Miracle-dz/UniFAR-FTUs huggingface dataset:
3D bioprinted tissue-specific spheroidal multicellular microarchitectures for advanced cell therapy

Intercellular interaction is the most crucial factor in promoting cell viability and functionality in an engineered tissue system. Of the various shapes available for cell-laden constructs, spheroidal multicellular microarchitectures (SMMs) have been introduced as building blocks and injectable cell carriers with substantial cell–cell and cell–extracellular matrix (ECM) interactions. Here, we developed a precise and expeditious SMM printing method that can create a tissue-specific microenvironment and thus be potentially useful for cell therapy. This printing strategy is designed to manufacture SMMs fabricated with optimal bioink blended with decellularized ECM and alginate to enhance the functional performance of the encapsulated cells. Experimental results showed that the proposed method allowed for size controllability and mass production of SMMs with high cell viability. Moreover, SMMs co-cultured with endothelial cells promoted lineage-specific maturation and increased functionality compared to monocultured SMMs. Overall, it was concluded that SMMs have the potential for use in cell therapy due to their high cell retention and proliferation rate compared to single-cell injection, particularly for efficient tissue regeneration after myocardial infarction. This study suggests that utilizing microextrusion-based 3D bioprinting technology to encapsulate cells in cell-niche-standardized SMMs can expand the range of possible applications.
Ancestral patterns of recessive dystrophic epidermolysis bullosa mutations in Hispanic populations suggest sephardic ancestry

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genodermatosis caused by mutations in the gene coding for type VII collagen (COL7A1). More than 800 different pathogenic mutations in COL7A1 have been described to date; however, the ancestral origins of many of these mutations have not been precisely identified. In this study, 32 RDEB patient samples from the Southwestern United States, Mexico, Chile, and Colombia carrying common mutations in the COL7A1 gene were investigated to determine the origins of these mutations and the extent to which shared ancestry contributes to disease prevalence. The results demonstrate both shared European and American origins of RDEB mutations in distinct populations in the Americas and suggest the influence of Sephardic ancestry in at least some RDEB mutations of European origins. Knowledge of ancestry and relatedness among RDEB patient populations will be crucial for the development of future clinical trials and the advancement of novel therapeutics.
Combination of Modified Biochar and Polyurea Microcapsules to Co-encapsulate a Fumigant via Interface Polymerization for Controlled Release and Enhanced Bioactivity.

BACKGROUND Soil fumigants-the most effective agrochemicals for managing soil-borne diseases-have been extensively used. However, high volatility, moderate toxicity, and insufficient effective duration considerably limit their application. In the present study, a combination of modified biochar and polyurea microcapsules (MCs) via interface polymerization to co-encapsulate allyl isothiocyanate (AITC) was developed as a model fumigant for controlled release (AITC@BC-MCs). RESULTS The physical characteristics of biochar modified by sand milling were significantly improved. In addition, chemical properties and morphological features of AITC@BC-MCs characterized by integrated methods revealed successful preparation of BC-MCs. Compared with monolayer MCs, BC-MCs could significantly delay AITC release due to the composite obstruction effect. Moreover, modified biochar endowed the cargo molecules with a pH-responsive release property. Additionally, this composite showed a longer persistent duration by prolonging AITC degradation half-life, which was 3.2-3.5 times that of the AITC technical concentrate under different soil conditions. Finally, the control efficacy of AITC@BC-MC against pathogens, including nematodes and fungi, as well as against weeds was significantly enhanced at the same dose, but it did not inhibit seed germination and growth after 10 days when fumigated soil was aerated. CONCLUSION Construction of a composite encapsulation system enhanced pesticide efficacy, reduced dose via controlled release, and delayed fumigant degradation in soil, indicating the great potential of this strategy for developing an effective and environmentally friendly fumigant formulation. This article is protected by copyright. All rights reserved.
Antibody responses induced by SHIV infection are more focused than those induced by soluble native HIV-1 envelope trimers in non-human primates

