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The aim of the study is to use the Surveillance, Epidemiology, and End Results (SEER) database to develop a useful clinical nomogram that uses prognosis prediction for pediatric melanoma patients. We obtained clinical information on pediatric melanoma patients from the SEER database between 2000 and 2018. Each patient was split into a training cohort or a validation cohort at random. Results between various subgroups were compared using Kaplan-Meier analyses. We created a nomogram to calculate the probability of survival for pediatric patients with melanoma. The performance of nomograms was assessed using calibration and discrimination. To assess the clinical use of this newly created model, decision curve analysis was also performed. In this study, a total of 890 eligible patients were chosen at random and allocated to 70% of training cohorts (n = 623) and 30% of validation cohorts (n = 267). After applying the chosen various components to create a nomogram, validated indexes showed that the nomogram had a strong capacity for discrimination. The training set's and validation set's C-index values were 0.817 and 0.832, respectively. The calibration plots demonstrated a strong correlation between the observation and the forecast. The model has a good clinical net benefit for pediatric melanoma patients, according to the clinical decision curve. In conclusion, we created an effective survival prediction model for pediatric melanoma. This nomogram is accurate and useful for clinical decision-making. Still, more external confirmation is required., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Degenerated endplate appears with cheese-like morphology and sensory innervation, contributing to low back pain and subsequently inducing intervertebral disc degeneration in the aged population. 1 However, the origin and development mechanism of the cheese-like morphology remain unclear. Here in this study, we report lumbar instability induced cartilage endplate remodeling is responsible for this pathological change. Transcriptome sequencing of the endplate chondrocytes under abnormal stress revealed that the Hippo signaling was key for this process. Activation of Hippo signaling or knockout of the key gene Yap1 in the cartilage endplate severed the cheese-like morphological change and disc degeneration after lumbar spine instability (LSI) surgery, while blocking the Hippo signaling reversed this process. Meanwhile, transcriptome sequencing data also showed osteoclast differentiation related gene set expression was up regulated in the endplate chondrocytes under abnormal mechanical stress, which was activated after the Hippo signaling. Among the discovered osteoclast differentiation gene set, CCL3 was found to be largely released from the chondrocytes under abnormal stress, which functioned to recruit and promote osteoclasts formation for cartilage endplate remodeling. Over-expression of Yap1 inhibited CCL3 transcription by blocking its promoter, which then reversed the endplate from remodeling to the cheese-like morphology. Finally, LSI-induced cartilage endplate remodeling was successfully rescued by local injection of an AAV5 wrapped Yap1 over-expression plasmid at the site. These findings suggest that the Hippo signaling induced osteoclast gene set activation in the cartilage endplate is a potential new target for the management of instability induced low back pain and lumbar degeneration., (© 2024. The Author(s).)

This study aimed to investigate the association between n -3 PUFA and lung function. First, a cross-sectional study was conducted based on the National Health and Nutrition Examination Survey (NHANES) 2007-2012 data. n -3 PUFA intake was obtained from 24-h dietary recalls. A multivariable linear regression model was used to assess the observational associations of n -3 PUFA intake with lung function. Subsequently, a two-sample Mendelian randomisation (MR) was performed to estimate the potential causal effect of n -3 PUFA on lung function. Genetic instrumental variables were extracted from published genome-wide association studies. Summary statistics about n -3 PUFA was from UK Biobank. Inverse variance weighted was the primary analysis approach. The observational study did not demonstrate a significant association between n -3 PUFA intake and most lung function measures; however, a notable exception was observed with significant findings in the highest quartile for forced vital capacity (FVC) and % predicted FVC. The MR results also showed no causal effect of circulating n -3 PUFA concentration on lung function (forced expiratory volume in one second (FEV 1 ), β = 0·01301, se = 0·01932, P = 0·5006; FVC, β = -0·001894, se = 0·01704, P = 0·9115; FEV 1 :FVC, β = 0·03118, se = 0·01743, P = 0·07359). These findings indicate the need for further investigation into the impact of higher n -3 PUFA consumption on lung health.

Aqueous aluminum-ion batteries (AAIBs) are considered as a promising alternative to lithium-ion batteries due to their large theoretical capacity, high safety, and low cost. However, the uneven deposition, hydrogen evolution reaction (HER), and corrosion during cycling impede the development of AAIBs, especially under a harsh environment. Here, a hydrated eutectic electrolyte (AATH40) composed of Al(OTf) 3 , acetonitrile (AN), triethyl phosphate (TEP), and H 2 O was designed to improve the electrochemical performance of AAIBs in a wide temperature range. The combination of molecular dynamics simulations and spectroscopy analysis reveals that AATH40 has a less-water-solvated structure [Al(AN) 2 (TEP)(OTf) 2 (H 2 O)] 3+ , which effectively inhibits side reactions, decreases the freezing point, and extends the electrochemical window of the electrolyte. Furthermore, the formation of a solid electrolyte interface, which effectively inhibits HER and corrosion, has been demonstrated by X-ray photoelectron spectroscopy, X-ray diffraction tests, and in situ differential electrochemical mass spectrometry. Additionally, operando synchrotron Fourier transform infrared spectroscopy and electrochemical quartz crystal microbalance with dissipation monitoring reveal a three-electron storage mechanism for the Al//polyaniline full cells. Consequently, AAIBs with this electrolyte exhibit improved cycling stability within the temperature range of -10-50 °C. This present study introduces a promising methodology for designing electrolytes suitable for low-cost, safe, and stable AAIBs over a wide temperature range.

YTHDF1, an N6‑methyladenosine (m6A)‑binding protein, is significantly upregulated in glioma tissues. The present study investigated the molecular mechanism underlying the regulatory effects of YTHDF1 on the viability, invasion and self‑renewal of glioma stem cells (GSCs). Glioma and normal brain tissues were collected, and reverse transcription‑quantitative PCR and western blotting were used to measure the gene and protein expression levels, respectively. Methylated RNA immunoprecipitation‑PCR was used to assess the m6A modification level of the target gene. Subsequently GSCs were induced, and YTHDF1 and LINC00900 gene regulation was carried out using lentiviral infection. The viability, invasion and self‑renewal of GSCs were assessed by Cell Counting Kit‑8, Transwell and sphere formation assays, respectively. Binding between YTHDF1 and LINC00900 was verified by RNA immunoprecipitation and RNA pull‑down assays. The targeted binding of microRNA (miR)‑1205 to the LINC00900/STAT3 3'‑UTR was verified using a luciferase reporter assay. The results revealed that YTHDF1 and LINC00900 expression levels were significantly upregulated in glioma tissues, and a high m6A modification level in LINC00900 transcripts was detected in glioma tissues. Overexpression of YTHDF1 promoted GSC viability, invasion and self‑renewal, whereas knockdown of YTHDF1 had the opposite effects. In addition, YTHDF1 maintained the stability of LINC00900 and upregulated its expression through binding to it, thereby promoting GSC viability, invasion and self‑renewal. Furthermore, LINC00900 promoted GSC viability, invasion, self‑renewal and tumor growth by regulating the miR‑1205/STAT3 axis. In conclusion, YTHDF1 promotes GSC viability and self‑renewal by regulating the LINC00900/miR‑1205/STAT3 axis.

Thrombosis is the pathological clot formation under abnormal hemodynamic conditions, which can result in vascular obstruction, causing ischemic strokes and myocardial infarction. Thrombus growth under moderate to low shear (<1000 s -1 ) relies on platelet activation and coagulation. Thrombosis at elevated high shear rates (>10,000 s -1 ) is predominantly driven by unactivated platelet binding and aggregating mediated by von Willebrand factor (VWF), while platelet activation and coagulation are secondary in supporting and reinforcing the thrombus. Given the molecular and cellular level information it can access, multiscale computational modeling informed by biology can provide new pathophysiological mechanisms that are otherwise not accessible experimentally, holding promise for novel first-principle-based therapeutics. In this review, we summarize the key aspects of platelet biorheology and mechanobiology, focusing on the molecular and cellular scale events and how they build up to thrombosis through platelet adhesion and aggregation in the presence or absence of platelet activation. In particular, we highlight recent advancements in multiscale modeling of platelet biorheology and mechanobiology and how they can lead to the better prediction and quantification of thrombus formation, exemplifying the exciting paradigm of digital medicine.

