A multi-scale numerical study of monoclonal antibodies uptake by initial lymphatics after subcutaneous injection.

This paper studies the transport of monoclonal antibodies through skin tissue and initial lymphatics, which impacts the pharmacokinetics of monoclonal antibodies. Our model integrates a macroscale representation of the entire skin tissue with a mesoscale model that focuses on the papillary dermis layer. Our results indicate that it takes hours for the drugs to disperse from the injection site to the papillary dermis before entering the initial lymphatics. Additionally, we observe an inhomogeneous drug distribution in the interstitial space of the papillary dermis, with higher drug concentrations near initial lymphatics and lower concentrations near blood capillaries. To validate our model, we compare our numerical simulation results with experimental data, finding a good alignment. Our parametric studies on the drug molecule properties and injection parameters suggest that a higher diffusion coefficient increases the transport and uptake rate while binding slows down these processes. Furthermore, shallower injection depths lead to faster lymphatic uptake, whereas the size of the injection plume has a minor effect on the uptake rate. These findings advance our understanding of drug transport and lymphatic absorption after subcutaneous injection, offering valuable insights for optimizing drug delivery strategies and the design of biotherapeutics.

sEMG-based Motion Recognition for Robotic Surgery Training - A Preliminary Study.

Robotic surgery represents a major breakthrough in the evolution of medical technology. Accordingly, efficient skill training and assessment methods should be developed to meet the surgeon's need of acquiring such robotic skills over a relatively short learning curve in a safe manner. Different from conventional training and assessment methods, we aim to explore the surface electromyography (sEMG) signal during the training process in order to obtain semantic and interpretable information to help the trainee better understand and improve his/her training performance. As a preliminary study, motion primitive recognition based on sEMG signal is studied in this work. Using machine learning (ML) technique, it is shown that the sEMG-based motion recognition method is feasible and promising for hand motions along 3 Cartesian axes in the virtual reality (VR) environment of a commercial robotic surgery training platform, which will hence serve as the basis for new robotic surgical skill assessment criterion and training guidance based on muscle activity information. Considering certain motion patterns were less accurately recognized than others, more data collection and deep learning-based analysis will be carried out to further improve the recognition accuracy in future research.

Numerical studies of the lymphatic uptake rate.

Lymphatic uptake is essential for transporting nutrients, wastes, immune cells, and therapeutic proteins. Despite its importance, the literature lacks a quantitative analysis of the factors that affect lymphatic uptake, including interstitial pressure, downstream pressure, and tissue deformation. In this paper, we present a coupled model of a poroelastic tissue with initial lymphatics and quantify the impact of these factors on the rate of lymphatic uptake. Our results indicate that the lymphatic uptake increases with the amplitude of the oscillating downstream pressure when the amplitude exceeds a threshold. Additionally, the cross-sectional area of initial lymphatics increases with the volumetric strain of the tissue, while the interstitial pressure increases when the strain rate becomes negative. Therefore, the lymphatic uptake reaches its maximum when the tissue has positive volumetric strain while being compressed. We have also investigated the effect of intersection angles and positions of two initial lymphatics and concluded that they have minor impacts on lymphatic uptake. However, the lymphatic uptake per unit length of initial lymphatics decreases with their total length. These findings advance our understanding of lymphatic uptake and can guide the development of strategies to accelerate the transport of therapeutics.

Lymphatic uptake of biotherapeutics through a 3D hybrid discrete-continuum vessel network in the skin tissue.

Subcutaneous administration is a common approach for the delivery of biotherapeutics, which is achieved mainly through the absorption across lymphatic vessels. In this paper, the drug transport and lymphatic uptake through a three-dimensional hybrid discrete-continuum vessel network in the skin tissue are investigated through high-fidelity numerical simulations. We find that the local lymphatic uptake through the explicit vessels significantly affects macroscopic drug absorption. The diffusion of drug solute through the explicit vessel network affects the lymphatic uptake after the injection. This effect, however, cannot be captured using previously developed continuum models. The lymphatic uptake is dominated by the convection due to lymphatic drainage driven by the pressure difference, which is rarely studied in experiments and simulations. Furthermore, the effects of injection volume and depth on the lymphatic uptake are investigated in a multi-layered domain. We find that the injection volume significantly affects the rate of lymphatic uptake through the heterogeneous vessel network, while the injection depth has little influence, which is consistent with the experimental results. At last, the binding and metabolism of drug molecules are studied to bridge the simulations to the drug clearance experients. We provide a new approach to study the diffusion and convection of drug molecules into the lymphatic system through the hybrid vessel network.

PacBio full-length cDNA sequencing integrated with RNA-seq reads drastically improves the discovery of splicing transcripts in rice.

