title: The mouse papillomavirus epigenetic signature is characterised by DNA hypermethylation after lesion regression

abstract:
The {beta} genus of human papillomaviruses (HPVs) infect cutaneous epidermis. They contribute to the development of cutaneous squamous cell carcinoma (cSCC) in individuals with epidermodysplasia verruciformis, and increase susceptibility to UV-induced cSCC. This has been demonstrated in UV-exposed mice previously infected with mouse papillomavirus (MmuPV1). However, the mechanism by which {beta}-HPVs contribute to cSCC is unclear. We propose that viral infection leaves a DNA methylation signature following resolution of the active lesion that may contribute to increased susceptibility to UV-induced cSCC.

To test this, we carried out Reduced Representation Bisulphite Sequencing on DNA from tail skin of mice with actively infected lesions, MmuPV1-infected then healed lesions (regressed infection), and mock-infected control mice. Genome-scale DNA methylation libraries were generated and analysed for differentially methylated regions throughout the genome, and for HPV sequences.

We found that DNA of active lesions was not differentially methylated compared to matched control mice. In contrast, 834 differentially methylated fragments were identified in regressed lesions compared to mock-infected control skin. An analysis of MmuPV1 viral DNA demonstrated retention of viral DNA in some of the lesions that had regressed. Overall, the viral sequences identified showed over-representation of sequences from the E4 region. The DNA hypermethylation that we found in regressed MmuPV1 lesions may be a factor in the increased susceptibility of mice to UV-induced cSCC.

AUTHOR SUMMARYPapillomavirus infections can be asymptomatic, can cause warts, and in some cases can lead to cancer. There is direct evidence for mouse papillomavirus infection resulting in increased susceptibility to UV-induced cutaneous squamous cell carcinoma in a mouse model. We propose that DNA methylation following viral infection may contribute to the increased susceptibility. We describe the DNA methylation landscape during an active infection with mouse papillomavirus and following regression of the lesion. We found that there were very few differentially methylated DNA fragments during active infection. In contrast, over 800 differentially methylated DNA fragments were identified following regression of the lesion. This is the first description of the genome-wide DNA methylation landscape for mouse papillomavirus, to our knowledge. The dramatic DNA hypermethylation that we observe following resolution of infection may contribute to a  hit and run mechanism for the increased susceptibility to UV-induced cancer by papillomaviruses.

category: pathology


title: Deep learning identifies pathological abnormalities predictive of graft loss in kidney transplant biopsies

abstract:
BackgroundInterstitial fibrosis, tubular atrophy, and inflammation are major contributors to renal allograft failure. Here we seek an objective, quantitative pathological assessment of these lesions to improve predictive utility.

MethodsWe constructed a deep-learning-based pipeline recognizing normal vs. abnormal kidney tissue compartments and mononuclear leukocyte (MNL) infiltrates from Periodic acid-Schiff (PAS) stained slides of transplant biopsies (training: n=60, testing: n=33) that quantified pathological lesions specific for interstitium, tubules and MNL infiltration. The pipeline was applied to 789 whole slide images (WSI) from baseline (n=478, pre-implantation) and 12-month post-transplant (n=311) protocol biopsies in two independent cohorts (GoCAR: 404 patients, AUSCAD: 212 patients) of transplant recipients to correlate composite lesion features with graft loss.

ResultsOur model accurately recognized kidney tissue compartments and MNLs. The digital features significantly correlated with Banff scores, but were more sensitive to subtle pathological changes below the thresholds in Banff scores. The Interstitial and Tubular Abnormality Score (ITAS) in baseline samples was highly predictive of 1-year graft loss (p=2.8e-05), while a Composite Damage Score (CDS) in 12-month post-transplant protocol biopsies predicted later graft loss (p=7.3e-05). ITAS and CDS outperformed Banff scores or clinical predictors with superior graft loss prediction accuracy. High/intermediate risk groups stratified by ITAS or CDS also demonstrated significantly higher incidence of eGFR decline and subsequent graft damage.

ConclusionsThis deep-learning approach accurately detected and quantified pathological lesions from baseline or post-transplant biopsies, and demonstrated superior ability for prediction of posttransplant graft loss with potential application as a prevention, risk stratification or monitoring tool.


title: Cannabidiol pretreatment attenuates locomotor alterations and cytokine production in an autoimmune hepatitis model

abstract: Cannabidiol (CBD) is a major active component of the Cannabis plant (Cannabis Sativa L.), which unlike tetrahydrocannabinol (THC) is devoid of euphoria-inducing properties. Broadly, CBD has demonstrated anxiolytic-like, anti-inflammatory and immunomodulatory effects. Concanavalin A (ConA) is a lectin found in the jack bean (Canavalia ensiformis) and it has been associated with a variety of toxicological effects (upon them mitogenic, cytotoxic and hepatotoxic). Intravenous administration of ConA is widely used for the induction of a model to study autoimmune hepatitis (AIH) in mice and the injury is mainly driven by activation and uptake of T-cells in liver. The aim of the present study was to investigate the effects of CBD administration (20 mg/kg), on adult mice, on locomotor activity and inflammatory markers, upon induction of AIH by ConA administration (20 mg/kg) on Balb/C mice. Inflammatory analysis was assessed by determining the IL-2, IL-4, IL-10 and INF-{gamma} levels on plasma and sickness-like behavior assessed with open-field test. The results indicate that CBD pretreatment ameliorates impaired locomotor activity. IL-2, IL-4 and INF-{gamma} levels on plasma were increased after ConA intoxication (inflammation index) and were reduced when mice were pre-treated with CBD. The detected IL-10 levels were increased when CBD pretreated, suggesting a protective anti-inflammatory effect.

category: pharmacology and toxicology


title: Positive modulation of cerebellar α6GABAA receptors for treating essential tremor: a proof-of-concept study in harmaline-treated mice

abstract:
BackgroundThe etiology of essential tremor (ET) remains unclear but may involve abnormal firing of Purkinje cells, which receive excitatory inputs from granule cells in the cerebellum. Since 6 subunit-containing GABAA receptors (6GABAARs) are abundantly expressed in granule cells, we validated a hypothesis that 6GABAAR-selective positive allosteric modulators (PAMs) are promising pharmacological interventions for ET therapy.

MethodsEmploying the harmaline-induced ET model in male ICR mice, we evaluated the possible anti-tremor effects of four 6GABAAR-selective PAMs, the pyrazoloquinolinones Compound 6 and LAU-463 and their respective deuterated derivatives. Propranolol, a clinical anti-tremor agent, was employed as positive control. To investigate the involvement of cerebellar 6GABAARs in the antitremor effect of intraperitoneal (i.p.) Compound 6, furosemide, an 6GABAAR antagonist, was intracerebellarly (i.cb.) co-administered with Compound 6. The burrowing activity, an indicator of wellbeing in rodents, was measured concurrently.

ResultsHarmaline (10-30 mg/kg, s.c.) induced action tremor in ICR mice dose-dependently and markedly reduced their burrowing activity. Compound 6 (3 and 10 mg/kg, i.p.) significantly attenuated harmaline (20 mg/kg)-induced action tremor and burrowing activity impairment. Propranolol (20 mg/kg, i.p.) diminished tremor but failed to restore the burrowing activity in harmaline-treated mice. Importantly, both anti-tremor and burrowing activity restorative effects of Compound 6 (10 mg/kg, i.p.) was significantly reversed by co-administration of i.cb. furosemide at a dose (10 nmol/0.5 l) having no effect per se. All four 6GABAAR PAMs exhibited a similar therapeutic efficacy.

Conclusion6GABAAR-selective PAMs significantly attenuated action tremor and restored physical well-being in a mouse model mimicking ET by acting in the cerebellum. Thus, 6GABAAR-selective PAMs may be potential therapeutic agents for ET.


title: Evidence for a multicellular symplasmic water pumping mechanism across vascular plant roots

abstract:
With global warming, climate zones are projected to shift poleward, and the frequency and intensity of droughts to increase, driving threats to crop production and ecosystems. Plant hydraulic traits play major roles in coping with such droughts, and process-based plant hydraulics (water flowing along decreasing pressure {Psi}p or total water potential {Psi}tot gradients) has newly been implemented in land surface models.

An enigma reported for the past 35 years is the observation of water flowing along increasing water potential gradients across roots. By combining the most advanced modelling tool from the emerging field of plant micro-hydrology with pioneering cell solute mapping data, we found that the current paradigm of water flow across roots of all vascular plants is incomplete: it lacks the impact of solute concentration (and thus negative osmotic potential {Psi}o) gradients across living cells. This gradient acts as a water pump as it reduces water tension without loading solutes in plant vasculature (xylem). Importantly, water tension adjustments in roots may have large impacts in leaves due to the tension-cavitation feedback along stems.

Here, we mathematically demonstrate the water pumping mechanism by solving water flow equations analytically on a triple-cell system. Then we show that the simplistic upscaled equations hold in 2- and 3-D maize, grapevine and Arabidopsis complex hydraulic anatomies, and that water may flow "uphill" of water potential gradients toward xylem as observed experimentally.

Besides its contribution to the fundamental understanding of plant water relations, this study lays new foundations for future multidisciplinary research encompassing plant physiology and ecohydrology, and has the ambition to mathematically capture a keystone process for the accurate forecasting of plant water status in crop models and LSMs.

Graphical Abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/439789v1_ufig1.gif" ALT="Figure 1">
View larger version (85K):
org.highwire.dtl.DTLVardef@a7db9borg.highwire.dtl.DTLVardef@42bb32org.highwire.dtl.DTLVardef@1100204org.highwire.dtl.DTLVardef@1f45a48_HPS_FORMAT_FIGEXP  M_FIG C_FIG Highlights- We provide a scale-consistent solution of water flow equations across root tissues
- Symplasmic osmotic potential gradients are missing in the current theory of root water uptake
- The model solves the empirical enigma of root water uptake uphill of water potential gradients

category: physiology


title: Air leaks: stapling affects porcine lungs biomechanics

abstract:
During thoracic operations, surgical staplers resect cancerous tumors and seal the spared lung. However, post-operative air leaks are undesirable clinical consequences: staple legs wound lung tissue. Subsequent to this trauma, air leaks from lung tissue into the pleural space. This affects the lungs physiology and patients recovery.