Several studies have indicated that circular RNAs (circRNAs) play vital roles in the progression of various diseases, including bladder cancer (BCa). However, the underlying mechanisms by which circRNAs drive BCa malignancy remain unclear. In this study, we identified a novel circRNA, circPSMA7 (circbaseID:has&#95;circ&#95;0003456), showing increased expression in BCa cell lines and tissues, by integrating the reported information with circRNA-seq and qRT-PCR. We revealed that circPSMA7 is associated with a higher tumor grade and stage in BCa. M 6 A modification was identified in circPSMA7, and IGF2BP3 recognized this modification and stabilized circPSMA7, subsequently increasing the circPSMA7 expression. In vitro and in vivo experiments showed that circPSMA7 promoted BCa proliferation and metastasis by regulating the cell cycle and EMT processes. CircPSMA7 acted as a sponge for miR-128-3p, which showed antitumor effects in BCa cell lines, increasing the expression of MAPK1. The tumor proliferation and metastasis suppression induced by silencing circPSMA7 could be partly reversed by miR-128-3p inhibition. Thus, the METTL3/IGF2BP3/circPSMA7/miR-128-3p/MAPK1 axis plays a critical role in BCa progression. Furthermore, circPSMA7 may be a potential diagnostic biomarker and novel therapeutic target for patients with BCa., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus with high pathogenicity. There has been a gradual increase in the number of reported cases in recent years, with high morbidity and mortality rates. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway plays an important role in the innate immune defense activated by viral infection; however, the role of the cGAS-STING signaling pathway during SFTSV infection is still unclear. In this study, we investigated the relationship between SFTSV infection and cGAS-STING signaling. We found that SFTSV infection caused the release of mitochondrial DNA into the cytoplasm and inhibits downstream innate immune signaling pathways by activating the cytoplasmic DNA receptor cGAS. We found that the SFTSV envelope glycoprotein Gn was a potent inhibitor of the cGAS-STING pathway and blocked the nuclear accumulation of interferon regulatory factor 3 and p65 to inhibit downstream innate immune signaling. Gn of SFTSV interacted with STING to inhibit STING dimerization and inhibited K27-ubiquitin modification of STING to disrupt the assembly of the STING-TANK-binding kinase 1 complex and downstream signaling. In addition, Gn was found to be involved in inducing STING degradation, further inhibiting the downstream immune response. In conclusion, this study identified the important role of the glycoprotein Gn in the antiviral innate immune response and revealed a novel mechanism of immune escape for SFTSV. Moreover, this study increases the understanding of the pathogenic mechanism of SFTSV and provides new insights for further treatment of SFTS., Importance: Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly discovered virus associated with severe hemorrhagic fever in humans. However, the role of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway during SFTSV infection is still unclear. We found that SFTSV infection inhibits downstream innate immune signaling pathways by activating the cytoplasmic DNA receptor cGAS. In addition, SFTSV Gn blocked the nuclear accumulation of interferon regulatory factor 3 and p65 to inhibit downstream innate immune signaling. Moreover, we determined that Gn of SFTSV inhibited K27-ubiquitin modification of STING to disrupt the assembly of the STING-TANK-binding kinase 1 complex and downstream signaling. We found that the SFTSV envelope glycoprotein Gn is a potent inhibitor of the cGAS-STING pathway. In conclusion, this study highlights the crucial function of the glycoprotein Gn in the antiviral innate immune response and reveals a new method of immune escape of SFTSV., Competing Interests: The authors declare no conflict of interest.

The practical implementation of aqueous zinc-ion batteries (AZIBs) encounters challenges such as dendrite growth, parasitic reactions, and severe decay in battery performance under harsh environments. Here, a novel hydrated eutectic electrolyte (HEE) composed of Zn(ClO 4 ) 2 ·6H 2 O, ethylene glycol (EG), and InCl 3 solution is introduced to effectively extend the lifespan of AZIBs over a wide temperature range from -50 to 50 °C. Molecular dynamics simulations and spectroscopy analysis demonstrate that the H 2 O molecules are confined within the liquid eutectic network through dual-interaction, involving coordination with Zn 2+ and hydrogen bonding with EG, thus weakening the activity of free water and extending the electrochemical window. Importantly, cryo-transmission electron microscopy and spectroscopy techniques reveal that HEE in situ forms a zincophobic/zincophilic bilayer interphase by the dissociation-reduction of eutectic molecules. Specifically, the zincophilic interphase reduces the energy barrier for Zn nucleation, promoting uniform Zn deposition, while the zincophobic interphase prevents active water from contacting the Zn surface, thus inhibiting the side reactions. Furthermore, the relationships between the structural evolution of the liquid eutectic network and interfacial chemistry at electrode/electrolyte interphase are further discussed in this work. The scalability of this design strategy can bring benefits to AZIBs operating over a wide temperature range., (© 2023 Wiley-VCH GmbH.)

Background: The COVID-19 pandemic raised wide concern from all walks of life globally. Social media platforms became an important channel for information dissemination and an effective medium for public sentiment transmission during the COVID-19 pandemic., Objective: Mining and analyzing social media text information can not only reflect the changes in public sentiment characteristics during the COVID-19 pandemic but also help the government understand the trends in public opinion and reasonably control public opinion., Methods: First, this study collected microblog comments related to the COVID-19 pandemic as a data set. Second, sentiment analysis was carried out based on the topic modeling method combining latent Dirichlet allocation (LDA) and Bidirectional Encoder Representations from Transformers (BERT). Finally, a machine learning linear regression (ML-LR) model combined with a sparse matrix was proposed to explore the evolutionary trend in public opinion on social media and verify the high accuracy of the model., Results: The experimental results show that, in different stages, the characteristics of public emotion are different, and the overall trend is from negative to positive., Conclusions: The proposed method can effectively reflect the characteristics of the different times and space of public opinion. The results provide theoretical support and practical reference in response to public health and safety events., (©Feipeng Guo, Zixiang Liu, Qibei Lu, Shaobo Ji, Chen Zhang. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 31.01.2024.)

Objective: Although spinal endoscopic techniques have shown great advantages in the treatment of single-segment lumbar disk herniation (LDH), the therapeutic advantages for double-segment LDH are controversial. To compare the outcomes of percutaneous endoscopic interlaminar discectomy (PEID) versus conventional open lumbar discectomy (COLD) for the treatment of L4/5 and L5/S1 double-segmental LDH., Methods: From January 2016 to September 2021, we included 50 patients with double-segmental LDH who underwent PEID (n = 25) or COLD (n = 25). The clinical outcomes between the two groups were evaluated using the visual analog scale (VAS), the Oswestry disability index (ODI), and the modified MacNab criteria. Moreover, the incision length, operation time, intraoperative fluoroscopy time, postoperative bedtime, hospital stays, and complications were also recorded and compared after surgery., Results: In both groups, the VAS and ODI scores at different timepoints postoperatively were significantly improved compared with those preoperatively (P < 0.05) According to the modified MacNab criteria, the excellent or good outcome rate was 92% in the PEID group and 88% in the COLD group. The PEID group had shorter incision length, postoperative bedtime, and hospital stays than the COLD group. However, the operation time was shorter and intraoperative fluoroscopy time was fewer in the COLD group. In addition, there was no significant difference between the two groups in terms of surgical complications during the postoperative follow-up period., Conclusions: Both PEID and COLD have good efficacy and high safety for management of L4/5 and L5/S1 double-segmental LDH. Compared with the COLD group, the PEID group had more operative time as well as more intraoperative fluoroscopy, but it had a more minimally invasive surgical incision as well as faster postoperative recovery., (© 2023. The Author(s).)