In eukaryotes, alternative splicing (AS) greatly expands the diversity of transcripts. However, it is challenging to accurately determine full-length splicing isoforms. Recently, more studies have taken advantage of Pacific Bioscience (PacBio) long-read sequencing to identify full-length transcripts. Nevertheless, the high error rate of PacBio reads seriously offsets the advantages of long reads, especially for accurately identifying splicing junctions. To best capitalize on the features of long reads, we used Illumina RNA-seq reads to improve PacBio circular consensus sequence (CCS) quality and to validate splicing patterns in the rice transcriptome. We evaluated the impact of CCS accuracy on the number and the validation rate of splicing isoforms, and integrated a comprehensive pipeline of splicing transcripts analysis by Iso-Seq and RNA-seq (STAIR) to identify the full-length multi-exon isoforms in rice seedling transcriptome (Oryza sativa L. ssp. japonica). STAIR discovered 11 733 full-length multi-exon isoforms, 6599 more than the SMRT Portal RS_IsoSeq pipeline did. Of these splicing isoforms identified, 4453 (37.9%) were missed in assembled transcripts from RNA-seq reads, and 5204 (44.4%), including 268 multi-exon long non-coding RNAs (lncRNAs), were not reported in the MSU_osa1r7 annotation. Some randomly selected unreported splicing junctions were verified by polymerase chain reaction (PCR) amplification. In addition, we investigated alternative polyadenylation (APA) events in transcripts and identified 829 major polyadenylation [poly(A)] site clusters (PACs). The analysis of splicing isoforms and APA events will facilitate the annotation of the rice genome and studies on the expression and polyadenylation of AS genes in different developmental stages or growth conditions of rice.

The rubber tree genome reveals new insights into rubber production and species adaptation.

The Para rubber tree (Hevea brasiliensis) is an economically important tropical tree species that produces natural rubber, an essential industrial raw material. Here we present a high-quality genome assembly of this species (1.37 Gb, scaffold N50 = 1.28 Mb) that covers 93.8% of the genome (1.47 Gb) and harbours 43,792 predicted protein-coding genes. A striking expansion of the REF/SRPP (rubber elongation factor/small rubber particle protein) gene family and its divergence into several laticifer-specific isoforms seem crucial for rubber biosynthesis. The REF/SRPP family has isoforms with sizes similar to or larger than SRPP1 (204 amino acids) in 17 other plants examined, but no isoforms with similar sizes to REF1 (138 amino acids), the predominant molecular variant. A pivotal point in Hevea evolution was the emergence of REF1, which is located on the surface of large rubber particles that account for 93% of rubber in the latex (despite constituting only 6% of total rubber particles, large and small). The stringent control of ethylene synthesis under active ethylene signalling and response in laticifers resolves a longstanding mystery of ethylene stimulation in rubber production. Our study, which includes the re-sequencing of five other Hevea cultivars and extensive RNA-seq data, provides a valuable resource for functional genomics and tools for breeding elite Hevea cultivars.

Differential Expression of Hepatic Genes of the Greater Horseshoe Bat (Rhinolophus ferrumequinum) between the Summer Active and Winter Torpid States.

Hibernation is one type of torpor, a hypometabolic state in heterothermic mammals, which can be used as an energy-conservation strategy in response to harsh environments, e.g. limited food resource. The liver, in particular, plays a crucial role in adaptive metabolic adjustment during hibernation. Studies on ground squirrels and bears reveal that many genes involved in metabolism are differentially expressed during hibernation. Especially, the genes involved in carbohydrate catabolism are down-regulated during hibernation, while genes responsible for lipid ß-oxidation are up-regulated. However, there is little transcriptional evidence to suggest physiological changes to the liver during hibernation in the greater horseshoe bat, a representative heterothermic bat. In this study, we explored the transcriptional changes in the livers of active and torpid greater horseshoe bats using the Illumina HiSeq 2000 platform. A total of 1358 genes were identified as differentially expressed during torpor. In the functional analyses, differentially expressed genes were mainly involved in metabolic depression, shifts in the fuel utilization, immune function and response to stresses. Our findings provide a comprehensive evidence of differential gene expression in the livers of greater horseshoe bats during active and torpid states and highlight potential evidence for physiological adaptations that occur in the liver during hibernation.

Submucosal tunneling endoscopic resection for upper gastrointestinal submucosal tumors originating from the muscularis propria layer.