The development of an effective human immunodeficiency virus (HIV-1) vaccine is a high global health priority. Soluble native-like HIV-1 envelope glycoprotein trimers (Env), including those based on the SOSIP design, have shown promise as vaccine candidates by inducing neutralizing antibody responses against the autologous virus in animal models. However, to overcome HIV-1’s extreme diversity a vaccine needs to induce broadly neutralizing antibodies (bNAbs). Such bNAbs can protect non-human primates (NHPs) and humans from infection. The prototypic BG505 SOSIP.664 immunogen is based on the BG505 env sequence isolated from an HIV-1-infected infant from Kenya who developed a bNAb response. Studying bNAb development during natural HIV-1 infection can inform vaccine design, however, it is unclear to what extent vaccine-induced antibody responses to Env are comparable to those induced by natural infection. Here, we compared Env antibody responses in BG505 SOSIP-immunized NHPs with those in BG505 SHIV-infected NHPs, by analyzing monoclonal antibodies (mAbs). We observed three major differences between BG505 SOSIP immunization and BG505 SHIV infection. First, SHIV infection resulted in more clonal expansion and less antibody diversity compared to SOSIP immunization, likely because of higher and/or prolonged antigenic stimulation and increased antigen diversity during infection. Second, while we retrieved comparatively fewer neutralizing mAbs (NAbs) from SOSIP-immunized animals, these NAbs targeted more diverse epitopes compared to NAbs from SHIV-infected animals. However, none of the NAbs, either elicited by vaccination or infection, showed any breadth. Finally, SOSIP immunization elicited antibodies against the base of the trimer, while infection did not, consistent with the base being placed onto the virus membrane in the latter setting. Together these data provide new insights into the antibody response against BG505 Env during infection and immunization and limitations that need to be overcome to induce better responses after vaccination.
Expanding the phenotype of ASXL3‐related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3

The study aimed at widening the clinical and genetic spectrum of ASXL3‐related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3‐related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3‐related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro‐behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low‐hanging columella. The presented data will inform clinical management of individuals with ASXL3‐related syndrome and improve interpretation of new ASXL3 sequence variants.
Adjuvant Effect of Titanium Brushes in Peri-Implant Surgical Treatment: A Systematic Review

Background: the prognosis of peri-implant surgery can be affected by poor decontamination of the implant surface, which could be improved with the use of titanium brushes. The objectives of this systematic review were to evaluate the effectiveness of titanium brushes in the decontamination of the implant surface in terms of plaque index, probing depth, bleeding on probing and bone loss/gain; as well as its effectiveness according to the type of peri-implant bone defect. Methods: an electronic search was carried out in the PubMed, Scopus, Cochrane and Embase databases, as well as a manual search. The search strategy included four keywords: “Peri-implantitis”, “Periimplantitis”, “Implant Surface Decontamination” and “Titanium Brush”. Randomized controlled studies published in the last 10 years were included and systematic reviews, in vitro studies and animal studies were excluded. Results: 142 references were found, from which only four articles met the inclusion criteria. All of the studies included in the present review reported beneficial results in terms of probing depth, gingival index and radiographic bone loss and gain after implant surface decontamination adjuvated by titanium brushes. Conclusions: titanium rotary brushes show improvements in the evolution and prognosis of peri-implant surgery, although more long-term studies are needed to draw more solid conclusions.
A prospective study on early PET/CT scans during the first cycle of salvage chemotherapy for relapsed or refractory diffuse large B-cell lymphoma

Abstract Many patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) will not respond to platinum-containing salvage chemotherapy. Predicting treatment failure earlier could help clinicians minimize chemotherapy toxicities for non-responders in favor of other treatments. We conducted a pilot study where 2 early PET/CTs were obtained on days 4 (D4) and 21 (D21) of cycle 1 (C1) of salvage therapy for DLBCL. Twenty-five patients were enrolled and have evaluable data. Ten (40%) had an unplanned therapy change after C1 and before end-of-treatment (EOT) evaluation due to treatment failure on early PET/CT as interpreted by the treating physician. Early PET/CT response at D4 or D21 was not associated with EOT response in evaluable patients. Disease specific survival was longer for patients with a persistent response on both D4 and D21 (p = 0.042). Early PET/CT may predict salvage chemotherapy failure and could inform future clinical trials investigating early therapy change to non-chemotherapy treatments.
Adult stem cell niches for tissue homeostasis

