Miracle-dz/UniFAR-FTUs huggingface dataset:
Inter and intra-tumor heterogeneity of paediatric type diffuse high-grade gliomas revealed by single-cell mass cytometry

Paediatric-type diffuse high-grade gliomas (PDHGG) are aggressive tumors affecting children and young adults, with no effective treatment. These highly heterogeneous malignancies arise in different sites of the Central Nervous System (CNS), carrying distinctive molecular alterations and clinical outcomes (inter-tumor heterogeneity). Moreover, deep cellular and molecular profiling studies highlighted the coexistence of genetically and phenotypically different subpopulations within the same tumor mass (intra-tumor heterogeneity). Despite the recent advances made in the field, the marked heterogeneity of PDHGGs still impedes the development of effective targeted therapies and the identification of suitable biomarkers. In order to fill the existing gap, we used mass cytometry to dissect PDHGG inter- and intra-heterogeneity. This is one of the most advanced technologies of the “-omics” era that, using antibodies conjugated to heavy metals, allows the simultaneous measurement of more than 40 markers at single-cell level. To this end, we analyzed eight PDHGG patient-derived cell lines from different locational and molecular subgroups. By using a panel of 15 antibodies, directly conjugated to metals or specifically customized to detect important histone variants, significant differences were highlighted in the expression of the considered antigens. The single-cell multiparametric approach realized has deepened our understanding of PDHGG, confirming a high degree of intra- and inter-tumoral heterogeneity and identifying some antigens that could represent useful biomarkers for the specific PDHGG locational or molecular subgroups.
A SVM-3D generalized algorithm for multilevel converters

A novel three dimensional space vector algorithm of multilevel converters for compensating harmonics and homopolar component in system with neutral is presented. This generalized method provides an online computation of the nearest switching vectors sequence to the reference vector and calculates the on-state durations of the respective switching state vectors without involving trigonometric functions, look-up tables or coordinate system transformations which increase the computational load corresponding to the modulation of multilevel converters. The low computational cost of the proposed method is always the same and it is independent of the number of levels of the converter. The conventional 2D space vector algorithms are particular cases of the proposed generalized modulation algorithm. The algorithm provides the switching sequence that minimizes the total harmonic distortion and the commutation number of the semiconductor devices.
Is Parceling Really Necessary? A Comparison of Results From Item Parceling and Categorical Variable Methodology

This study examined the efficacy of 4 different parceling methods for modeling categorical data with 2, 3, and 4 categories and with normal, moderately nonnormal, and severely nonnormal distributions. The parceling methods investigated were isolated parceling in which items were parceled with other items sharing the same source of variance, and distributed parceling in which items were parceled with items influenced by different factors. These parceling strategies were crossed with strategies in which items were either parceled with similarly distributed or differently distributed items, to create 4 different parceling methods. Overall, parceling together items influenced by different factors and with different distributions resulted in better model fit, but high levels of parameter estimate bias. Across all parceling methods, parameter estimate bias ranged from 20% to over 130%. Parceling strategies were contrasted with use of the WLSMV estimator for categorical, unparceled data. Results based on this estimator are encouraging, although some bias was found when high levels of nonnormality were present. Values of the chi-square and root mean squared error of approximation based on WLSMV also resulted in Type II error rates for misspecified models when data were severely nonnormally distributed.
Stepwise acquisition of unique epigenetic signatures during differentiation of tissue Treg cells

Regulatory T cells in non-lymphoid tissues are not only critical for maintaining self-tolerance, but are also important for promoting organ homeostasis and tissue repair. It is proposed that the generation of tissue Treg cells is a stepwise, multi-site process, accompanied by extensive epigenome remodeling, finally leading to the acquisition of unique tissue-specific epigenetic signatures. This process is initiated in the thymus, where Treg cells acquire core phenotypic and functional properties, followed by a priming step in secondary lymphoid organs that permits Treg cells to exit the lymphoid organs and seed into non-lymphoid tissues. There, a final specialization process takes place in response to unique microenvironmental cues in the respective tissue. In this review, we will summarize recent findings on this multi-site tissue Treg cell differentiation and highlight the importance of epigenetic remodeling during these stepwise events.
Gut brain interaction theory reveals gut microbiota mediated neurogenesis and traditional Chinese medicine research strategies

