Miracle-dz/UniFAR-FTUs huggingface dataset:
The influence of axonal beading and undulation on axonal diameter mapping

We consider the effect of non-cylindrical axonal shape on axonal diameter mapping with diffusion MRI. Practical sensitivity to axon diameter is attained at strong diffusion weightings b, where the deviation from the scaling yields the finite transverse diffusivity, which is then translated into axon diameter. While axons are usually modeled as perfectly straight, impermeable cylinders, the local variations in diameter (caliber variation or beading) and direction (undulation) have been observed in microscopy data of human axons. Here we quantify the influence of cellular-level features such as caliber variation and undulation on axon diameter estimation. For that, we simulate the diffusion MRI signal in realistic axons segmented from 3-dimensional electron microscopy of a human brain sample. We then create artificial fibers with the same features and tune the amplitude of their caliber variations and undulations. Numerical simulations of diffusion in fibers with such tunable features show that caliber variations and undulations result in under- and over-estimation of axon diameters, correspondingly; this bias can be as large as 100%. Given that increased axonal beading and undulations have been observed in pathological tissues, such as traumatic brain injury and ischemia, the interpretation of axon diameter alterations in pathology may be significantly confounded.
The condition for dynamic stability in humans walking with feedback control

The walking human body is mechanically unstable. Loss of stability and falling is more likely in certain groups of people, such as older adults or people with neuromotor impairments, as well as in certain situations, such as when experiencing conflicting or distracting sensory inputs. Stability during walking is often characterized biomechanically, by measures based on body dynamics and the base of support. Neural control of upright stability, on the other hand, does not factor into commonly used stability measures. Here we analyze stability of human walking accounting for both biomechanics and neural control, using a modeling approach. We define a walking system as a combination of biomechanics, using the well known inverted pendulum model, and neural control, using a proportional-derivative controller for foot placement based on the state of the center of mass at midstance. We analyze this system formally and show that for any choice of system parameters there is always one periodic orbit. We then determine when this periodic orbit is stable, i.e. how the neural control gain values have to be chosen for stable walking. Following the formal analysis, we use this model to make predictions about neural control gains and compare these predictions with the literature and existing experimental data. The model predicts that control gains should increase with decreasing cadence. This finding appears in agreement with literature showing stronger effects of visual or vestibular manipulations at different walking speeds. Author summary The walking human body is mechanically unstable and humans frequently lose upright stability and fall while walking. Stability of human walking is usually analyzed from a biomechanical perspective. We argue that sensorimotor control is an essential aspect of walking stability. We model a walking system as a combination of inverted pendulum biomechanics and a neural feedback controller for foot placement and analyze the properties of this hybrid dynamical system. We find that there is always exactly one periodic orbit and derive a criterion for the asymptotic stability of this periodic orbit. This analytic criterion allows us to characterize the region in the parameter space where the walking system is stable. We use these theoretical results to analyze stability of human walking depending on different sensorimotor control gains. The model predicts that control gains should be larger for slower-paced walking, which is partially consistent with the available experimental data.
Impacts of heat stress and its mitigation by capsaicin in health status and digestive enzymes in house sparrows (Passer domesticus)

Heatwaves and warm spells at global level, product of climate change, causes alterations on homeostasis in animals (heat stress), so they must respond to these changes in order to survive. The response involves several physiological changes, such as releasing of glucocorticoids and catecholamines, to restore homeostasis. Due the lack of knowledge on this subject in wild birds, the objective of the present work was study the effect of heat stress on body condition and digestive system in house sparrows (Passer domesticus), as well as a possible role of capsaicin as a dietary additive in mitigating heat stress. In this work, we measure heterophils/lymphocytes ratio (as proxy of stress), body mass, hematocrit, uric acid and digestive enzymes (intestinal and pancreatic) under stress conditions at 32°±2 °C and under normal conditions at 22°±2 °C. In addition, we evaluate the effect of capsaicin in both situations (heat stress at 32°C and normal condition 22°C). We found an increase of H/L ratio and uric acid in plasma under heat stress, and decrease of H/L ratio with capsaicin on animals exposed to heat stress. Although a loss of intestinal mass was observed in animals exposed at 32°C, digestive enzyme activity does not change under heat stress or under capsaicin administration. Improving knowledge in this field is relevant at the level of animal nutrition and veterinary medicine, reducing the stress of wild birds in captivity and improving dietary mixes for future global warming scenarios.
Single-cell analysis reveals distinct fibroblast plasticity during tenocyte regeneration in zebrafish