The objective is to biomechanically and visually characterize porcine lung tissue with and without staples in order to gain knowledge on air leakage following pulmonary resection. Therefore, a syringe pump filled with air inflates and deflates eleven porcine lungs cyclically without exceeding 10 cmH2O of pressure. Cameras capture stereo-images of the deformed lung surface at regular intervals while a microcontroller simultaneously records the alveolar pressure and the volume of air pumped. The raw images are then used to compute tri-dimensional displacements and strains with the Digital Image Correlation method (DIC).

Air bubbles originated at staple holes of inner row from exposed porcine lung tissue due to torn pleural on costal surface. Compared during inflation, left upper or lower lobe resections have similar compliance (slope of the pressure vs volume curve), which are 9% lower than healthy lung compliance. However, lower lobes statistically burst at lower pressures than upper lobes (p-value<0.046) in ex vivo conditions confirming previous clinical in vivo studies. In parallel, the lung deformed mostly in the vicinity of staple holes and presented maximum shear strain near the observed leak location. To conclude, a novel technique DIC provided concrete evidence of the post-operative air leaks biomechanics. Further studies could investigate causal relationships between the mechanical parameters and the development of an air leak.


title: Novel genome characteristics contribute to the invasiveness of Phragmites australis (common reed)

abstract: The rapid invasion of the non-native Phragmites australis (Poaceae, subfamily Arundinoideae) is a major threat to native ecosystems in North America. We describe a 1.14 Gbp reference genome for P. australis and compare invasive (ssp. australis) and native (ssp. americanus) genotypes collected across the Laurentian Great Lakes to deduce genomic bases driving its invasive success. We report novel genomic features including a lineage-specific whole genome duplication, followed by gene loss and preferential retention of genes associated with transcription factors and regulatory functions in the remaining duplicates. The comparative transcriptomic analyses revealed that genes associated with biotic stress and defense responses were expressed at a higher basal level in invasive genotypes, but the native genotypes showed a stronger induction of defense responses following fungal inoculation. The reference genome and transcriptomes, combined with previous ecological and environmental data, support the development of novel, genomics-assisted management approaches for invasive Phragmites.

category: plant biology


title: Cytosolic fumarase acts as a metabolic fail-safe for both high and low temperature acclimation of Arabidopsis thaliana

abstract: Plants acclimate their photosynthetic capacity in response to changing environmental conditions. In Arabidopsis thaliana, photosynthetic acclimation to cold requires the accumulation of the organic acid fumarate, catalysed by a cytosolic fumarase FUM2. However, the role of this accumulation is currently unknown. In this study, we use an integrated experimental and modelling approach to examine the role of FUM2 and fumarate across the physiological temperature range. Using physiological and biochemical analyses, we demonstrate that FUM2 is necessary for high as well as low temperature acclimation. We have adapted a reliability engineering technique, Failure Mode and Effect Analysis (FMEA), to formalize a rigorous approach for ranking metabolites according to the potential risk that they pose to the metabolic system. FMEA identifies fumarate as a low-risk metabolite, while its precursor, malate, is shown to be high-risk and liable to cause system instability. We conclude that the role of cytosolic fumarase, FUM2, is to provide a fail-safe, controlling malate concentration, maintaining system stability in a changing environment. We argue that FMEA is a technique that is not only useful in understanding plant metabolism but can also be used to study reliability in other systems and synthetic pathways.


title: Effects of straw returning with potassium fertilizer on the stem lodging resistance, grain quality and yield of spring maize (Zea mays L.)

abstract: The effects of straw returning with potassium fertilizer on the stem lodging resistance, grain quality and yield of spring maize were investigated to provide a scientific basis for the rational utilization of Inner Mongolia spring maize straw and potassium fertilizer resources. This study utilized Xianyu 335 as the test material, and a split plot design was carried out in three ecological regions from eastern to western Inner Mongolia (Tumochuan Plain irrigation area, Hetao Plain irrigation area and Lingnan warm dry zone), with the straw returning method as the main plot and potassium fertilizer dosage as the subplot. The stem resistance index, grain quality and yield were systematically identified. Both application of potassium fertilizer and straw returning improved the resistance and yield indicators of spring maize. Straw returning increased the effectiveness of potassium fertilizer application on spring maize plant height, ear height, fresh weight of stems, brix of stems and stem puncture strength by 2.82%-5.22%, 3.11%-5.90%, 15.96%-19.78%, 4.35%-4.50% and 8.89%-14.82%, respectively. Straw returning increased the effectiveness of potassium fertilizer application on the spring maize grain protein content, spring maize grain crude fat content, maize yield and yield variation coefficient by 3.49%-6.50%, 2.09%-4.43%, 4.87%-12.50% and 5.07%-7.55%, respectively. Straw returning can be combined with reasonable application of potassium fertilizer to increase the effectiveness of potassium fertilizer and enhance lodging resistance. Along with increased maize yield, straw returning also improves grain quality and enhances yield stability, providing a theoretical basis for high-yield and stress-resistant cultivation of Inner Mongolia spring maize, which can be popularized and applied in the spring maize planting areas of Inner Mongolia.


title: Correlated Functional Connectivity and Glucose Metabolism in Brain White Matter Revealed by Simultaneous MRI/PET

abstract: Blood oxygenation level-dependent (BOLD) signals in white matter (WM) have usually been ignored or undetected, consistent with the lower vascular density and metabolic demands in WM than in gray matter (GM). Despite converging evidence demonstrating the reliable detection of BOLD signals in WM evoked by neural stimulation and in a resting state, few studies have examined the relationship between BOLD functional signals and tissue metabolism in WM. By analyzing simultaneous recordings of MRI and PET data, we found that the correlations between low frequency resting state BOLD signals in WM are spatially correlated with local glucose uptake, which also covaried with the amplitude of spontaneous low frequency fluctuations in BOLD signals. These results provide further evidence that BOLD signals in WM reflect variations in metabolic demand associated with neural activity, and suggest they should be incorporated into more complete models of brain function.

category: neuroscience


title: Cytoskeletal vimentin regulates cell size and autophagy through mTORC1 signaling

abstract: The nutrient-activated mTORC1 (mechanistic target of rapamycin kinase complex 1) signaling pathway determines cell size by controlling mRNA translation, ribosome biogenesis, protein synthesis, and autophagy. Here we show that vimentin, a cytoskeletal intermediate filament protein that we know to be important for wound healing and cancer progression, determines cell size through mTORC1 signaling, an effect that is also manifested at the organism level in mice. We found that vimentin maintains normal cell size by supporting mTORC1 activation and through inhibition of autophagic flux. This regulation is manifested at all levels of downstream target activation and regulation of protein synthesis. We show that vimentin controls mTORC1 mobility by allowing access to lysosomes. Vimentin inhibits the autophagic flux in normal fibroblasts even under starved conditions, indicating a growth factor-independent inhibition of autophagy at the level of mTORC1. Our findings demonstrate that vimentin couples cell size signaling and autophagy with the biomechanic, sensing, and kinetic functions of the cytoskeleton.

category: cell biology


title: Fine tuning the mechanism of Antigen 43 self-association to modulate aggregation levels of Escherichia coli pathogens

abstract: Bacterial aggregates and biofilms allow bacteria to colonise a diverse array of surfaces that can ultimately lead to infections, where the protection they afford permits bacteria to resist anti-microbials and host immune factors. Despite these advantages there is a trade-off, whereby bacterial spread is reduced. As such, biofilm development needs to be regulated appropriately to suit the required niche. Here we investigate members from one of largest groups of bacterial adhesins, the autotransporters, for their critical role in the formation of bacterial aggregates and biofilms. We describe the structural and functional characterisation of autotransporter Ag43 homologues from diverse pathogenic Escherichia strains. We reveal a common mode of trans-association that leads to cell clumping and show that subtle variations in these interactions governs their aggregation kinetics. Our in depth investigation reveals an underlying molecular basis for the  tuning of bacterial aggregation.

category: biochemistry


title: A Fatty Acid Anabolic Pathway in Specialized-Cells Remotely Controls Oocyte Activation in Drosophila

abstract: Pheromone-mediated partner recognition is crucial for maintenance of animal species. Here, we discover a metabolic link between pheromone and gamete physiology. In female genital tract, oocyte maturation is arrested at a specific meiotic-phase. Release of this arrest, called oocyte-activation, is triggered by a species-dependent signal. We show in Drosophila melanogaster that oenocytes, which produce the fatty acids (FAs) used as precursors of cuticular hydrocarbons (CHCs), including pheromones, are also essential for oocyte activation. We identified a set of FA-anabolic enzymes required within oenocytes for the synthesis of a particular FA that is not a CHC precursor but controls oocyte activation. Our study thus reveals that two tightly linked FA-anabolic pathways act in parallel, one to produce sexual pheromones, the other to initiate embryonic development. Given that pheromone-deficient Drosophila melanogaster females are highly attractive for males irrespective of their species, this oenocyte function might have evolved to prevent hybrid development.


title: Real-Time EEG Neurofeedback as a Tool to Improve Neural Entrainment to Speech

abstract: Neurofeedback represents a particular type of biofeedback whose aim is to teach self-control of brain function by measuring brain activity and presenting a feedback signal in real-time. Traditionally, neurofeedback has been used to complement interventions for various neuropsychological disorders through techniques like frequency training, which attempts to change the power ratio of certain EEG frequency bands. However, to date, there are no neurofeedback approaches that look directly into modulating the neural entrainment to speech. Speech-brain entrainment, which stands for the alignment of the neural activity to the envelope of the speech input, has been shown to be key to speech comprehension. In fact, atypical neural entrainment to speech seems to be consistently found in language development disorders such as dyslexia. Thus, making speech entrainment neurofeedback a promising technique to obtain behavioral improvements. In this work, we present the first open-source brain-computer interface system that can be reliably used to provide speech entrainment neurofeedback while still being flexible enough to deliver more traditional coherence-based neurofeedback. In addition, it has the potential of being an open-source alternative to deliver other types of neurofeedback if configured to do so.

category: bioengineering


title: Cellular and molecular mechanisms involved in LTP induced by mild theta-burst stimulation in hippocampal slices from young male rats: from weaning to adulthood.

abstract:
Long-term potentiation (LTP) is a highly studied cellular process yet determining the transduction and GABAergic pathways that are the essential vs. modulatory for LTP elicited by theta-burst stimulation (TBS) in the hippocampal CA1 area is still elusive, due to the use of different TBS intensities, patterns, or different rodent/cellular models. We now characterized the developmental maturation and the transduction and GABAergic pathways required for mild TBS-induced LTP in hippocampal CA1 area in male rats. LTP induced by TBS (5x4) (5 bursts of 4 pulses delivered at 100Hz) lasted for up to 3h and was increasingly larger from weaning to adulthood. Stronger TBS patterns - TBS (15x4) or three TBS (15x4) separated by 6 min induced nearly maximal LTP not being the best choice to study the value of LTP-enhancing drugs. LTP induced by TBS (5x4) in young adults was fully dependent on NMDA receptor and CaMKII activity but independent of PKA or PKC activity. Furthermore, it was partially dependent on GABAB receptor activation and was potentiated by GABAA receptor blockade and less by GAT-1 transporter blockade. AMPA GluA1 phosphorylation on Ser831 (CaMKII target) but not GluA1 Ser845 (PKA target) was essential for LTP expression. The phosphorylation of the Kv4.2 channel was observed at Ser438 (CaMKII target) but not at Thr602 or Thr607 (ERK/MAPK pathway target). This suggests that cellular kinases like PKA, PKC or kinases of the ERK/MAPK family although important modulators of TBS (5x4)-induced LTP may not be essential for its expression in the CA1 area of the hippocampus.

