Miracle-dz/UniFAR-FTUs huggingface dataset:
Heterogeneous strains in tissue collagen show that high strains locally suppress degradation by collagenase

Collagen, the most abundant protein in mammals, contributes to the physical properties of different tissues during development, homeostasis, and disease. The adaptation of physical properties of tissues to mechanical stimuli is thus dependent on the control of tissue collagen levels by well-regulated synthesis and degradation of collagen. Importantly, how various molecular-level events within a tissue sustaining a range of mechanical strains contribute towards maintaining its collagen levels, remains unclear to date. Such molecular level processes in tissues are studied here in the case of isolated tendons consisting of collagen fibrils oriented along tissue loading-axis and beating embryonic hearts to gain understanding of mechanical load dependent tissue sculpting. Using a novel bioreactor design, starved mice tail tendon fascicles were used as a “cell-free” model and were subjected to heterogeneous and uniaxial deformation modes. Patterned photobleaching of fluorescent probes, a novel Aza-peptide or dye, on fascicles used to quantify tissue strains. Tissue microstructure was simultaneously imaged using second harmonic generation (SHG) signal to assess tissue collagen content while deformed fascicle samples were exposed to purified matrix metalloproteinase-1 (MMP-1) or bacterial collagenase (BC). A decrease in the degradation rate (relative to strain-free) was observed for physiological strain limits of tendon tissue (i.e. ∼5-8%) while at higher strains (i.e. pathological) the degradation rate was independent of strain magnitude changes. Interestingly, the strain dependence of degradation rate was independent of cleavage-site specificity of the collagenase molecules and the mode of tendon tissue deformation. Although spatially different within a tissue sample, the values of strain, degradation rate and collagen fiber organization with time during degradation of each tendon fascicle region were highly correlated. Tendon regions dominated by collagen fibers inclined to fascicle-axis were observed to follow non-affine deformation. The dependence of the degradation rate on mechanical strain is due to sequestration of collagen cleavage sites within fibrils. Permeation, tissue mass density and mobility of fluorescent collagenase and dextran are strain-independent for fascicle strains up to ∼5-8% while the degradation rate is positively correlated to unfolded triple-helical collagen content. Normal beating chick hearts subjected to ∼5% peak strain in a spatiotemporal coordinate contractile wave were observed to maintain their collagen mass until the beating strain is suppressed by inhibition of myosin-II. Based on the presence of exogeneous MMP inhibitors, endogenous MMPs within the non-beating hearts degrade the collagens immediately (in ∼30-60 mins). Both tissue systems under mechanical strains suggest degradative sculpting where mechanical strain-dependent collagen fibril architecture changes appear to play a key role in determining collagen lifetime within tissues. Graphical abstract
Predicted distribution of a rare and understudied forest carnivore: Humboldt marten (Martes caurina humboldtensis)

Background A suite of mammalian species have experienced range contractions following European settlement and post-settlement development of the North American continent. For example, while North American martens (American marten, Martes americana; Pacific marten, M. caurina) generally have a broad range across northern latitudes, local populations have experienced substantial reductions in distribution and some extant populations are small and geographically isolated. The Humboldt marten (M. c. humboldtensis), a subspecies of Pacific marten that occurs in coastal Oregon and northern California, was recently designated as federally threatened in part due to its reduced distribution. To inform strategic conservation actions, we assessed Humboldt marten occurrence by compiling all known records from their range. Methods We compiled Humboldt marten locations since their rediscover to present (1,692 marten locations, 1996-2020). We spatially-thinned locations to 500-m to assess correlations with variables across contemporary Humboldt marten distribution (n=384). Using maximum entropy modeling (Maxent), we created distribution models with variables optimized for spatial scale; pre-selected scales were associated with marten ecology (50 to 1170 m radius). Marten locations were most correlated with abiotic factors (e.g., precipitation), which are unalterable and therefore uninformative within the context of restoration or management actions. Thus, we created variables to focus on hypothesized marten habitat relationships, including understory conditions such as predicted suitability of shrub species. Results Humboldt marten locations were positively associated with increased shrub cover (salal (Gautheria shallon), mast producing trees), increased pine (Pinus sp) overstory cover and precipitation at home-range spatial scales, areas with low and high amounts of canopy cover and slope, and cooler August temperatures. Unlike other recent literature on the species, we found little evidence that Humboldt marten locations were associated with old growth structural indices, perhaps because of a potential mismatch in the association between this index and shrub cover. As with any species distribution model, there were gaps in predicted distribution where Humboldt martens have been located during more recent surveys, for instance the southeastern portion of Oregon’s coast range. Conservation efforts and our assessment of potential risks to Humboldt marten populations would benefit from additional information on range extent, population sizes, and fine-scale habitat use. Like many rare and lesser-known species, this case study provides an example of how limited information can provide differing interpretations, emphasizing the need for study-level replication in ecology.
Privacy-Preserving Genotype Imputation in a Trusted Execution Environment

