scMoresDB: A comprehensive database of single-cell multi-omics data for human respiratory system.

The human respiratory system is a complex and important system that can suffer a variety of diseases. Single-cell sequencing technologies, applied in many respiratory disease studies, have enhanced our ability in characterizing molecular and phenotypic features at a single-cell resolution. The exponentially increasing data from these studies have consequently led to difficulties in data sharing and analysis. Here, we present scMoresDB, a single-cell multi-omics database platform with extensive omics types tailored for human respiratory diseases. scMoresDB re-analyzes single-cell multi-omics datasets, providing a user-friendly interface with cross-omics search capabilities, interactive visualizations, and analytical tools for comprehensive data sharing and integrative analysis. Our example applications highlight the potential significance of BSG receptor in SARS-CoV-2 infection as well as the involvement of HHIP and TGFB2 in the development and progression of chronic obstructive pulmonary disease. scMoresDB significantly increases accessibility and utility of single-cell data relevant to human respiratory system and associated diseases.

A clinical consensus-compliant deep learning approach to quantitatively evaluate human in vitro fertilization early embryonic development with optical microscope images.

The selection of embryos is a key for the success of in vitro fertilization (IVF). However, automatic quality assessment on human IVF embryos with optical microscope images is still challenging. In this study, we developed a clinical consensus-compliant deep learning approach, named Esava (Embryo Segmentation and Viability Assessment), to quantitatively evaluate the development of IVF embryos using optical microscope images. In total 551 optical microscope images of human IVF embryos of day-2 to day-3 were collected, preprocessed, and annotated. Using the Faster R-CNN model as baseline, our Esava model was constructed, refined, trained, and validated for precise and robust blastomere detection. A novel algorithm Crowd-NMS was proposed and employed in Esava to enhance the object detection and to precisely quantify the embryonic cells and their size uniformity. Additionally, an innovative GrabCut-based unsupervised module was integrated for the segmentation of blastomeres and embryos. Independently tested on 94 embryo images for blastomere detection, Esava obtained the high rates of 0.9940, 0.9121, and 0.9531 for precision, recall, and mAP respectively, and gained significant advances compared with previous computational methods. Intraclass correlation coefficients indicated the consistency between Esava and three experienced embryologists. Another test on 51 extra images demonstrated that Esava surpassed other tools significantly, achieving the highest average precision 0.9025. Moreover, it also accurately identified the borders of blastomeres with mIoU over 0.88 on the independent testing dataset. Esava is compliant with the Istanbul clinical consensus and compatible to senior embryologists. Taken together, Esava improves the accuracy and efficiency of embryonic development assessment with optical microscope images.

Multi-omic analysis characterizes molecular susceptibility of receptors to SARS-CoV-2 spike protein.

In the post COVID-19 era, new SARS-CoV-2 variant strains may continue emerging and long COVID is poised to be another public health challenge. Deciphering the molecular susceptibility of receptors to SARS-CoV-2 spike protein is critical for understanding the immune responses in COVID-19 and the rationale of multi-organ injuries. Currently, such systematic exploration remains limited. Here, we conduct multi-omic analysis of protein binding affinities, transcriptomic expressions, and single-cell atlases to characterize the molecular susceptibility of receptors to SARS-CoV-2 spike protein. Initial affinity analysis explains the domination of delta and omicron variants and demonstrates the strongest affinities between BSG (CD147) receptor and most variants. Further transcriptomic data analysis on 4100 experimental samples and single-cell atlases of 1.4 million cells suggest the potential involvement of BSG in multi-organ injuries and long COVID, and explain the high prevalence of COVID-19 in elders as well as the different risks for patients with underlying diseases. Correlation analysis validated moderate associations between BSG and viral RNA abundance in multiple cell types. Moreover, similar patterns were observed in primates and validated in proteomic expressions. Overall, our findings implicate important therapeutic targets for the development of receptor-specific vaccines and drugs for COVID-19.

An FcRn-targeted mucosal vaccine against SARS-CoV-2 infection and transmission.