Graphical abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/440440v2_ufig1.gif" ALT="Figure 1">
View larger version (23K):
org.highwire.dtl.DTLVardef@cf78caorg.highwire.dtl.DTLVardef@1031737org.highwire.dtl.DTLVardef@1e91d6corg.highwire.dtl.DTLVardef@18abe3b_HPS_FORMAT_FIGEXP  M_FIG C_FIG LTP induced by theta-burst stimulation (TBS) in young adult male rat hippocampal CA1 area is increasingly more robust with the number of bursts and number of spaced TBS trains. LTP induced by TBS shows developmental maturation increasing potentiation from weaning to adulthood. Expression of LTP induced by mild TBS (5x4) in young adults requires NMDA receptor and CaMKII activity and AMPA Ser831 phosphorylation, but not PKA or PKC activity, and is likely curtailed by Kv4.2 Ser438 phosphorylation.


title: Pooling in a predictive model of V1 explains functional and structural diversity across species

abstract:
Neurons in the primary visual cortex are selective to orientation with various degrees of selectivity to the spatial phase, from high selectivity in simple cells to low selectivity in complex cells. Various computational models have suggested a possible link between the presence of phase invariant cells and the existence of cortical orientation maps in higher mammals V1. These models, however, do not explain the emergence of complex cells in animals that do not show orientation maps. In this study, we build a model of V1 based on a convolutional network called Sparse Deep Predictive Coding (SDPC) and show that a single computational mechanism, pooling, allows the SDPC model to account for the emergence of complex cells as well as cortical orientation maps in V1, as observed in distinct species of mammals. By using different pooling functions, our model developed complex cells in networks that exhibit orientation maps (e.g., like in carnivores and primates) or not (e.g., rodents and lagomorphs). The SDPC can therefore be viewed as a unifying framework that explains the diversity of structural and functional phenomena observed in V1. In particular, we show that orientation maps emerge naturally as the most cost-efficient structure to generate complex cells under the predictive coding principle.

SignificanceCortical orientation maps are among the most fascinating structures observed in higher mammals brains: In such maps, similar orientations in the input image activate neighboring cells in the cortical surface. However, the computational advantage brought by these structures remains unclear, as some species (rodents and lagomorphs) completely lack orientation maps. In this study, we introduce a computational model that links the presence of orientation maps to a class of nonlinear neurons called complex cells. In particular, we propose that the presence or absence orientation maps correspond to different strategies employed by different species to generate invariance to complex stimuli.


title: Bone innervation and vascularization regulated by osteoclasts contribute to refractive pain-related behavior in the collagen antibody-induced arthritis model

abstract:
ObjectiveRheumatoid arthritis is often characterized by eroded joints and chronic pain that outlasts disease activity. Whilst several reports show strong associations between bone resorption and nociception, the underlying mechanisms remain to be unraveled. Here, we used the collagen antibody-induced arthritis (CAIA) model to examine the contribution of osteoclasts in pain regulation. The antinociceptive effects of osteoclasts inhibitors and their mechanisms of actions involving bone vascularization and innervation were also explored.

MethodsBALB/c female mice were subjected to CAIA by intravenous injection of a collagen type-II antibody cocktail, followed by intraperitoneal injection of lipopolysaccharide. Degree of arthritis, bone resorption, mechanical hypersensitivity, vascularization and innervation in the ankle joint were assessed. Animals were treated with osteoclast inhibitors, zoledronate and cathepsin K inhibitor (T06), and netrin-1 neutralizing antibody. Potential pronociceptive factors were examined in primary osteoclast cultures.

ResultsCAIA induced local bone loss in the calcaneus with ongoing increased osteoclast activity during the inflammatory phase of the model, but not after inflammation has resolved. Mechanical hypersensitivity was reversed by zoledronate in late but not inflammatory phase CAIA. This effect was coupled to the ability of osteoclasts to modulate bone vascularization and innervation, which was inhibited by osteoclast inhibitors. CAIA-induced hypersensitivity in the late phase was also reversed by anti-netrin-1 antibody.

ConclusionOsteoclasts induce pain-like behavior in the CAIA model independent of inflammation via effects on bone vascularization and innervation.

Key messagesWhat is already known about this subject? O_LIPain and residual signs of erosive lesions are frequently present in rheumatoid arthritis (RA) patients with good disease control
C_LIO_LIOsteoclasts can induce nociceptive signaling but the exact mechanism with respect to RA-induced pain is not clear
C_LI

What does this study add? O_LIThe pronociceptive actions of osteoclasts extend beyond flares of joint inflammation and erosive activity by increasing bone innervation, bone vascularization and netrin-1 release
C_LIO_LIOsteoclast inhibitors and neutralizing netrin-1 antibodies reverse refractive pain-related behaviors in the collagen antibody-induced arthritis model
C_LI

How might this impact on clinical practice or future developments? O_LIThis study provides insights to the potential of osteoclast inhibition as a therapeutic strategy for persistent pain in RA
C_LI


title: The Psychoacoustics of Automatic Speech Recognition

abstract: Deep neural networks have had considerable success in neuroscience as models of the visual system, and recent work has suggested this may also extend to the auditory system. We tested the behaviour of a range of state of the art deep learning-based automatic speech recognition systems on a wide collection of manipulated sounds used in standard human psychometric experiments. While some systems showed qualitative agreement with humans in certain tests, in others all tested systems diverged markedly from humans. In particular, all systems used spectral invariance, temporal fine structure and speech periodicity differently from humans. We conclude that despite some promising results, none of the tested automatic speech recognition systems can yet act as a strong proxy for human speech recognition. However, we note that the more recent systems with better performance also tend to better match human results, suggesting that continued cross-fertilisation of ideas between human and automatic speech recognition may be fruitful. Our open source toolbox allows researchers to assess future automatic speech recognition systems or add additional psychoacoustic measures.


title: The Psychometrics of Automatic Speech Recognition


title: Improved post-stroke spontaneous recovery by astrocytic extracellular vesicles

abstract: Spontaneous recovery after a stroke accounts for a major part of the neurological recovery in patients. However limited, the spontaneous recovery is mechanistically driven by axonal restorative processes for which several molecular cues have been previously described. We report the acceleration of spontaneous recovery in a preclinical model of ischemia/reperfusion in rats via a single intracerebroventricular administration of extracellular vesicles released from primary cortical astrocytes. We used MRI, confocal and multiphoton microscopy to correlate the structural remodeling of the corpus callosum and striatocortical circuits with neurological performance over 21 days. We also evaluated the functionality of the corpus callosum by repetitive recordings of compound action potentials to show that the recovery facilitated by astrocytic extracellular vesicles was both anatomical and functional. Our data provide compelling evidence that astrocytes can hasten the basal recovery that naturally occurs post-stroke through the release of cellular mediators contained in extracellular vesicles.


title: Dimensionality reduction for neural population decoding

abstract: Rapidly developing technology for large scale neural recordings has allowed researchers to measure the activity of hundreds to thousands of neurons at single cell resolution in vivo. Neural decoding analyses are a widely used tool used for investigating what information is represented in this complex, high-dimensional neural population activity. Most population decoding methods assume that correlated activity between neurons has been estimated accurately. In practice, this requires large amounts of data, both across observations and across neurons. Unfortunately, most experiments are fundamentally constrained by practical variables that limit the number of times the neural population can be observed under a single stimulus and/or behavior condition. Therefore, new analytical tools are required to study neural population coding while taking into account these limitations. Here, we present a simple and interpretable method for dimensionality reduction that allows neural decoding metrics to be calculated reliably, even when experimental trial numbers are limited. We illustrate the method using simulations and compare its performance to standard approaches for dimensionality reduction and decoding by applying it to single-unit electrophysiological data collected from auditory cortex.


title: MRI-derived brain age as a biomarker of ageing in rats: validation using a healthy lifestyle intervention

abstract:
MRI data can be used as input to machine learning models to accurately predict brain age in healthy human subjects. A large difference between predicted and chronological brain age (the so-called BrainAGE score) has been associated with disease and neurodegeneration, indicating the potential utility of neuroimaging-based ageing biomarkers. So far, most brain age prediction studies have been carried out on humans. However, it is important for such a biomarker to be validated on laboratory animals too, in order to better account for specific environmental or genetic factors within a more controlled laboratory framework.

In this work, we developed a new algorithm for rat brain age prediction based on the combination of Gaussian process regression and a logistic regression classifier. The algorithm was trained on a cohort of 31 normal rats. High prediction accuracy was achieved using leave-one-out cross-validation (mean absolute error = 4.87 weeks, correlation between predicted and chronological age r = 0.92), supporting the validity and potential of the method.

Furthermore, the trained model was tested on two independent groups of 24 rats each: a new normal control group and a "healthy lifestyle" group that underwent long-term environmental enrichment and dietary restriction (EEDR) between 3 and 17 months of age. After fitting a linear mixed-effects model, the BrainAGE values were found to increase more slowly with chronological age in the EEDR group than in the controls (slope = 0.52 vs. 0.61; p = 0.015 for the interaction term). When survival analysis was performed with a Cox regression model, the BrainAGE score at 5 months of age had a significant prediction power (p = 0.03).