Background: Cell transplantation has been demonstrated as a promising approach in tissue regeneration. However, the reactive oxygen species (ROS) accumulation and inflammation condition establish a harsh microenvironment in degenerated tissue, which makes the transplanted cells difficult to survive., Methods: In this study, we constructed a keep-charging hydrogel microsphere system to enable cells actively proliferate and function in the degenerated intervertebral disc. Specifically, we combined Mg 2+ to histidine-functionalized hyaluronic acid (HA-His-Mg 2+ ) through coordination reaction, which was further intercrossed with GelMA to construct a double-network hydrogel microsphere (GelMA/HA-His-Mg 2+ , GHHM) with microfluidic methods. In vitro, the GHHM loaded with nucleus pulposus cells (GHHM@NPCs) was further tested for its ability to promote NPCs proliferation and anti-inflammatory properties. In vivo, the ability of GHHM@NPCs to promote regeneration of NP tissue and rescue intervertebral disc degeneration (IVDD) was evaluated by the rat intervertebral disc acupuncture model., Results: The GHHM significantly enhanced NPCs adhesion and proliferation, providing an ideal platform for the NPCs to grow on. The loaded NPCs were kept active in the degenerative intervertebral disc microenvironment as charged by the Mg 2+ in GHHM microspheres to effectively support the loaded NPCs to reply against the ROS-induced inflammation and senescence. Moreover, we observed that GHHM@NPCs effectively alleviated nucleus pulposus degeneration and promoted its regeneration in the rat IVDD model., Conclusion: In conclusion, we constructed a keep charging system with a double-network hydrogel microsphere as a framework and Mg 2+ as a cell activity enhancer, which effectively maintains NPCs active to fight against the harsh microenvironment in the degenerative intervertebral disc. The GHHM@NPCs system provides a promising approach for IVDD management., (© 2023. The Author(s).)

To assess the clinical and radiographic effectiveness of unilateral and bilateral percutaneous kyphoplasty (PKP) in the treatment of osteoporotic vertebral compression fractures (OVCF) associated with scoliosis, 52 patients with OVCF associated with scoliosis who underwent PKP were retrospectively analysed. The patients were divided into the unilateral PKP group (n=26) and the bilateral PKP group (n=26). The operation time, bone cement injection volume and frequency of intraoperative fluoroscopy were recorded and compared between the groups. Additionally, visual analogue scale (VAS) and Oswestry disability index (ODI) scores, as well as postoperative complications, including bone cement leakage and adjacent vertebral fractures, were also assessed. The operation time, bone cement injection volume and intraoperative fluoroscopy frequency were significantly lower in the unilateral compared with the bilateral group (P<0.001). The VAS score, ODI score, average vertebral body height and kyphotic angle (KA) were improved after surgery in each group with no difference in these clinical parameters between the two groups both before and after surgery. Furthermore, the proportion of cases with bone cement leakage in the unilateral group was significantly lower compared with that in the bilateral group (P<0.05). During the follow-up, there were three cases (11.5%) in the unilateral group and two cases (7.7%) in the bilateral group who suffered adjacent vertebral fractures, but there was no statistically significant difference between the two groups (P>0.05). For treating patients with OVCF accompanied by scoliosis, both unilateral and bilateral PKP could effectively relieve the acute back pain and correct the KA. However, unilateral PKP presents more advantages, such as a short operation duration and reduced intraoperative fluoroscopy frequency and bone cement leakage., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Liu et al.)

Sustainable organic electrode materials, as promising alternatives to conventional inorganic electrode materials for sodium-ion batteries (SIBs), are still challenging to realize long-lifetime and high-rate batteries because of their poor conductivity, limited electroactivity, and severe dissolution. It is also urgent to deeply reveal their electrochemical mechanism and evolution processes. A porous organic polymer (POP) with a conjugated and hierarchical structure is designed and synthesized here. The unique molecule and structure endow the POP with electron delocalization, high ionic diffusivity, plentiful active sites, exceptional structure stability, and limited solubility in electrolytes. When evaluated as an anode for SIBs, the POP exhibits appealing electrochemical properties regarding reversible capacity, rate behaviors, and long-duration life. Importantly, using judiciously combined experiments and theoretical computation, including in situ transmission electron microscopy (TEM), and ex situ spectroscopy, we reveal the Na-storage mechanism and dynamic evolution processes of the POP, including 12-electron reaction process with Na, low volume expansion (125-106% vs the initial 100%), and stable composition and structure evolution during repeating sodiation/de-sodiation processes. This quantitative design for ultrafast and highly durable sodium storage in the POP could be of immediate benefit for the rational design of organic electrode materials with ideal electrochemical properties., (© 2023 Wiley-VCH GmbH.)

The spleen clears altered red blood cells (RBCs) from circulation, contributing to the balance between RBC formation (erythropoiesis) and removal. The splenic RBC retention and elimination occur predominantly in open circulation where RBCs flow through macrophages and inter-endothelial slits (IESs). The mechanisms underlying and interconnecting these processes significantly impact clinical outcomes. In sickle cell disease (SCD), blockage of intrasplenic sickled RBCs is observed in infants splenectomized due to acute splenic sequestration crisis (ASSC). This life-threatening RBC pooling and organ swelling event is plausibly triggered or enhanced by intra-tissular hypoxia. We present an oxygen-mediated spleen-on-a-chip platform for in vitro investigations of the homeostatic balance in the spleen. To demonstrate and validate the benefits of this general microfluidic platform, we focus on SCD and study the effects of hypoxia on splenic RBC retention and elimination. We observe that RBC retention by IESs and RBC-macrophage adhesion are faster in blood samples from SCD patients than those from healthy subjects. This difference is markedly exacerbated under hypoxia. Moreover, the sickled RBCs under hypoxia show distinctly different phagocytosis processes from those non-sickled RBCs under hypoxia or normoxia. We find that reoxygenation significantly alleviates RBC retention at IESs, and leads to rapid unsickling and fragmentation of the ingested sickled RBCs inside macrophages. These results provide unique mechanistic insights into how the spleen maintains its homeostatic balance between splenic RBC retention and elimination, and shed light on how disruptions in this balance could lead to anemia, splenomegaly, and ASSC in SCD and possible clinical manifestations in other hematologic diseases.

Aqueous zinc-ion batteries (AZIBs) have attracted attention for their low cost and environmental friendliness. Unfortunately, commercialization has been hampered by several problems with dendrite growth and side reactions. Herein, we select sodium tartrate (TA-Na) as a dual-functional electrolyte additive to enhance the reversibility of AZIBs. The tartrate anions are preferentially adsorbed on the Zn surface, and then the highly nucleophilic carboxylate will coordinate with Zn 2+ to promote the desolvation of [Zn(H 2 O) 6 ] 2+ , leading to uniform Zn deposition on the beneficial (002) plane and inhibiting side reactions and dendrite growth. Consequently, the Zn|Zn cells show a long-term cycling stability of over 1500 cycles at 0.5 mA cm -2 . Moreover, the Ta-Na additive improves the performance of Zn||MnO 2 full cells, evidenced by a cycling life of 1000 cycles at 1 A g -1 under practical conditions with a limited Zn anode (negative/positive capacity ratio of 10/1) and controlled electrolyte (electrolyte/capacity ratio of 20 μL mAh -1 ).

In this work, we systematically investigate the photocatalytic mechanism of g-C 3 N 4 /BiOI (001) through hybrid functional calculations based on first-principles theory. The staggered band structure is observed in the g-C 3 N 4 /BiOI (001); meanwhile, a built-in electric field exists from the g-C 3 N 4 monolayer to the BiOI surface at the interface. BiOI has lower band edges, which bend downward at the interface; whereas g-C 3 N 4 has higher band edges, which bend upward. With Coulomb interaction and the built-in electric field, photo-generated electrons in the conduction bands (CB) of BiOI recombine with photo-generated holes in the valence bands (VB) of g-C 3 N 4 . Meanwhile, the stronger reduction capacity for photo-excited electrons in the g-C 3 N 4 's CB and the stronger oxidation capacity for photo-generated holes in the BiOI (001)'s VB are retained. Therefore, a direct Z-scheme heterostructure character is presented. As a result, the electrons and holes generated by the photons can be separated and migrate highly effectively at the interface. The separated electrons and holes can effectively participate in the redox reactions with water/pollutants to produce the photocatalytically reactive species superoxide ions (˙O 2 - ) and hydroxyl radicals (˙OH), respectively. This is consistent with the experimental results. It is also worth noting that the g-C 3 N 4 /BiOI (001) heterostructure shows a larger difference in the effective mass of carriers. Therefore, the direct Z-scheme charge transfer and separation mechanism and the larger effective mass difference of carriers lead to the superior photocatalytic activity of the g-C 3 N 4 /BiOI (001) in experiments. A few speculations and controversies that arose from the experiments are clarified.