Genotype imputation is an essential tool in genetics research, whereby missing genotypes are inferred based on a panel of reference genomes to enhance the power of downstream analyses. Recently, public imputation servers have been developed to allow researchers to leverage increasingly large-scale and diverse genetic data repositories for imputation. However, privacy concerns associated with uploading one’s genetic data to a third-party server greatly limit the utility of these services. In this paper, we introduce a practical, secure hardware-based solution for a privacy-preserving imputation service, which keeps the input genomes private from the service provider by processing the data only within a Trusted Execution Environment (TEE) offered by the Intel SGX technology. Our solution features SMac, an efficient, side-channel-resilient imputation algorithm designed for Intel SGX, which employs the hidden Markov model (HMM)-based imputation strategy also utilized by a state-of-the-art imputation software Minimac. SMac achieves imputation accuracies virtually identical to those of Minimac and provides protection against known attacks on SGX while maintaining scalability to large datasets. We additionally show the necessity of our strategies for mitigating side-channel risks by identifying vulnerabilities in existing imputation software and controlling their information exposure. Overall, our work provides a guideline for practical and secure implementation of genetic analysis tools in SGX, representing a step toward privacy-preserving analysis services that can facilitate data sharing and accelerate genetics research. † Availability Our software is available at https://github.com/ndokmai/sgx-genotype-imputation.
Global warming readiness: Feasibility of enhanced biological phosphorus removal from wastewater at 35°C

Recent research has shown enhanced biological phosphorus removal (EBPR) from municipal wastewater at warmer temperatures around 30°C to be stable in both laboratory-scale reactors and full-scale treatment plants. In the context of a changing climate, the feasibility of EBPR at even higher temperatures is of interest. We operated two lab-scale EBPR sequencing batch reactors with alternating anaerobic and aerobic phases for over 300 days at 30°C and 35°C, respectively, and followed the dynamics of the communities of phosphorus accumulating organisms (PAOs) and competing glycogen accumulating organisms (GAOs) using a combination of 16S rRNA gene metabarcoding, quantitative PCR and fluorescent in-situ hybridization analyses. Stable and nearly complete P removal was achieved at 30°C; similarly, long term P removal was stable at 35°C with effluent PO43−-P concentrations < 0.5 mg/L on half of all monitored days. Diverse and abundant Ca. Accumulibacter amplicon sequence variants were closely related to those found in temperate environments, suggesting that EBPR at this temperature does not require a highly specialized PAO community. The slow-feeding strategy used effectively limited the carbon uptake rates of GAOs, allowing PAOs to outcompete GAOs at both temperatures. Candidatus Competibacter was the main GAO, along with cluster III Defluviicoccus members. These organisms withstood the slow-feeding regime, suggesting that their bioenergetic characteristics of carbon uptake differ from those of their tetrad-forming relatives. This specific lineage of GAOs warrants further study to establish how complete P removal can be maintained. Comparative cycle studies at two temperatures for each reactor revealed higher activity of Ca. Accumulibacter when the temperature was increased from 30°C to 35°C, suggesting that the stress was a result of the higher carbon (and/or P) metabolic rates of PAOs and GAOs, the resultant carbon deficiency, and additional community competition. An increase in the TOC to PO43--P ratio (from 25:1 to 40:1) effectively eased the carbon deficiency and benefited the proliferation of PAOs. In general, the slow-feeding strategy and sufficiently high carbon input benefited a high and stable EBPR at elevated temperature and represent basic conditions for full-scale applications.
Phellem translational landscape throughout secondary development in Arabidopsis roots

