CNKSR2 interactome analysis indicates its association with the centrosome/microtubule system.

JOURNAL/nrgr/04.03/01300535-202508000-00031/figure1/v/2024-09-30T120553Z/r/image-tiff The protein connector enhancer of kinase suppressor of Ras 2 (CNKSR2), present in both the postsynaptic density and cytoplasm of neurons, is a scaffolding protein with several protein-binding domains. Variants of the CNKSR2 gene have been implicated in neurodevelopmental disorders, particularly intellectual disability, although the precise mechanism involved has not yet been fully understood. Research has demonstrated that CNKSR2 plays a role in facilitating the localization of postsynaptic density protein complexes to the membrane, thereby influencing synaptic signaling and the morphogenesis of dendritic spines. However, the function of CNKSR2 in the cytoplasm remains to be elucidated. In this study, we used immunoprecipitation and high-resolution liquid chromatography-mass spectrometry to identify the interactors of CNKSR2. Through a combination of bioinformatic analysis and cytological experiments, we found that the CNKSR2 interactors were significantly enriched in the proteome of the centrosome. We also showed that CNKSR2 interacted with the microtubule protein DYNC1H1 and with the centrosome marker CEP290. Subsequent colocalization analysis confirmed the centrosomal localization of CNKSR2. When we downregulated CNKSR2 expression in mouse neuroblastoma cells (Neuro 2A), we observed significant changes in the expression of numerous centrosomal genes. This manipulation also affected centrosome-related functions, including cell size and shape, cell proliferation, and motility. Furthermore, we found that CNKSR2 interactors were highly enriched in de novo variants associated with intellectual disability and autism spectrum disorder. Our findings establish a connection between CNKSR2 and the centrosome, and offer new insights into the underlying mechanisms of neurodevelopmental disorders.

Genome-wide identification of R2R3-MYB transcription factor subfamily genes involved in salt stress in rice (Oryza sativa L.).

BACKGROUND: R2R3-MYB transcription factors belong to one of the largest gene subfamilies in plants, and they are involved in diverse biological processes. However, the role of R2R3-MYB transcription factor subfamily genes in the response of rice (Oryza sativa L.) to salt stress has been rarely reported. RESULTS: In this study, we performed a genome-wide characterization and expression identification of rice R2R3-MYB transcription factor subfamily genes. We identified a total of 117 R2R3-MYB genes in rice and characterized their gene structure, chromosomal location, and cis-regulatory elements. According to the phylogenetic relationships and amino acid sequence homologies, the R2R3-MYB genes were divided into four groups. qRT-PCR of the R2R3-MYB genes showed that the expression levels of 10 genes significantly increased after 3 days of 0.8% NaCl treatment. We selected a high expression gene OsMYB2-115 for further analysis. OsMYB2-115 was highly expressed in the roots, stem, leaf, and leaf sheath. OsMYB2-115 was found to be localized in the nucleus, and the yeast hybrid assay showed that OsMYB2-115 has transcriptional activation activity. CONCLUSION: This result provides important information for the functional analyses of rice R2R3-MYB transcription factor subfamily genes related to the salt stress response and reveals that OsMYB2-115 may be an important gene associated with salt tolerance in rice.

Modeling drug transport and absorption in subcutaneous injection of monoclonal antibodies: Impact of tissue deformation, devices, and physiology.

The pharmaceutical industry has experienced a remarkable increase in the use of subcutaneous injection of monoclonal antibodies (mAbs), attributed mainly to its advantages in reducing healthcare-related costs and enhancing patient compliance. Despite this growth, there is a limited understanding of how tissue mechanics, physiological parameters, and different injection devices and techniques influence the transport and absorption of the drug. In this work, we propose a high-fidelity computational model to study drug transport and absorption during and after subcutaneous injection of mAbs. Our numerical model includes large-deformation mechanics, fluid flow, drug transport, and blood and lymphatic uptake. Through this computational framework, we analyze the tissue material responses, plume dynamics, and drug absorption. We analyze different devices, injection techniques, and physiological parameters such as BMI, flow rate, and injection depth. Finally, we compare our numerical results against the experimental data from the literature.