Escherichia coli serine hydroxymethyltransferase (GlyA) converts serine to glycine, and glyA mutants are auxotrophic for glycine. CycA is a transporter that mediates glycine uptake. Deleting glyA in E. coli strain W3110 led to activation of CysB, which was related to novobiocin (NOV) susceptibility. Moreover, deleting glyA resulted in increased sensitivity to NOV, and this could be reversed by high concentrations of glycine. Reverse mutants of Δ glyA were selected and one of them had a mutation in yrdC , the gene encoding threonylcarbamoyl-AMP synthase. Subsequent proteome analysis showed that deleting glyA led to increased expression of TcyP and TdcB, making this bacterium dependent on CycA for glycine assimilation. Furthermore, deleting cycA in a Δ glyA background caused a severe growth defect on Luria-Bertani medium, which could be complemented by high concentrations of exogenous glycine. Mutation of yrdC led to decreased expression of TdcB but increased expression of ThrA/B/C and LtaE, which favored the conversion of threonine to glycine and thus avoided the dependence on CycA. Correspondingly, deleting of tcyP , tdcB , or gshA could reverse the NOV-sensitive phenotype of Δ glyA mutants. Overexpression of cycA resulted in increased sensitivity to NOV, whereas deleting this gene caused NOV resistance. Moreover, overexpression of cycA led to increased accumulation of NOV upon drug treatment. Therefore, inactivation of glyA in E. coli led to CycA-dependent glycine assimilation, which enhanced the accumulation of NOV and then made the bacterium more sensitive to this drug. These findings broaden our understanding of glycine metabolism and mechanisms of NOV susceptibility. IMPORTANCE Novobiocin (NOV) has been used in clinical practice as an ATPase inhibitor for decades. However, because it has been withdrawn from the market, pharmaceutical companies are searching for other ATPase inhibitors. Thus, probing the mechanisms of susceptibility to NOV will be beneficial to those efforts. In this study, we showed that inactivation of glyA in E. coli led to CycA-dependent glycine assimilation, which accompanied the accumulation of NOV and thereby increased the sensitivity to this drug. To date, this is the first report demonstrating the linkage between glycine assimilation and NOV susceptibility, and it is also the first report showing that YrdC is able to modulate the metabolic flux of threonine.

The periosteum on the skeletal surface creates a unique micro-environment for cortical bone homeostasis, but how this micro-environment is formed remains a mystery. In our study, we observed the cells in the periosteum presented elongated spindle-like morphology within the aligned collagen fibers, which is in accordance with the differentiated osteoblasts lining on the cortical surface. We planted the bone marrow stromal cells(BMSCs), the regular shaped progenitor cells, on collagen-coated aligned fibers, presenting similar cell morphology as observed in the natural periosteum. The aligned collagen topology induced the elongation of BMSCs, whichfacilitated the osteogenic process. Transcriptome analysis suggested the aligned collagen induced the regular shaped cells to present part of the periosteum derived stromal cells(PDSCs) characteristics by showing close correlation of the two cell populations. In addition, the elevated expression of PDSCs markers in the cells grown on the aligned collagen-coated fibers further indicated the function of periosteal topology in manipulating cells' behavior. Enrichment analysis revealed cell-extracellular matrix interaction was the major pathway initiating this process, which created an osteo-friendly micro-environment as well. At last, we found the aligned topology of collagen induced mechano-growth factor expression as the result of Igf1 alternative splicing, guiding the progenitor cells behavior and osteogenic process in the periosteum. This study uncovers the key role of the aligned topology of collagen in the periosteum and explains the mechanism in creating the periosteal micro-environment, which gives the inspiration for artificial periosteum design., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Objective: This study aims to investigate the clinical outcome of single and double incision for double-level percutaneous interlaminar lumbar discectomy., Methods: A retrospective analysis was performed involving patients with L4/5 and L5/S1 double-level lumbar disc herniation who received percutaneous interlaminar lumbar discectomy (PEID) in our hospital from January 2017 to December 2020. These enrolled patients were divided into single- and double-incision groups, with 25 patients in each group. We compared the incision length, operation time, fluoroscopy times, and length of hospital stay between the two groups. Meanwhile, the postoperative visual analogue scale (VAS), Oswestry Disability Index (ODI), Japanese Orthopedic Association score (JOA), and modified MacNab standard were used to evaluate the outcomes of the patients within the two groups., Results: It showed that the single-incision group performed better than double-incision group in incision length, operation time, and fluoroscopy times ( P  < 0.001). The VAS score, JOA score, and ODI index in the two groups were significantly decreased at the time points of postsurgery, 1 month after surgery, and the last follow-up ( P  < 0.01), but there was no statistical significance between the two groups involving above parameters ( P  > 0.05). At the last follow-up, the excellent and good rates of MacNab efficacy in the two groups were 92% and 88%, respectively, but no significant difference was observed between the two groups ( P  > 0.05)., Conclusion: Both the single- and double-incision approaches are effective and safe for managing L4/5 and L5/S1 double-level LDH. Single-incision PEID for treating L4/5 and L5/S1 double-segment lumbar disc herniation has advantages of less trauma, fewer intraoperative fluoroscopy times, and shorter operation time, as compared to double-incision PEID. However, the operation of double-segment LDH through a single laminar incision is difficult, the learning curve is steep, and professional skill is highly required. Importantly, the surgical indications should be strictly grasped., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Tang, Liu, Liu, Zhang, Zhu, Qian, Yang, Mao, Zhang, Chen and Chen.)

Purpose: To compare the clinical and radiological outcomes of percutaneous kyphoplasty (PKP) and percutaneous vertebroplasty (PVP) in the treatment of stage III Kummell disease without neurological deficit., Methods: This retrospective study involved 41 patients with stage III Kummell disease without neurological deficit who underwent PKP or PVP from January 2018 to December 2019. Demographic data and clinical characteristics were comparable between these two groups before surgery. Operation time, volume of injected bone cement, intraoperative blood loss and time of hospital stay were analyzed. Visual analog scale (VAS) scoring and Oswestry disability index (ODI) scoring were assessed for each patient before and after operation. Radiographic follow-up was assessed by the height of anterior (Ha), the height of middle (Hm), Cobb's angle, and Vertebral wedge ratio (VWR). The preoperative and postoperative recovery values of these data were used for comparison., Results: The two groups showed no significant difference in demographic features (p > 0.05). What's more, the operation time, intraoperative blood loss, and time of hospital stay revealed no sharp statistical distinctions either (p > 0.05), except PKP used more bone cement than PVP (7.4 ± 1.7 mL vs 4.7 ± 1.4 mL, p < 0.05). Radiographic data, such as the Ha improvement ratio (35.1 ± 10.2% vs 16.2 ± 9.4%), the Hm improvement ratio (41.8 ± 11.3% vs 22.4 ± 9.0%), the Cobb's angle improvement (10.0 ± 4.3° vs 3.5 ± 2.1°) and the VWR improvement ratio (30.0 ± 10.6% vs 12.7 ± 12.0%), were all better in PKP group than that in PVP group (p < 0.05). There were no statistical differences in the improvement of VAS and ODI 1-day after the surgery between these two groups (p > 0.05). However, at the final follow-up, VAS and ODI in PKP group were better than that in PVP (p < 0.05). Cement leakage, one of the most common complications, was less common in the PKP group than that in the PVP group (14.3% vs 45.0%, p < 0.05). And there was 1 case of adjacent vertebral fractures in both PKP and PVP (4.8% vs 5.0%, p > 0.05), which showed no statistical difference, and there were no severe complications recorded., Conclusions: For stage III Kummell disease, both PKP and PVP can relieve pain effectively. Moreover, PKP can obtain more satisfactory reduction effects and less cement leakage than PVP. We suggested that PKP was more suitable for stage III Kummell disease without neurological deficit compared to PVP from a vertebral reduction point of view., (© 2022. The Author(s).)

FTO, as an m 6 A mRNA demethylase, is involved in various cancers. However, the role of FTO in clear cell renal cell carcinoma (ccRCC) remains unclear. In the present study, we discovered FTO is upregulated in ccRCC. Functionally, knockdown of FTO significantly impairs the proliferation and migration ability of ccRCC cells. Mechanistically, our data suggest FTO promotes the proliferation and migration of ccRCC through preventing degradation of PDK1 mRNA induced by YTHDF2 in an m 6 A-dependent mechanism. Overall, our results identify the protumorigenic role of FTO through the m 6 A/YTHDF2/PDK1 pathway, which could be a promising therapeutic target for ccRCC., (© 2022. The Author(s).)