SARS-CoV-2 is primarily transmitted through droplets and airborne aerosols, and in order to prevent infection and reduce viral spread vaccines should elicit protective immunity in the airways. The neonatal Fc receptor (FcRn) transfers IgG across epithelial barriers and can enhance mucosal delivery of antigens. Here we explore FcRn-mediated respiratory delivery of SARS-CoV-2 spike (S). A monomeric IgG Fc was fused to a stabilized spike; the resulting S-Fc bound to S-specific antibodies and FcRn. Intranasal immunization of mice with S-Fc and CpG significantly induced antibody responses compared to the vaccination with S alone or PBS. Furthermore, we intranasally immunized mice or hamsters with S-Fc. A significant reduction of virus replication in nasal turbinate, lung, and brain was observed following nasal challenges with SARS-CoV-2 and its variants. Intranasal immunization also significantly reduced viral airborne transmission in hamsters. Nasal IgA, neutralizing antibodies, lung-resident memory T cells, and bone-marrow S-specific plasma cells mediated protection. Hence, FcRn delivers an S-Fc antigen effectively into the airway and induces protection against SARS-CoV-2 infection and transmission.

Inhibition of SARS-CoV-2 infection in human airway epithelium with a xeno-nucleic acid aptamer.

BACKGROUND: SARS-CoV-2, the agent responsible for the COVID-19 pandemic, enters cells through viral spike glycoprotein binding to the cellular receptor, angiotensin-converting enzyme 2 (ACE2). Given the lack of effective antivirals targeting SARS-CoV-2, we previously utilized systematic evolution of ligands by exponential enrichment (SELEX) and selected fluoro-arabino nucleic acid (FANA) aptamer R8-9 that was able to block the interaction between the viral receptor-binding domain and ACE2. METHODS: Here, we further assessed FANA-R8-9 as an entry inhibitor in contexts that recapitulate infection in vivo. RESULTS: We demonstrate that FANA-R8-9 inhibits spike-bearing pseudovirus particle uptake in cell lines. Then, using an in-vitro model of human airway epithelium (HAE) and SARS-CoV-2 virus, we show that FANA-R8-9 significantly reduces viral infection when added either at the time of inoculation, or several hours later. These results were specific to the R8-9 sequence, not the xeno-nucleic acid utilized to make the aptamer. Importantly, we also show that FANA-R8-9 is stable in HAE culture secretions and has no overt cytotoxic effects. CONCLUSIONS: Together, these results suggest that FANA-R8-9 effectively prevents infection by specific SARS-CoV-2 variants and indicate that aptamer technology could be utilized to target other clinically-relevant viruses in the respiratory mucosa.

Inhibition of SARS-CoV-2 Infection in Human Airway Epithelium with a Xeno-Nucleic Acid Aptamer.

Background: SARS-CoV-2, the agent responsible for the COVID-19 pandemic, enters cells through viral spike glycoprotein binding to the cellular receptor, angiotensin-converting enzyme 2 (ACE2). Given the lack of effective antivirals targeting SARS-CoV-2, we previously utilized systematic evolution of ligands by exponential enrichment (SELEX) and selected fluoro-arabino nucleic acid (FANA) aptamer R8-9 that was able to block the interaction between the viral receptor-binding domain and ACE2. Methods: Here, we further assessed FANA-R8-9 as an entry inhibitor in contexts that recapitulate infection in vivo. Results: We demonstrate that FANA-R8-9 inhibits spike-bearing pseudovirus particle uptake in cell lines. Then, using an in-vitro model of human airway epithelium (HAE) and SARS-CoV-2 virus, we show that FANA-R8-9 significantly reduces viral infection when added either at the time of inoculation, or several hours later. These results were specific to the R8-9 sequence, not the xeno-nucleic acid utilized to make the aptamer. Importantly, we also show that FANA-R8-9 is stable in HAE culture secretions and has no overt cytotoxic effects. Conclusions: Together, these results suggest that FANA-R8-9 effectively prevents infection by specific SARS-CoV-2 variants and indicate that aptamer technology could be utilized to target other clinically-relevant viruses in the respiratory mucosa.