The phellem is a specialized boundary tissue providing the first line of defense against abiotic and biotic stresses in organs undergoing secondary growth. Phellem cells undergo several differentiation steps, which include cell wall suberization, cell expansion and programmed cell death. Yet, the molecular players acting particularly in phellem cell differentiation remain poorly described, particularly in the widely used model plant Arabidopsis thaliana. Using specific marker lines we followed the onset and progression of phellem differentiation in A. thaliana roots, and further targeted the translatome of new developed phellem cells using Translating Ribosome Affinity Purification followed by mRNA sequencing (TRAP-SEQ). We showed that phellem suberization is initiated early after phellogen (cork cambium) division. The specific translational landscape was organized in three main domains related to energy production, synthesis and transport of cell wall components, and response to stimulus. Novel players in phellem differentiation, related to suberin monomer transport and assembly, as well as novel transcription regulators were identified. This strategy provided an unprecedented resolution of the transcriptome of developing phellem cells, giving a detailed and specific view on the molecular mechanisms controlling cell differentiation in periderm tissues of the model plant Arabidopsis. Significance statement To improve the understanding of phellem differentiation into a suberized protective layer, we followed the establishment of periderm in Arabidopsis roots and sequenced the phellem-specific translatome. We found that phellem suberization occurs shortly after pericycle cell divisions with the induction of pivotal suberin biosynthesis genes. In parallel, we detected the activation of three central genetic modules acting throughout the phellem differentiation. This study provides a unique and targeted genetic resource for further functional studies of phellem tissues.
Inhibiting glycogen synthase kinase 3 suppresses TDP-43-mediated neurotoxicity in a caspase-dependant manner

Amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) is a progressive and ultimately fatal disease spectrum characterised by 43-kDa TAR DNA-binding protein (TDP-43) pathology. Current disease modifying drugs have modest effects and novel therapies are sorely needed. We previously showed that deletion of glycogen synthase kinase-3 (GSK3) suppresses TDP-43-mediated motor neuron degeneration in Drosophila. Here, we investigated the potential of GSK3 inhibition to ameliorate TDP43-mediated toxicity in mammalian neurons. Expression of TDP-43 was found to both activate GSK3 and promote caspase mediated cleavage of TDP-43. Inhibition of GSK3 reduced the abundance of full-length and cleaved TDP-43 in rodent neurons expressing wild-type or disease-associated mutant TDP-43 and also ameliorated neurotoxicity. Our results suggest that TDP-43 turnover is promoted by GSK3 inhibition in a caspase-dependent manner, and that targeting GSK3 activity could have therapeutic value.
Population genetics as a tool to elucidate pathogen reservoirs: Lessons from Pseudogymnoascus destructans, the causative agent of white-nose disease in bats

