Effectiveness of acupuncture in the governor vessel and Yangming meridian for the treatment of acute ischemic stroke: A systematic review and network meta-analysis.

BACKGROUND: Acupuncture of the governor vessel and Yangming meridian are widely used in the treatment of acute ischemic stroke (AIS). However, the optimal meridian for acupuncture in the treatment of AIS remains uncertain. PURPOSE: This network meta-analysis study aimed to compare the clinical effectiveness of acupuncture at governor vessel and Yangming meridian in the treatment of AIS. METHODS: All relevant studies published in CNKI, WANFANG, VIP, Sinomed, Cochrane Library, Web of Science, Pub Med, and Embase before January 13, 2024 were systematically retrieved. The two researchers independently screened the studies and extracted the data. Cochrane ROB tool was used to evaluate the quality of the studies, and Stata 14.0 software was used to conduct a network meta-analysis of neurological deficit score, activities of daily living (ADL), clinical effective rate and Fugl-meyer motor function evaluation (FMA). RESULTS: A total of 401 studies were obtained, and 17 studies met the inclusion criteria. The surface under the cumulative ranking curve (SUCRA) values of the four outcome indexes were all ranked by "Governor vessel acupuncture + Conventional neurology treatment(GVAc+CT) > Yangming meridian acupuncture + Conventional neurology treatment(YMAc+CT) > Conventional neurology treatment (CT)". Compared to YMAc+CT and CT, GVAc+CT had the best effect in reducing the degree of neurological deficit score (SMD = -0.72, 95%CI = [-1.22,-0.21] and SMD = -1.07,95%CI = [-1.45,-0.69], respectively) and promoting the recovery of ADL((SMD = 0.59,95%CI = [0.31,0.88] and SMD = 0.96,95%CI = [0.70,1.21], respectively). Compared to CT, GVAc+CT also had a better clinical effective rate in the treatment of AIS (RR = 1.14,95%CI = [1.04,1.25]). CONCLUSIONS: Governor vessel acupuncture combined with conventional neurology treatment has the best effect in reducing the degree of neurological deficit score and promoting the recovery of ADL in AIS patientscompared to YMAc+CT and CT. Governor Vessel acupuncture is the most preferable acupoint scheme for clinical acupuncture treatment of AIS.

SARS-CoV-2 Neutralization by Cell Membrane-Coated Antifouling Nanoparticles.

The global outbreak of the COVID-19 pandemic has indisputably wreaked havoc on societies worldwide, compelling the scientific community to seek urgently needed therapeutic agents with low-cost and low-side effect profiles. Numerous approaches have been investigated in the quest to prevent or treat COVID-19, but many of them exhibit unwelcome side effects, such as dysfunctional viral immune responses and inflammation. Herein, we present the preparation of solid natural human pulmonary alveolar epithelial cell (ATII) membrane-coated PLGA NPs (PLGA NPs@ATII-M), which demonstrate remarkable affinity and competitiveness to neutralize the SARS-CoV-2 S1 protein-coated NPs (SCMMA NPs-S1), which are employed as a surrogate for coronavirus particles. In addition, we first considered the antifouling properties of these types of NPs, and we found that this membrane-coated NP formulation boasts excellent antifouling capabilities, which serve to protect their neutralization properties out of shielding by protein coronas in blood circulation. Moreover, this formulation is easily prepared and stored with a low-cost profile and exhibits good specificity, high targeting efficiency, and potentially side effect avoiding, thus making it a highly promising candidate for COVID-19 treatment.

Nano-induced endothelial leakiness-reversing nanoparticles for targeting, penetration and restoration of endothelial cell barrier.

Nano-induced endothelial leakiness (NanoEL) can improve the ability of nanoparticles (NPs) to enter the tumor environment, nevertheless, it can inadvertently trigger adverse effects such as tumor metastasis. To overcome these concerns, it becomes important to develop a NPs design strategy that capitalizes on the NanoEL effect while averting unwanted side effects during the drug delivery process. Herein, we introduce the PLGA-ICG-PEI-Ang1@M NP which has a core comprising poly (lactic-co-glycolic acid) (PLGA) and the inner shell with a highly positively charged polyethyleneimine (PEI) and the anti-permeability growth factor Angiopoietin 1 (Ang1), while the outer shell is camouflaged with a Jurkat cell membrane. During the drug delivery process, our NPs exhibit their capability to selectively target and penetrate endothelial cell layers. Once the NPs penetrate the endothelial layer, the proton sponge effect triggered by PEI in the acidic environment surrounding the tumor site can rupture the cell membrane on the NPs' surface. This rupture, in turn, enables the positively charged Ang1 to be released due to the electrostatic repulsion from PEI and the disrupted endothelial layer can be restored. Consequently, the designed NPs can penetrate endothelial layers, promote the cell layer recovery, restrict the tumor metastasis, and facilitate efficient cancer therapy. STATEMENT OF SIGNIFICANCE.

Modulation of cell cycle increases CRISPR-mediated homology-directed DNA repair.