Our results demonstrate that BrainAGE, as computed by the proposed approach, is significantly modulated by EEDR intervention, hence it is a sensitive marker of biological ageing. These findings also support the potential of lifestyle-related prevention approaches to slow down the brain ageing process. Moreover, the results of the survival analysis further demonstrate that BrainAGE is indeed a predictor of ageing outcome.


title: The association between Hfq and RNase E in long-term nitrogen starved Escherichia coli

abstract: Under conditions of nutrient adversity, bacteria adjust metabolism to minimise cellular energy usage. This is often achieved by controlling the synthesis and degradation of RNA. In Escherichia coli, RNase E is the central enzyme involved in RNA degradation and serves as a scaffold for the assembly of the multiprotein complex known as the RNA degradosome. The activity of RNase E against specific mRNAs can also be regulated by the action of small RNAs (sRNA). In this case, the ubiquitous bacterial chaperone Hfq bound to sRNAs can interact with the RNA degradosome for the sRNA guided degradation of target RNAs. The RNA degradosome and Hfq have never been visualised together in live bacteria. We now show that in long-term nitrogen starved E. coli, both RNase E and Hfq co-localise in a single, large focus. This subcellular assembly, which we refer to as the H-body, forms by a liquid-liquid phase separation type mechanism and includes components of the RNA degradosome, namely, the helicase RhlB and the exoribonuclease polynucleotide phosphorylase. The results support the existence of an hitherto unreported subcellular compartmentalisation of a process(s) associated with RNA management in stressed bacteria.

category: microbiology


title: Chromatin profiling reveals genome stability heterogeneity in clinical isolates of the human pathogen Aspergillus fumigatus

abstract: Invasive Pulmonary aspergillosis is a life-threatening infection in immunosuppressed patients caused by the filamentous fungus Aspergillus fumigatus. Chromatin structure regulation is important for genome stability maintenance and has the potential to lead to genome rearrangements driving differences in virulence and pathogenesis of different A. fumigatus isolates. Here, we compared the chromatin activities of the most investigated clinical isolates Af293 and CEA17 and uncovered striking differences in the number, locations and expression of transposable elements. We found evidence for higher genome instability in Af293 as compared to CEA17 and identified a spontaneous Af293 variant that exhibits gross chromosomal alterations including the loss of a 320 kb long segment in chromosome VIII and the amplification of a biosynthetic gene cluster. As a consequence of these re-arrangements, the variant shows increased secondary metabolites production, growth and virulence. Our work emphasizes genome stability heterogeneity as an evolutionary driver of A. fumigatus fitness and virulence.

category: molecular biology


title: Alternative splicing of pericentrin contributes to cell cycle control in cardiomyocytes

abstract: Induction of cardiomyocyte proliferation is a promising option to regenerate the heart. Thus, it is important to elucidate mechanisms that contribute to the cell cycle arrest of mammalian cardiomyocytes. Here, we assessed the contribution of the pericentrin (Pcnt) S isoform to the cell cycle arrest in postnatal cardiomyocytes. Immunofluorescence staining of Pcnt isoforms combined with siRNA-mediated depletion indicates that Pcnt S preferentially localizes to the nuclear envelope, while the Pcnt B isoform is enriched at centrosomes. This is further supported by the localization of ectopically expressed FLAG-tagged Pcnt S and Pcnt B in postnatal cardiomyocytes. Analysis of centriole configuration upon Pcnt depletion revealed that Pcnt B but not Pcnt S is required for centriole cohesion. Importantly, ectopic expression of Pcnt S induced centriole splitting in a heterologous system, ARPE-19 cells, and was sufficient to impair DNA synthesis in C2C12 myoblasts. Moreover, Pcnt S depletion enhanced serum-induced cell cycle re-entry in postnatal cardiomyocytes. Analysis of mitosis, binucleation rate, and cell number suggests that Pcnt S depletion promotes progression of postnatal cardiomyocytes through the cell cycle resulting in cell division. Collectively, our data indicate that alternative splicing of Pcnt contributes to the establishment of cardiomyocyte cell cycle arrest shortly after birth.


title: Controlled Fluorescent Labelling of Metal Oxide Nanoparticles for Artefact-free Live Cell Microscopy

abstract:
Nanotechnologies hold great promise for various applications. To predict and guarantee the safety of novel nanomaterials, it is essential to understand their mechanism of action in an organism, causally connecting adverse outcomes with early molecular events. They are best investigated using non-invasive advanced optical methods, such as high-resolution live-cell fluorescence microscopy, which require stable labelling of nanoparticles with fluorescent dyes. When performed inadequately, unbound fluorophores and inadvertently altered chemical and physical properties of the nanoparticles can, however, result in experimental artefacts and erroneous conclusions.

To prevent such unintentional errors, we here describe a minimal combination of experimental methods to enable artefact-free fluorescent labelling of metal-oxide nanoparticles - the largest subpopulation of nanoparticles by industrial production and applications - and demonstrate its application in the case of TiO2 nanotubes. We 1) characterize potential changes of the nanoparticles surface charge and morphology that might occur during labelling, and 2) assess stable binding of the fluorescent dye to nanomaterial, which ensures correct nanoparticle localization. Together, these steps warrant the reliability and reproducibility of advanced optical tracking, which is necessary to explore nanomaterials mechanism of action and will foster widespread and safe use of new nanomaterials.

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category: biophysics


title: Ligands binding to the cellular prion protein induce its protective proteolytic release with therapeutic potential in neurodegenerative proteinopathies

abstract: The cellular prion protein (PrPC) is a central player in neurodegenerative diseases caused by protein misfolding, such as prion diseases or Alzheimers disease (AD). Expression levels of this GPI-anchored glycoprotein, especially at the neuronal cell surface, critically correlate with various pathomechanistic aspects underlying these diseases, such as templated misfolding (in prion diseases) and neurotoxicity and, hence, with disease progression and severity. In stark contrast to cell-associated PrPC, soluble extracellular forms or fragments of PrP are linked with neuroprotective effects, which is likely due to their ability to interfere with neurotoxic disease-associated protein conformers in the interstitial fluid. Fittingly, the endogenous proteolytic release of PrPC by the metalloprotease ADAM10 ( shedding) was characterized as a protective mechanism. Here, using a recently generated cleavage-site specific antibody, we shed new light on earlier studies by demonstrating that shed PrP (sPrP) negatively correlates with conformational conversion (in prion disease) and is markedly redistributed in murine brain in the presence of prion deposits or AD-associated amyloid plaques indicating a blocking and sequestrating activity. Importantly, we reveal that administration of certain PrP-directed antibodies and other ligands results in increased PrP shedding in cells and organotypic brain slice cultures. We also provide mechanistic and structural insight into this shedding-stimulating effect. In addition, we identified a striking exception to this, as one particular neuroprotective antibody, due to its special binding characteristics, did not cause increased shedding but rather strong surface clustering followed by fast endocytosis and degradation of PrPC. Both mechanisms may contribute to the beneficial action described for some PrP-directed antibodies/ligands and pave the way for new therapeutic strategies against devastating and currently incurable neurodegenerative diseases.


title: Basal forebrain parvalbumin neurons modulate vigilant attention.

abstract:
Attention is impaired in many neuropsychiatric disorders1 and by sleep disruption, leading to decreased workplace productivity and increased risk of accidents2-4. Thus, understanding the underlying neural substrates is important for developing treatments. The basal forebrain (BF) is a brain region which degenerates in dementia5-7 and is implicated in the negative effects of sleep disruption on vigilance and cognition8,9. Previous studies demonstrated that the BF controls cortical fast oscillations that underlie attention10-12 and revealed the important role of cholinergic neurons13-15. However, the role of other neurochemically defined BF subtypes is unknown. Recent work has shown that one population of BF GABAergic neurons containing the calcium-binding protein parvalbumin (PV) control cortical fast oscillations and arousals from sleep16-19 but their role in awake behavior is unclear. Thus, here we test the hypothesis that BF-PV neurons modulate vigilant attention in mice. A lever release version of the rodent psychomotor vigilance test (rPVT) was used to assess vigilant attention as measured by reaction time. Brief and continuous low power optogenetic excitation of BF-PV neurons (1s,473nm@5mW) that preceded the cue light signal by 0.5s improved vigilant attention as indicated by quicker reaction times. In contrast, both sleep deprivation (8h) and optogenetic inhibition of BF-PV neurons (1s,530nm@10mW) slowed reaction times. Importantly, BF-PV excitation rescued the reaction time deficits in sleep deprived mice. These findings reveal for the first time a role for BF-PV neurons in attention.

HIGHLIGHTSO_LIOptogenetic methods tested the neural circuitry of vigilant attention in mice
C_LIO_LIExcitation of basal forebrain parvalbumin neurons quickened reaction times
C_LIO_LISleep deprivation or inhibition of parvalbumin neurons slowed reaction times
C_LIO_LIExcitation of parvalbumin neurons rescued deficits produced by sleep deprivation
C_LI


title: Flexible Simultaneous Mesoscale Two-Photon Imaging of Neural Activity at High Speeds

abstract: Understanding brain function requires monitoring local and global brain dynamics. Two-photon imaging of the brain across mesoscopic scales has presented trade-offs between imaging area and acquisition speed. We describe a flexible cellular resolution two-photon microscope capable of simultaneous video rate acquisition of four independently targetable brain regions spanning an approximate five-millimeter field of view. With this system, we demonstrate the ability to measure calcium activity across mouse sensorimotor cortex at behaviorally relevant timescales.


title: Redundant neural circuits regulate olfactory masking

abstract:
Olfactory masking is a complex olfactory response found in humans. However, the mechanisms whereby the presence of one odorant masks the sensory and behavioral responses elicited by another odorant are poorly understood. Here, we report that Caenorhabditis elegans displays olfactory masking and that the presence of a repulsive odorant, 2-nonanone, that signals threat strongly masks the attraction of other odorants, such as isoamyl alcohol (IAA) or benzaldehyde that signals food. Using a forward genetic screen, we found that several genes, osm-5, osm-1, and dyf-7, known to regulate the structure and function of sensory neurons played a critical role in olfactory masking. Loss of these genes mildly reduces the response to 2-nonanone and disrupts the masking effect of 2-nonanone. Restoring the function of OSM-5 in either AWB or ASH, two sensory neurons known to mediate 2-nonanone-evoked avoidance, is sufficient to rescue olfactory masking. AWB is activated by the removal of 2-nonanone stimulation or the onset of IAA; however, the mixture of 2-nonanone and IAA stimulates AWB similarly as 2-nonanone alone, masking the cellular effect of IAA. The latency of the AWB response is critical for the masking effect. Thus, our results identify redundant neural circuits that regulate the robust masking effect of a repulsive odorant and uncover the neuronal and cellular basis for this complex olfactory task.