Dexmedetomidine with different concentrations added to local anesthetics in erector spinae plane block: a meta-analysis of randomized controlled trials.

Background: Dexmedetomidine has been used as a perineural local anesthetic (LA) adjuvant to facilitate the potency of erector spinal plane block (ESPB). This quantitative review aimed to evaluate whether perineural dexmedetomidine for ESPB can improve the effects of analgesia compared to LA alone. Methods: Randomized controlled trials (RCTs) that investigated the addition of dexmedetomidine to LA compared to LA alone in ESPB were included. The pain scores, duration of sensory block, the time to first analgesia requirement, postoperative morphine consumption, rescue analgesia, and dexmedetomidine-related side effects were analyzed and combined using random-effects models. Results: A total of 823 patients from 13 RCTs were analyzed. Dexmedetomidine was used at the concentration of 0.5 µg/kg in three trials and 1 µg/kg in nine trials, and both in one trial. Both concentrations of dexmedetomidine perineurally administrated significantly reduced the rest VAS scores postoperatively at 12 h (0.5 µg/kg dexmedetomidine: MD = -0.86; 95% CI: -1.59 to -0.12; p = 0.02; 1 µg/kg dexmedetomidine: MD = -0.49; 95% CI: -0.83 to -0.16; p = 0.004), and 24 h (0.5 µg/kg dexmedetomidine: MD = -0.43; 95% CI: -0.74 to -0.13; p = 0.005; 1 µg/kg dexmedetomidine: MD = -0.62; 95% CI: -0.84 to -0.41; p < 0.00001). Both concentrations of dexmedetomidine added in LAs improved the dynamic VAS scores postoperatively at 12 h (0.5 µg/kg dexmedetomidine: MD = -0.55; 95% CI: -0.95 to -0.15; p = 0.007; 1 µg/kg dexmedetomidine: MD = -0.66; 95% CI: -1.05 to -0.28; p = 0.0006) and 24 h (0.5 µg/kg dexmedetomidine: MD = -0.52; 95% CI: -0.94 to -0.10; p = 0.01; 1 µg/kg dexmedetomidine: MD = -0.46; 95% CI: -0.75 to -0.16; p = 0.002). Furthermore, perineural dexmedetomidine prolonged the duration of the sensory block and the time to first analgesia requirement, reduced postoperative morphine consumption, and lowered the incidence of rescue analgesia and chronic pain. Conclusion: The meta-analysis showed that using perineural dexmedetomidine at either 0.5 µg/kg or 1 µg/kg doses in ESPB can effectively and safely enhance pain relief. Systematic review registration: PROSPERO (CRD42023424532: https://www.crd.york.ac.uk/PROSPERO/).

Activity of the Sodium Leak Channel Maintains the Excitability of Paraventricular Thalamus Glutamatergic Neurons to Resist Anesthetic Effects of Sevoflurane in Mice.

