Miracle-dz/UniFAR-FTUs huggingface dataset:
Neural network embedding of functional microconnectome

Our brain works as a complex network system. Experiential knowledge seems to be coded into the organism’s network architecture rather than retaining only properties of individual neurons. In order to be better able to consider the high complexity of this network architecture, extracting simple rules through both automated as well as interpretable analysis of topological patterns will be necessary in order to allow more useful observations of interrelationships within the complex neural architecture. By combining these two types of analysis methods, we could automatically compress and naturally interpret topological patterns of functional connectivities, which produced electrical activities from many neurons simultaneously from acute slices of mice brain for 2.5 hours [Kajiwara et al. 2021]. As the first type of analysis, this study trained an artificial neural network system called Neural Network Embedding (NNE), and automatically compressed the functional connectivities into only small (25%) dimensions. As the second type of analysis, we widely compared the compressed features with ~15 representative network metrics, having clear interpretations, including > 5 centrality-type metrics and newly developed network metrics, that quantify degrees or ratio of hubs distanced by several-nodes from initially focused hubs. As the result, although we could give interpretations for only 55-60% of the extracted features, these new metrics, together with the commonly utilized network metrics, enabled interpretations for 80-100% features, using automated analysis. The result demonstrates not only the fact that the NNE method surpasses limitations of commonly used human-made variables, but also the possibility that acknowledgement of our own limitations drives us to extend interpretable possibilities by developing new analytic methodologies.
A within-host infection model to explore tolerance and resistance

How are some individuals surviving infections while others die? The answer lies in how infected individuals invest into controlling pathogen proliferation and mitigating damage, two strategies respectively called resistance and disease tolerance. Pathogen within-host dynamics (WHD), influenced by resistance, and its connection to host survival, determined by tolerance, decide the infection outcome. To grasp these intricate effects of resistance and tolerance, we used a deterministic theoretical model where pathogens interact with the immune system of a host. The model describes the positive and negative regulation of the immune response, consider the way damage accumulate during the infection and predicts WHD. When chronic, infections stabilize at a Set-Point Pathogen Load (SPPL). Our model predicts that this situation can be transient, the SPPL being then a predictor of life span which depends on initial condition (e.g. inoculum). When stable, the SPPL is rather diagnostic of non lethal chronic infections. In lethal infections, hosts die at a Pathogen Load Upon Death (PLUD) which is almost independent from the initial conditions. As the SPPL, the PLUD is affected by both resistance and tolerance but we demonstrate that it can be used in conjunction with mortality measurement to distinguish the effect of disease tolerance from that of resistance. We validate empirically this new approach, using Drosophila, melanogaster and the pathogen Providencia rettgeri.
Facing the Green Threat: A Water Flea’s Defenses against a Carnivorous Plant

Water fleas of the family Daphniidae are keystone species in many lentic ecosystems and, as most abundant filter feeders, link the primary production to higher trophic levels. As a response to the high predatory pressures, water fleas have evolved a range of defenses, including inducible defenses against animal predators. Here we show in Ceriodaphnia dubia a first example of such defenses induced by the presence of a coexisting plant predator, i.e. the carnivorous southern bladderwort (Utricularia australis, Lentibulariaceae), which possesses ultrafast underwater suction traps. When the bladderwort is present, C. dubia shows changes in morphology, life-history and behavior. While the morphological and behavioral adaptations improve C. dubia’s survival rate in the presence of this predator, the life-history parameters likely reflect trade-offs for the defense. Our study demonstrates plant-induced animal defenses, implying their potential relevance in freshwater ecosystems and contributing to an overall yet underestimated biodiversity of inducible defenses. Open Research Statement Data is not finally prepared for upload yet. Once most fitting file types are determined and metadata is created we aim to upload all raw data as supporting information.
A low-cost, open-source centrifuge adaptor for separating large volume clinical blood samples