AUTHOR SUMMARYIn their natural environment, animals, including humans, encounter complex olfactory stimuli. However, regardless how complex the stimuli are, the behavioral output can only be one. Thus, how the brain processes multiple sensory cues to generate a coherent behavioral output is critical for the survival of the animal. In the present study, we combined molecular cellular genetics, optical physiology and behavioral analysis to study olfactory masking, a common olfactory phenomenon in which the presence of one odorant masks the stimulation of another odorant. Our results show that olfactory masking is regulated by redundant neuronal circuits, a mechanism that likely ensures the robust behavioral response to the sensory cue representing information critical for the survival.


title: "Thinking out loud": an open-access EEG-based BCI dataset for inner speech recognition

abstract: Surface electroencephalography is a standard and noninvasive way to measure electrical brain activity. Recent advances in artificial intelligence led to significant improvements in the automatic detection of brain patterns, allowing increasingly faster, more reliable and accessible Brain-Computer Interfaces. Different paradigms have been used to enable the human-machine interaction and the last few years have broad a mark increase in the interest for interpreting and characterizing the "inner voice" phenomenon. This paradigm, called inner speech, raises the possibility of executing an order just by thinking about it, allowing a "natural" way of controlling external devices. Unfortunately, the lack of publicly available electroencephalography datasets, restricts the development of new techniques for inner speech recognition. A ten-subjects dataset acquired under this and two others related paradigms, obtained with an acquisition system of 136 channels, is presented. The main purpose of this work is to provide the scientific community with an open-access multiclass electroencephalography database of inner speech commands that could be used for better understanding of the related brain mechanisms.


title: A novel proneural function of Asense, integrated with of L'sc and Notch, promotes the Neuroepithelial to Neuroblast transition

abstract:
In the developing Drosophila optic lobe, neuroepithelial (NE) cells are transformed progressively into neurogenic progenitors called neuroblasts (NBs). The progenitors undergoing this transition are identified by the expression of the Acheate Scute Complex (AS-C) factor Lethal of Scute (Lsc).

Here we found that Asense (Ase), another AS-C factor, presents a peak of expression in the cells neighboring those transition Lsc expressing cells. This peak of Ase identifies a new transition step and it is necessary and sufficient to promote the NE to NB transition. Thus, our data provide the first direct evidence for a proneural role of Ase in CNS neurogenesis. Furthermore, we found that the peak of Ase is induced in a non-cell autonomous manner by Lsc through the activation of Notch signaling in the adjacent cells. This suggests that the two classic proneural activities, promoting neurogenesis and Notch signaling, have been split between Ase and Lsc. Thus, our data fit with a model in which the key proneural role of Ase is integrated with Notch and Lsc activities, facilitating the progressive transformation of NE cells into NBs.

SUMMARY STATEMENTThe switch of progenitor cells towards neuron production is crucial for proper brain development. The transcription factor Asense promotes this transition through a mechanism integrated with timing and neurogenic signals.

category: developmental biology


title: Transient dopamine neuron activity precedes and encodes the vigor of contralateral movements

abstract:
Dopamine neurons (DANs) in the substantia nigra pars compacta (SNc) have been related to movement vigor, and loss of these neurons leads to bradykinesia in Parkinsons disease. However, it remains unclear whether DANs encode a general motivation signal or modulate movement kinematics. We imaged activity of SNc DANs in mice trained in a novel operant task which relies on individual forelimb sequences. We uncovered that a similar proportion of SNc DANs increased their activity before ipsi- vs. contralateral sequences. However, the magnitude of this activity was higher for contralateral actions, and was related to contralateral but not ipsilateral sequence length. In contrast, the activity of reward-related DANs, largely distinct from those modulated by movement, was not lateralized. Finally, unilateral dopamine depletion impaired contralateral, but not ipsilateral, sequence length. These results indicate that movement-initiation DANs encode more than a general motivation signal, and invigorate kinematic aspects of contralateral movements.

TeaserTransient activity in substantia nigra compacta dopamine neurons encodes contralateral, but not ipsilateral action vigor.


title: Central nervous system hypomyelination disrupts axonal conduction and behaviour in larval zebrafish

abstract: Myelination is essential for central nervous system (CNS) formation, health and function. As a model organism, larval zebrafish have been extensively employed to investigate the molecular and cellular basis of CNS myelination, due to their genetic tractability and suitability for non-invasive live cell imaging. However, it has not been assessed to what extent CNS myelination affects neural circuit function in zebrafish larvae, prohibiting the integration of molecular and cellular analyses of myelination with concomitant network maturation. To test whether larval zebrafish might serve as a suitable platform with which to study the effects of CNS myelination and its dysregulation on circuit function, we generated zebrafish myelin regulatory factor (myrf) mutants with CNS-specific hypomyelination and investigated how this affected their axonal conduction properties and behaviour. We found that myrf mutant larvae exhibited increased latency to perform startle responses following defined acoustic stimuli. Furthermore, we found that hypomyelinated animals often selected an impaired response to acoustic stimuli, exhibiting a bias towards reorientation behaviour instead of the stimulus-appropriate startle response. To begin to study how myelination affected the underlying circuitry, we established electrophysiological protocols to assess various conduction properties along single axons. We found that the hypomyelinated myrf mutants exhibited reduced action potential conduction velocity and an impaired ability to sustain high frequency action potential firing. This study indicates that larval zebrafish can be used to bridge molecular and cellular investigation of CNS myelination with multiscale assessment of neural circuit function.


title: Expansion microscopy facilitates quantitative super-resolution studies of cytoskeletal structures in kinetoplastid parasites

abstract: Expansion microscopy (ExM) has become a powerful super-resolution method in cell biology. It is a simple, yet robust approach, which does not require any instrumentation or reagents beyond those present in a standard microscopy facility. In this study, we used kinetoplastid parasites Trypanosoma brucei and Leishmania major, which possess a complex, yet well-defined microtubule-based cytoskeleton, to demonstrate that this method recapitulates faithfully morphology of structures as previously revealed by a combination of sophisticated electron microscopy (EM) approaches. Importantly, we also show that due to rapidness of image acquisition and 3D reconstruction of cellular volumes ExM is capable of complementing EM approaches by providing more quantitative data. This is demonstrated on examples of less well-appreciated microtubule structures, such as the neck microtubule of T. brucei or the pocket, cytosolic, and multivesicular tubule-associated microtubules of L. major. We further demonstrate that ExM enables identifying cell types rare in a population, such as cells in mitosis and cytokinesis. 3D reconstruction of an entire volume of these cells provided details on morphology of the mitotic spindle and the cleavage furrow. Finally, we show that established antibody markers of major cytoskeletal structures function well in ExM, which together with the ability to visualize proteins tagged with small epitope tags will facilitate studies of the kinetoplastid cytoskeleton.


title: Ultrastructure Expansion Microscopy in Trypanosoma brucei

abstract: Abstract-IntroductionThe recently developed ultrastructure expansion microscopy (U-ExM) technique allows to increase the spatial resolution within a cell or tissue for microscopic imaging through the physical expansion of the sample. In this study we validate the use of U-ExM in Trypanosoma brucei by visualizing the nucleus and kDNA as well as proteins of the cytoskeleton, the basal body, the mitochondrion and the ER. T. brucei is a unicellular flagellated protozoan parasite and the causative agent of human African sleeping sickness and Nagana in cattle.The highly polarized parasite cell body is about 25 m in length and is shaped by the subpellicular microtubule corset. Its single flagellum emanates from the posterior part of the cell and is attached along the entire cell body. T. brucei The cell contains all typical organelles of eukaryotic cells including ER, Golgi and mitochondrion. Interestingly, Golgi and mitochondrion are single unit organelles in this protozoan parasite. The signature feature of trypanosomes is the single unit mitochondrial genome, the kinetoplast DNA (kDNA) that is organized in a complex structure of interlocked mini- and maxicircles. The kDNA is segregated during cell division by the tripartite attachment complex (TAC) that connects it via the mitochondrial membranes to the base of the flagellum.


title: Sox8 is sufficient to reprogram ectoderm into ear vesicles and associated neurons

abstract: The vertebrate inner ear arises from a pool of progenitors with the potential to contribute to all the sense organs and cranial ganglia in the head. Here we explore the molecular mechanisms that control ear specification from these precursors. Using a multi-omics approach combined with loss-of-function experiments we identify a core transcriptional circuit that imparts ear identity, along with the first genome-wide characterization of non-coding elements that integrate this information. This analysis places the transcription factor Sox8 at the top of the ear determination network. Introducing Sox8 into cranial ectoderm not only converts non-ear cells into ear progenitors, but also activates the cellular programs for ear morphogenesis and neurogenesis. Thus, Sox8 has the unique ability to remodel transcriptional networks in the cranial ectoderm towards ear identity.


title: Sox8 remodels the cranial ectoderm to generate the ear


title: Negative regulation of a ribonucleoprotein condensate driven by dilute phase oligomerization

abstract:
Ribonucleoprotein bodies are exemplars of membraneless biomolecular condensates that can form via spontaneous or driven phase transitions. The fungal protein Whi3 forms ribonucleoprotein condensates with different RNA molecules, and these condensates are implicated in key processes such as cell-cycle control and generating cell polarity. Whi3 has a modular architecture that includes a Q-rich intrinsically disordered region (IDR) and a tandem RNA recognition module. Here, we demonstrate that a 21-residue stretch within the Q-rich IDR has a weak intrinsic preference for forming alpha-helical conformations. Through mutagenesis, we find that increased alpha helicity enhances oligomerization in the dilute phase. One consequence of enhanced oligomerization is a dilution of Whi3 in the dense phase. The opposite behavior is observed when helicity within the 21-residue stretch of the Q-rich region is abrogated. Thus, the formation of dilute phase oligomers, driven by a specific sequence motif and potential synergies with the rest of the IDR, opposes incorporation of the Whi3 protein into the dense phase, thereby altering the dense phase stoichiometry of protein to RNA. Our findings, which stand in contrast to other systems where oligomerization has been shown to enhance the drive for phase separation, point to a novel mechanism that might be operative for influencing compositions of condensates. Our work also points to routes for designing synthetic ribonucleoprotein condensates whereby modulation of protein oligomerization via homotypic interactions can impact dense phase concentrations, stoichiometries, and material properties.