Correction: Li et al. Novel Therapies for Tongue Squamous Cell Carcinoma Patients with High-Grade Tumors. Life 2021, 11, 813.

Yinghua Li was not included as an author in the original publication [...].

Response of Carex breviculmis to phosphorus deficiency and drought stress.

Introduction: The drought and phosphorus deficiency have inevitably become environmental issues globally in the future. The analysis of plants functional trait variation and response strategies under the stress of phosphorus deficiency and drought is important to explore their ability to respond to potential ecological stress. Methods: In this study, Carex breviculmis was selected as the research object, and a 14-week pot experiment was conducted in a greenhouse, with two phosphorus treatment (add 0.5mmol/L or 0.05µmol/L phosphorus) and four drought treatment (add 0-5%PEG6000), totaling eight treatments. Biomass allocation characteristics, leaf anatomical characteristics, biochemical parameters, root morphology, chemical element content, and photosynthetic parameters were measured. Results: The results showed that the anatomical characteristics, chemical elements, and photosynthetic parameters of Carex breviculmis responded more significantly to main effect of phosphorus deficiency. Stomatal width, leaf phosphorus content and maximum net photosynthetic rate decreased by 11.38%, 59.39%, 38.18% significantly (p<0.05), while the change in biomass was not significant (p>0.05). Biomass allocation characteristics and root morphology responded more significantly to main effect of drought. Severe drought significantly decreased leaf fresh weight by 61% and increased root shoot ratio by 223.3% compared to the control group (p<0.05). The combined effect of severe drought and phosphorus deficiency produced the highest leaf N/P ratio (291.1% of the control) and MDA concentration (243.6% of the control). Correlation analysis and redundancy analysis showed that the contributions of phosphorus and drought to functional trait variation were similar. Lower epidermal cell thickness was positively correlated with maximum net photosynthetic rate, leaf phosphorus, chlorophyll ab, and leaf fresh weight (p<0.05). Discussion: In terms of response strategy, Carex breviculmis was affected at the microscopic level under phosphorus deficiency stress, but could maintain the aboveground and underground biomass well through a series of mechanisms. When affected by drought, it adopted the strategy of reducing leaf yield and improving root efficiency to maintain life activities. Carex breviculmis could maintain its traits well under low phosphorus and moderate drought, or better conditions. So it may have good ecological service potential in corresponding areas if promoted. This study also provided a reference for plant response to combined drought and phosphorus deficiency stresses.

Longitudinal flux balance analyses of a patient with episodic colonic inflammation reveals microbiome metabolic dynamics.

We report the first use of constraint-based microbial community modeling on a single individual with episodic inflammation of the gastrointestinal tract, who has a well documented set of colonic inflammatory biomarkers, as well as metagenomically-sequenced fecal time series covering seven dates over 16 months. Between the first two time steps the individual was treated with both steroids and antibiotics. Our methodology enabled us to identify numerous time-correlated microbial species and metabolites. We found that the individual's dynamical microbial ecology in the disease state led to time-varying in silico overproduction, compared to healthy controls, of more than 24 biologically important metabolites, including methane, thiamine, formaldehyde, trimethylamine N-oxide, folic acid, serotonin, histamine, and tryptamine. The microbe-metabolite contribution analysis revealed that some Dialister species changed metabolic pathways according to the inflammation phases. At the first time point, characterized by the highest levels of serum (complex reactive protein) and fecal (calprotectin) inflammation biomarkers, they produced L-serine or formate. The production of the compounds, through a cascade effect, was mediated by the interaction with pathogenic Escherichia coli strains and Desulfovibrio piger. We integrated the microbial community metabolic models of each time point with a male whole-body, organ-resolved model of human metabolism to track the metabolic consequences of dysbiosis at different body sites. The presence of D. piger in the gut microbiome influenced the sulfur metabolism with a domino effect affecting the liver. These results revealed large longitudinal variations in an individual's gut microbiome ecology and metabolite production, potentially impacting other organs in the body. Future simulations with more time points from an individual could permit us to assess how external drivers, such as diet change or medical interventions, drive microbial community dynamics.