Blood plasma separation is a prerequisite in numerous biomedical assays involving low abundance plasma-borne biomarkers and thus is the fundamental step before many bioanalytical steps. Conventionally, plasma separation is performed using high-capacity refrigerated centrifuges which have the advantage of handling large volume blood samples. These centrifuges are bulky, and prohibitively expensive for low-resource settings, with prices starting from $1,500. Although commercial and existing open-source micro-centrifuges are relatively low-cost, they cannot handle large volume blood samples. Microfluidic blood plasma separation also has been adopted by many researchers to enable low-cost plasma separation, however, these systems still present yield and purity issues for extremely low abundance biomarker detection such as the detection of various fractions of circulating cell-free DNA. To overcome this, we customised the rotor of a commercially available micro-centrifuge ∼$125) using fused filament fabrication to enable centrifugation of large clinical blood samples in resource poor-settings. Our designed adaptor ($15) can hold two 9 mL S-Monovette tubes and maintain the same separation performance (yield, cell count, hemolysis, albumin levels) as the control benchtop refrigerated centrifuge. This low-cost open-source centrifugation system capable of processing clinical blood tubes could be valuable to low-funded laboratories or low-resource settings where centrifugation is required immediately after blood withdrawal for further testing.
Ultrasound-mediated delivery of novel tau-specific monoclonal antibody enhances brain uptake but not therapeutic efficacy

Tau-specific immunotherapy is an attractive therapeutic strategy for the treatment of Alzheimer’s disease and other tauopathies. However, targeting tau effectively remains a considerable challenge due to the restrictive nature of the blood-brain barrier (BBB), which excludes 99.9% of peripherally administered antibodies. We have previously shown that the delivery of tau-specific monoclonal antibody (mAb) with low-intensity scanning ultrasound in combination with intravenously injected microbubbles (SUS+MB) increases the passage of IgG antibodies into the brain. SUS+MB transiently opens tight junctions to allow paracellular transport, but also facilitates transcellular transport, particularly for larger cargoes. However, therapeutic efficacy after enhanced brain delivery has not been explored. To assess whether ultrasound-mediated delivery of tau-specific mAbs leads to an enhanced therapeutic response, K369I tau transgenic K3 mice were passively immunised once weekly for 12 weeks with a novel mAb, RNF5, in combination with SUS+MB. While none of the treatment arms improved behaviour or motor functions in these mice, we found that both RNF5 and SUS+MB treatments on their own reduced tau pathology, but, surprisingly, the combination of both (RNF5+SUS+MB) did not achieve an additive reduction in tau pathology. This was despite observing increased antibody penetration in the brain. Interestingly, a significant fraction of the antibody in the combination treatment was visualized in brain endothelial cells, suggesting that paracellular transport may not be the preferred uptake mechanism for RNF5. Taken altogether, more research is warranted to develop SUS+MB as a delivery modality for anti-tau antibodies.
Inverse Potts model improves accuracy of phylogenetic profiling

Phylogenetic profiling is a powerful computational method for revealing the functions of function-unknown genes. Although conventional similarity evaluation measures in phylogenetic profiling showed high prediction accuracy, they have two estimation biases: an evolutionary bias and a spurious correlation bias. Existing studies have focused on the evolutionary bias, but the spurious correlation bias has not been analyzed. To eliminate the spurious correlation bias, we applied an evaluation measure based on the inverse Potts model (IPM) to phylogenetic profiling. We also proposed an evaluation measure to remove both the evolutionary and spurious correlation biases using the IPM. In an empirical dataset analysis, we demonstrated that these IPM-based evaluation measures improved the prediction performance of phylogenetic profiling. In addition, we found that the integration of several evaluation measures, including the IPM-based evaluation measures, had superior performance to a single evaluation measure. The source code is freely available at https://github.com/fukunagatsu/Ipm.
Tumor Stage-Based Gross Tumor Volume of Resectable Esophageal Squamous Cell Carcinoma Measured on CT: Association With Early Recurrence After Esophagectomy