BACKGROUND: Stimulation of the paraventricular thalamus has been found to enhance anesthesia recovery; however, the underlying molecular mechanism by which general anesthetics modulate paraventricular thalamus is unclear. This study aimed to test the hypothesis that the sodium leak channel (NALCN) maintains neuronal activity in the paraventricular thalamus to resist anesthetic effects of sevoflurane in mice. METHODS: Chemogenetic and optogenetic manipulations, in vivo multiple-channel recordings, and electroencephalogram recordings were used to investigate the role of paraventricular thalamus neuronal activity in sevoflurane anesthesia. Virus-mediated knockdown and/or overexpression was applied to determine how NALCN influenced excitability of paraventricular thalamus glutamatergic neurons under sevoflurane. Viral tracers and local field potentials were used to explore the downstream pathway. RESULTS: Single neuronal spikes in the paraventricular thalamus were suppressed by sevoflurane anesthesia and recovered during emergence. Optogenetic activation of paraventricular thalamus glutamatergic neurons shortened the emergence period from sevoflurane anesthesia, while chemogenetic inhibition had the opposite effect. Knockdown of the NALCN in the paraventricular thalamus delayed the emergence from sevoflurane anesthesia (recovery time: from 24 ± 14 to 64 ± 19 s, P < 0.001; concentration for recovery of the righting reflex: from 1.13% ± 0.10% to 0.97% ± 0.13%, P < 0.01). As expected, the overexpression of the NALCN in the paraventricular thalamus produced the opposite effects. At the circuit level, knockdown of the NALCN in the paraventricular thalamus decreased the neuronal activity of the nucleus accumbens, as indicated by the local field potential and decreased single neuronal spikes in the nucleus accumbens. Additionally, the effects of NALCN knockdown in the paraventricular thalamus on sevoflurane actions were reversed by optical stimulation of the nucleus accumbens. CONCLUSIONS: Activity of the NALCN maintains the excitability of paraventricular thalamus glutamatergic neurons to resist the anesthetic effects of sevoflurane in mice.

Emergency response to ecological protection in maritime phenol spills: Emergency monitor, ecological risk assessment, and reduction.

Recently, hundreds of maritime accidental spills of hazardous chemicals have raised public concerns, especially for phenol due to its potential of spills and highly toxicity. Therefore, for marine ecological protection, this article prepared specific strategies of emergency response to phenol spills. Through the identification for phenol behavior at sea, migration prediction, emergency monitor, as well as their new methods were reviewed. Further, ecological risk assessment and seawater quality criteria were conducted by using a species sensitivity distribution (SSD) approach, wherein, risk quotient (RQ) indicated phenol of simulated marine spills posed a high risk (RQ > 1) in 30 days. The method with eco-friendliness and high-efficiency for phenol reduction was constructed by combination of dredging equipment such as pneumatic dredgers (Airlift) and bioremediation, where marine microorganisms that degraded phenol were summarized, as well as future research needs. This study provided a guidance for emergency response and policy development of phenol spills.

Pharmacologically significant constituents collectively responsible for anti-sepsis action of XueBiJing, a Chinese herb-based intravenous formulation.

Sepsis, a life-threatening health issue, lacks effective medicine targeting the septic response. In China, treatment combining the intravenous herbal medicine XueBiJing with conventional procedures reduces the 28-day mortality of critically ill patients by modulating septic response. In this study, we identified the combined active constituents that are responsible for the XueBiJing's anti-sepsis action. Sepsis was induced in rats by cecal ligation and puncture (CLP). The compounds were identified based on their systemic exposure levels and anti-sepsis activities in CLP rats that were given an intravenous bolus dose of XueBiJing. Furthermore, the identified compounds in combination were assessed, by comparing with XueBiJing, for levels of primary therapeutic outcome, pharmacokinetic equivalence, and pharmacokinetic compatibility. We showed that a total of 12 XueBiJing compounds, unchanged or metabolized, circulated with significant systemic exposure in CLP rats that received XueBiJing. Among these compounds, hydroxysafflor yellow A, paeoniflorin, oxypaeoniflorin, albiflorin, senkyunolide I, and tanshinol displayed significant anti-sepsis activities, which involved regulating immune responses, inhibiting excessive inflammation, modulating hemostasis, and improving organ function. A combination of the six compounds, with the same respective doses as in XueBiJing, displayed percentage survival and systemic exposure in CLP rats similar to those by XueBiJing. Both the combination and XueBiJing showed high degrees of pharmacokinetic compatibility regarding interactions among the six active compounds and influences of other circulating XueBiJing compounds. The identification of XueBiJing's pharmacologically significant constituents supports the medicine's anti-sepsis use and provides insights into a polypharmacology-based approach to develop medicines for effective sepsis management.