Dabie bandavirus (DBV) is an emerging Bandavirus that causes multiorgan failure with a high fatality rate in humans. While many viruses can manipulate the actin cytoskeleton to facilitate viral growth, the regulation pattern of the actin cytoskeleton and the molecular mechanisms involved in DBV entry into the host cells remain unclear. In this study, we demonstrate that expression of nonstructural protein (NSs) or infection with DBV induces actin rearrangement, which presents a point-like distribution, and this destruction is dependent on inclusion bodies (IBs). Further experiments showed that NSs inhibits viral adsorption by destroying the filopodium structure. In addition, NSs also compromised the viral entry by inhibiting clathrin aggregation on the cell surface and capturing clathrin into IBs. Furthermore, NSs induced clathrin light chain B (CLTB) degradation through the K48-linked ubiquitin proteasome pathway, which could negatively regulate clathrin-mediated endocytosis, inhibiting the viral entry. Finally, we confirmed that this NSs-induced antiviral mechanism is broadly applicable to other viruses, such as enterovirus 71 (EV71) and influenza virus, A/PR8/34 (PR8), which use the same clathrin-mediated endocytosis to enter host cells. In conclusion, our study provides new insights into the role of NSs in inhibiting endocytosis and a novel strategy for treating DBV infections. IMPORTANCE Dabie bandavirus (DBV), a member of the Phenuiviridae family, is a newly emerging tick-borne pathogen that causes multifunctional organ failure and even death in humans. The actin cytoskeleton is involved in various crucial cellular processes and plays an important role in viral life activities. However, the relationship between DBV infection and the actin cytoskeleton has not been described in detail. Here, we show for the first time the interaction between NSs and actin to induce actin rearrangement, which inhibits the viral adsorption and entry. We also identify a key mechanism underlying NSs-induced entry inhibition in which NSs prevents clathrin aggregation on the cell surface by hijacking clathrin into the inclusion body and induces CLTB degradation through the K48-linked ubiquitination modification. This paper is the first to reveal the antiviral mechanism of NSs and provides a theoretical basis for the search for new antiviral targets.

Shear-induced platelet aggregation (SIPA) occurs under elevated shear rates (10 000 s-1) found in stenotic coronary and carotid arteries. The pathologically high shear environment can lead to occlusive thrombosis by SIPA from the interaction of nonactivated platelets and von Willebrand factor (VWF) via glycoprotein Ib-A1 binding. This process under high shear rates is difficult to visualize experimentally with concurrent molecular- and cellular-resolutions. To understand this fast bonding, we employ a validated multiscale in silico model incorporating measured molecular kinetics and a thrombosis-on-a-chip device to delineate the flow-mediated biophysics of VWF and platelets assembly into mural microthrombi. We show that SIPA begins with VWF elongation, followed by agglomeration of platelets in the flow by soluble VWF entanglement before mural capture of the agglomerate by immobilized VWF. The entire SIPA process occurs on the order of 10 milliseconds with the agglomerate traveling a lag distance of a few hundred microns before capture, matching in vitro results. Increasing soluble VWF concentration by ∼20 times in silico leads to a ∼2 to 3 times increase in SIPA rates, matching the increase in occlusion rates found in vitro. The morphology of mural aggregates is primarily controlled by VWF molecular weight (length), where normal-length VWF leads to cluster or elongated aggregates and ultra-long VWF leads to loose aggregates seen by others' experiments. Finally, we present phase diagrams of SIPA, which provides biomechanistic rationales for a variety of thrombotic and hemostatic events in terms of platelet agglomeration and capture., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objective: To retrospectively analyze the short and long-term efficacies of O-arm-navigated percutaneous short segment pedicle screw fixation, with or without screwing of the fractured vertebra., Methods: A total of 42 patients who underwent O-arm-navigated percutaneous short segment pedicle screw fixation for the treatment of thoracolumbar fractures from February 2015 to December 2018 were selected for analysis. The patients were divided into two groups according to the surgical intervention they received: Group A received percutaneous short segment pedicle screw fixation with screwing of the fractured vertebra and Group B received percutaneous short segment pedicle screw fixation without screwing of the fractured vertebra. Radiographic analysis included Cobb angles and percentage of anterior vertebral height (AVH%). Clinical functional outcomes were assessed using the visual analog scale (VAS) for back pain and the oswestry disability index (ODI) scores., Results: No significant differences were observed in the operation time and intraoperative blood loss between the two groups (P > 0.05). The length of incision was statistically significantly different between the two groups (P < 0.05). There was no significant difference in Cobb angle and AVH% between the two groups before and after the surgery (P > 0.05). However, the Cobb angle and AVH% were both significantly larger in Group A than Group B at the final follow-up (P < 0.05). In terms of clinical outcomes, there were no statistically significant differences in VAS and ODI scores between the two groups (P > 0.05)., Conclusion: In the short term, both minimally invasive treatments were safe and effective in treating thoracolumbar fracture. Although there was significant difference between the two groups in Cobb angle and vertebral body height at the last follow-up, the difference was small. Therefore, these specific parameters will be an important outcome measure in further investigations., (© 2022. The Author(s).)

Because of their compromised deformability, heat denatured erythrocytes have been used as labeled probes to visualize spleen tissue or to assess the ability of the spleen to retain stiff red blood cells (RBCs) for over three decades, e.g., see Looareesuwan et al. N. Engl. J. Med. (1987). Despite their good accessibility, it is still an open question how heated RBCs compare to certain diseased RBCs in terms of their biomechanical and biorheological responses, which may undermine their effective usage and even lead to misleading experimental observations. To help answering this question, we perform a systematic computational study of the hemorheological properties of heated RBCs with several physiologically relevant static and hemodynamic settings, including optical-tweezers test, relaxation of prestretched RBCs, RBC traversal through a capillary-like channel and a spleen-like slit, and a viscometric rheology test. We show that our in silico RBC models agree well with existing experiments. Moreover, under static tests, heated RBCs exhibit deformability deterioration comparable to certain disease-impaired RBCs such as those in malaria. For RBC traversal under confinement (through microchannel or slit), heated RBCs show prolonged transit time or retention depending on the level of confinement and heating procedure, suggesting that carefully heat-treated RBCs may be useful for studying splenic- or vaso-occlusion in vascular pathologies. For the rheology test, we expand the existing bulk viscosity data of heated RBCs to a wider range of shear rates (1-1000 s -1 ) to represent most pathophysiological conditions in macro- or microcirculation. Although heated RBC suspension shows elevated viscosity comparable to certain diseased RBC suspensions under relatively high shear rates (100-1000 s -1 ), they underestimate the elevated viscosity (e.g., in sickle cell anemia) at low shear rates (<10 s -1 ). Our work provides mechanistic rationale for selective usage of heated RBC as a potentially useful model for studying the abnormal traversal dynamics and hemorheology in certain blood disorders., (Published by Elsevier Inc.)

The spleen, the largest secondary lymphoid organ in humans, not only fulfils a broad range of immune functions, but also plays an important role in red blood cell's (RBC) life cycle. Although much progress has been made to elucidate the critical biological processes involved in the maturation of young RBCs (reticulocytes) as well as removal of senescent RBCs in the spleen, the underlying mechanisms driving these processes are still obscure. Herein, we perform a computational study to simulate the passage of RBCs through interendothelial slits (IES) in the spleen at different stages of their lifespan and investigate the role of the spleen in facilitating the maturation of reticulocytes and in clearing the senescent RBCs. Our simulations reveal that at the beginning of the RBC life cycle, intracellular non-deformable particles in reticulocytes can be biomechanically expelled from the cell upon passage through IES, an insightful explanation of why this peculiar "pitting" process is spleen-specific. Our results also show that immature RBCs shed surface area by releasing vesicles after crossing IES and progressively acquire the biconcave shape of mature RBCs. These findings likely explain why RBCs from splenectomized patients are significantly larger than those from nonsplenectomized subjects. Finally, we show that at the end of their life span, senescent RBCs are not only retained by IES due to reduced deformability but also become susceptible to mechanical lysis under shear stress. This finding supports the recent hypothesis that transformation into a hemolyzed ghost is a prerequisite for phagocytosis of senescent RBCs. Altogether, our computational investigation illustrates critical biological processes in the spleen that cannot be observed in vivo or in vitro and offer insights into the role of the spleen in the RBC physiology., Competing Interests: The authors have declared that no competing interests exist.