Adult stem cells are fundamental to maintain tissue homeostasis, growth, and regeneration. They reside in specialized environments called niches. Following activating signals, they proliferate and differentiate into functional cells that are able to preserve tissue physiology, either to guarantee normal turnover or to counteract tissue damage caused by injury or disease. Multiple interactions occur within the niche between stem cell‐intrinsic factors, supporting cells, the extracellular matrix, and signaling pathways. Altogether, these interactions govern cell fate, preserving the stem cell pool, and regulating stem cell proliferation and differentiation. Based on their response to body needs, tissues can be largely classified into three main categories: tissues that even in normal conditions are characterized by an impressive turnover to replace rapidly exhausting cells (blood, epidermis, or intestinal epithelium); tissues that normally require only a basal cell replacement, though able to efficiently respond to increased tissue needs, injury, or disease (skeletal muscle); tissues that are equipped with less powerful stem cell niches, whose repairing ability is not able to overcome severe damage (heart or nervous tissue). The purpose of this review is to describe the main characteristics of stem cell niches in these different tissues, highlighting the various components influencing stem cell activity. Although much has been done, more work is needed to further increase our knowledge of niche interactions. This would be important not only to shed light on this fundamental chapter of human physiology but also to help the development of cell‐based strategies for clinical therapeutic applications, especially when other approaches fail.
The Anti-Viral Applications of Marine Resources for COVID-19 Treatment: An Overview

The ongoing pandemic has led to an urgent need for novel drug discovery and potential therapeutics for Sars-CoV-2 infected patients. Although Remdesivir and the anti-inflammatory agent dexamethasone are currently on the market for treatment, Remdesivir lacks full efficacy and thus, more drugs are needed. This review was conducted through literature search of PubMed, MDPI, Google Scholar and Scopus. Upon review of existing literature, it is evident that marine organisms harbor numerous active metabolites with anti-viral properties that serve as potential leads for COVID-19 therapy. Inorganic polyphosphates (polyP) naturally found in marine bacteria and sponges have been shown to prevent viral entry, induce the innate immune response, and downregulate human ACE-2. Furthermore, several marine metabolites isolated from diverse sponges and algae have been shown to inhibit main protease (Mpro), a crucial protein required for the viral life cycle. Sulfated polysaccharides have also been shown to have potent anti-viral effects due to their anionic properties and high molecular weight. Likewise, select marine sponges produce bromotyrosines which have been shown to prevent viral entry, replication and protein synthesis. The numerous compounds isolated from marine resources demonstrate significant potential against COVID-19. The present review for the first time highlights marine bioactive compounds, their sources, and their anti-viral mechanisms of action, with a focus on potential COVID-19 treatment.
Sodium butyrate pretreatment mitigates lipopolysaccharide-induced inflammation through the TLR4/NF-κB signaling pathway in bovine embryo trachea cells

Abstract The present study investigated the anti-inflammatory effects and potential mechanisms of sodium butyrate (SB) in bovine embryo tracheal cells (EBTr) stimulated with lipopolysaccharide (LPS). EBTr were exposed to either 1 mmol/L SB for 18 h for the SB group (SB) or to 0.4 μg/mL LPS for 6 h for the LPS group (LPS). PBS was added to EBTr for a control group (CON). EBTr were pretreated with SB for 18 h followed by 6 h of LPS stimulation for the LSB group (LSB). Results showed that with LPS stimulation, the gene expression of TLR4, NF-κB, IL6, and IL8, as well as cytokine production of IL6 and TNF-α, were significantly increased compared with the CON group. In contrast, protein expression of IL10 was decreased. However, these inflammatory effects induced by LPS were reversed in the LSB group. Compared with the CON group, protein expression of TLR4, phospho-NF-κB p65, phospho-IκBα, and IL1α were increased in the LPS group and these were decreased in the LSB group. Similarly, increased nuclear translocation of phospho-NF-κB p65 in the LPS group was suppressed with SB pretreatment. In conclusion, SB can reduce inflammation induced by LPS in EBTr, and this positive effect is mediated through the TLR4 and NF-κB signaling pathway.
Low sun exposure acts synergistically with high Epstein−Barr nuclear antigen 1 (EBNA‐1) antibody levels in multiple sclerosis etiology

