Biportal endoscopic paraspinal decompression for epidural cement leakage removal: A technical note.

OBJECTIVE: We aimed to preliminarily explore the efficacy and safety of unilateral biportal endoscopy (UBE) for the treatment of epidural cement leaks. We report a patient who underwent epidural cement leakage removal and achieved endoscopic spinal decompression. METHODS: A 67-year-old female patient underwent biportal endoscopic paraspinal decompression following percutaneous vertebroplasty for an osteoporotic fracture that resulted in neurologic impairment due to epidural cement leakage. A transforaminal biportal endoscopic surgery was performed to remove the leaked cement, and the left L1 and bilateral L2 nerves were decompressed. RESULTS: The patient's postoperative clinical course was uneventful. CONCLUSIONS: A paraspinal approach that avoids a posterior approach reduces the need to remove stabilizing facet bone, is truly minimally invasive and does not involve an instrumented fusion, maybe a helpful addition in the minimally invasive spine surgeon's armamentarium.

Application of high intensity focused ultrasound combined with nanomaterials in anti-tumor therapy.

High intensity focused ultrasound (HIFU) has demonstrated its safety, efficacy and noninvasiveness in the ablation of solid tumor. However, its further application is limited by its inherent deficiencies, such as postoperative recurrence caused by incomplete ablation and excessive intensity affecting surrounding healthy tissues. Recent research has indicated that the integration of nanomaterials with HIFU exhibits a promising synergistic effect in tumor ablation. The concurrent utilization of nanomaterials with HIFU can help overcome the limitations of HIFU by improving targeting and ablation efficiency, expanding operation area, increasing operation accuracy, enhancing stability and bio-safety during the process. It also provides a platform for multi-therapy and multi-mode imaging guidance. The present review comprehensively expounds upon the synergistic mechanism between nanomaterials and HIFU, summarizes the research progress of nanomaterials as cavitation nuclei and drug carriers in combination with HIFU for tumor ablation. Furthermore, this review highlights the potential for further exploration in the development of novel nanomaterials that enhance the synergistic effect with HIFU on tumor ablation.

Capturing Protein-Protein Interactions with Acidic Amino Acids Reactive Cross-Linkers.

Acidic residues (Asp and Glu) have a high prevalence on protein surfaces, but cross-linking reactions targeting these residues are limited. Existing methods either require high-concentration coupling reagents or have low structural compatibility. Here a previously reported "plant-and-cast" strategy is extended to develop heterobifunctional cross-linkers. These cross-linkers first react rapidly with Lys sidechains and then react with Asp and Glu sidechains, in a proximity-enhanced fashion. The cross-linking reaction proceeds at neutral pH and room temperature without coupling reagents. The efficiency and robustness of cross-linking using model proteins, ranging from small monomeric proteins to large protein complexes are demonstrated. Importantly, it is shown that this type of cross-linkers are efficient at identifying protein-protein interactions involving acidic domains. The Cross-linking mass spectrometry (XL-MS) study with p53 identified 87 putative binders of the C-terminal domain of p53. Among them, SARNP, ZRAB2, and WBP11 are shown to regulate the expression and alternative splicing of p53 target genes. Thus, these carboxylate-reactive cross-linkers will further expand the power of XL-MS in the analysis of protein structures and protein-protein interactions.

MAVS deSUMOylation by SENP1 inhibits its aggregation and antagonizes IRF3 activation.

Mitochondrial antiviral signaling protein (MAVS) is an adapter that recruits and activates IRF3. However, the mechanisms underpinning the interplay between MAVS and IRF3 are largely unknown. Here we show that small ubiquitin-like modifier (SUMO)-specific protease 1 negatively regulates antiviral immunity by deSUMOylating MAVS. Upon virus infection, PIAS3-induced poly-SUMOylation promotes lysine 63-linked poly-ubiquitination and aggregation of MAVS. Notably, we observe that SUMO conjugation is required for MAVS to efficiently produce phase-separated droplets through association with a newly identified SUMO-interacting motif (SIM) in MAVS. We further identify a yet-unknown SIM in IRF3 that mediates its enrichment to the multivalent MAVS droplets. Conversely, IRF3 phosphorylation at crucial residues close to SIM rapidly disables SUMO-SIM interactions and releases activated IRF3 from MAVS. Our findings implicate SUMOylation in MAVS phase separation and suggest a thus far unknown regulatory process by which IRF3 can be efficiently recruited and released to facilitate timely activation of antiviral responses.

LPA maintains innate antiviral immunity in a pro-active state via STK38L-mediated IRF3 Ser303 phosphorylation.