Chordoma is a relatively rare malignant bone tumor with high local recurrence. To date, the mechanism remains unclear. lncRNAs play a pivotal role in tumorigenesis by acting as competitive endogenous RNAs of microRNAs. However, the biological role of lncRNA is still unclear in chordoma. In this research, our aim is to investigate the roles and regulation mechanisms of lncRNA NONHSAT114552 in chordoma development. The expression level of NONHSAT114552 and miR-320d in chordoma tissues was determined by qRT-PCR. Meantime, the correlation between NONHSAT114552 and clinical prognosis was also studied. Bioinformatics analysis and luciferase reporter assays were used to verify the relationship between NONHSAT114552 and miR-320d, and between miR-320d and Neuropilin 1 (NRP1). In addition, effects of NONHSAT114552 on chordoma cells (U-CH1 and U-CH2) proliferation and invasion and its regulation on miR-320d were also evaluated. Furthermore, the influences of NONHSAT114552/miR-320d/NRP1 axis on chordoma tumorigenesis were investigated in vivo . NONHSAT114552 was overexpressed while miR-320d was down-regulated in chordoma tissue compared to fetal nucleus pulposus. Kaplan-Meier survival analysis showed that NONHSAT114552 overexpression was associated with patients' poor prognosis. Knockdown of NONHSAT114552 significantly suppressed chordoma cell proliferation and invasion. In vitro studies confirmed that NONHSAT114552 acted as ceRNA to regulate NRP1 by directly sponging miR-320d, thus facilitating chordoma cell proliferation and invasion. In vivo study demonstrated that NONHSAT114552 moderated chordoma growth by sponging miR-320d to regulating NRP1. Our findings indicate that lncRNA NONHSAT114552 exhibits a critical role in the tumorigenesis and development of chordoma and it may become one potential prognostic marker and therapeutic target for this disease. ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Liu, Tang, Shao, Hua, Liu, Yang and Chen.)

Background: Chordoma, an extremely rare malignant tumor, remains difficult to be cured because of its strong local invasiveness and high recurrence rate. Long non-coding RNAs (lncRNAs) have been demonstrated to play multiple roles in various cancers. The purpose of this study was to investigate the modulatory function of lncRNA MDFIC-7 in chordoma and to elucidate its underlying mechanisms., Methods: Quantitative real-time polymerase chain reaction was performed to detect the expression of lncRNA MDFIC-7 in tumor tissues and adjacent nontumorous tissues collected from 15 chordoma patients, as well as in chordoma cell lines. Gene silencing and overexpression experiments were carried out by RNA interference and lentiviral transduction. The effect of lncRNA MDFIC-7 on the proliferation of chordoma cells was evaluated by cell counting kit-8 assay, colony formation assay and xenograft tumor experiments. RNA immunoprecipitation and dual luciferase reporter assays were conducted to evaluate the binding between lncRNA MDFIC-7 and miRNA-525-5p and the interaction between miR-525-5p and the 3' untranslated region of ADP-ribosylation factor 6 (ARF6) mRNA. The glycolytic capacity and mitochondrial function of chordoma cells were measured by the Seahorse Bioscience XF96 Extracellular Flux Analyzer., Results: The expression of lncRNA MDFIC-7 was higher in chordoma tumor tissues than in adjacent non-tumor tissues. Downregulation of lncRNA MDFIC-7 reduced colony formation and cell proliferation in chordoma cells and decreased xenograft tumor growth in a nude mouse model. Moreover, lncRNA MDFIC-7 knockdown attenuated the Warburg effect in chordoma cells and xenograft tumors. LncRNA MDFIC-7 knockdown elevated miR-525-5p levels and decreased ARF6 expressions. Overexpression of ARF6 reversed the inhibitory effect of lncRNA MDFIC-7 knockdown on cell proliferation and the Warburg effect in chordoma cells and xenograft tumors. Mechanistically, lncRNA MDFIC-7, as a molecular sponge of miR-525-5p, negatively regulated miR-525-5p expression and promoted the gene expression of ARF6, a miR-525-5p target., Conclusion: Our findings demonstrate that lncRNA MDFIC-7 acts as a molecular sponge to competitively bind to miR-525-5p and promote expression of ARF6. The lncRNA MDFIC-7/miR-525-5p/ARF6 axis regulates chordoma progression and the Warburg effect in chordoma, suggesting that lncRNA MDFIC-7 and miR-525-5p could be promising therapeutic targets for the treatment of chordoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Liu, Wang, Zhou, Shao, Hua, Mao, Yang, Ren and Chen.)

It is necessary to select the appropriate parameters defining a aspheric lens for coupling the light from a laser diode into the optical fiber by cap aspheric lenses. In this paper, the ant colony optimization algorithm is applied to the optimization of structural parameters of the cap aspheric lens, and the merit function defining the optimization problem and detailed design steps are given. A cap aspheric lens with center thickness of 1.1019 mm and effective focal length of 1.10331 mm is designed using a self-made MATLAB program of ant colony optimization algorithm, which can couple the light emitting from a laser diode into a single mode fiber with a diameter of 9 um, the light-emitting surface of the LD is 3 µm × 2 µm, and beam-divergence angle in the X and Y directions are ± 35° and ± 23.58°, respectively. The theoretical coupling efficiency is 89.8%, and the experiment shows that the maximum coupling efficiency and average coupling efficiency are 88.63% and 79.39%, respectively. Design and experimental results prove that the design method in this paper is feasible and effective., (© 2021. The Author(s).)

Purpose: Nucleolar and spindle-associated protein 1 (NUSAP1) is a significant mitotic regulator and has been found to be implicated in carcinogenesis of several cancers. The aim of this study was to explore the functional role and underlying mechanisms of NUSAP1 in osteosarcoma., Methods: Western blot assay and Real-time fluorescent quantitative polymerase chain reaction (RT-qPCR) were employed to assess the expressions of NUSAP1, cell division cycle 20 homologue (CDC20) and cyclin A2 (CCNA2) in osteosarcoma cells. Cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8) assay and 5-ethynyl-2'-deoxyuridine (EdU) assay, and flow cytometry was applied for exploring cell cycle. In addition, an osteosarcoma tumor-bearing mouse model was established by injection of transfected osteosarcoma cells. Tumor volume and protein expressions of Ki67 and PCNA were examined. Bioinformatics analysis and immunoprecipitation were used to identify the combination of NUSAP1 with CDC20 and CCNA2., Results: The mRNA and protein expression of NUSAP1 were extremely upregulated in osteosarcoma cells. Overexpression of NUSAP1 promoted whereas NUSAP1 silencing suppressed cell proliferation and cell cycle progression in transfected osteosarcoma cells. In osteosarcoma mouse model, NUSAP1 expression affected tumor volume and levels of Ki67 and PCNA. Moreover, CDC20 or CCNA2 silencing inhibited NUSAP1-induced cell proliferation and cell cycle in osteosarcoma cells., Conclusion: Our data demonstrated that upregulated NUSAP1 may exacerbate the development of osteosarcoma by accelerating the proliferation and cell cycle process of osteosarcoma cells by binding to CDC20 and CCNA2, suggesting NUSAP1 as a possible therapeutic target for treatment of osteosarcoma., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Wang et al.)

