embryo implantation, and trophoblast invasion. Herein, using testicular transgenesis, we developed transgenic mice that expressed an shRNA against HOXA10 and observed that in these animals there was nearly 70% reduction in the expression of HOXA10. We termed these animals as HOXA10 hypomorphs and observed that downregulation of HOXA10 led to the development of endometrial hyperplasia and most animals developed well-differentiated endometrial adenocarcinoma with age. There was an increased proliferation of the uterine glands and stromal cells in the hypomorphs along with a gain of OVGP1 expression and increased levels of ER and ER{beta}. In parallel, there was increased expression of Wnt4 and {beta}-Catenin, SOX9 and YAP1. We propose that chronic reduction in HOXA10 expression disrupts multiple pathways in the uterus that aids in the development of endometrial hyperplasia which progresses to endometrial cancer with age.


title: The catalytic domain of cellulose synthase (CESA) is involved in vesicle trafficking and protein dynamics

abstract: Cellulose, as the main component of the plant cell wall, is synthesized by a multimeric protein complex named the cellulose synthase (CESA) complex or CSC. In plant cells, CSCs are transported through the endomembrane system to the PM, but how catalytic activity or conserved motifs around the catalytic core domain influence vesicle trafficking or protein dynamics is not well understood. Here, we used a functional YFP-tagged AtCESA6 and site-directed mutagenesis to create 18 single amino acid replacement mutants in key motifs of the catalytic domain including DDG, DXD, TED and QXXRW, to comprehensively analyze how catalytic activity affects plant growth, cellulose biosynthesis, as well as CSC dynamics and trafficking. Plant growth and cellulose content were reduced by nearly all mutations. Moreover, mutations in most conserved motifs reduced the velocity of CSC movement in the PM as well as delivery of CSCs to the PM. Interestingly, the abundance of YFP-CESA6 in the Golgi apparatus was increased or reduced by mutations in DDG and QXXRW motifs, respectively. Post-Golgi trafficking of CSCs was also differentially perturbed by these mutations and, based on these phenotypes, the 18 mutants could be divided into two major groups. Group I comprises mutations causing significantly increased Golgi fluorescence intensity with either an increase or no change in the abundance of cortical SmaCCs compared with wild-type. In contrast, Group II represents mutations with significantly decreased Golgi fluorescence intensity and/or reduced SmaCC density. We propose that Group I mutations cause CSC trafficking defects whereas Group II mutations affect normal CSC rosette formation and hence interfere with subsequent CSC trafficking. Collectively, our results demonstrate that the catalytic domain of CESA6 is essential not only for cellulose biosynthesis, but also complex formation, protein folding and dynamics, vesicle trafficking, or all of the above.

category: plant biology