Objective To investigate relationship of tumor stage-based gross tumor volume (GTV) of esophageal squamous cell carcinoma (ESCC) measured on computed tomography (CT) with early recurrence (ER) after esophagectomy. Materials and Methods Two hundred and four consecutive patients with resectable ESCC including 159 patients enrolled in the training cohort (TC) and 45 patients in validation cohort (VC) underwent contrast-enhanced CT less than 2 weeks before esophagectomy. GTV was retrospectively measured by multiplying sums of all tumor areas by section thickness. For the TC, univariate and multivariate analyses were performed to determine factors associated with ER. Mann-Whitney U test was conducted to compare GTV in patients with and without ER. Receiver operating characteristic (ROC) analysis was performed to determine if tumor stage-based GTV could predict ER. For the VC, unweighted Cohen’s Kappa tests were used to evaluate the performances of the previous ROC predictive models. Results ER occurred in 63 of 159 patients (39.6%) in the TC. According to the univariate analysis, histologic differentiation, cT stage, cN stage, and GTV were associated with ER after esophagectomy (all P-values < 0.05). Multivariate analysis revealed that cT stage and GTV were independent risk factors with hazard ratios of 3.382 [95% confidence interval (CI): 1.533–7.459] and 1.222 (95% CI: 1.125–1.327), respectively (all P-values < 0.05). Mann-Whitney U tests showed that GTV could help differentiate between ESCC with and without ER in stages cT1-4a, cT2, and cT3 (all P-values < 0.001), and the ROC analysis demonstrated the corresponding cutoffs of 13.31, 17.22, and 17.83 cm3 with areas under the curve of more than 0.8, respectively. In the VC, the Kappa tests validated that the ROC predictive models had good performances for differentiating between ESCC with and without ER in stages cT1-4a, cT2, and cT3 with Cohen k of 0.696 (95% CI, 0.498–0.894), 0.733 (95% CI, 0.386–1.080), and 0.862 (95% CI, 0.603–1.121), respectively. Conclusion GTV and cT stage can be independent risk factors of ER in ESCC after esophagectomy, and tumor stage-based GTV measured on CT can help predict ER.
Altered Pseudomonas Strategies to Inhibit Surface Aspergillus Colonies

Pseudomonas aeruginosa and Aspergillus fumigatus infections frequently co-localize in lungs of immunocompromised patients and individuals with cystic fibrosis (CF). The antifungal activity of P. aeruginosa has been described for its filtrates. Pyoverdine and pyocyanin are the principal antifungal P. aeruginosa molecules active against A. fumigatus biofilm metabolism present in iron-limited or iron-replete planktonic P. aeruginosa culture filtrates, respectively. Using various P. aeruginosa laboratory wild-type strains (PA14, PAO1, PAK), we found antifungal activity against Aspergillus colonies on agar. Comparing 36 PA14 and 7 PAO1 mutants, we found that mutants lacking both major siderophores, pyoverdine and pyochelin, display higher antifungal activity on agar than their wild types, while quorum sensing mutants lost antifungal activity. Addition of ferric iron, but not calcium or magnesium, reduced the antifungal effects of P. aeruginosa on agar, whereas iron-poor agar enhanced antifungal effects. Antifungal activity on agar was mediated by PQS and HHQ, via MvfR. Among the MvfR downstream factors, rhamnolipids and elastase were produced in larger quantities by pyoverdine–pyochelin double mutants and showed antifungal activity on agar. In summary, antifungal factors produced by P. aeruginosa on agar differ from those produced by bacteria grown in liquid cultures, are dependent on quorum sensing, and are downregulated by the availability of ferric iron. Rhamnolipids and elastase seem to be major mediators of Pseudomonas’ antifungal activity on a solid surface.
Exploring the Relationship Between Anxiety, Depression, and Sleep Disturbance Among HIV Patients in China From a Network Perspective