Adult neurogenesis is the process of differentiation of neural stem cells (NSCs) into neurons and glial cells in certain areas of the adult brain. Defects in neurogenesis can lead to neurodegenerative diseases, mental disorders, and other maladies. This process is directionally regulated by transcription factors, the Wnt and Notch pathway, the extracellular matrix, and various growth factors. External factors like stress, physical exercise, diet, medications, etc., affect neurogenesis and the gut microbiota. The gut microbiota may affect NSCs through vagal, immune and chemical pathways, and other pathways. Traditional Chinese medicine (TCM) has been proven to affect NSCs proliferation and differentiation and can regulate the abundance and metabolites produced by intestinal microorganisms. However, the underlying mechanisms by which these factors regulate neurogenesis through the gut microbiota are not fully understood. In this review, we describe the recent evidence on the role of the gut microbiota in neurogenesis. Moreover, we hypothesize on the characteristics of the microbiota-gut-brain axis based on bacterial phyla, including microbiota’s metabolites, and neuronal and immune pathways while providing an outlook on TCM’s potential effects on adult neurogenesis by regulating gut microbiota.
Comparative chloroplast genomics provides insights into the genealogical relationships of endangered Tetraena mongolica and the chloroplast genome evolution of related Zygophyllaceae species

A comprehensive understanding of genetic background for rare species will provide an important theoretical basis for the future species management, monitoring and conservation. Tetraena mongolica is restrictedly distributed in the western Ordos plateau of China and has been listed as a national protected plant. We generated 13 chloroplast (cp) genomes of T. mongolica (size range of 106,062–106,230 bp) and conducted a series of comparative analyses of six Zygophyllaceae cp genomes. T. mongolica cp genome exhibited a quadripartite structure with drastically reduced inverted repeats (IRs, 4,315 bp) and undergone the loss of a suit of ndh genes and a copy of rRNAs. Furthermore, all the T. mongolica populations were divided into two genetic groups based on complete cp phylogenomics. In addition, notably variable genome size, gene order and structural changes had been observed among the six Zygophyllaceae cp genomes. Overall, our findings provide insights into the cp genome evolution mode and intraspecific relationships of T. mongolica, and provide a molecular basis for scientific conservation of this endangered plant.
Editorial: The developments of metal-based agents against lung cancer

Lung cancer is a major public health concern globally, with approximately 1.8 million people diagnosed and 1.6 million people succumbing to this disease annually (Sung et al., 2021). Moreover, the 5-year survival rate is lower than 17 percent (Hirsch et al., 2017). Therefore, the research and development of anti-lung cancer agents is critical. Metalbased agents have several potential advantages over organic-based agents, such as multiple available redox states, several coordination geometries and numbers, as well as the intrinsic properties of the metal ion (van Rijt and Sadler, 2009; Barry and Sadler, 2013). Therefore, metal-based agents provide more opportunities for the development of antilung cancer agents compared to organic agents. This topic “The Developments of MetalBased Agents Against Lung Cancer” reports on the recent advances in metal-based agents for treating lung cancer, thereby providing a new perspective on the treatment of lung cancer. Although platinumand ruthenium-based agents have been successful in clinical trials or clinical use, serious side effects and drug resistance have hindered their use (Gou et al., 2021). Stimuli-responsive Ptand Ru-complexes are effective strategies for reducing side effects and improving clinical efficacy. Furthermore, they allow targeted delivery of Pt/Rucomplexes and activation at the target site, which aids in regulating their efficacy and avoiding side effects. Zhang et al. systematically reviewed the representative (exo-stimuliresponsive, endo-stimuli-responsive, and dual-stimuli-responsive) stimulant-responsive platinumand ruthenium-based agents utilized in lung cancer therapy. They described various representative examples of stimulus-responsive Pt/Ru-complexes in terms of structural design, response mechanisms, and potential medical applications. They also analyzed the challenges these responsive Pt/Ru-complexes face, such as the need for precise control and initiation of the response system, the requirement for exploring new therapeutic targets and their druggability, and systemic toxicity. Nanocarrier-based combination chemotherapy can reduce the side effects of Pt-based agents. Fang et al. summarized recent progress made in the field of nanocarriers (such as carbon nanohorns, liposomes, and OPEN ACCESS
Reviewing the role of gut microbiota in the pathogenesis of depression and exploring new therapeutic options