OBJECTIVE: To estimate the safety and efficacy of submucosal tunneling endoscopic resection (STER) for upper gastrointestinal submucosal tumors (SMTs) originating from the muscularis propria layer. METHODS: During October 2011 and May 2014, a total of 80 patients with SMTs underwent STER at our hospital. A submucosal tunnel was created from 3-5 cm above the tumor. Endoscopic submucosal dissection of the SMT was performed, and then the mucosal incision was closed with several clips after the tumor was removed. RESULTS: All the 80 patients underwent STER successfully, with a mean operation time of 61.2 min. Eighty-three SMTs were removed; among these, 67 were located in the esophagus and 16 in the gastric cardia, 68 were leiomyoma, and 15 were gastrointestinal stromal tumors, and 13 had a diameter no less than 35 mm. The mean tumor size was 23.2 mm; en-bloc resection was performed in 97.6% (81/83) of the tumors. Complications were noted in 8.75% (7/80) of the cases, and all of them resolved without the need for additional surgery. No recurrence was noted during a mean follow-up of 10.2 months. CONCLUSION: STER appears to be a feasible, safe, and effective method for upper gastrointestinal SMTs originating from the muscularis propria layer, even when the size of the tumor was larger than 35 mm.

Transcript profiles of Panax quinquefolius from flower, leaf and root bring new insights into genes related to ginsenosides biosynthesis and transcriptional regulation.

American ginseng (Panax quinquefolius L.) has been used for a wide range of therapeutic purposes in China. The major bioactive phytochemicals responsible for this plant's pharmacological features are ginsenosides. Thus far, little is known regarding the genes involved in ginsenosides biosynthesis in this species. As a non-model plant, information about its genomes is generally not available. In this study, we generated 6678 expressed sequence tags (ESTs) from the flower, leaf and root cDNA libraries of American ginseng. Assembly of ESTs resulted in 3349 unigenes including 534 contigs (with ESTs number ranging from 2 to 52) and 2815 singletons. By analyzing the predominant transcripts within specific tissues, a gene expression pattern was obtained in a tissue-specific manner. They were assigned according to the functional classification of unigenes to broad ranges of Gene Ontology categories which include biological processes, cellular components and molecular functions. Based on blastx search results, 24 unigenes representing candidates related to ginsenosides biosynthesis were identified. Cloning and characterization of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR, EC: 1.1.1.34), the rate-limiting enzyme in mevalonic acid pathway, demonstrated that it belonged to the plant HMGR family and was highly expressed in leaves. Putative transcription factors were detected in 63 unigenes, including zinc finger, WRKY, homeobox and MADS-box family proteins. Five hundred and eighty-eight simple sequence repeat motifs were identified, of which, dimer was the most abundant motif. These data will provide useful information on transcript profiles, gene discovery, transcriptional regulation, flower biogenesis and marker-assisted selections. The analysis and information from this study will greatly contribute to the improvement of this medicinal plant as well as of other species in the Araliaceae family, for the purpose of ensuring adequate drug resources.

[Analysis of expressed sequence tags (EST) from Panax quinquefolium root].

To investigate the profile of gene expression in American ginseng (Panax quinquefolium L.) and discover its functional genes, for the first time, expressed sequence tags (EST) library of four-year-old American ginseng roots has been established. According to BLAST and Gene Ontology analysis, eleven genes, encoding cytochrome P450, glucosyltransferase, farnesyltransferase and cyclase family protein, are found to be associated with ginsenosides biosynthesis. Six other genes are obtained encoding auxin-regulated protein, auxin response factor 4 and auxin-repressed protein in the roots of American ginseng. In addition, thirteen expressed transcripts are stress-connected proteins and twelve expressed other transcripts are closely related to plant defense in four-year-old American ginseng roots. Furthermore, 62 genes no hit in BLAST and in Interproscan may be new genes. These results indicate EST is an useful tool for research on functional genomics of P. quinquefolium and it can be applied to the molecular modification of the ginsenosides biosynthetic pathway ultimately for improving the quality of American ginseng germplasm.

Construction of a bacterial artificial chromosome (BAC) library of common wild rice (Oryza rufipogon Griff.) for map-based cloning of genes selected during the domestication of rice.

As a prerequisite for the map-based cloning of genes from common wild rice (Oryza rufipogon Griff.), which plays an important role in the domestication of cultivated rice (O. sativa L.), we constructed a median-insert size bacterial artificial chromosome (BAC) library of the common wild rice isolate, YJCWR, collected from Yuanjiang, Yunnan Province, China. The library consists of 52,992 clones, with an average insert size of 50 kb, and all clones were pooled into 46 three-dimensional super-pools to facilitate library screening through the PCR method. Seventeen candidate clones were isolated by five markers and some clones containing putative target regions were sequenced. Furthermore, in analyzing the sequences of YJCWR, a retrotransposon, SZ-55, that might contribute to the evolution of Oryza was found.