Background: Mental disorder of people living with HIV (PLWH) has become a common and increasing worldwide public health concern. We aimed to explore the relationship between anxiety, depression, and sleep disturbance for PLWH from a network perspective. Methods: The network model featured 28 symptoms on the Hospital Anxiety and Depression scale questionnaire and Pittsburgh Sleep Quality Index questionnaire in a sample of 4,091 HIV-infected persons. Node predictability and strength were computed to assess the importance of items. We estimated and compared 20 different networks based on subpopulations such as males and females to analyze similarities and differences in network structure, connections, and symptoms. Results: Several consistent patterns and interesting differences emerged across subgroups. Pertaining to the connections, some symptoms such as S12–S13 (“sleepy”—“without enthusiasm”) shown a strong positive relationship, indicating that feeling sleepy was a good predictor of lacking enthusiasm, and vice versa. While other symptoms, such as A3–D3 (“worried”—“cheerful”), were negatively related in all networks, revealing that nodes A3 and D3 were bridge symptoms between anxiety and depression. Across all subgroups, the most central symptom was A7 “panic” and S2 “awake”, which had the greatest potential to affect an individual's mental state. While S3 “bathroom” and S5 “cough or snore” shown consistent lower node importance, which would be of limited therapeutic use. Conclusions: Mental conditions of PLWH varied considerably among subgroups, inspiring psychiatrists and clinicians that personalized invention to a particular subgroup was essential and might be more effective during treatment than adopting the same therapeutic schedule.
The Efficacy and Safety of Multiple Dose Regimens of Kudzu (Pueraria lobata) Root Extract on Bone and Cartilage Turnover and Menopausal Symptoms

Background: Menopause is associated with detrimental changes in turnover of bone and cartilage and a variety of symptoms with negative impact on the quality of life. Naturally occurring isoflavones from Radix Pueraria lobata, Kudzu root, may possess chondroprotective and symptom-relieving properties, but efficacy and safety of dosing and dose frequencies required for pharmacological action is unclear. Purpose: This clinical trial evaluates the efficacy on bone and cartilage turnover, menopausal symptoms, and safety of five dose regimens of Kudzu root extract administered either once, twice or three times daily in women with at least mild menopausal symptoms. Materials and Methods: Fifty postmenopausal women were randomized equally into five different dose regimen groups of Kudzu root extract in a four-week, parallel group, open-label, single-center, exploratory study design. Biomarkers CTX-I and CTX-II reflecting bone and cartilage degradation, respectively, were assessed in blood samples and 24-h urine samples. Change from baseline in the Menopause Rating Scale (MRS) and subscales was evaluated. Safety endpoints were frequency of adverse events, changes in hematology and safety chemistry data, vital signs and electrocardiogram. Results: Fifty women (Age 54.2 years, SD: 2.9) were randomized. After 4 weeks of treatment, biomarkers of bone resorption and cartilage degradation were statistically significantly reduced from baseline levels in the group receiving two capsules three times a day, serum/urine CTX-I (−18.4%, 95% CI: −8.1 to −27.5, p = 0.001/−34.2%, 95% CI: −21.6 to −44.7, p < 0.0001), urine CTX-II (−17.4% 95% CI: −2.5 to −30.0, p = 0.02). The observed effects were consistent across study groups but appeared to favour three times daily dosing. Four weeks of treatment led to statistically significant reductions in the MRS Total Score (p < 0.0001–0.03) in four out of five treatment groups. Kudzu root extract was well tolerated in all dose regimens, and no serious adverse events were reported. Conclusion: The results indicate that Kudzu extract may possess beneficial effects on bone and cartilage health and may be a promising natural alternative to existing treatments for menopausal symptoms. Kudzu root extract was well tolerated for short-term treatment of mild to severe menopausal symptoms in women in all tested doses and dose frequencies.
Non-Invasive in Vivo Quantification of Directional Dependent Variation in Mechanical Properties for Human Skin