SignificanceA large sub-class of biomolecular condensates are linked to RNA regulation and are known as ribonucleoprotein (RNP) bodies. While extensive work has identified driving forces for biomolecular condensate formation, relatively little is known about forces that oppose assembly. Here, using a fungal RNP protein, Whi3, we show that a portion of its intrinsically disordered, glutamine-rich region modulates phase separation by forming transient alpha helical structures that promote the assembly of dilute phase oligomers. These oligomers detour Whi3 proteins from condensates, thereby impacting the driving forces for phase separation, the protein-to-RNA ratio in condensates, and the material properties of condensates. Our findings show how nanoscale conformational and oligomerization equilibria can influence mesoscale phase equilibria.


title: Dilute phase oligomerization can oppose phase separation and modulate material properties of a ribonucleoprotein condensate


title: Molecular architecture of black widow spider neurotoxins

abstract:
Latrotoxins (LaTXs) are presynaptic pore-forming neurotoxins found in the venom of Latrodectus spiders. The venom contains a toxic cocktail of seven LaTXs, with one of them targeting vertebrates (-latrotoxin (-LTX)), five specialized on insects (, {beta}, {gamma}, {delta}, {varepsilon}-latroinsectotoxins (LITs), and one on crustaceans (-latrocrustatoxin (-LCT)). LaTXs bind to specific receptors on the surface of neuronal cells, inducing the release of neurotransmitters either by directly stimulating exocytosis or by forming Ca2+-conductive tetrameric pores in the membrane. Despite extensive studies in the past decades, a high-resolution structure of a LaTX is not yet available and the precise mechanism of LaTX action remains unclear.

Here, we report cryoEM structures of the -LCT monomer and the {delta}-LIT dimer. The structures reveal that LaTXs are organized in four domains. A C-terminal domain of ankyrin-like repeats shields a central membrane insertion domain of six parallel -helices. Both domains are flexibly linked via an N-terminal -helical domain and a small {beta}-sheet domain. A comparison between the structures suggests that oligomerization involves major conformational changes in LaTXs with longer C-terminal domains. Based on our data we propose a cyclic mechanism of oligomerization, taking place prior membrane insertion. Both recombinant -LCT and {delta}-LIT form channels in artificial membrane bilayers, that are stabilized by Ca2+ ions and allow calcium flux at negative membrane potentials. Our comparative analysis between -LCT and {delta}-LIT provides first crucial insights towards understanding the molecular mechanism of the LaTX family.


title: Babytwins Study Sweden (BATSS): A multi-method infant twin study of genetic and environmental factors influencing infant brain and behavioral development

abstract: Twin studies can help us understand the relative contributions of genes and environment to phenotypic trait variation including attentional and brain activation measures. In terms of applying methodologies like electroencephalography (EEG) and eye tracking, which are key methods in developmental neuroscience, infant twin studies are almost non-existent. Here we describe the Babytwins Study Sweden (BATSS), a multi-method longitudinal twin study of 177 MZ and 134 DZ twin pairs (i.e. 622 individual infants) covering the 5 - 36 month time period. The study includes EEG, eye tracking and genetics, together with more traditional measures based on in-person testing, direct observation and questionnaires. The results show that interest in participation in research among twin parents is high, despite the comprehensive protocol. DNA analysis from saliva samples was possible in virtually all participants, allowing for both zygosity confirmation and polygenic score analyses. Combining a longitudinal twin design with advanced technologies in developmental cognitive neuroscience and genomics, BATSS represents a new approach in infancy research, which we hope to have impact across multiple disciplines in the coming years.


title: Burkholderia PglL enzymes are serine preferring oligosaccharidetransferases which target conserved proteins across the Burkholderia genus

abstract: Glycosylation is increasingly recognised as a common protein modification within bacterial proteomes. While great strides have been made in identifying species that contain glycosylation systems, our understanding of the proteins and sites targeted by these enzymes is far more limited. Within this work we explore the conservation of glycoproteins and O-linked glycosylation sites across the pan-Burkholderia glycoproteome. Using a multi-protease glycoproteomic approach we generate high-confidence glycoproteomes and associated glycosylation sites in two widely utilized B. cenocepacia strains, K56-2 and H111. This resource reveals glycosylation occurs exclusively at serine residues and that glycoproteins/glycosylation sites are highly conserved across 294 publicly available B. cenocepacia genomes. Consistent with this we demonstrate that the substitution of Serine for Threonine residues in a model protein results in a dramatic decrease in glycosylation efficiency by the oligosaccharidetransferase pglLBC even when pglLBC is overexpressed. This preference for glycosylation at Serine residues is observed across at least 9 Burkholderia glycoproteomes supporting that Serine is the dominant residue targeted by pglL-mediated glycosylation across the Burkholderia genus. Using population genomics we observe that pglL targeted glycosylated proteins are common across Burkholderia species. Combined, this work demonstrates that PglL enzymes of the Burkholderia genus are Serine-preferring oligosaccharidetransferases that target conserved and shared protein substrates across the Burkholderia genus.


title: Oncogenic signaling inhibits c-FLIP expression and promotes cancer cell survival during ECM-detachment

abstract: Inhibition of programmed cell death pathways is frequently observed in cancer cells where it functions to facilitate tumor progression. However, some proteins involved in the regulation of cell death function dichotomously to both promote and inhibit cell death depending on the cellular context. As such, understanding how cell death proteins are regulated in a context-dependent fashion in cancer cells is of utmost importance. We have uncovered evidence that cellular FLICE-like Inhibitory Protein (c-FLIP), a well-known anti-apoptotic protein, is often downregulated in tumor tissue when compared to adjacent normal tissue. These data argue that c-FLIP may have activity distinct from its canonical role in antagonizing cell death. Interestingly, we have discovered that detachment from extracellular matrix (ECM) serves as a signal to elevate c-FLIP transcription and that oncogenic signaling blocks ECM-detachment-induced c-FLIP elevation. In addition, our data reveal that downregulation of c-FLIP promotes the survival of ECM-detached cells and that c-FLIP overexpression in cancer cells restricts the viability of cancer cells grown in anchorage-independent conditions. Taken together, our study reveals an unexpected role for c-FLIP in constraining the viability of cancer cells during ECM-detachment and raises the idea that c-FLIP may have context-dependent pro- and anti-cell death roles during tumorigenesis.


title: Redefining replication in multi-ancestry genome-wide association studies

abstract: Since 2005, genome-wide association (GWA) datasets have been largely biased toward sampling European ancestry individuals, and recent studies have shown that GWA results estimated from self-identified European individuals are not transferable to non-European individuals due to various confounding challenges. Here, we demonstrate that enrichment analyses which aggregate SNP-level association statistics at multiple genomic scales--from genes to genomic regions and pathways--have been underutilized in the GWA era and can generate biologically interpretable hypotheses regarding the genetic basis of complex trait architecture. We illustrate examples of the robust associations generated by enrichment analyses while studying 25 continuous traits assayed in 566,786 individuals from seven diverse self-identified human ancestries in the UK Biobank and the Biobank Japan, as well as 44,348 admixed individuals from the PAGE consortium including cohorts of African-American, Hispanic and Latin American, Native Hawaiian, and American Indian/Alaska Native individuals. We identify 1,000 gene-level associations that are genome-wide significant in at least two ancestry cohorts across these 25 traits, as well as highly conserved pathway associations with triglyceride levels in European, East Asian, and Native Hawaiian cohorts.

category: genomics


title: Enrichment analyses identify shared associations for 25 quantitative traits in over 600,000 individuals from seven diverse ancestries


title: Working Memory Performance after Daily Caffeine Intake: Compromised Performance and Reduced Hippocampal Activity.

abstract: Neuroprotective effects of caffeine have been frequently reported in the context of disease and cognitive dysfunction as well as in epidemiological studies in humans. However, evidence on caffeine effects on neural and memory functions during daily intake in a healthy cognitive state remains scarce. This randomized double-blind placebo-controlled crossover study investigated working memory functions by N-back tasks and functional magnetic resonance imaging (fMRI) after daily caffeine intake compared to a placebo baseline and to acute caffeine withdrawal in 20 young healthy volunteers. Each volunteer was given 3 times 150 mg caffeine for 10 days in the daily caffeine condition, 3 times 150 mg mannitol for 10 days in the placebo condition, and 9-day caffeine plus 1-day mannitol in the acute withdrawal condition. During the 10th day, participants performed 4 N-back sessions (two loads each: 0- and 3-back) under controlled laboratory conditions. During the 4th session of N-Back (i.e. at 5.5 h, 36.5 h and > 10 days after the last caffeine intake in the caffeine, withdrawal, and placebo condition, respectively) we assessed blood-oxygen-level-dependent (BOLD) activity. During the entire 10th day, in 0-back tasks, we observed longer reaction times (RTs) in the withdrawal compared to the placebo (Cohens d = 0.7) and caffeine condition (Cohens d = 0.6), but no significant effects of conditions on error rates. In contrast, in 3-back tasks (controlled for 0-back), the RTs in the caffeine condition were longer compared to placebo (Cohens d = 0.6) and withdrawal (Cohens d = 0.5). Error rates were higher during both caffeine and withdrawal conditions compared to placebo (Cohens d of both contrasts = 0.4). Whole-brain analyses on fMRI data did not reveal significant condition-dependent differences in activities between task loads. Across task loads, however, we observed a reduced hippocampal activation (Cohens d = -1.3) during the caffeine condition compared to placebo, while no significant difference in brain activities between withdrawal and placebo conditions. Taken together, the worse working memory function and the hippocampal hypoactivation implicate a potential detrimental effect of daily caffeine intake on neurocognitive functions of healthy adults. Moreover, they echo the hippocampal volumetric reduction reported previously in the same volunteers. Lastly, acute withdrawal from daily caffeine intake impairs both low-order cognitive processes and working memory performance. Taking earlier studies on acute caffeine effects into account, our findings indicate that daily caffeine intake elicits a dynamic change in cerebral activities during the course of repeated consumption, with unknown consequences in the long run.