The relationship between gut microbiota (GM) and mental health is one of the focuses of psychobiology research. In recent years, the microbial-gut-brain axis (MGBA) concept has gradually formed about this bidirectional communication between gut and brain. But how the GM is involved in regulating brain function and how they affect emotional disorders these mechanisms are tenuous and limited to animal research, and often controversial. Therefore, in this review, we attempt to summarize and categorize the latest advances in current research on the mechanisms of GM and depression to provide valid information for future diagnoses and therapy of mental disorders. Finally, we introduced some antidepressant regimens that can help restore gut dysbiosis, including classic antidepressants, Chinese materia medica (CMM), diet, and exogenous strains. These studies provide further insight into GM’s role and potential pathways in emotion-related diseases, which holds essential possible clinical outcomes for people with depression or related psychiatric disorders. Future research should focus on clarifying the causal role of GM in disease and developing microbial targets, applying these findings to the prevention and treatment of depression.
Smartphone-based particle image velocimetry for cardiovascular flows applications: A focus on coronary arteries

An experimental set-up is presented for the in vitro characterization of the fluid dynamics in personalized phantoms of healthy and stenosed coronary arteries. The proposed set-up was fine-tuned with the aim of obtaining a compact, flexible, low-cost test-bench for biomedical applications. Technically, velocity vector fields were measured adopting a so-called smart-PIV approach, consisting of a smartphone camera and a low-power continuous laser (30 mW). Experiments were conducted in realistic healthy and stenosed 3D-printed phantoms of left anterior descending coronary artery reconstructed from angiographic images. Time resolved image acquisition was made possible by the combination of the image acquisition frame rate of last generation commercial smartphones and the flow regimes characterizing coronary hemodynamics (velocities in the order of 10 cm/s). Different flow regimes (Reynolds numbers ranging from 20 to 200) were analyzed. The smart-PIV approach was able to provide both qualitative flow visualizations and quantitative results. A comparison between smart-PIV and conventional PIV (i.e., the gold-standard experimental technique for bioflows characterization) measurements showed a good agreement in the measured velocity vector fields for both the healthy and the stenosed coronary phantoms. Displacement errors and uncertainties, estimated by applying the particle disparity method, confirmed the soundness of the proposed smart-PIV approach, as their values fell within the same range for both smart and conventional PIV measured data (≈5% for the normalized estimated displacement error and below 1.2 pixels for displacement uncertainty). In conclusion, smart-PIV represents an easy-to-implement, low-cost methodology for obtaining an adequately robust experimental characterization of cardiovascular flows. The proposed approach, to be intended as a proof of concept, candidates to become an easy-to-handle test bench suitable for use also outside of research labs, e.g., for educational or industrial purposes, or as first-line investigation to direct and guide subsequent conventional PIV measurements.
“Seminal testosterone”, rising viewpoint of local spermatogenesis in nonobstructive azoospermia: One center long-term bidirectional cohort study