Among multiple sclerosis (MS) patients, an association has been observed between low levels of vitamin D and high Epstein‐Barr nuclear antigen 1 (EBNA‐1) antibody levels. However, whether sun exposure/vitamin D moderates the role of Epstein‐Barr virus (EBV) infection in MS etiology is unclear. We aimed to investigate potential synergistic effects between low sun exposure and elevated EBNA‐1 antibody levels regarding MS risk.
Teaching old mice new tricks: the utility of aged mouse models of C. difficile infection to study pathogenesis and rejuvenate immune response

ABSTRACT Background Clostridioides difficile is a serious problem for the aging population. Aged mouse model of C. difficile infection (CDI) has emerged as a valuable tool to evaluate the mechanism of aging in CDI. Methods We reviewed five published studies utilizing aged mice (7–28 months) for CDI model for findings that may advance our understanding of how aging influences outcome from CDI. Results Aged mouse models of CDI uniformly demonstrated more severe disease in the old compared to young mice. Diminished neutrophil recruitment to intestinal tissue in aged mice is the most consistent finding. Differences in innate and humoral immune responses were also observed. The effects of aging on the outcome of infection were reversed by pharmacologic or microbiota-targeted interventions. Conclusion The aged mouse presents an important in vivo model to study CDI and elucidate the mechanisms underlying advanced age as an important risk factor for severe disease.
Fam20C Regulates Bone Resorption and Breast Cancer Bone Metastasis through Osteopontin and BMP4

Osteoclastogenesis and bone metastasis are suppressed by myeloid-derived Fam20C, but enhanced by breast cancer-associated Fam20C, uncovering novel Fam20C functions and new therapeutic strategies via targeting Fam20C substrates OPN and BMP4. Fam20C is a kinase that generates the majority of secreted phosphoproteins and regulates biomineralization. However, its potential roles in bone resorption and breast cancer bone metastasis are unknown. Here we show that Fam20C in the myeloid lineage suppresses osteoclastogenesis and bone resorption, during which, osteopontin (OPN) is the most abundant phosphoprotein secreted in a Fam20C-dependent manner. OPN phosphorylation by Fam20C decreased OPN secretion, and OPN neutralization reduced Fam20C deficiency–induced osteoclast differentiation and bone metastasis. In contrast, Fam20C in breast cancer cells promoted bone metastasis by facilitating the phosphorylation and secretion of BMP4, which in turn enhanced osteoclastogenesis. Mutation of the BMP4 phosphorylation site elevated BMP4 lysosomal degradation and reduced BMP4 secretion. In breast cancer cells, BMP4 depletion or treatment with a BMP4 signaling inhibitor diminished osteoclast differentiation and bone metastasis and abolished Fam20C-mediated regulation of these processes. Collectively, this study discovers distinct roles for Fam20C in myeloid cells and breast cancer cells and highlights OPN and BMP4 as potential therapeutic targets for breast cancer bone metastasis. Significance: Osteoclastogenesis and bone metastasis are suppressed by myeloid-derived Fam20C, but enhanced by breast cancer–associated Fam20C, uncovering novel Fam20C functions and new therapeutic strategies via targeting Fam20C substrates OPN and BMP4.
Mediation of circ_RPPH1 on miR-146b-3p/E2F2 pathway to hinder the growth and metastasis of breast carcinoma cells