title: Ultrapotent SARS-CoV-2 neutralizing antibodies with protective efficacy against newly emerged mutational variants

abstract: Accumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus displayed remarkable efficacy against authentic B.1.351 virus. Each of these 3 mAbs in combination with one neutralizing Ab recognizing non-competing epitope exhibited synergistic effect against authentic SARS-CoV-2 virus. Surprisingly, structural analysis revealed that 58G6 and 13G9, encoded by the IGHV1-58 and the IGKV3-20 germline genes, both recognized the steric region S470-495 on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly bound to another region S450-458 in the RBD. Significantly, 58G6 and 510A5 both demonstrated prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. These 2 ultrapotent neutralizing Abs can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic.

category: immunology


title: Drug repurposing to face Covid-19: Celastrol, a potential leading drug capable of inhibiting SARS-CoV-2 replication and induced inflammation

abstract: The global emergence of Covid-19 has caused huge human casualties. Clinical manifestations of the disease vary from asymptomatic to lethal, and the symptomatic form can be associated with cytokine storm and non-homeostatic inflammatory response. In face of the urgent demand for effective drugs to treat Covid-19, we have searched for candidate compounds using a drug repurposing approach based on in silico analysis followed by biological validation. Here we identified celastrol, a pentacyclic triterpene isolated from Tripterygium wilfordii Hook F - a plant used in traditional Chinese medicine - as one of the best compounds out of 39 repurposed drug candidates. Celastrol reverted gene expression signature from SARS-CoV-2-infected cells; bound with high-affinity energy to viral molecular targets such as main protease (Mpro) and receptor-biding domain (RBD); inhibited SARS-CoV-2 replication in monkey (Vero and Vero-ACE2) and human (Caco-2 and Calu-3) cell lines; and decreased interleukin-6 (IL-6) secretion in SARS-CoV-2-infected human cell lines. Interestingly, celastrol acted in a concentration-dependent manner, with undetectable signs of cytotoxicity. Therefore, celastrol is a promising lead drug candidate to treat Covid-19 due to its ability to suppress SARS-CoV-2 replication and IL-6 production in infected cells, two critical events in the pathophysiology of this disease.


title: Comparison of Mucosal and Intramuscular Immunization against SARS-CoV-2 with Replication-Defective and Replicating Single-cycle Adenovirus Vaccines

abstract:
SARS-CoV-2 enters the body at mucosal surfaces, such as the nose and lungs. These events involve a small number of virions at these mucosal barriers and are therefore a strategic point to stop a COVID-19 infection before it starts. Despite this, most vaccines against COVID-19 are being injected into the muscle where they will not generate the highest levels of mucosal protection. The vaccines that are approved for use in humans are all replication-defective (RD) mRNA, DNA, or adenovirus (Ad) vaccines that do not amplify antigen transgenes. We developed single cycle adenovirus (SC-Ad) vectors that replicate antigen genes up to 10,000-fold in human cells, but that are disabled from producing infectious Ad particles. We show here that SC-Ad expressing the full-length SARS-CoV-2 spike protein produces 100-fold more spike protein than a matched RD-Ad-Spike vector. When Ad-permissive hamsters were immunized with these vaccines by intranasal (IN) or intramuscular (IM) routes, SC-Ad produced significantly stronger antibody responses as compared to RD-Ad against the spike protein that rose over 14 weeks after one immunization. Single IN or IM immunizations generated significant antibody responses in serum and in bronchoalveolar lavages (BALs). IN priming, but not IM priming, generated HLA-restricted CD8 T cell responses in BALs. SC-Ad-Spike generated antibodies that retain binding to spike receptor binding domains (RBDs) with mutations from new viral variants. These data suggest empowering the genomes of gene-based vaccines with the ability to amplify antigen genes can increase potency. This may be particularly advantageous when applying mucosal vaccines to combat mucosal pathogens like SARS-CoV-2.

One Sentence SummaryArming adenovirus vaccines with the ability to replicate vaccine antigen genes may increase potency for systemic, or more importantly, mucosal immunization against mucosal pathogens.


title: Inactivation of SARS-CoV-2 in chlorinated swimming pool water

abstract: SARS-CoV-2 transmission remains a global problem which exerts a significant direct cost to public health. Additionally, other aspects of physical and mental health can be affected by limited access to social and exercise venues as a result of lockdowns in the community or personal reluctance due to safety concerns. Swimming pools have reopened in the UK as of April 12th, but the effect of swimming pool water on inactivation of SARS-CoV-2 has not yet been directly demonstrated. Here we demonstrate that water which adheres to UK swimming pool guidelines is sufficient to reduce SARS-CoV-2 infectious titre by at least 3 orders of magnitude.


title: Herbivory enhances leaky sex expression in the dioecious herb Mercurialis annua

abstract: Plant reproductive traits are widely understood to be responsive to the selective pressures exerted by pollinators, but there is also increasing evidence for an important role of antagonists such as herbivores in shaping these traits. Many dioecious species show leaky sex expression, with males and females occasionally producing flowers of the opposite sex. Here we show that leaky sex expression in both males and females of the wind-pollinated dioecious herb Mercurialis annua (Euphorbiaceae) is enhanced in response to simulated herbivory, increasing the probability and the degree of leakiness in both sexes. We also found that leakiness was greater in larger females but not in larger males. We discuss hypotheses for a possible functional link between herbivory and leaky sex expression, and consider what herbivory-induced leakiness might imply for the evolutionary ecology of plant reproductive systems, especially the breakdown of dioecy and the evolution of hermaphroditism.

category: ecology


title: Genome assembly of the popular Korean soybean cultivar Hwangkeum

abstract: Massive resequencing efforts have been undertaken to catalog allelic variants in major crop species including soybean, but the scope of the information for genetic variation often depends on short sequence reads mapped to the extant reference genome. Additional de novo assembled genome sequences provide a unique opportunity to explore a dispensable genome fraction in the pan-genome of a species. Here, we report the de novo assembly and annotation of Hwangkeum, a popular soybean cultivar in Korea. The assembly was constructed using PromethION nanopore sequencing data and two genetic maps, and was then error-corrected using Illumina short-reads and PacBio SMRT reads. The 933.12 Mb assembly was annotated 79,870 transcripts for 58,550 genes using RNA-Seq data and the public soybean annotation set. Comparison of the Hwangkeum assembly with the Williams 82 soybean reference genome sequence revealed 1.8 million single-nucleotide polymorphisms, 0.5 million indels, and 25 thousand putative structural variants. However, there was no natural megabase-scale chromosomal rearrangement. Incidentally, by adding two novel groups, we found that soybean contains four clearly separated groups of centromeric satellite repeats. Analyses of satellite repeats and gene content suggested that the Hwangkeum assembly is a high-quality assembly. This was further supported by comparison of the marker arrangement of anthocyanin biosynthesis genes and of gene arrangement at the Rsv3 locus. Therefore, the results indicate that the de novo assembly of Hwangkeum is a valuable additional reference genome resource for characterizing traits for the improvement of this important crop species.


title: In BRCA1 and BRCA2 breast cancers, chromosome breaks occur near herpes tumor virus sequences

abstract: Inherited mutations in BRCA1 and BRCA2 genes increase risks for breast, ovarian, and other cancers. Both genes encode proteins for accurately repairing chromosome breaks. If mutations inactivate this function, broken chromosome fragments get lost or reattach indiscriminately. These mistakes are characteristic of hereditary breast cancer. We tested the hypothesis that mistakes in reattaching broken chromosomes preferentially occur near viral sequences on human chromosomes. We tested millions of DNA bases around breast cancer breakpoints for similarities to all known viral DNA. DNA around breakpoints often closely matched the Epstein-Barr virus (EBV) tumor variants HKHD40 and HKNPC60. Almost all breakpoints were near EBV anchor sites, EBV tumor variant homologies, and EBV-associated regulatory marks. On chromosome 2, EBV binding sites accounted for 90% of breakpoints (p<0.0001). On chromosome 4, 51/52 inter-chromosomal breakpoints were close to EBV variant sequences. Five viral anchor sites at critical genes were near breast cancer breakpoints. Twenty-five breast cancer breakpoints were within 1.25% of breakpoints in model EBV cancers. EBV-like sequence patterns around breast cancer breakpoints resemble gene fusion breakpoints in model EBV cancers. All BRCA1 and BRCA2 breast cancers had mutated genes essential for immune responses. Because of this immune compromise, herpes viruses can attach and produce nucleases that break chromosomes. Alternatively, anchored viruses can retard break repairs, whatever the causes. The results imply proactive treatment and prevention of herpes viral infections may benefit BRCA mutation carriers.


title: Repair of critical-size porcine craniofacial bone defects using a collagen-polycaprolactone composite biomaterial

abstract: Regenerative medicine approaches for massive craniomaxillofacial bone defects face challenges associated with the scale of missing bone, the need for rapid graft-defect integration, and challenges related to inflammation and infection. Mineralized collagen scaffolds have been shown to promote mesenchymal stem cell osteogenesis due to their porous nature and material properties, but are mechanically weak, limiting surgical practicality. Previously, these scaffolds were combined with 3D-printed polycaprolactone mesh to form a scaffold-mesh composite to increase strength and promote bone formation in sub-critical sized porcine ramus defects. Here, we compare the performance of mineralized collagen-polycaprolactone composites to the polycaprolactone mesh in a critical-sized porcine ramus defect model. While there were no differences in overall healing response between groups, our data demonstrated broadly variable metrics of healing regarding new bone infiltration and fibrous tissue formation. Abscesses were present surrounding some implants and polycaprolactone polymer was still present after 9-10 months of implantation. Overall, while there was limited successful healing, with 2 of 22 implants showed substantial levels of bone regeneration, and others demonstrating some form of new bone formation, the results suggest targeted improvements to improve repair of large animal models to more accurately represent craniomaxillofacial bone healing. Notably, strategies to increase osteogenesis throughout the implant, modulate the immune system to support repair, and employ shape-fitting tactics to avoid implant micromotion and resultant fibrosis. Improvements to the mineralized collagen scaffolds involve changes in pore size and shape to increase cell migration and osteogenesis and inclusion or delivery of factors to aid vascular ingrowth and bone regeneration.