Distress tolerance as a mechanism of mindfulness for depression and anxiety: Cross-sectional and diary evidence

Background: Both trait and state mindfulness are associated with less depression and anxiety, but the mechanisms remain unknown. Distress tolerance, an important transdiagnostic factor of emotional disorders, may mediate the relationship between mindfulness and depression/anxiety. Method: Study 1 examined the mediation model at the between-person level in a large cross-sectional sample (n = 905). In Study 2, a daily diary study (n = 110) was conducted to examine within-person changes. Participants were invited to complete daily diaries measuring daily mindfulness, distress tolerance, depression and anxiety for 14 consecutive days. Results: In Study 1, results of simple mediation analyses indicated that distress tolerance mediated the relationship between mindfulness and depression/anxiety at the between-person level. In Study 2, results of multilevel mediation analyses indicated that, in both the concurrent model and time-lagged model, daily distress tolerance mediated the effects of daily mindfulness on daily depression/anxiety at both the within- and between-person level. Conclusions: Distress tolerance is a mechanism underlying the relationship between mindfulness and depression/anxiety. Individuals with high or fluctuating depression and anxiety may benefit from short-term or long-term mindfulness training to increase distress tolerance. (AU)

Computational modeling of the effect of skin pinch and stretch on subcutaneous injection of monoclonal antibodies using autoinjector devices.

Subcutaneous injection of monoclonal antibodies (mAbs) has experienced unprecedented growth in the pharmaceutical industry due to its benefits in patient compliance and cost-effectiveness. However, the impact of different injection techniques and autoinjector devices on the drug's transport and uptake is poorly understood. Here, we develop a biphasic large-deformation chemomechanical model that accounts for the components of the extracellular matrix that govern solid deformation and fluid flow within the subcutaneous tissue: interstitial fluid, collagen fibers and negatively charged proteoglycan aggregates. We use this model to build a high-fidelity representation of a virtual patient performing a subcutaneous injection of mAbs. We analyze the impact of the pinch and stretch methods on the injection dynamics and the use of different handheld autoinjector devices. The results suggest that autoinjector base plates with a larger device-skin contact area cause significantly lower tissue mechanical stress, fluid pressure and fluid velocity during the injection process. Our simulations indicate that the stretch technique presents a higher risk of intramuscular injection for autoinjectors with a relatively long needle insertion depth.

Network pharmacology analysis combined with experimental validation to explore the therapeutic mechanism of salidroside on intestine ischemia reperfusion.

ETHNOPHARMACOLOGICAL RELEVANCE: Salidroside (SAL), a phenolic natural product present in Rhodiola rosea, are commonly used in the treatment of various ischemic-hypoxic diseases, including intestinal ischemia-reperfusion (IR) injury. However, their efficacy and potential mechanisms in the treatment of intestinal IR injury have not been investigated. OBJECTIVE: The objective of the present study is to investigate the pharmacological mechanism of action of SAL on intestinal IR injury using a network pharmacology approach combined with experimental validation. METHODS: In the present study, we used the Traditional Chinese Medicine Systematic Pharmacology (TCMSP) database and analysis platform and Comparative Toxicogenomics Database (CTD) to predict possible target genes of SAL, collected relevant target genes of intestinal IR injury from GeneCards and DisGenet websites, and collected summary data to screen common target genes. Then, the protein-protein interaction (PPI) target network was constructed and analyzed by STRING database and Cytoscape 3.8.2 with the above intersecting genes. Then, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed and the component-target-pathway network was constructed, followed by the use of molecular docking and molecular dynamic simulation to verify the possible binding conformation between SAL and candidate targets to further explore the potential targets of SAL in the treatment of intestinal IR injury. Finally, an in vivo model of mouse superior mesenteric artery ligation was established to assess the anti-intestinal IR injury effect of SAL by assessing histopathological changes in mouse small intestine by HE staining, detecting inflammatory factor expression by ELISA kit, and detecting the expression of key protein targets by Western blotting. RESULTS: A total of 166 SAL target genes and 1740 disease-related targets were retrieved, and 88 overlapping proteins were obtained as potential therapeutic targets. The pathway enrichment analysis revealed that the pharmacological effects of SAL on intestinal IR injury were anti-hypoxic, anti-inflammatory and metabolic pathway related, and the molecular docking and molecular dynamic simulation results showed that the core bioactive components had good binding affinity for TXNIP and AMPK, and the immunoblotting results indicated that the expression levels of TXNIP and AMPK in the small intestinal tissues of mice in the drug-treated group compared with the model group were significantly changed. CONCLUSION: SAL may target AMPK and TXNIP domains to act as a therapeutic agent for intestinal IR. These findings comprehensively reveal the potential therapeutic targets for SAL against intestinal IR and provide theoretical basis for the clinical application of SAL in the treatment of intestinal IR.