Background: Nova Circular RNA (circRNA) of non-coding RNA has gradually become an important regulatory factor, and it has made people attach great concern over the occurrence and development of many diseases, particularly carcinomas. circ_RPPH1 is a newly discovered circRNA. Gene Expression Omnibus (GEO) analysis showed that there are high contents of circ_RPPH1 in breast cancer (BC), but the mechanism of circRNA in BC remains unclear. Methods: Real-time quantitative PCR (qRT-PCR) was applied to test the role of circ_RPPH1 in BC patients, and functional experiments were applied to test the role of circ_RPPH1 on BC tumor. Fluorescence in situ hybridization, double luciferase reporter gene analysis, RNA pull-down and RNA immunoprecipitation experiments were performed to explore the correlation of circ_RPPH1 with miR-146b-3p/E2F2 in BC. Results: circ_RPPH1 was evidently enhanced in BC, and its content was related to the clinical stage and pathological grade. circ_RPPH1 can accelerate the proliferation, migration and invasion, and promote tumorigenesis and metastasis. Mechanism exploration indicated that circ_RPPH1 acted as ceRNA (competing endogenous RNA) of miR-146b-3p, so as to reduce the inhibitory role of miR-146b-3p on its target E2F2. Conclusion: Circ_RPPH1/miR-146b-3p/E2F2 axis can promote the progression of BC, and it might be a latent therapeutic target for clinical BC.
Persistent human bocavirus 1 infection and tonsillar immune responses

Abstract Background Persistent human bocavirus 1 (HBoV1) infection is a common finding in patients suffering from chronic tonsillar disease. However, the associations between HBoV1 infection and specific immune reactions are not completely known. We aimed to compare in vivo expression of T‐cell cytokines, transcription factors, and type I/III interferons in human tonsils between HBoV1‐positive and ‐negative tonsillectomy patients. Methods Tonsil tissue samples, nasopharyngeal aspirate (NPA), and serum samples were obtained from 143 immunocompetent adult and child tonsillectomy patients. HBoV1 and 14 other respiratory viruses were detected in NPAs and tonsil tissues by polymerase chain reaction (PCR). Serology and semi‐quantitative PCR were used for diagnosing HBoV1 infections. Expression of 14 cytokines and transcription factors (IFN‐α, IFN‐β, IFN‐γ, IL‐10, IL‐13, IL‐17, IL‐28, IL‐29, IL‐37, TGF‐β, FOXP3, GATA3, RORC2, Tbet) was analyzed by quantitative reverse‐transcription (RT)‐PCR in tonsil tissues. Results HBoV1 was detected by PCR in NPA and tonsils from 25 (17%) study patients. Serology results indicated prior nonacute infections in 81% of cases. Tonsillar cytokine responses were affected by HBoV1 infection. The suppression of two transcription factors, RORC2 and FOXP3, was associated with HBoV1 infection (p < 0.05). Furthermore, intratonsillar HBoV1‐DNA loads correlated negatively with IFN‐λ family cytokines and IL‐13. Conclusions Our study shows distinctively decreased T‐helper17 and T‐regulatory type immune responses in local lymphoid tissue in HBoV1‐positive tonsillectomy patients. HBoV1 may act as a suppressive immune modulator.
In Vitro Anticancer Drug Sensitivity Sensing through Single-Cell Raman Spectroscopy

Traditional in vitro anticancer drug sensitivity testing at the population level suffers from lengthy procedures and high false positive rates. To overcome these defects, we built a confocal Raman microscopy sensing system and proposed a single-cell approach via Raman-deuterium isotope probing (Raman-DIP) as a rapid and reliable in vitro drug efficacy evaluation method. Raman-DIP detected the incorporation of deuterium into the cell, which correlated with the metabolic activity of the cell. The human non-small cell lung cancer cell line HCC827 and human breast cancer cell line MCF-7 were tested against eight different anticancer drugs. The metabolic activity of cancer cells could be detected as early as 12 h, independent of cell growth. Incubation of cells in 30% heavy water (D2O) did not show any negative effect on cell viability. Compared with traditional methods, Raman-DIP could accurately determine the drug effect, meanwhile, it could reduce the testing period from 72–144 h to 48 h. Moreover, the heterogeneity of cells responding to anticancer drugs was observed at the single-cell level. This proof-of-concept study demonstrated the potential of Raman-DIP to be a reliable tool for cancer drug discovery and drug susceptibility testing.