Despite their importance in tissue maintenance and repair, fibroblast diversity and plasticity remain poorly understood. Using single-cell RNA sequencing, we uncover distinct sclerotome-derived fibroblast populations in zebrafish, including progenitor-like perivascular/interstitial fibroblasts, and specialized fibroblasts such as tenocytes. To determine fibroblast plasticity in vivo, we develop a laser-induced tendon ablation and regeneration model. Lineage tracing reveals that laser-ablated tenocytes are quickly regenerated by preexisting fibroblasts. By combining single-cell clonal analysis and live imaging, we demonstrate that perivascular/interstitial fibroblasts actively migrate to the injury site, where they proliferate and give rise to new tenocytes. By contrast, perivascular fibroblast-derived pericytes or specialized fibroblasts, including tenocytes, exhibit no regenerative plasticity. Interestingly, active Hedgehog (Hh) signaling is required for the proliferation of activated fibroblasts to ensure efficient tenocyte regeneration. Together, our work highlights the functional diversity of fibroblasts and establishes perivascular/interstitial fibroblasts as tenocyte progenitors that promote tendon regeneration in a Hh signaling-dependent manner. TEASER Perivascular/interstitial fibroblasts function as plastic progenitors during tenocyte regeneration.
Derivation of trophoblast stem cells unveils unrestrained potential of mouse ESCs and epiblast

mESCs and epiblast are considered to follow strict lineage adherence and lack the potential to contribute to trophoectoderm. Here, we report the derivation of trophoblast stem cells (ESTS) from the mESCs. The single-cell transcriptome and molecular characterization of ESTS show similarity with TSCs. They efficiently integrate into the TE compartment of the blastocyst and contribute to the placenta during development. We discovered GSK3β as a critical regulator of the TE fate of ESCs. It plays a vital stage-specific role during ESTS derivation. We further show β-CATENIN and an intron-I regulatory element of Cdx2 are essential for the TE fate of ESCs. We further show that the mouse epiblast can readily differentiate into TE lineage. In contrast to the paradigm of the restricted potential of pluripotent ESCs and epiblast, our data shows that murine ESCs and epiblast have the unrestrained developmental potential for extraembryonic lineages.
From scalp to cortex, the whole isn’t greater than the sum of its parts: introducing GetTissueThickness (GTT) to assess age and sex differences in tissue thicknesses

Noninvasive techniques to record and stimulate the brain rely on passing through the tissues in between the scalp and cortex. Currently, there is no method to obtain detailed information about these scalp-to-cortex distance (SCD) tissues. We introduce GetTissueThickness (GTT), an open-source, automated approach to quantify SCD, and unveil how tissue thicknesses differ across age groups, sexes and brain regions (n = 250). We show that men have larger SCD in lower scalp regions and women have similar-to-larger SCD in regions closer to the vertex, with aging resulting in increased SCD in fronto-central regions. Soft tissue thickness varies by sex and age, with thicker layers and greater age-related decreases in men. Compact and spongy bone thickness also differ across sexes and age groups, with thicker compact bone in women in both age groups and an age-related thickening. Older men generally have the thickest cerebrospinal fluid layer and younger women and men having similar cerebrospinal fluid layers. Aging mostly results in grey matter thinning. Concerning SCD, the whole isn’t greater than the sum of its parts. GTT enables rapid quantification of the SCD tissues. The distinctive sensitivity of noninvasive recording and stimulation modalities to different tissues underscores the relevance of GTT.
A conserved extracellular ribonuclease with broad-spectrum cytotoxic activity enables smut fungi to compete with host-associated bacteria

Ribotoxins are secreted ribonucleases that specifically target and cleave the universally conserved sarcin-ricin loop sequence of rRNA, which leads to inhibition of protein biosynthesis and subsequently to cell death. We have identified and characterized a secreted Ribo1 protein of plant pathogenic smut fungi. Heterologous expression in different model systems showed that smut Ribo1 has cytotoxic activity against bacteria, yeast, host and non-host plants. Recombinant expression of Ribo1 in Nicotiana benthamiana induced plant cell death; however, an active site mutant induced cell death only when expressed as a secreted protein. In the maize smut Ustilago maydis, transcription of Ribo1 is specifically induced in early infection stages. While a knock-out mutant revealed that Ribo1 is dispensable for U. maydis virulence, the overexpression of Ribo1 in-planta had a strong dominant negative effect on virulence and induced host defense responses including cell death. This suggests a function of Ribo1 during the epiphytic development rather than for invasive colonization of the host. Accordingly, in presence of the biocontrol bacteria Pantoea sp. , which were isolated from maize leaves, the ribo1 knock-out mutant was significantly impaired in virulence. Together, we conclude that Ribo1 enables smut fungi to compete with host-associated bacteria during epiphytic development.
Dynamic Analysis of a Timoshenko Beam on a Semi-Infinite Elastic Subgrade using an Ordinary Differential Equation Method