Innate immunity is critical for the early detection and elimination of viral invasion. Extracellular signals are crucial for host resistance; however, how extracellular factors prepare the innate immunity for rapid antiviral response remains elusive. Here, we find that serum deprivation largely restricts the innate antiviral responses to RNA and DNA viruses. When serum is supplied, serine/threonine-protein kinase 38-like (STK38L), induced by serum response factor (SRF), phosphorylates IRF3 at Ser303, which prevents IRF3 from proteasome-mediated degradation in the rest state (non-infected), and ensures that enough IRF3 is called in the primed state (infected). STK38L-deficient mice exhibit compromised innate antiviral responses and elevated viral proliferation and mortality. Moreover, lysophosphatidic acid (LPA) or sphingosine 1-phosphate (S1P), the crucial activators of SRF, rescue immunosuppression caused by serum deprivation. These findings identify the SRF-STK38L-IRF3 axis as a novel mechanism that maintains the host in a pro-active state when not infected, which ensures the rapid immune response against virus.

Augmenting antibody response to EGF-depleting immunotherapy: Findings from a phase I trial of CIMAvax-EGF in combination with nivolumab in advanced stage NSCLC.

Background: CIMAvax-EGF is an epidermal growth factor (EGF)-depleting immunotherapy which has shown survival benefit as a switch maintenance treatment after platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC). The primary objective of this trial is to establish the safety and recommended phase II dose (RP2D) of CIMAvax-EGF in combination with nivolumab as second-line therapy for NSCLC. Methods: Patients with immune checkpoint inhibitor-naive metastatic NSCLC were enrolled using a "3+3" dose-escalation design. Toxicities were graded according to CTCAE V4.03. Thirteen patients (one unevaluable), the majority with PD-L1 0%, were enrolled into two dose levels of CIMAvax-EGF. Findings: The combination was determined to be safe and tolerable. The recommended phase 2 dose of CIMAvax-EGF was 2.4 mg. Humoral response to CIMAvax-EGF was achieved earlier and in a greater number of patients with the combination compared to historical control. Four out of 12 evaluable patients had an objective response.

Deactylation by SIRT1 enables liquid-liquid phase separation of IRF3/IRF7 in innate antiviral immunity.

Innate antiviral immunity deteriorates with aging but how this occurs is not entirely clear. Here we identified SIRT1-mediated DNA-binding domain (DBD) deacetylation as a critical step for IRF3/7 activation that is inhibited during aging. Viral-stimulated IRF3 underwent liquid-liquid phase separation (LLPS) with interferon (IFN)-stimulated response element DNA and compartmentalized IRF7 in the nucleus, thereby stimulating type I IFN (IFN-I) expression. SIRT1 deficiency resulted in IRF3/IRF7 hyperacetylation in the DBD, which inhibited LLPS and innate immunity, resulting in increased viral load and mortality in mice. By developing a genetic code expansion orthogonal system, we demonstrated the presence of an acetyl moiety at specific IRF3/IRF7 DBD site/s abolish IRF3/IRF7 LLPS and IFN-I induction. SIRT1 agonists rescued SIRT1 activity in aged mice, restored IFN signaling and thus antagonized viral replication. These findings not only identify a mechanism by which SIRT1 regulates IFN production by affecting IRF3/IRF7 LLPS, but also provide information on the drivers of innate immunosenescence.

Alterations in microbiota of patients with COVID-19: potential mechanisms and therapeutic interventions.

The global coronavirus disease 2019 (COVID-19) pandemic is currently ongoing. It is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A high proportion of COVID-19 patients exhibit gastrointestinal manifestations such as diarrhea, nausea, or vomiting. Moreover, the respiratory and gastrointestinal tracts are the primary habitats of human microbiota and targets for SARS-CoV-2 infection as they express angiotensin-converting enzyme-2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) at high levels. There is accumulating evidence that the microbiota are significantly altered in patients with COVID-19 and post-acute COVID-19 syndrome (PACS). Microbiota are powerful immunomodulatory factors in various human diseases, such as diabetes, obesity, cancers, ulcerative colitis, Crohn's disease, and certain viral infections. In the present review, we explore the associations between host microbiota and COVID-19 in terms of their clinical relevance. Microbiota-derived metabolites or components are the main mediators of microbiota-host interactions that influence host immunity. Hence, we discuss the potential mechanisms by which microbiota-derived metabolites or components modulate the host immune responses to SARS-CoV-2 infection. Finally, we review and discuss a variety of possible microbiota-based prophylaxes and therapies for COVID-19 and PACS, including fecal microbiota transplantation (FMT), probiotics, prebiotics, microbiota-derived metabolites, and engineered symbiotic bacteria. This treatment strategy could modulate host microbiota and mitigate virus-induced inflammation.