Extracellular Matrix Stiffness Regulates Microvascular Stability by Controlling Endothelial Paracrine Signaling to Determine Pericyte Fate.

BACKGROUND: The differentiation of pericytes into myofibroblasts causes microvascular degeneration, ECM (extracellular matrix) accumulation, and tissue stiffening, characteristics of fibrotic diseases. It is unclear how pericyte-myofibroblast differentiation is regulated in the microvascular environment. Our previous study established a novel 2-dimensional platform for coculturing microvascular endothelial cells (ECs) and pericytes derived from the same tissue. This study investigated how ECM stiffness regulated microvascular ECs, pericytes, and their interactions. METHODS: Primary microvessels were cultured in the TGM2D medium (tubular microvascular growth medium on 2-dimensional substrates). Stiff ECM was prepared by incubating ECM solution in regular culture dishes for 1 hour followed by PBS wash. Soft ECM with Young modulus of ≈6 kPa was used unless otherwise noted. Bone grafts were prepared from the rat skull. Immunostaining, RNA sequencing, RT-qPCR (real-time quantitative polymerase chain reaction), Western blotting, and knockdown experiments were performed on the cells. RESULTS: Primary microvascular pericytes differentiated into myofibroblasts (NG2+αSMA+) on stiff ECM, even with the TGFß (transforming growth factor beta) signaling inhibitor A83-01. Soft ECM and A83-01 cooperatively maintained microvascular stability while inhibiting pericyte-myofibroblast differentiation (NG2+αSMA-/low). We thus defined 2 pericyte subpopulations: primary (NG2+αSMA-/low) and activated (NG2+αSMA+) pericytes. Soft ECM promoted microvascular regeneration and inhibited fibrosis in bone graft transplantation in vivo. As integrins are the major mechanosensor, we performed RT-qPCR screening of integrin family members and found Itgb1 (integrin ß1) was the major subunit downregulated by soft ECM and A83-01 treatment. Knocking down Itgb1 suppressed myofibroblast differentiation on stiff ECM. Interestingly, ITGB1 phosphorylation (Y783) was mainly located on microvascular ECs on stiff ECM, which promoted EC secretion of paracrine factors, including CTGF (connective tissue growth factor), to induce pericyte-myofibroblast differentiation. CTGF knockdown or monoclonal antibody treatment partially reduced myofibroblast differentiation, implying the participation of multiple pathways in fibrosis formation. CONCLUSIONS: ECM stiffness and TGFß signaling cooperatively regulate microvascular stability and pericyte-myofibroblast differentiation. Stiff ECM promotes EC ITGB1 phosphorylation (Y783) and CTGF secretion, which induces pericyte-myofibroblast differentiation.

The OsNAC24-OsNAP protein complex activates OsGBSSI and OsSBEI expression to fine-tune starch biosynthesis in rice endosperm.