A novel numerically analytical method is proposed for the analysis of a Timoshenko beam resting on a semi-infinite elastic subgrade in this paper. The deflection of the neutral surface of a Timoshenko beam and the cross- sectional rotation around the neutral axis are chosen as two basic unknown functions. By using a Hamilton principle, the free vibration problem of the Timoshenko beam is then translated into ordinary differential equations composed of the two unknown functions, which can be solved by an ordinary differential equation solver. Consequently, the natural frequencies and modes of the beam are obtained, and the influence of the subgrade stiffness and size as well as the material of the beam on dynamic property of the system can be readily analysed. The numerical results demonstrate that the proposed method is rational and powerful for the dynamic analysis of various Timoshenko beams.
The impact of innate immunity on malaria parasite infection dynamics in rodent models

Decades of research have investigated the molecular and cellular mechanisms that control the immune response to malaria. Yet, many studies offer conflicting results on the functional impact of innate immunity for controlling parasite replication early in infection. We conduct a meta-analysis to probe for consensus on the effect of innate immunity on parasite replication, examining three different species of rodent malaria parasite. Screening published studies that span four decades of research we collate, curate and statistically analyse infection dynamics in immune deficient or augmented mice to identify and quantify consensus and identify sources of disagreement among studies. Additionally, we estimate whether host factors or experimental methodology shape the impact of immune perturbations on parasite burden. First, we detected meta-analytic mean effect sizes (absolute Cohen’s h) for the difference in parasite burden between treatment and control groups ranging from 0.1498 to 0.2321 across parasite species. This range is considered a small effect size and translates to a modest change in parasitaemia of roughly 6-12% on average at the peak of infection. Second, we reveal that variation across studies using P. chabaudi or P. yoelii is best explained by stochasticity (due to small sample sizes) rather than by host factors or experimental design. Third, we find that for P. berghei the impact of immune perturbation is increased when young or female mice are used and is greatest when effector molecules (as opposed to upstream signalling molecules) are disrupted (up to an 18% difference in peak parasitaemia). Finally, we find little evidence of publication bias suggesting that our results are robust. The small effects sizes we observe, across three parasite species, following experimental perturbations of the innate immune system may be explained by redundancy in a complex biological system or by incomplete (or inappropriate) data reporting for meta-analysis. Alternatively, our findings might indicate a need to re-evaluate the efficiency with which innate immunity controls parasite replication early in infection. Testing these explanations is necessary to translate understanding from model systems to human malaria infections, manage immunopathology, and facilitate realism in mathematical models.
Discovery of broadly‐neutralizing antibodies against brown recluse spider and Gadim scorpion sphingomyelinases using consensus toxins as antigens

Broadly-neutralizing monoclonal antibodies are becoming increasingly important tools for treating infectious diseases and animal envenomings. However, designing and developing broadly-neutralizing antibodies can be cumbersome using traditional low-throughput iterative protein engineering methods. Here, we present a new high-throughput approach for the standardized discovery of broadly-neutralizing monoclonal antibodies relying on phage display technology and consensus antigens representing an average sequence of related proteins. We showcase the utility of this approach by applying it to toxic sphingomyelinases from the venoms of very distant orders of the animal kingdom, the recluse spider and Gadim scorpion. First, we designed a consensus sphingomyelinase and performed three rounds of phage display selection, followed by DELFIA-based screening and ranking, and benchmarked this to a similar campaign involving cross-panning against recombinant versions of the native toxins. Second, we identified two scFvs that not only bind the consensus toxins, but which can also neutralize sphingomyelinase activity in vitro. Finally, we conclude that the phage display campaign involving the use of the consensus toxin was more successful in yielding cross-neutralizing scFvs than the phage display campaign involving cross-panning.
Integrating Expert Knowledge with Deep Learning Improves QSAR Models for CADD Modeling

In recent years several applications of graph neural networks (GNNs) to molecular tasks have emerged. Whether GNNs outperform the traditional descriptor-based methods in the quantitative structure activity relationship (QSAR) modeling in early computer-aided drug discovery (CADD) remains an open question. This paper introduces a simple yet effective strategy to boost the predictive power of QSAR deep learning models. The strategy proposes to train GNNs together with traditional descriptors, combining the strengths of both methods. The enhanced model consistently outperforms vanilla descriptors or GNN methods on nine well-curated high throughput screening datasets over diverse therapeutic targets.
Raman Sideband Cooling and Coherent Manipulation of Trapped Ions