The way of SARS-CoV-2 vaccine development: success and challenges.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). To halt the pandemic, multiple SARS-CoV-2 vaccines have been developed and several have been allowed for emergency use and rollout worldwide. With novel SARS-CoV-2 variants emerging and circulating widely, whether the original vaccines that were designed based on the wild-type SARS-CoV-2 were effective against these variants has been a contentious discussion. Moreover, some studies revealed the long-term changes of immune responses post SARS-CoV-2 infection or vaccination and the factors that might impact the vaccine-induced immunity. Thus, in this review, we have summarized the influence of mutational hotspots on the vaccine efficacy and characteristics of variants of interest and concern. We have also discussed the reasons that might result in discrepancies in the efficacy of different vaccines estimated in different trials. Furthermore, we provided an overview of the duration of immune responses after natural infection or vaccination and shed light on the factors that may affect the immunity induced by the vaccines, such as special disease conditions, sex, and pre-existing immunity, with the aim of aiding in combating COVID-19 and distributing SARS-CoV-2 vaccines under the prevalence of diverse SARS-CoV-2 variants.

Liquid-liquid phase separation in human health and diseases.

Emerging evidence suggests that liquid-liquid phase separation (LLPS) represents a vital and ubiquitous phenomenon underlying the formation of membraneless organelles in eukaryotic cells (also known as biomolecular condensates or droplets). Recent studies have revealed evidences that indicate that LLPS plays a vital role in human health and diseases. In this review, we describe our current understanding of LLPS and summarize its physiological functions. We further describe the role of LLPS in the development of human diseases. Additionally, we review the recently developed methods for studying LLPS. Although LLPS research is in its infancy-but is fast-growing-it is clear that LLPS plays an essential role in the development of pathophysiological conditions. This highlights the need for an overview of the recent advances in the field to translate our current knowledge regarding LLPS into therapeutic discoveries.

Targeting liquid-liquid phase separation of SARS-CoV-2 nucleocapsid protein promotes innate antiviral immunity by elevating MAVS activity.

Patients with Coronavirus disease 2019 exhibit low expression of interferon-stimulated genes, contributing to a limited antiviral response. Uncovering the underlying mechanism of innate immune suppression and rescuing the innate antiviral response remain urgent issues in the current pandemic. Here we identified that the dimerization domain of the SARS-CoV-2 nucleocapsid protein (SARS2-NP) is required for SARS2-NP to undergo liquid-liquid phase separation with RNA, which inhibits Lys63-linked poly-ubiquitination and aggregation of MAVS and thereby suppresses the innate antiviral immune response. Mice infected with an RNA virus carrying SARS2-NP exhibited reduced innate immunity, an increased viral load and high morbidity. Notably, we identified SARS2-NP acetylation at Lys375 by host acetyltransferase and reported frequently occurring acetylation-mimicking mutations of Lys375, all of which impaired SARS2-NP liquid-liquid phase separation with RNA. Importantly, a peptide targeting the dimerization domain was screened out to disrupt the SARS2-NP liquid-liquid phase separation and demonstrated to inhibit SARS-CoV-2 replication and rescue innate antiviral immunity both in vitro and in vivo.

Protein N-myristoylation: functions and mechanisms in control of innate immunity.

Protein N-myristoylation is an important fatty acylation catalyzed by N-myristoyltransferases (NMTs), which are ubiquitous enzymes in eukaryotes. Specifically, attachment of a myristoyl group is vital for proteins participating in various biological functions, including signal transduction, cellular localization, and oncogenesis. Recent studies have revealed unexpected mechanisms indicating that protein N-myristoylation is involved in host defense against microbial and viral infections. In this review, we describe the current understanding of protein N-myristoylation (mainly focusing on myristoyl switches) and summarize its crucial roles in regulating innate immune responses, including TLR4-dependent inflammatory responses and demyristoylation-induced innate immunosuppression during Shigella flexneri infection. Furthermore, we examine the role of myristoylation in viral assembly, intracellular host interactions, and viral spread during human immunodeficiency virus-1 (HIV-1) infection. Deeper insight into the relationship between protein N-myristoylation and innate immunity might enable us to clarify the pathogenesis of certain infectious diseases and better harness protein N-myristoylation for new therapeutics.

A Dual Role of Type I Interferons in Antitumor Immunity.