Objective Reproductive hormones are a traditional good method to evaluate spermatogenesis but might not accurately represent local spermatogenesis. To find a more accurate method, seminal reproductive hormones were studied. Methods A bidirectional cohort study was performed. A total of 126 infertile men from 2018 to 2019 were retrospectively analyzed. They were divided into nonobstructive azoospermia (NOA), oligozoospermia (OLZ) and normal (NOR) groups. A prospective study was conducted on patients in the NOA and OLZ groups for 2 years. Microscopic testicular sperm extraction was performed for NOA patients, who were divided into a focal spermatogenesis group (FS) and an idiopathic azoospermia group (IA). Drug treatment was for OLZ patients, who were divided into a valid group (VA) and an invalid group (IN). The differences in sperm parameters and reproductive hormones were compared. ANOSIM analysis was used between and within groups. Pearson correlation analysis, CO inertia analysis and Proctor’s analysis were for relationships. ROC curve for the specificity and sensitivity. Time series analysis was for the trends between hormones and time. Results The b-FSH, b-LH, s-T and ΔT in the NOA group were significantly higher than those in the OLZ and NOR groups. However, the s-FSH, s-E2, s-P, ΔFSH, ΔLH, ΔP and ΔE2 were lower. Thirty-one NOA patients underwent MTSE, of whom 12 had sperm (FS) and 19 had no sperm (IA). The s-FSH and s-E2 of the FS group were higher than those of the IA group. Twenty-six OLZ patients completed 30 days of treatment, of which 11 had an improved sperm count (VA) and 15 had no (IN). The ΔT of the VA group was higher than that of the IN group. After follow-up for 2 years, 18 patients’ results showed that b-FSH, b-LH and s-T were different over time, with delays of 19, 3 and -19 days. SC is closely related to pH, s-FSH, s-LH, s-E2, s-P, s-T, b-FSH, b-LH, ΔFSH, ΔLH, ΔP, ΔE2 and ΔT. There were complex common trends and relationships between different kinds of hormones. s-FSH, s-LH, s-E2, s-P, s-T, b-FSH and b-LH were useful to judge spermatogenesis, of which s-T, b-FSH and b-LH were more sensitive. If s-T, b-FSH and b-LH reached 64.4, 9.4 and 4.7, respectively, their prediction performance was the strongest. Conclusion Seminal testosterone is sensitive for judging local spermatogenesis in nonobstructive azoospermia patients, which may be the direction of local spermatogenesis in nonobstructive azoospermia. Clinical trial registration http://www.chictr. org.cn/index.aspx, identifier ChiCTR2200060463.
Worldwide impact of lifestyle predictors of dementia prevalence: An eXplainable Artificial Intelligence analysis

Introduction Dementia is an umbrella term indicating a group of diseases that affect the cognitive sphere. Dementia is not a mere individual health issue, since its interference with the ability to carry out daily activities entails a series of collateral problems, comprising exclusion of patients from civil rights and welfare, unpaid caregiving work, mostly performed by women, and an additional burden on the public healthcare systems. Thus, gender and wealth inequalities (both among individuals and among countries) tend to amplify the social impact of such a disease. Since at present there is no cure for dementia but only drug treatments to slow down its progress and mitigate the symptoms, it is essential to work on prevention and early diagnosis, identifying the risk factors that increase the probability of its onset. The complex and multifactorial etiology of dementia, resulting from an interplay between genetics and environmental factors, can benefit from a multidisciplinary approach that follows the “One Health” guidelines of the World Health Organization. Methods In this work, we apply methods of Artificial Intelligence and complex systems physics to investigate the possibility to predict dementia prevalence throughout world countries from a set of variables concerning individual health, food consumption, substance use and abuse, healthcare system efficiency. The analysis uses publicly available indicator values at a country level, referred to a time window of 26 years. Results Employing methods based on eXplainable Artificial Intelligence (XAI) and complex networks, we identify a group of lifestyle factors, mostly concerning nutrition, that contribute the most to dementia incidence prediction. Discussion The proposed approach provides a methodological basis to develop quantitative tools for action patterns against such a disease, which involves issues deeply related with sustainable, such as good health and resposible food consumption.
Patients with positive HER-2 amplification advanced gastroesophageal junction cancer achieved complete response with combined chemotherapy of AK104/cadonilimab (PD-1/CTLA-4 bispecific): A case report