Skin is the body’s largest organ, and it shows non-linear and anisotropic behavior under the deformation. This behavior of the skin is due to the waviness and preferred orientation (in a particular direction) of collagen fibers. This preferred orientation of collagen fibers results in natural pre-tension and anisotropy of the skin. The knowledge of natural skin pre-tension and anisotropy is essential during incisions and surgery. The available suction-based devices quantify the anisotropy through the displacement field and cannot measure the stress-strain relation in particular directions. Therefore, in the current study, an in vivo full-field measurement suction apparatus was developed to measure the stress and strain of skin in all planar directions through a single experiment. First, this apparatus was tested on silicone substrates of known properties, and then it was used to test the skin of 12 human forearms. Further, to check the effect of hand stability on the measurements, the obtained results of the skin were compared with the results of a standard test performed in the same skin using a steady setup. The consistency between these two results confirms that the stability of the hand does not influence the measurements of skin properties. Furthermore, using the developed apparatus, the skin’s anisotropy and its relation with the Kraissl’s lines orientation was quantified by measuring the toe and linear moduli at an interval of one degree. The minimum and maximum values of the toe and linear moduli were 0.52 ± 0.09 and 0.59 ± 0.11 MPa, and 3.09 ± 0.47 and 5.52 ± 1.13 MPa, respectively. Also, the direction of maximum moduli was found almost similar to Kraissl’s lines’ orientation. These results confirm the contribution of skin pre-tension on the anisotropy of the skin. The present apparatus mimics the tissue expansion procedure, where observation of the test may be helpful in the selection of size and shape of the expander.
Rapid Determination of Trace Element Compositions in Peridotites by LA‐ICP‐MS Using an Albite Fusion Method

A rapid sample preparation procedure is described to determine trace element compositions of peridotites using LA‐ICP‐MS. Peridotite powders were fused with albite in a molybdenum–graphite assembly to obtain homogeneous glasses. Best conditions for the fusion procedure (heating at 1500–1550 °C for 10–15 min with a sample‐to‐flux ratio of 1:2) were constrained with melting experiments on two USGS reference materials, PCC‐1 and DTS‐2B. Mass fractions of first series transition elements, Ba and Pb, in quenched glasses of PCC‐1 and DTS‐2B are consistent with published data within 10% RSD. Three spinel peridotite xenoliths from eastern China were analysed following both our method and conventional solution ICP‐MS. Compared with solution ICP‐MS, the relative deviations of our method for most elements were within 10%, while for the REE, Ta, Pb, Th and U, the relative deviations were within 20%. In particular, volatile elements (e.g., Pb and Zn) are retained in the glass. Compared with conventional wet chemistry digestion, our method is faster. Additional advantages are complete sample fusion, especially useful for samples with acid‐resistant minerals (spinel and rutile), and long‐term conservation of glasses allowing unlimited repeated measurements with microbeam techniques. The same approach can be used for analyses of other mantle rocks, such as eclogites and pyroxenites.
Liver Fibrosis and MAFLD: From Molecular Aspects to Novel Pharmacological Strategies

Metabolic-associated fatty liver disease (MAFLD) is a new disease definition, and this nomenclature MAFLD was proposed to renovate its former name, non-alcoholic fatty liver disease (NAFLD). MAFLD/NAFLD have shared and predominate causes from nutrition overload to persistent liver damage and eventually lead to the development of liver fibrosis and cirrhosis. Unfortunately, there is an absence of effective treatments to reverse MAFLD/NAFLD-associated fibrosis. Due to the significant burden of MAFLD/NAFLD and its complications, there are active investigations on the development of novel targets and pharmacotherapeutics for treating this disease. In this review, we cover recent discoveries in new targets and molecules for antifibrotic treatment, which target pathways intertwined with the fibrogenesis process, including lipid metabolism, inflammation, cell apoptosis, oxidative stress, and extracellular matrix formation. Although marked advances have been made in the development of antifibrotic therapeutics, none of the treatments have achieved the endpoints evaluated by liver biopsy or without significant side effects in a large-scale trial. In addition to the discovery of new druggable targets and pharmacotherapeutics, personalized medication, and combinatorial therapies targeting multiple profibrotic pathways could be promising in achieving successful antifibrotic interventions in patients with MAFLD/NAFLD.