Emerging infectious diseases pose a major threat to human, animal, and plant health. The risk of species-extinctions increases when pathogens can survive in the absence of the host, for example in environmental reservoirs. However, identifying such reservoirs and modes of infection is often highly challenging. In this study, we investigated the presence and nature of an environmental reservoir for the ascomycete fungus Pseudogymnoascus destructans, the causative agent of white-nose disease. We also characterised the modes and timing of transmission of the pathogen; key elements to better understand the disease dynamics. Using 18 microsatellite markers, we determined the genotypic and genic (based on allele frequencies) differentiation between 1,497 P. destructans isolates collected from nine closely situated hibernacula in North-Eastern Germany. One hibernaculum was the focus of intensive sampling in which both the bats and walls of the site were sampled at regular intervals over five consecutive winter seasons (1,062 isolates). We found significant genic differentiation between sites and few multi-locus genotypes shared across hibernacula (genotypic differentiation). This demonstrates that each hibernaculum has an essentially unique population of the fungus. This would be expected if bats purge viable P. destructans over the summer, preventing the mixing and exchange of the pathogen in maternity colonies, where bats from all of the studied hibernacula meet. Results from the intensively sampled site show higher measures of genotypic richness on walls compared to bats, the absence of genic differentiation between bats and walls, and stable relative abundance of multi-locus genotypes over multiple winter seasons. This clearly implicates hibernacula walls as the main environmental reservoir of the pathogen, from which bats become re-infected annually.
Myocardial Disease and Long-Distance Space Travel: Solving the Radiation Problem

Radiation-induced cardiovascular disease is a well-known complication of radiation exposure. Over the last few years, planning for deep space missions has increased interest in the effects of space radiation on the cardiovascular system, as an increasing number of astronauts will be exposed to space radiation for longer periods of time. Research has shown that exposure to different types of particles found in space radiation can lead to the development of diverse cardiovascular disease via fibrotic myocardial remodeling, accelerated atherosclerosis and microvascular damage. Several underlying mechanisms for radiation-induced cardiovascular disease have been identified, but many aspects of the pathophysiology remain unclear. Existing pharmacological compounds have been evaluated to protect the cardiovascular system from space radiation-induced damage, but currently no radioprotective compounds have been approved. This review critically analyzes the effects of space radiation on the cardiovascular system, the underlying mechanisms and potential countermeasures to space radiation-induced cardiovascular disease.
Modulation of Immune Responses by Particle Size and Shape

The immune system has to cope with a wide range of irregularly shaped pathogens that can actively move (e.g., by flagella) and also dynamically remodel their shape (e.g., transition from yeast-shaped to hyphal fungi). The goal of this review is to draw general conclusions of how the size and geometry of a pathogen affect its uptake and processing by phagocytes of the immune system. We compared both theoretical and experimental studies with different cells, model particles, and pathogenic microbes (particularly fungi) showing that particle size, shape, rigidity, and surface roughness are important parameters for cellular uptake and subsequent immune responses, particularly inflammasome activation and T cell activation. Understanding how the physical properties of particles affect immune responses can aid the design of better vaccines.
Strong-Motions From Damaging Moderate Magnitude (5.9 ≥ Mw) Earthquakes in Japan Recorded by K-NET and KiK-net

Strong-motions from 79 moderate magnitude (5.9 ≥ Mw) earthquakes that caused various degrees of impact on humans and built-environment in Japan between 1996 and 2019, after the start of K-NET and KiK-net, are presented. As such, most of the earthquakes occurred beneath the land, and agencies had reported damages from events as small as Mw 4.1. Together, large peak ground accelerations exceeding 500 cm/s2 were recorded during 15 earthquakes, reaching approximately 1128 cm/s2 during one event. Similarly, large peak ground velocities exceeding 30 cm/s were recorded during ten earthquakes, reaching about 76 cm/s to the maximum. Most of the large values aforementioned were recorded within a hypocentral distance of approximately 30 km and on soil site conditions. Intermediate to long-period ground motions are of growing concerns in urban areas located on sedimentary basins with mid-rise and high-rise buildings. The threshold magnitude for the large ground motions at the periods of about 2–5 s is not well understood. In March 2013, the Japan Meteorological Agency introduced four levels of long-period ground motion intensity (LPGMI) based on absolute velocity response spectra (AVRS) between 1.6 and 7.8 s. In the present data set, LPGMI of level 3 (AVRS 50–100 cm/s) and level 4 (AVRS >100 cm/s) were observed each at a single site from shallow-focus earthquakes of Mw 5.8 and 5.9 at distances of approximately 12 and 15 km, respectively. However, the peak response periods were relatively short (1.6–1.8 s). The data showed that LPGM from moderate earthquakes is of lower concern regarding earthquake early warning at distances beyond 200 km. The 2018 Mw 5.5 North Osaka earthquake, despite the moderate magnitude, caused the loss of six human lives and brought significant damage to buildings and lifelines. Comparing the data with the ground motion prediction equations (GMPEs) and other events suggested that the North Osaka earthquake was probably a higher stress drop event. These moderate earthquakes’ observations hinted that the commonly used GMPEs in Japan may not sufficiently grasp these earthquakes' hazards.
Deep Neural Networks Outperform the CAPRA Score in Predicting Biochemical Recurrence After Prostatectomy