Background Human epidermal growth factor receptor 2 (HER2) is the most prominent therapeutic target for advanced gastric (G)/GEJ cancer. However, targeted therapy did not significantly improve survival. Currently, there are no regimens for the treatment of HER-2 amplification that exclude targeted agents. Case presentation A 42-year-old man was diagnosed with adenocarcinoma of GEJ (stage IV) with liver metastasis and lung metastasis. The patient was enrolled in a trial that excluded patients with known HER2-positivity: AK104, a PD-1/CTLA-4 bispecific antibody, combined with chemotherapy (mXELOX) as first-line therapy for advanced gastric G/GEJ cancer (NCT03852251). After six cycles of AK104 combined with chemotherapy therapy, immune-related pulmonary toxicity was observed. We rechallenged AK104 after hormone therapy, and no further pulmonary toxicity was observed. Immune-related hepatitis occurred in the patient during immunotherapy combined with single-drug capecitabine therapy. After combining steroid therapy with mycophenolate mofetil, the patient’s immune hepatitis improved. Nevertheless, the patient was excluded from the clinical study due to the long-term absence of medication. Antitumor therapy was also discontinued in view of the patient’s adverse immune response. The patient did not receive subsequent immune antitumor therapy, and immune-related hepatitis still occurred intermittently, but the disease evaluation was maintained at PR. A complete response was confirmed by PET/CT and the biopsy specimen from gastroscopy on 2020-06-10. Next generation sequencing of biopsy tissue was used to guide subsequent therapy at a recent follow-up visit. The results indicated that ERBB2 mutations occurred at copy number 58.4934 (HER-2), TMB = 3.1, MSS. IHC: EBV (−), PD-L1 CPS = 3, HER-2 (3+). Conclusion Patients with HER-2-positive advanced GEJ cancer received PD-1/CTLA-4 bispecific immunotherapy combined with chemotherapy and achieved complete remission. It offers a novel, highly specific, and highly potent therapeutic option for HER-2-positive patients. Its use should be considered as a new treatment when trastuzumab is not viable. Currently, we are working to overcome this resistance.
G2/M checkpoint regulation and apoptosis facilitate the nuclear egress of parvoviral capsids

The nuclear export factor CRM1-mediated pathway is known to be important for the nuclear egress of progeny parvovirus capsids in the host cells with virus-mediated cell cycle arrest at G2/M. However, it is still unclear whether this is the only pathway by which capsids exit the nucleus. Our studies show that the nuclear egress of DNA-containing full canine parvovirus. capsids was reduced but not fully inhibited when CRM1-mediated nuclear export was prevented by leptomycin B. This suggests that canine parvovirus capsids might use additional routes for nuclear escape. This hypothesis was further supported by our findings that nuclear envelope (NE) permeability was increased at the late stages of infection. Inhibitors of cell cycle regulatory protein cyclin-dependent kinase 1 (Cdk1) and pro-apoptotic caspase 3 prevented the NE leakage. The change in NE permeability could be explained by the regulation of the G2/M checkpoint which is accompanied by early mitotic and apoptotic events. The model of G2/M checkpoint activation was supported by infection-induced nuclear accumulation of cyclin B1 and Cdk1. Both NE permeability and nuclear egress of capsids were reduced by the inhibition of Cdk1. Additional proof of checkpoint function regulation and promotion of apoptotic events was the nucleocytoplasmic redistribution of nuclear transport factors, importins, and Ran, in late infection. Consistent with our findings, post-translational histone acetylation that promotes the regulation of several genes related to cell cycle transition and arrest was detected. In conclusion, the model we propose implies that parvoviral capsid egress partially depends on infection-induced G2/M checkpoint regulation involving early mitotic and apoptotic events.