Type I interferons (IFN-Is) are a family of cytokines that exert direct antiviral effects and regulate innate and adaptive immune responses through direct and indirect mechanisms. It is generally believed that IFN-Is repress tumor development via restricting tumor proliferation and inducing antitumor immune responses. However, recent emerging evidence suggests that IFN-Is play a dual role in antitumor immunity. That is, in the early stage of tumorigenesis, IFN-Is promote the antitumor immune response by enhancing antigen presentation in antigen-presenting cells and activating CD8+ T cells. However, in the late stage of tumor progression, persistent expression of IFN-Is induces the expression of immunosuppressive factors (PD-L1, IDO, and IL-10) on the surface of dendritic cells and other bone marrow cells and inhibits their antitumor immunity. This review outlines these dual functions of IFN-Is in antitumor immunity and elucidates the involved mechanisms, as well as their applications in tumor therapy.

A systematic review of SARS-CoV-2 vaccine candidates.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging virus that is highly pathogenic and has caused the recent worldwide pandemic officially named coronavirus disease (COVID-19). Currently, considerable efforts have been put into developing effective and safe drugs and vaccines against SARS-CoV-2. Vaccines, such as inactivated vaccines, nucleic acid-based vaccines, and vector vaccines, have already entered clinical trials. In this review, we provide an overview of the experimental and clinical data obtained from recent SARS-CoV-2 vaccines trials, and highlight certain potential safety issues that require consideration when developing vaccines. Furthermore, we summarize several strategies utilized in the development of vaccines against other infectious viruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), with the aim of aiding in the design of effective therapeutic approaches against SARS-CoV-2.

Coronavirus in Continuous Flux: From SARS-CoV to SARS-CoV-2.

The world is currently experiencing a global pandemic caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes severe respiratory disease similar to SARS. Previous studies have suggested that SARS-CoV-2 shares 79% and 96% sequence identity to SARS-CoV and to bat coronavirus RaTG13, respectively, at the whole-genome level. Furthermore, a series of studies have shown that SARS-CoV-2 induces clusters of severe respiratory illnesses (i.e., pneumonia, acute lung injury, acute respiratory distress syndrome) resembling SARS-CoV. Moreover, the pathological syndrome may, in part, be caused by cytokine storms and dysregulated immune responses. Thus, in this work the recent literature surrounding the biology, clinical manifestations, and immunology of SARS-CoV-2 is summarized, with the aim of aiding prevention, diagnosis, and treatment for SARS-CoV-2 infection.

The interactions between cGAS-STING pathway and pathogens.

Cytosolic DNA is an indicator of pathogen invasion or DNA damage. The cytosolic DNA sensor cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) detects DNA and then mediates downstream immune responses through the molecule stimulator of interferon genes (STING, also known as MITA, MPYS, ERIS and TMEM173). Recent studies focusing on the roles of the cGAS-STING pathway in evolutionary distant species have partly sketched how the mammalian cGAS-STING pathways are shaped and have revealed its evolutionarily conserved mechanism in combating pathogens. Both this pathway and pathogens have developed sophisticated strategies to counteract each other for their survival. Here, we summarise current knowledge on the interactions between the cGAS-STING pathway and pathogens from both evolutionary and mechanistic perspectives. Deeper insight into these interactions might enable us to clarify the pathogenesis of certain infectious diseases and better harness the cGAS-STING pathway for antimicrobial methods.

3.5 W long-wave infrared ZnGeP2 optical parametric oscillator at 9.8 µm.

We demonstrated a high-power long-wave infrared optical parametric oscillator at 9.8 µm based on a type-I phase-matching ${{\rm ZnGeP}_2}$ZnGeP2 crystal. By using a ${Q}$Q-switched 2091 nm Ho:YAG laser with pulse repetition frequency of 10 kHz as the pump source, the maximum average output power of 3.51 W at 9.8 µm was achieved with incident pump power of 90 W, corresponding to a slope efficiency of 4.81% and conversion efficiency at maximum pump power of 3.9%. The pulse width of 19.6 ns and linewidth of 142 nm were obtained at maximum output level. In addition, the beam quality factor ${M^2}$M2 was measured to be ${\sim}{2.2}$∼2.2.

Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164.