Occlusive thrombosis in arteries causes heart attacks and strokes. The rapid growth of thrombus at elevated shear rates (~10,000 1/s) relies on shear-induced platelet aggregation (SIPA) thought to come about from the entanglement of von Willebrand factor (VWF) molecules. The mechanism for SIPA is not yet understood in terms of cell- and molecule-level dynamics in fast flowing bloodstreams. Towards this end, we develop a multiscale computational model to recreate SIPA in silico, where the suspension dynamics and interactions of individual platelets and VWF multimers are resolved directly. The platelet-VWF interaction via GP1b-A1 bonds is prescribed with intrinsic binding rates theoretically derived and informed by single-molecule measurements. The model is validated against existing microfluidic SIPA experiments, showing good agreement with the in vitro observations in terms of the morphology, traveling distance and capture time of the platelet aggregates. Particularly, the capture of aggregates can occur in a few milliseconds, comparable to the platelet transit time through pathologic arterial stenotic sections and much shorter than the time for shear-induced platelet activation. The multiscale SIPA simulator provides a cross-scale tool for exploring the biophysical mechanisms of SIPA in silico that are difficult to access with single-molecule measurements or micro-/macro-fluidic assays only., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The structural, elastic and electronic properties of 2D naphyne and naphdiyne sheets, which consist of naphthyl rings and acetylenic linkages, are investigated using first-principles calculations. Both naphyne and naphdiyne belong to the orthorhombic lattice family and exhibit the Cmmm plane group. The structural stability of naphyne and naphdiyne are comparable to those of experimentally synthesized graphdiyne and graphtetrayne, respectively. The increase of acetylenic linkages provides naphdiyne with a larger pore size, a lower planar packing density and a lower in-plane stiffness than naphyne. Naphyne is found to be an indirect semiconductor with a band gap of 0.273 eV, while naphdiyne has no band gap and has a Dirac point. The band gaps of naphyne and naphdiyne are found to be modified by applied strain in the elastic range. These facts make naphyne and naphdiyne potential candidates for a wide variety of membrane separations and for fabrication of soft and strain-tunable nanoelectronic devices., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The development of novel antifungal agents with high efficacy, low drug tolerance and few side effects is urgent. MSI-1 (GIWKFLKKAKKFWK-NH 2 ), a cationic antimicrobial peptide, may be an attractive antifungal agent because of its structural characteristics, perfect stability against pH and high-temperature/salt, low toxicity towards mammalian cells and low potential for emergence of drug tolerance. In this study, the antifungal activity of MSI-1 in vitro and in a murine model of cryptococcal meningoencephalitis was evaluated. Zeta potential assay, flow cytometry, fluorescence microscope, transmission electron microscopy and microscale thermophoresis were performed to clarify the mechanisms underlying MSI-1 against C. neoformans. The results showed that MSI-1 exerted effective anti-cryptococcal activity in vitro, with MICs of 8-16 μg/mL and MFCs of 8-32 μg/mL, and in a C neoformans-infected mouse model, with significantly improved animal survival, decreased production of pro-inflammatory cytokines and alleviated lung injury, because the potent and rapid fungicidal activity of MSI-1 could effectively eliminate fungal counts in mouse organs. We confirmed that the positively charged peptide bound to C. neoformans by electrostatic attraction after interacting with glucuronoxylomannan (the primary component of C. neoformans capsule). Subsequently, MSI-1 increased the membrane fluidity of fungal cells and the cell membrane permeability, causing destabilized membrane integrity and leading to the final death of fungi. Collectively, MSI-1 possessed potent anti-cryptococcal activity via its notable membrane disruption effect and may be a potential candidate for use in antifungal infection induced by C. neoformans, especially azole-resistant cryptococcus., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Expression levels of the cell adhesion molecule syndecan-1 (SDC1) have been shown to be inversely proportional to tumor differentiation and prognosis. However, its role in the development of gallbladder cancer (GBC) remains unclear., Methods: We knocked down SDC1 in GBC cells by RNA interference and determined its roles in cell proliferation, apoptosis, invasion, and migration by Cell Counting Kit-8, colony-formation, flow cytometry, Hoechst 33342 staining, transwell invasion, and scratch wound assays. Expression levels of epithelial-mesenchymal transition (EMT)-related and extracellular signal-regulated kinase (ERK)/Snail pathway proteins were determined by western blotting and immunofluorescence., Results: Cell proliferation, invasion, and migration were all increased in GBC cells with SDC1 knockdown, compared with cells in the blank control and negative control groups, but apoptosis was similar in all three groups. E-cadherin and β-catenin expression levels were significantly lower and N-cadherin, vimentin, p-ERK1/2, and Snail expression were significantly higher in the SDC1 knockdown group compared with both controls, while ERK1/2 levels were similar in all groups. Reduced E-cadherin and increased vimentin levels were confirmed by immunofluorescence., Conclusions: SDC1 knockdown promotes the proliferation, invasion, and migration of GBC cells, possibly by regulating ERK/Snail signaling and inducing EMT and cancer cell invasion.

Blood flowing through microvascular bifurcations has been an active research topic for many decades, while the partitioning pattern of nanoscale solutes in the blood remains relatively unexplored. Here we demonstrate a multiscale computational framework for direct numerical simulation of the nanoparticle (NP) partitioning through physiologically relevant vascular bifurcations in the presence of red blood cells (RBCs). The computational framework is established by embedding a particulate suspension inflow-outflow boundary condition into a multiscale blood flow solver. The computational framework is verified by recovering a tubular blood flow without a bifurcation and validated against the experimental measurement of an intravital bifurcation flow. The classic Zweifach-Fung (ZF) effect is shown to be well captured by the method. Moreover, we observe that NPs exhibit a ZF-like heterogeneous partition in response to the heterogeneous partition of the RBC phase. The NP partitioning prioritizes the high-flow-rate daughter branch except for extreme (large or small) suspension flow partition ratios under which the complete phase separation tends to occur. By analyzing the flow field and the particle trajectories, we show that the ZF-like heterogeneity in the NP partition can be explained by the RBC-entrainment effect caused by the deviation of the flow separatrix preceded by the tank treading of RBCs near the bifurcation junction. The recovery of homogeneity in the NP partition under extreme flow partition ratios is due to the plasma skimming of NPs in the cell-free layer. These findings, based on the multiscale computational framework, provide biophysical insights to the heterogeneous distribution of NPs in microvascular beds that are observed pathophysiologically.

Background: The antibiotic resistance and biofilm formation of pathogenic microbes exacerbate the difficulties of anti-infection therapy in the clinic. The structural modification of antimicrobial peptides (AMP) is an effective strategy to develop novel anti-infective agents., Method: Seventeen amino acids (AA) in the longer chain of EeCentrocin 1 (from the edible sea-urchin Echinus esculentus) were truncated and underwent further modification. To produce lead peptides with low toxicity and high efficacy, the antimicrobial activity or cytotoxicity of peptides was evaluated against various multidrug-resistant bacteria/fungi or mammalian cells in vivo/ in vitro. In addition, the stability and modes of action of the lead peptide were investigated., Findings: EC1-17KV displayed potent activity and an expanded antimicrobial spectrum, especially against drug-resistant gram-negative bacteria and fungi, attributable to its enhanced amphiphilicity and net charge. In addition, it exhibits bactericidal/fungicidal activity and effectively increased the animal survival rate and mitigated the histopathological damage induced by multidrug-resistant P. aeruginosa or C. albicans in infected mice or G. mellonella. Moreover, EC1-17KV had a poor ability to induce resistance in bacteria and fungi and exhibited desirable high-salt/high-temperature tolerance properties. In bacteria, EC1-17KV promoted divalent cation release to damage bacterial membrane integrity. In fungi, it changed C. albicans membrane fluidity to increase membrane permeabilization or reduced hyphal formation to suppress biofilm formation., Interpretation: EC1-17KV is a promising lead peptide for the development of antimicrobial agents against antibiotic resistant bacteria and fungi., Funding: This work was funded by the National Natural Science Foundation of China (No. 81673483, 81803591); National Science and Technology Major Project Foundation of China (2019ZX09721001-004-005); National Key Research and Development Program of China (2018YFA0902000); "Double First-Class" University project (CPU2018GF/GY16); Natural Science Foundation of Jiangsu Province of China (No. BK20180563); and A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: This study aims to determine the methods of percutaneous release procedures in the lumbar ligamentum flavum (LF) under ultrasound guidance by acupotomy and provide an anatomical basis for intrusive treatment of lumbar disc herniation and lumbar spinal canal stenosis., Methods: Twelve cadavers including 4 females and 8 males aged 60 to 90 years (73.42 ± 14.57 years), without formalin fixation, were selected. Guided by an ultrasound transducer, we punctured acupotomy to release lumbar LF in L3/L4, L4/L5, and L5/S1 segments. In the transverse-axis approach, the probe was placed transversely, while in the longitudinal-axis approach, the probe was placed longitudinally. The depth of needle penetration (A), the distance between the puncture point and spinous process (B), and the distance between the puncture point and sacral cornu (C) were measured on cadavers, and the depth of needle penetration (U-A), the distance between the puncture point and spinous process (U-B), and the angle for acupotomy (D) on ultrasound images were also measured. Statistical analyses were carried out using SPSS. Paired sample t -tests and homogeneity of variance tests and one-way analysis of variance (ANOVA) were performed. The Pearson correlation coefficients and linear correlation coefficients were calculated for the data obtained from ultrasound and cadaver measurements., Results: No obvious blood vessels and nerves were observed in the puncture path, and the spinal dura was intact. There was no statistical difference between the left and right side measurements obtained from the ultrasound images and the cadavers. The penetration depth in the transverse-axis approach was less than that in the longitudinal-axis approach, and the angle of the needle in the transverse-axis approach was greater than that in the longitudinal-axis approach. The measured data for the transverse-axis approach for L3/L4, L4/L5, and L5/S1 segments showed that there were no differences in the needle angle, the depth of needle penetration, and the distance from the spinous process to the puncture point among the three segments. There was a strong correlation between the depth of needle penetration and the distance from the spinous process to the puncture point on the ultrasonic images and the cadavers on the path of acupotomy. Linear equation A = 2.02 + 0.83  ∗  U-A, R 2  = 0.352; B = 1.37 + 0.71  ∗  U-B, R 2  = 0.252, where A/B refers to the data measured on the cadavers and U-A/U-B refers to the data measured on the ultrasound images., Conclusion: In this study, ultrasound guidance was applied, which better guaranteed the safety and feasibility of acupotomy therapy. Before performing the treatment, the depth of needle penetration in the human body can be determined by measuring the distance between the needle point and the target position on the ultrasound image. Under ultrasound guidance, the transverse-axis approach has a smaller puncture depth and greater puncture angle than the longitudinal-axis approach. Hence, this study believes that the transverse-axis approach is safer for the clinical application of ultrasound-guided LF acupotomy lysis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2019 Xinyue Zhu et al.)