Starch accounts for up to 90% of the dry weight of rice endosperm and is a key determinant of grain quality. Although starch biosynthesis enzymes have been comprehensively studied, transcriptional regulation of starch-synthesis enzyme-coding genes (SECGs) is largely unknown. In this study, we explored the role of a NAC transcription factor, OsNAC24, in regulating starch biosynthesis in rice. OsNAC24 is highly expressed in developing endosperm. The endosperm of osnac24 mutants is normal in appearance as is starch granule morphology, while total starch content, amylose content, chain length distribution of amylopectin and the physicochemical properties of the starch are changed. In addition, the expression of several SECGs was altered in osnac24 mutant plants. OsNAC24 is a transcriptional activator that targets the promoters of six SECGs; OsGBSSI, OsSBEI, OsAGPS2, OsSSI, OsSSIIIa and OsSSIVb. Since both the mRNA and protein abundances of OsGBSSI and OsSBEI were decreased in the mutants, OsNAC24 functions to regulate starch synthesis mainly through OsGBSSI and OsSBEI. Furthermore, OsNAC24 binds to the newly identified motifs TTGACAA, AGAAGA and ACAAGA as well as the core NAC-binding motif CACG. Another NAC family member, OsNAP, interacts with OsNAC24 and coactivates target gene expression. Loss-of-function of OsNAP led to altered expression in all tested SECGs and reduced the starch content. These results demonstrate that the OsNAC24-OsNAP complex plays key roles in fine-tuning starch synthesis in rice endosperm and further suggest that manipulating the OsNAC24-OsNAP complex regulatory network could be a potential strategy for breeding rice cultivars with improved cooking and eating quality.

Distress tolerance as a mechanism of mindfulness for depression and anxiety: Cross-sectional and diary evidence.

Background: Both trait and state mindfulness are associated with less depression and anxiety, but the mechanisms remain unknown. Distress tolerance, an important transdiagnostic factor of emotional disorders, may mediate the relationship between mindfulness and depression/anxiety. Method: Study 1 examined the mediation model at the between-person level in a large cross-sectional sample (n = 905). In Study 2, a daily diary study (n = 110) was conducted to examine within-person changes. Participants were invited to complete daily diaries measuring daily mindfulness, distress tolerance, depression and anxiety for 14 consecutive days. Results: In Study 1, results of simple mediation analyses indicated that distress tolerance mediated the relationship between mindfulness and depression/anxiety at the between-person level. In Study 2, results of multilevel mediation analyses indicated that, in both the concurrent model and time-lagged model, daily distress tolerance mediated the effects of daily mindfulness on daily depression/anxiety at both the within- and between-person level. Conclusions: Distress tolerance is a mechanism underlying the relationship between mindfulness and depression/anxiety. Individuals with high or fluctuating depression and anxiety may benefit from short-term or long-term mindfulness training to increase distress tolerance.

Role of Circular RNAs in Prostate Cancer.

OBJECTIVES: This study aims to summarize the current literature to demonstrate the importance of circular RNAs (circRNAs) in multiple aspects of prostate cancer (PCa) occurrence, progression, and treatment resistance and explore the potential role in therapeutic strategies aimed at targeting this molecule in PCa. METHODS: The relevant literature from PubMed and Medline databases is reviewed in this article. RESULTS: Non-coding RNA has been proven to play a vital role in regulating tumor progression. Among them, circular RNA plays a more unique role due to its nonlinear structure. Lots of circRNAs were found to be differentially expressed in PCa and regulate cell signaling pathways by regulating particular gene expressions. Recent studies have demonstrated that circRNAs are associated with the chemoresistance of urinary tumors, suggesting that circRNAs might be a novel therapeutic target and a marker for therapeutic response and prognosis assessment. CONCLUSION: The potential crosstalk of circRNAs modifications in PCa development, therapy, and regulation of tumor metabolism is portrayed in this review. However, more preclinical and clinical trials of this targeted strategy are necessary for the treatment of urinary tumors.

Control of Raman Scattering Quantum Interference Pathways in Graphene.