PURPOSE: KEYNOTE-164 (NCT02460198) evaluated the antitumor activity of pembrolizumab in previously treated, metastatic, microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer (CRC). METHODS: This phase II open-label study involved 128 centers worldwide. Eligible patients were age ≥ 18 years and had metastatic MSI-H/dMMR CRC treated with ≥ 2 prior lines of standard therapy, including fluoropyrimidine, oxaliplatin, and irinotecan with or without anti-vascular endothelial growth factor/epidermal growth factor receptor monoclonal antibody (cohort A) or ≥ 1 prior line of therapy (cohort B). MSI-H/dMMR status was assessed locally. Patients received pembrolizumab 200 mg every 3 weeks for up to 2 years until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate by RECIST version 1.1 by independent central review. Secondary end points were duration of response, progression-free survival (PFS), overall survival, safety, and tolerability. RESULTS: A total of 124 patients with MSI-H/dMMR CRC (61 in cohort A, 63 in cohort B) enrolled. At data cutoff, median follow-up was 31.3 months (range, 0.2-35.6 months) for cohort A and 24.2 months (range, 0.1-27.1 months) for cohort B. Objective response rate was 33% (95% CI, 21% to 46%) and 33% (95% CI, 22% to 46%), respectively, with median duration of response not reached in either cohort. Median PFS was 2.3 months (95% CI, 2.1 to 8.1 months) and 4.1 months (95% CI, 2.1 to 18.9 months). Median overall survival was 31.4 months (95% CI, 21.4 months to not reached) and not reached (95% CI, 19.2 months to not reached). Treatment-related grade 3-4 adverse events occurred in 10 patients (16%) in cohort A and 8 (13%) in cohort B, with the most common occurring in ≥ 2 patients being pancreatitis, fatigue, increased alanine aminotransferase, and increased lipase (2 patients each; 3%) in cohort A. CONCLUSION: Pembrolizumab is effective with a manageable safety profile in patients with MSI-H/dMMR CRC.

Effects of copper treatment on mineral nutrient absorption and cell ultrastructure of spinach seedlings.

The accumulation of heavy metals in soil has serious influence on plant growth and ecosystem balance. It is of great importance to explore the mechanism of plant tolerance to heavy me-tals. Although spinach is supposed to have strong Cu tolerance, the effects of Cu on mineral element absorption and cell ultrastructure are still unclear. In this study, the growth of spinach seedlings, the absorption of mineral elements and the ultrastructure of leaf cells were examined in a pot experiment. The results showed that Cu2+ accumulation in the root of spinach seedling was less than that in the shoot when CuSO4 concentration was 100 mg·L-1, with root growth being increased and shoot growth being slightly decreased. When copper concentration continued to increase, the growth parameters continuously declined. When the CuSO4 concentrations were less than 400 mg·L-1, the foliar N, K, Ca, Mg and Fe concentrations of spinach seedling increased, and that of P decreased. The concentrations of N, P and K in roots went down and that of Ca, Mg and Fe went up. All organelles in leaf cells were clearly visible. The basal granule layer was arranged orderly, and the inner and outer membranes of chloroplasts were intact. When the CuSO4 concentrations exceeded 600 mg·L-1, foliar N concentration increased while that of P, K, Ca, Mg and Fe decreased. The concentrations of N, P, K, Ca, Mg and Fe in roots declined. The cell ultrastructure of spinach seedlings substantially changed with the increases of CuSO4 treated concentrations. The chloroplast in leaf cells became rounder, the chloroplast membrane became thinner, the stroma and basal granule layer became less, and the layer accumulation height decreased. The nucleus was broken up and small black spots were found in vacuoles and cell walls, which might be attributed to the enhancement of intracellular swelling pressure caused by high accumulation of Cu2+. In conclusion, low concentration of CuSO4 had little negative effect on the life activities of spinach seedlings, and the high concentrations of CuSO4 did not terminate their growth, indicating that spinach seedlings had strong copper resistance.

High repetition rate 102 W middle infrared ZnGeP2 master oscillator power amplifier system with thermal lens compensation.

We demonstrate a 102 W middle infrared ZnGeP2 (ZGP) optical parametric amplifier (OPA) pumped by a 2097-nm Q-switched Ho:YAG laser at a pulse repetition frequency of 10 kHz. The seed middle infrared laser was produced by a ZGP optical parametric oscillator. Its average power was 28.4 W pumped by a 50 W 2097-nm laser. By thermal lens compensation, the beam factor M2 reduced from 3.1 to 2.1. When the incident Ho pump power was 120 W, the middle infrared ZGP OPA yielded the maximum average output power of 102 W and slope efficiency of 61.7%. The overall optical conversion efficiency of 60% from Ho to middle infrared was obtained for the whole middle infrared laser system. In addition, at the maximum average output power, the beam quality factors of the middle infrared ZGP OPA were measured to be about 2.7 and 2.8 for horizontal and vertical directions, respectively.