Odontoblasts release exosomes to regulate the odontoblastic differentiation of dental pulp stem cells.

BACKGROUND: Dental pulp stem cells (DPSCs) play a crucial role in dentin-pulp complex regeneration. Further understanding of the mechanism by which DPSCs remain in a quiescent state could contribute to improvements in the dentin-pulp complex and dentinogenesis. METHODS: TSC1 conditional knockout (DMP1-Cre+; TSC1f/f, hereafter CKO) mice were generated to increase the activity of mechanistic target of rapamycin complex 1 (mTORC1). H&E staining, immunofluorescence and micro-CT analysis were performed with these CKO mice and littermate controls. In vitro, exosomes were collected from the supernatants of MDPC23 cells with different levels of mTORC1 activity and then characterized by transmission electron microscopy and nanoparticle tracking analysis. DPSCs were cocultured with MDPC23 cells and MDPC23 cell-derived exosomes. Alizarin Red S staining, ALP staining, qRT‒PCR, western blotting analysis and micro-RNA sequencing were performed. RESULTS: Our study showed that mTORC1 activation in odontoblasts resulted in thicker dentin and higher dentin volume/tooth volume of molars, and it increased the expression levels of the exosome markers CD63 and Alix. In vitro, when DPSCs were cocultured with MDPC23 cells, odontoblastic differentiation was inhibited. However, the inhibition of odontoblastic differentiation was reversed when DPSCs were cocultured with MDPC23 cells with mTORC1 overactivation. To further study the effects of mTORC1 on exosome release from odontoblasts, MDPC23 cells were treated with rapamycin or shRNA-TSC1 to inactivate or activate mTORC1, respectively. The results revealed that exosome release from odontoblasts was negatively correlated with mTORC1 activity. Moreover, exosomes derived from MDPC23 cells with active or inactive mTORC1 inhibited the odontoblastic differentiation of DPSCs at the same concentration. miRNA sequencing analysis of exosomes that were derived from shTSC1-transfected MDPC23 cells, rapamycin-treated MDPC23 cells or nontreated MDPC23 cells revealed that the majority of the miRNAs were similar among these groups. In addition, exosomes derived from odontoblasts inhibited the odontoblastic differentiation of DPSCs, and the inhibitory effect was positively correlated with exosome concentration. CONCLUSION: mTORC1 regulates exosome release from odontoblasts to inhibit the odontoblastic differentiation of DPSCs, but it does not alter exosomal contents. These findings might provide a new understanding of dental pulp complex regeneration.

Climate change mitigation potential of kitchen waste utilization in China for combined heat and power production.

Given the concerns about climate change, energy sustainability, and public health, the reuse of kitchen wastes (KW) is attracting increasing interest. In China, the municipal solid waste sorting scheme has increased the available KW. To assess the available KW and the climate change mitigation potential of KW utilization for bioenergy in China, three scenarios (base, conservative, and ambitious) were defined. A new framework was implemented to assess the climate change impacts of bioenergy. The annual available KW ranged from 11.450 million dry tons (in metric) under the conservative scenario to 22.898 million dry tons in the ambitious scenario, and had the potential to produce 12.37 × 106-24.74 × 106 MWh heat and 9.62 × 106-19.24 × 106 MWh power. The total potential climate change impacts of KW for combined heat and power were 3.339-6.717 million tons CO2 eq in China. The highest eight provinces and municipalities contributed over half of the national total. Among the three components of the new framework, fossil fuel-derived greenhouse gas emissions and biogenic CO2 emissions were positive. The difference in carbon sequestration was negative and ensured a lower integrated life-cycle climate change impacts than that of natural gas-derived combined heat and power. The mitigation effects of using KW as a substitute for natural gas and synthetic fertilizers were 2.477-8.080 million tons CO2 eq. These outcomes can inform relevant policymaking and benchmark climate change mitigation in China. The conceptual framework of this study can also be adapted for applications in other countries or regions worldwide.

GLUE multimodal single cell data.

A commentary on "Multi-omics single-cell data integration and regulatory inference with graph-linked embedding".