Background Use of predictive models for the prediction of biochemical recurrence (BCR) is gaining attention for prostate cancer (PCa). Specifically, BCR occurs in approximately 20–40% of patients five years after radical prostatectomy (RP) and the ability to predict BCR may help clinicians to make better treatment decisions. We aim to investigate the accuracy of CAPRA score compared to others models in predicting the 3-year BCR of PCa patients. Material and Methods A total of 5043 men who underwent RP were analyzed retrospectively. The accuracy of CAPRA score, Cox regression analysis, logistic regression, K-nearest neighbor (KNN), random forest (RF) and a densely connected feed-forward neural network (DNN) classifier were compared in terms of 3-year BCR predictive value. The area under the receiver operating characteristic curve was mainly used to assess the performance of the predictive models in predicting the 3 years BCR of PCa patients. Pre-operative data such as PSA level, Gleason grade, and T stage were included in the multivariate analysis. To measure potential improvements to the model performance due to additional data, each model was trained once more with an additional set of post-operative surgical data from definitive pathology. Results Using the CAPRA score variables, DNN predictive model showed the highest AUC value of 0.7 comparing to the CAPRA score, logistic regression, KNN, RF, and cox regression with 0.63, 0.63, 0.55, 0.64, and 0.64, respectively. After including the post-operative variables to the model, the AUC values based on KNN, RF, and cox regression and DNN were improved to 0.77, 0.74, 0.75, and 0.84, respectively. Conclusions Our results showed that the DNN has the potential to predict the 3-year BCR and outperformed the CAPRA score and other predictive models.
Exploiting Joint-Resident Stem Cells by Exogenous SOX9 for Cartilage Regeneration for Therapy of Osteoarthritis

The lack of effective treatment options for osteoarthritis (OA) is mostly due to the very limited regenerative capacity of articular cartilage. Mesenchymal stem cells (MSCs) have been most extensively explored for cell-based therapy to induce cartilage regeneration for OA. However, current in vitro expanded MSC-based approaches have significant drawbacks. On the other hand, osteoarthritic joints contain chondrocyte progenitors and MSCs in several niches which have the potential yet fail to differentiate into chondrocytes for cartilage regeneration. One of the underlying mechanisms of the failure is that these chondrocyte progenitors and MSCs in OA joints are deficient in the activity of chondrogenic transcription factor SOX9 (SRY-type high-mobility group box-9). Thereby, replenishing with exogenous SOX9 would reactivate the potential of these stem cells to differentiate into chondrocytes. Cell-permeable, super-positively charged SOX9 (scSOX9) protein is able to promote hyaline-like cartilage regeneration by inducing chondrogenic differentiation of bone marrow derived MSCs in vivo. This scSOX9 protein can be administered into osteoarthritic joints by intra-articular injection. This one-step, cell-free supplement of exogenous SOX9 may harness the regenerative potential of the intrinsic MSCs within the joint cavity to stimulate cartilage regeneration in OA.