Thrombus formation in major arteries is life threatening. In this review article, we discuss how an arterial thrombus can form under pathologically high shear stresses, with bonding rates estimated to be the fastest K o n values in biochemistry. During occlusive thrombosis in arteries, the growth rate of the thrombus explodes to capture a billion platelets in about 10 min. Close to 100% of all platelets passing the thrombus are captured by long von Willebrand factor (vWF) strands that quickly form tethered nets. The nets grow in patches where shear stress is high, and the local concentration of vWF is elevated due to α -granule release by previously captured platelets. This rapidly formed thrombus has few red blood cells and so has a white appearance and is much stronger and more porous than clots formed through coagulation. Understanding and modeling the biophysics of this event can predict totally new approaches to prevent and treat heart attacks and strokes., (© Author(s).)

Parkinson's disease caused by lack of dopamine in brain is a common neurodegenerative disorder. The traditional treatment is to replenish levodopa since it could pass through blood brain barrier and form dopamine. However, its accumulation can cause patients' movement disorders and uncontrollable emotion. Therefore, it is critical to control the levodopa dosage accuracy to improve the curative effect in clinical. In this study, a smartphone-based electrochemical detection system was developed for rapid monitoring of levodopa. The system involved a disposable sensor, a hand-held electrochemical detector, and a smartphone with designed application. Single-wall carbon nanotubes and gold nanoparticles modified screen-printed electrodes were used to convert and amplify the electrochemical current signals upon presence of levodopa molecules. The electrochemical detectors were used to generate electrochemical excitation signals and detect the resultant currents. Smartphone was connected to the detector, which was used to control the detector, calculate data, and plot graph in real-time. The smartphone-based differential pulse amperometry system was demonstrated to monitor levodopa at concentrations as low as 0.5 µM in human serum. Furthermore, it has also been verified to be able to distinguish levodopa from other representative substances in the body. Therefore, its performance was more sensitive and rapid than electrochemical workstation. With these advantages, the system can be used in the field of point-of-care testing (POCT) to detect levodopa and provide the possibility to solve clinical demand for levodopa detection., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Analysis of rare cells in heterogenous mixtures is proven to be beneficial for regenerative medicine, cancer treatment and prenatal diagnostics. Scarcity of these cells, however, makes the isolation process extremely challenging. Efficiency in cell isolation is still low and therefore, novel cell isolation strategies with new biomarkers need exploration. In this study, we investigated the feasibility of using the mechanical stiffness difference to detect and isolate the rare cells from the surrounding cells without labelling them. Fluid and solid mechanics simulations have shown that cell isolation can be performed at high efficiency using stiffness-based isolation. Accuracy of the numerical simulations is established using microfluidic flow chamber experiments., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Ascorbic acid, dopamine, and uric acid are important electroactive biomolecules for health monitoring and they coexist in serum or urine. Their quantitative determination by electrochemistry could provide the accurate reference for diseases diagnosis and treatment. However, the traditional electrochemical workstations are too large for on-field inspection. Hence, the design of handheld electrochemical system for the detection of biomolecules is significant for point-of-care testing (POCT). In this paper, a smartphone-based integrated voltammetry system using modified electrode was developed for simultaneous detection of biomolecules. The system contained a disposable sensor, a coin-size detector, and a smartphone equipped with application program. Screen-printed electrodes were used as sensors for the detection, on which reduced graphene oxide and gold nanoparticles were electrochemically deposited by the system. The detector was used with voltammetric methods, in which excitation voltage was applied on the sensors and subsequent current responses were detected. The smartphone is the core component to communicate with the detector, calculate data, and plot voltammograms in real-time. Then, the system was applied to detect standard solutions of the biomolecules and their mixtures as examples. The results showed that the peak currents of each substance increased with higher concentration and the method allowed the discrimination of the different potentials of the studied species. Finally, the practical applications of the system were tested through detections of the biomolecules in artificial urine. The results exhibited that the system could be used to detect electrochemical activity of biomolecules with linear, high sensitivity, and specific responses in point-of-care testing., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Rationale: Tendinitis of the longus colli muscle is an aseptic inflammatory process leading to acute posterior neck pain, neck stiffness, and dysphagia or odynophagia. We present a patient exhibiting an infrequent symptom, vertigo. This is the first description of the occurrence of vertigo symptoms caused by longus colli tendinitis., Patient Concerns: A 38-year-old man was diagnosed with vertigo, presenting with a 1-month history of dizziness, palpitations, and numbness in the hands., Diagnosis: Longus colli tendinitis. The diagnosis was established using magnetic resonance imaging fat-suppression sequences., Interventions: Treatment with corticosteroid injections and acupotomy., Outcomes: The symptoms relieved immediately after the treatment and complete resolution of the symptoms was observed after 1 week., Lessons: Longus colli tendinitis with vertigo is an under-reported condition in the literature and physicians should be aware of its existence. A lack of familiarity with the anatomy of the prevertebral space and its variable radiographic appearance makes the diagnosis of longus colli tendinitis clinically difficult. Misdiagnosis of this condition may lead to unnecessary interventions in vertigo.

Cytoplasmic viscosity-dependent margination of red blood cells (RBC) for flow inside microchannels was studied using numerical simulations, and the results were verified with microfluidic experiments. Wide range of suspension volume fractions or hematocrits was considered in this study. Lattice Boltzmann method for fluid-phase coupled with spectrin-link method for RBC membrane deformation was used for accurate analysis of cell margination. RBC margination behavior shows strong dependence on the internal viscosity of the RBCs. At equilibrium, RBCs with higher internal viscosity marginate closer to the channel wall and the RBCs with normal internal viscosity migrate to the central core of the channel. Same margination pattern has been verified through experiments conducted with straight channel microfluidic devices. Segregation between RBCs of different internal viscosity is enhanced as the shear rate and the hematocrit increases. Stronger separation between normal RBCs and RBCs with high internal viscosity is obtained as the width of a high aspect ratio channel is reduced. Overall, the margination behavior of RBCs with different internal viscosities resembles with the margination behavior of RBCs with different levels of deformability. Observations from this work will be useful in designing microfluidic devices for separating the subpopulations of RBCs with different levels of deformability that appear in many hematologic diseases such as sickle cell disease (SCD), malaria, or cancer.

Platelet accumulation under high shear rates at the site of atherosclerotic plaque rupture leads to myocardial infarction and stroke. Current antiplatelet therapies remain ineffective within a large percentage of the population, while presenting significant risks for bleeding. We explore a novel way to inhibit arterial thrombus formation by biophysical means without the use of platelet inactivating drugs. Our computational multi-scale dynamics model has predicted that charged particles of a specific size may entangle von Willebrand Factor (vWF) polymers and reduce the amount of elongation at high shear rates. We tested this hypothesis experimentally for negatively charged nanoparticles (CNP) to inhibit arterial thrombus formation. CNP of a particular size and charge inhibited thrombus formation, with a 10-fold peak inhibition over control conditions of thrombotic occlusion. Particles of differing material composition, size, and charge had little effect as predicted by computational studies. Surprisingly, the dose response curve was not sigmoidal, but exhibited a peak at 1.5 CNP:vWF proteins, which was not predicted by the model. This study describes a new antithrombotic agent that may have a different mechanism of action than current pharmaceutical therapies.