A Case of Neutrophilic Dermatoses-Sweet's Syndrome Coexisting with SAPHO Syndrome.

SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome is a rare disease characterized by osteoarticular and cutaneous manifestations. SAPHO syndrome mostly involves the skin, mainly presented as palmoplantar pustulosis and severe acne. Sweet's syndrome (SS) is a neutrophilic dermatosis of unknown cause, which may be caused by autoinflammation. So far, SAPHO syndrome complicated with SS has been rarely reported worldwide. Here, we present a rare case diagnosed in our hospital with detailed clinical information. This patient presented pain and swelling in her right leg. Later, she developed red papules on her right lower eyelid and a skin biopsy showed diffuse lymphocytic and neutrophilic infiltration in the superficial dermis. She was diagnosed with SAPHO syndrome and SS according to medical history and examination. These two diseases share parts of autoinflammatory signaling pathways and might be different variations of the spectrum of autoinflammatory diseases. Through this case, we aim to provide a new horizon for the regulation of neutrophils in SAPHO syndrome and skin lesions like SS.

Numerical simulation of laser-produced plasma expansion on a droplet surface.

In this study, a numerical model of the plasma expansion on a droplet surface based on the initial plasma method was proposed. The initial plasma was obtained through the pressure inlet boundary condition, and the effect of ambient pressure on the initial plasma and adiabatic expansion of the plasma on the droplet surface, including the effect on the velocity and temperature distribution, were investigated. The simulation results showed that the ambient pressure decreased, leading to an increase in the expansion rate and temperature, and therefore a larger plasma size was formed. Plasma expansion creates a backward driving force and eventually envelops the entire droplet, indicating a significant difference compared to planar targets.

SAPHO syndrome with Takayasu arteritis successfully treated with tofacitinib.

SAPHO syndrome is an autoinflammatory disease with a variety of clinical manifestations, which may be accompanied by other systemic inflammatory diseases in addition to the typical manifestations of common synovitis, acne, pustulosis, hyperostosis, and osteitis. Here, we report the first case of SAPHO syndrome combined with Takayasu arteritis.

Dome1-JAK-STAT signaling between parasite and host integrates vector immunity and development.

Ancestral signaling pathways serve critical roles in metazoan development, physiology, and immunity. We report an evolutionary interspecies communication pathway involving a central Ixodes scapularis tick receptor termed Dome1, which acquired a mammalian cytokine receptor motif exhibiting high affinity for interferon-gamma (IFN-γ). Host-derived IFN-γ facilitates Dome1-mediated activation of the Ixodes JAK-STAT pathway. This accelerates tick blood meal acquisition and development while upregulating antimicrobial components. The Dome1-JAK-STAT pathway, which exists in most Ixodid tick genomes, regulates the regeneration and proliferation of gut cells-including stem cells-and dictates metamorphosis through the Hedgehog and Notch-Delta networks, ultimately affecting Ixodes vectorial competence. We highlight the evolutionary dependence of I. scapularis on mammalian hosts through cross-species signaling mechanisms that dually influence arthropod immunity and development.

Analysis of serum metabolism in premature infants before and after feeding using GC-MS and the relationship with necrotizing enterocolitis.

Preterm birth and enteral feeding are two main factors leading to necrotizing enterocolitis (NEC). The metabolomics of preterm infants before and after feeding can provide a basis for the prediction of NEC. Using the method of cross-sectional study, the mode was established with the serum samples of 19 premature infants at birth and after feeding as the control group. The serum was analyzed using GC-MS. Chemometric analysis includes principal component analysis, partial least squares-discriminant analysis, and orthogonal partial least squares-discriminant analysis. Spectral separation of serum metabolites occurred in premature infants before and after feeding. The levels of xylose, d-talose, phosphoglycolic acid, maleimide, l-gulonolactone, maleic acid, ß-hydroxypyruvate, itaconic acid, and pantothenic acid in the serum of premature infants after feeding were significant in both multidimensional and single-dimensional modes (variable importance in projection >2, P < 0.01). There was a moderate correlation between total bilirubin and l-gulonolactone and ß-hydroxypyruvate (0.8 > r > 0.5). Maleimide, maleic acid, and itaconic acid have diagnostic value (area under the curve >0.9). The results indicated that serum metabolism of preterm infants changes significantly after feeding. Some metabolites have potential value in predicting NEC.