title: A fossil fish assemblage from the middle Miocene of the Cocinetas Basin, northern Colombia

abstract: Freshwater fossil fish faunas have been long used to infer past drainage connections, as they are bounded by physical freshwater barriers. Here we study a middle Miocene (15.0--15.5 Ma) freshwater fish fossil fauna (Makaraipao) from the Castilletes Formation in northern Colombia, nowadays west of the Andes. We record the presence of lungfishes (Lepidosiren), pacus (Mylossoma and Piaractus), armored catfishes (Callichthyidae), and red-tail catfishes (Phractocephalus). Extant members of all those groups (except the Callichthyidae, due to lack of taxonomic resolution) are found in Amazonian faunas east of the Andes and are absent from faunas west of the Andes, indicating that the riverine systems of the Guajira Peninsula were connected to Amazonia during the middle Miocene. The similarity of La Venta (west of the Andes) and Rio Acre (east of the Andes) fish faunas during the late Miocene further indicates that the northern Andean uplift was not a complete barrier at least until[~] 11 Myr ago. However, there is a continental-wide structuring of the Miocene fish faunas that is also found in the extant faunas, suggesting that other factors such as ecological conditions, in addition to the uplift of the Andes, have shaped the biogeographic evolution of South American fish faunas.

category: paleontology


title: An Evaluation of Curriculum change in Physiology: A Mixed method research design

abstract:
IntroductionThe quality of both teaching and learning techniques in health sciences determines the competency of the doctors produced and the patient care. Realizing the necessity of active learning at the undergraduate level, curricular reforms were crucial to ensure that students play an active role in the learning process and imbibe all the prerequisite qualities of a competent health professional. The objective of this study was to implement and evaluate case-based learning in the physiology curriculum.

MethodsThe study included 150 first-year MBBS students. We followed a mixed research design in this study. A short lecture on anemia was followed by two sessions of CBL with a gap of one week. A structured questionnaire on a 5-point Likert scale was used to collect students perceptions. The internal consistency of the questionnaire was Cronbach -statistic = 0.8. Faculties feedback was collected through Focus Group Discussion (FGD).

ResultsOut of 145 participants, 117 responded to feedback. Students perceived that the CBL method was effective in understanding anemia topic (71%); promoted meaningful learning (83%); encouraged teamwork (69%); improved communication skills (65%); helps in future application of knowledge (81%); motivated self-directed learning (66%); helped to understand physiology concepts better (72%); leads to the development of problem-solving abilities (70%); and better student-teacher relationship (72%). Faculties suggested developing an assessment plan for future CBL sessions.

ConclusionIn our experience, CBL is an effective, active teaching-learning tool that improves students understanding of basic concepts, clinical knowledge, problem-solving abilities, teamwork, communication skills, student-teacher relationship, and self-directed learning.

category: scientific communication and education


title: A Multiscale Model of Traumatic Brain Injury Suggests Possible Mechanisms of Post-Traumatic Psychosis

abstract: Traumatic brain injury is a devastating injury to the brain that can have permanent or fatal effects, leading to life-long deficits or death. Among these effects is psychosis and schizophrenia, sometimes reported in the population of TBI sufferers. Here we evaluate a possible mechanism of post-traumatic psychosis, shedding light on the anomalous nature of psychosis as over-activity and brain injury as destruction. Using a multiscale model of the brain to relate molecular pathology to connectomic and macroscopic features of the brain, we identify cell lysis and membrane deformation as a possible mechanism for psychosis after injury. We also evaluate the reorganisation of functional networks and cortical activation post-injury, and find the features of a simulated brain under traumatic injury correlate with recorded results on the schizophrenic functional connectome. This provides a possible mechanism for post-traumatic psychosis, as well as a proof-of-principle of advanced multiscale modelling methods in computational psychiatry and neuromedicine. It also elaborates on the relationship between structure and function in the brain, information processing, and the delicate regulation of activity in healthy brains.


title: T cells expressing multiple co-inhibitory molecules in acute malaria are not exhausted but exert a suppressive function

abstract: Overwhelming activation of T cells in acute malaria is associated with severe outcomes. Thus, counter-regulation by anti-inflammatory mechanisms is indispensable for an optimal resolution of disease. Using Plasmodium berghei ANKA (PbA) infection of C57BL/6 mice, we performed a comprehensive analysis of co-inhibitory molecules expressed on CD4+ and CD8+ T cells using an unbiased cluster analysis approach. We identified similar T cell clusters co-expressing several co-inhibitory molecules like programmed cell death protein 1 (PD-1) and lymphocyte activation gene 3 (LAG-3) in the CD4+ and the CD8+ T cell compartment. Interestingly, despite expressing co-inhibitory molecules, which are associated with T cell exhaustion in chronic settings, these T cells were more functional compared to activated T cells that were negative for co-inhibitory molecules. However, T cells expressing high levels of PD-1 and LAG-3 also conferred suppressive capacity and thus resembled type I regulatory T cells. To our knowledge, this is the first description of malaria-induced CD8+ T cells with suppressive capacity. Importantly, we found an induction of T cells with a similar co-inhibitory rich phenotype in Plasmodium falciparum infected patients. In conclusion, we demonstrate that malaria-induced T cells expressing co-inhibitory molecules are not exhausted, but acquire additional suppressive capacity, which might represent an immune regulatory pathway to prevent further activation of T cells during acute malaria.


title: The Impact of a Dynamic Working Environment on Human Gut Microbiota

abstract: Gut microbiota dysbiosis is associated with a variety of diseases, such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), metabolic diseases, allergic diseases, neurodevelopmental disorders and cancer. The human gut microbiota can be influenced by a variety of factors, including geography, dietary habits, living environment, age and altered lifestyle etc. This study was conducted to explore the gut microbiota compositions in officials who are in a stable working environment and train drivers who are in a dynamic working environment. Microbiota communities in the feces of 80 officials and 88 train drivers were analyzed using Illumina MiSeq sequencing targeting the V3-V4 region of 16S ribosomal RNA (rRNA) gene and ITS1 region of fungi. There were significant differences between the two groups in diversity and richness of gut microbiota, while the microbial community compositions of the two groups were similar. The relationship between gut microbiota and clinical characteristics was investigated. We found that more bacteria and fungi were positively correlated with clinical characteristics. Functional prediction analysis of the gut microbiota between the two groups by PICRUSt2 revealed significant differences between the official group and the train driver group. Elucidating these differences of the microbiome between the two groups will provide a foundation understanding of the impact of a dynamic environment on gut microbiota.


title: Optogenetic relaxation of actomyosin contractility uncovers mechanistic roles of cortical tension during cytokinesis

abstract: Actomyosin contractility generated cooperatively by nonmuscle myosin II and actin filaments plays essential roles in a wide range of biological processes, such as cell motility, cytokinesis, and tissue morphogenesis. However, it is still unknown how actomyosin contractility generates force and maintains cellular morphology. Here, we demonstrate an optogenetic method to induce relaxation of actomyosin contractility. The system, named OptoMYPT, combines a catalytic subunit of the type I phosphatase-binding domain of MYPT1 with an optogenetic dimerizer, so that it allows light-dependent recruitment of endogenous PP1c to the plasma membrane. Blue-light illumination was sufficient to induce dephosphorylation of myosin regulatory light chains and decrease in traction force at the subcellular level. The OptoMYPT system was further employed to understand the mechanics of actomyosin-based cortical tension and contractile ring tension during cytokinesis. We found that the relaxation of cortical tension at both poles by OptoMYPT accelerated the furrow ingression rate, revealing that the cortical tension substantially antagonizes constriction of the cleavage furrow. Based on these results, the OptoMYPT system will provide new opportunities to understand cellular and tissue mechanics.


title: Tire abrasion particles negatively affect plant growth even at low concentrations and alter soil biogeochemical cycling

abstract: Tire particles (TPs) are a major source of microplastic on land, and considering their chemical composition, they represent a potential hazard for the terrestrial environment. We studied the effects of TPs at environmentally relevant concentrations along a wide concentration gradient (0 - 160 mg g-1) and tested the effects on plant growth, soil pH and the key ecosystem process of litter decomposition and soil respiration. The addition of TPs negatively affected shoot and root growth already at low concentrations. Tea litter decomposition slightly increased with lower additions of TPs but decreased later on. Soil pH increased until a TP concentration of 80 mg kg-1 and leveled off afterwards. Soil respiration clearly increased with increasing concentration of added TPs. Plant growth was likely reduced with starting contamination and stopped when contamination reached a certain level in the soil. The presence of TPs altered a number of biogeochemical soil parameters that can have further effects on plant performance. Considering the quantities of yearly produced TPs, their persistence, and toxic potential, we assume that these particles will eventually have a significant impact on terrestrial ecosystems.


title: The salmon-peloton: hydraulic habitat shifts of adult Atlantic salmon (Salmo salar) due to behaviour thermoregulation

abstract: In recent decades there has been an increase in conservation and restoration projects targeting Atlantic salmon (Salmo salar - AS), as populations in eastern Canada decline. Missing however, is an understanding of thermo-hydraulic habitat use by adult AS during summer, and thus the actual benefits of altering in-river physical structures. Here, we illustrated how optical and thermal infrared (TIR) imagery acquired from a UAV can be used in concert with in-situ depth and velocity data to map adult AS and develop models of thermo-hydraulic habitats in the Miramichi River, New Brunswick. We found during optimal thermal conditions (< 19 {degrees}C) proximity to boulders and Froude numbers, a non-dimensional hydraulic metric, were key parameters that characterized adult AS habitat. However, during behavioural thermoregulation events (>19 {degrees}C), proximity to the cool thermal plume and Froude number, a non-dimensional hydraulic parameter, were critical controls on habitat use. We also observed AS formed a distinct geometric formation during behavioural thermoregulation events, and term this formation a  thermal-peloton. The primary function of the peloton is undoubtedly to reduce thermally induced stressed; however, we conceptualize the geometry of the peloton attenuates hydraulic-drag, and reduces energetic expenditure of individuals practicing behavioural thermoregulation. These data provide an unrivaled viewpoint of thermo-hydraulic habitat selection by adult AS, and a blue print for restoration work. The use of UAV-based sensors has the potential to instigate a paradigm shift for river sciences. The age of applying hyper-resolution, remote sensing for river science and aquatic ecology is immensely exciting.