This thesis describes experiments primarily concerned with the manipulation of the spin and quantum motional state of single trapped ions and pairs of ions. A two stage photoionization system is described. This allows the loading of ions of a specific isotope of calcium into our trap. We measure the absolute cross section for photoionization from the 4s4p P1 state of neutral Ca. We demonstrate the loading and cooling of all the naturally occurring isotopes of calcium, including of pure crystals of 43Ca+. A magnetic resonance is used to determine accurately the Zeeman splitting of the ground state of a 40Ca+ ion. The coherent manipulation of the spin state of a 40Ca+ ion using this magnetic resonance is shown. We observe high quality Rabi oscillations between the two spin states with π times of order 100 μs and with decay times of order milliseconds. By using multiple pulses of this magnetic resonance in a Ramsey type experiment we are able to measure the net light shift induced on the two spin states by a circularly polarised far-off-resonant beam, and thus deduce its intensity precisely, and also ensure that such a beam is linearly polarised to high accuracy. We demonstrate a laser-driven rotation of the qubit with a π time of order a few microseconds. We also implement Rabi flopping by Raman carrier transitions, with a similar π time. We investigate three Raman sideband cooling methods applied to a single 40Ca+ ion. Two of these provide continuous cooling, with the lasers which drive the Raman transitions also providing the repumping. A simple theoretical model for this continuous cooling process is presented. The third method is pulsed sideband cooling, using pulses of far-offresonant Raman beams to drive the first red motional sideband of the ion, and then use a near-resonant beam to act as a repumper. The mean vibrational excitation of the ion is measured by comparing sideband heights, for these three cooling schemes. We achieve maximum ground state occupation probabilities of over 85%. We also demonstrate sub-Doppler cooling of a pair of trapped ions. Using a continuous cooling method followed by pulsed sideband cooling of the two axial motional modes we demonstrate cooling of both modes into the Lamb-Dicke regime. We present a rate equations program developed to study 43Ca+, which we intend to use to embody our qubit in future experiments. We use our program to fit data taken from a trapped 43Ca+ ion during photoionization experiments and to study the effect of the hyperfine structure of the ion on producing a high scattering rate during Doppler cooling of the ion.
Initiation of breakdown in strings of bubbles immersed in transformer oil and water: string orientation and proximity of bubbles

We computationally investigated the properties of positive streamers propagating inside strings of bubbles filled with humid air at atmospheric pressure, immersed in liquids and aligned along the electric field or transversal to it. We show that orientation of the string and proximity of bubbles are crucial for the streamer formation and re-initiation in the neighboring bubbles. For the vertical string (aligned along the electric field) there is a small field depletion inside the bubbles due to mutual polarization compared to the field in an isolated bubble. As a result, in a vertical string the ‘streamer hopping’ is more sensitive to the bubble separation. The streamer hopping is observed only when the separation is smaller than 300 μm. Polarization of the horizontal string of bubbles results in higher electric field inside the bubbles as compared to that in an isolated bubble. In this case, ‘streamer hopping’ is observed for the bubble separation 500 μm or larger. We also investigated the arrays of five and nine bubbles and showed that the enhancement of the electric field and streamer development depend on how many field depleting poles or field enhancing equators are in close proximity to the particular bubble.
The Role of Wind Tunnel Experiments in CFD Validation

Forty years ago, the design and development of aeronautical engines were initially carried out using basic wind tunnel experiments and flight testing. Numerical predictive methods were based on approximated fluid flow theories and engineering methods, validated by comparisons with wind tunnel data measurements that were mainly including flow visualizations, overall air loads forces and moments, global power/thrust, local surface pressure measurements, and skin friction distributions along the walls (Mc Croskey, Carr and Mc Alister, 1971; Landgrebe, 1971). Over the last two decades, computational fluids dynamics (CFD) activities have been concentrated on the development of improved numerical algorithms and have experienced rapid progresses that led to a large variety of numerical
A New Method to Solve the Kinematic Problem of Parallel Robots Using an Equivalent Structure

This paper proposed a new method to downgrade the kinematic mathematical model of parallel robots. A technique of complement mathematical models uses constraints to change the form of objective functions. An equivalent structure is used to replace the original structure of investigated robots. The difficulties encountered in solving problems having the transcendental form can be avoided by downgrading formula of the new mathematical model. The original formula which is usually in quaternary order can be downgraded to quadratic form. The main advantages of this method are understandable mathematical basis, high accuracy, and quick convergence. Carrying out solutions for pracitical kinematic problems of parallel robots becomes very promissable.