An FcRn-targeted mucosal vaccine against SARS-CoV-2 infection and transmission.

SARS-CoV-2 and its variants cause COVID-19, which is primarily transmitted through droplets and airborne aerosols. To prevent viral infection and reduce viral spread, vaccine strategies must elicit protective immunity in the airways. FcRn transfers IgG across epithelial barriers; we explore FcRn-mediated respiratory delivery of SARS-CoV-2 spike (S). A monomeric IgG Fc was fused to a stabilized S protein; the resulting S-Fc bound to S-specific antibodies (Ab) and FcRn. A significant increase in Ab responses was observed following the intranasal immunization of mice with S-Fc formulated in CpG as compared to the immunization with S alone or PBS. Furthermore, we intranasally immunize adult or aged mice and hamsters with S-Fc. A significant reduction of virus replication in nasal turbinate, lung, and brain was observed following nasal challenges with SARS-CoV-2, including Delta and Omicron variants. Intranasal immunization also significantly reduced viral transmission between immunized and naive hamsters. Protection was mediated by nasal IgA, serum-neutralizing Abs, tissue-resident memory T cells, and bone marrow S-specific plasma cells. Hence FcRn delivers an S-Fc antigen effectively into the airway and induces protection against SARS-CoV-2 infection and transmission. Based on these findings, FcRn-targeted non-invasive respiratory immunizations are superior strategies for preventing highly contagious respiratory viruses from spreading.

NETome: A model to Decode the Human Genome and Proteome of Neutrophil Extracellular Traps.

Neutrophils are the most abundant type of white blood cells in humans with biological roles relevant to inflammation, and fighting off infections. Neutrophil Extracellular Traps (NETs) act as enxogenous agents controlling invasion by bacteria, viruses, fungi, metabolic, and traumatic agents. Traditionally, studies have focused on elucidating molecular and cellular pathways preceding NET formation. Here, we developed a model to decode the human genome and proteome of developted NETs. Via in vitro system to differentiate HL-60 human myeloid cell line into neutrophil extracellular trap (ecTrap) producing cells, we isolated and captured ectrap derived DNA and proteins for shotgun sequencing. The genomic sequences revealed accurate delineation of gene composition including immune response genes and mitochondrial enrichment, while providing a reference database for future interrogation. Shotgun proteomics showed global proteins in differentiated cells with specific immune pathways when compared to undifferentiated counterparts. Coupled with omics' approaches, we validated our system by functional assays and began to dissect host-microbial interactions. Our work provides a new understanding of the genomic and proteomic sequences, establishing the first human database deposition of neutrophil extracellular traps.

Short term outcomes of extremely low birth weight infants from a multicenter cohort study in Guangdong of China.

With the increase in extremely low birth weight (ELBW) infants, their outcome attracted worldwide attention. However, in China, the related studies are rare. The hospitalized records of ELBW infants discharged from twenty-six neonatal intensive care units in Guangdong Province of China during 2008-2017 were analyzed. A total of 2575 ELBW infants were enrolled and the overall survival rate was 55.11%. From 2008 to 2017, the number of ELBW infants increased rapidly from 91 to 466, and the survival rate improved steadily from 41.76% to 62.02%. Increased survival is closely related to birth weight (BW), regional economic development, and specialized hospital. The incidence of complications was neonatal respiratory distress syndrome (85.2%), oxygen dependency at 28 days (63.7%), retinopathy of prematurity (39.3%), intraventricular hemorrhage (29.4%), necrotizing enterocolitis (12.0%), and periventricular leukomalacia (8.0%). Among the 1156 nonsurvivors, 90.0% of infants died during the neonatal period (≤ 28 days). A total of 768 ELBW infants died after treatment withdrawal, for reasons of economic and/or poor outcome. The number of ELBW infants is increasing in Guangdong Province of China, and the overall survival rate is improving steadily.