Graphene is an ideal platform to study the coherence of quantum interference pathways by tuning doping or laser excitation energy. The latter produces a Raman excitation profile that provides direct insight into the lifetimes of intermediate electronic excitations and, therefore, on quantum interference, which has so far remained elusive. Here, we control the Raman scattering pathways by tuning the laser excitation energy in graphene doped up to 1.05 eV. The Raman excitation profile of the G mode indicates its position and full width at half-maximum are linearly dependent on doping. Doping-enhanced electron-electron interactions dominate the lifetimes of Raman scattering pathways and reduce Raman interference. This will provide guidance for engineering quantum pathways for doped graphene, nanotubes, and topological insulators.

MPET2: a multi-network poroelastic and transport theory for predicting absorption of monoclonal antibodies delivered by subcutaneous injection.

Subcutaneous injection of monoclonal antibodies (mAbs) has attracted much attention in the pharmaceutical industry. During the injection, the drug is delivered into the tissue producing strong fluid flow and tissue deformation. While data indicate that the drug is initially uptaken by the lymphatic system due to the large size of mAbs, many of the critical absorption processes that occur at the injection site remain poorly understood. Here, we propose the MPET2 approach, a multi-network poroelastic and transport model to predict the absorption of mAbs during and after subcutaneous injection. Our model is based on physical principles of tissue biomechanics and fluid dynamics. The subcutaneous tissue is modeled as a mixture of three compartments, i.e., interstitial tissue, blood vessels, and lymphatic vessels, with each compartment modeled as a porous medium. The proposed biomechanical model describes tissue deformation, fluid flow in each compartment, the fluid exchanges between compartments, the absorption of mAbs in blood vessels and lymphatic vessels, as well as the transport of mAbs in each compartment. We used our model to perform a high-fidelity simulation of an injection of mAbs in subcutaneous tissue and evaluated the long-term drug absorption. Our model results show good agreement with experimental data in depot clearance tests.

Modeling large-volume subcutaneous injection of monoclonal antibodies with anisotropic porohyperelastic models and data-driven tissue layer geometries.

Subcutaneous injection of therapeutic monoclonal antibodies (mAbs) has become one of the fastest-growing fields in the pharmaceutical industry. The transport and mechanical processes behind large volume injections are poorly understood. Here, we leverage a large-deformation poroelastic model to study high-dose, high-speed subcutaneous injection. We account for the anisotropy of subcutaneous tissue using of a fibril-reinforced porohyperelastic model. We also incorporate the multi-layer structure of the skin tissue, generating data-driven geometrical models of the tissue layers using histological data. We analyze the impact of handheld autoinjectors on the injection dynamics for different patient forces. Our simulations show the importance of considering the large deformation approach to model large injection volumes. This work opens opportunities to better understand the mechanics and transport processes that occur in large-volume subcutaneous injections of mAbs.

Epidemiololgical and etiological analysis of two clusters of severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease, caused by severe fever with thrombocytopenia syndrome virus (SFTSV), which is primarily transmitted via tick bites. Clusters of SFTS caused by human-to-human transmission have been reported both at home and abroad, mainly focused on the transmission or exposure modes. However, the correlation between SFTS clusters and viral genotypes has not been investigated. This study mainly reported two clusters of SFTS in Xinyang City, Henan Province, from 2022 to 2023, discussed the possible route of person-to-person transmission of SFTSV infection and analyzed the association between SFTS clusters and virus genotypes. We found that two groups of SFTSV in two clusters were clustered separately into different genotypes through viral sequence analysis of 4 confirmed patients. We also performed phylogenetic analysis, after including SFTSV sequences obtained from SFTS clusters deposited in the GenBank. Three SFTSV genotypes have been reported among cases of human-to-human transmission, suggesting that the occurrence of SFTS clusters may not be related to SFTSV genotypes. This study provided genetic evidence for revealing the chain of human-to-human transmission of SFTS clusters, indicating that contact with patients' blood is an important transmission route of SFTSV. The findings laid the foundation for preventing and controlling human-to-human transmission of SFTS.