BACKGROUND: Gene knock-in (KI) in animal cells via homology-directed repair (HDR) is an inefficient process, requiring a laborious work for screening from few modified cells. HDR tends to occur in the S and G2/M phases of cell cycle; therefore, strategies that enhance the proportion of cells in these specific phases could improve HDR efficiency. RESULTS: We used various types of cell cycle inhibitors to synchronize the cell cycle in S and G2/M phases in order to investigate their effect on regulating CRISPR/Cas9-mediated HDR. Our results indicated that the four small molecules-docetaxel, irinotecan, nocodazole and mitomycin C-promoted CRISPR/Cas9-mediated KI with different homologous donor types in various animal cells. Moreover, the small molecule inhibitors enhanced KI in animal embryos. Molecular analysis identified common signal pathways activated during crosstalk between cell cycle and DNA repair. Synchronization of the cell cycle in the S and G2/M phases results in CDK1/CCNB1 protein accumulation, which can initiate the HDR process by activating HDR factors to facilitate effective end resection of CRISPR-cleaved double-strand breaks. We have demonstrated that augmenting protein levels of factors associated with the cell cycle via overexpression can facilitate KI in animal cells, consistent with the effect of small molecules. CONCLUSION: Small molecules that induce cell cycle synchronization in S and G2/M phases promote CRISPR/Cas9-mediated HDR efficiency in animal cells and embryos. Our research reveals the common molecular mechanisms that bridge cell cycle progression and HDR activity, which will inform further work to use HDR as an effective tool for preparing genetically modified animals or for gene therapy.

Micronano Titanium Accelerates Mesenchymal Stem Cells Aging through the Activation of Senescence-Associated Secretory Phenotype.

Stem cell senescence is one of the most representative events of organism aging and is responsible for many physiological abnormalities and disorders. In the scenario of orthopedic disease treatment, stem cell aging may affect the implantation outcome and even lead to operation failure. To explore whether stem cell aging will affect the osteointegration effect of titanium implant, a widely used micronano titanium (MNT) was fabricated. We first verified the expected osteointegration effect of the MNT, which could be attributed to the improvement of stem cell adhesion and osteogenic differentiation. Then, we obtained aged-derived bone marrow mesenchymal stem cells (BMSCs) and studied their biological behaviors on MNT both in vitro and in vivo. We found that compared with normal rats, MNT did not significantly improve the osteointegration in aged rats. Compared with normal rats, fewer endogenous stem cells were observed at the implant-host interface, and the expression of p21 (senescence marker) was also higher. We further confirmed that MNT promoted the nuclear localization of NF-κB in senescent stem cells through the activation of p38 MAPK, thereby inducing the occurrence of the senescence-associated secretory phenotype (SASP) and ultimately leading to the depletion of the stem-cell pool at the implant-host interface. However, the activation of p38 MAPK can still promote the osteogenic differentiation of nonsenescent BMSCs. These results showed an interesting paradoxical balance between osteogenesis and senescence on MNT surfaces and also provided insights for the design of orthopedic implants for aging patients.

Causal relationship between depression and aging: a bidirectional two-sample Mendelian randomization study.

BACKGROUND: The causal relationship and the direction of the effect between depression and aging remain controversial. METHODS: We used a bidirectional two-sample Mendelian randomization analysis to examine the relationship between depression and age proxy indicators. We obtained pooled statistics from genome-wide association studies (GWAS) on depression and the age proxy indicators. We employed five MR analysis methods to address potential biases and ensure robustness of our results, with the inverse variance weighted (IVW) method being the primary outcome. We also conducted outlier exclusion using Radial MR, MRPRESSO, and MR Steiger filters. Additionally, sensitivity analyses were performed to assess heterogeneity and pleiotropy. RESULTS: Our MR analysis revealed that depression causally leads to shortened telomere length (ß = - 0.014; P = 0.038), increased frailty index (ß = 0.076; P = 0.000), and accelerated GrimAge (ß = 0.249; P = 0.024). Furthermore, our findings showed that the frailty index (OR = 1.679; P = 0.001) was causally associated with an increased risk of depression. Additionally, we found that appendicular lean mass (OR = 0.929; P = 0.000) and left-hand grip strength (OR = 0.836; P = 0.014) were causally associated with a reduced risk of depression. Sensitivity analyses demonstrated the robustness of our findings. CONCLUSIONS: Our study provides evidence that depression contributes to the accelerated aging process, resulting in decreased telomere length, increased frailty index, and accelerated GrimAge. Additionally, we found that the frailty index increases the risk of depression, while appendicular lean mass and left-handed grip strength reduce the risk of depression.

PBX3 promotes pentose phosphate pathway and colorectal cancer progression by enhancing G6PD expression.

Metabolic reprogramming is a hallmark of cancers crucial for fulfilling the needs of energy, building blocks, and antioxidants to support tumor cells' rapid proliferation and to cope with the harsh microenvironment. Pre-B-cell leukemia transcription factor 3 (PBX3) is a member of the PBX family whose expression is up-regulated in various tumors, however, whether it is involved in tumor cell metabolic reprogramming remains unclear. Herein, we report that PBX3 is a positive regulator of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway (PPP). PBX3 promoted G6PD transcriptional activity in tumor cells by binding directly to its promoter, leading to PPP stimulation and enhancing the production of nucleotides and NADPH, a crucial reductant, thereby promoting nucleic acid and lipid biosynthesis while decreasing intracellular reactive oxygen species levels. The PBX3/G6PD axis also promoted tumorigenic potential in vitro and in vivo. Collectively, these findings reveal a novel function of PBX3 as a regulator of G6PD, linking its oncogenic activity with tumor cell metabolic reprogramming, especially PPP. Furthermore, our results suggested that PBX3 is a potential target for metabolic-based anti-tumor therapeutic strategies.

Causal relationship between telomere length and epilepsy: A bidirectional Mendelian randomization study.

OBJECTIVE: Observational studies have suggested a link between telomere length (TL) and epilepsy, but the direction of the effect and whether it is causal or not is still being debated. The objective of this study was to investigate the causal relationship between TL and epilepsy using Mendelian randomization (MR) analysis. METHODS: We performed a bidirectional two-sample MR analysis using pooled statistics from genome-wide association studies (GWAS) of TL and epilepsy. Additionally, we conducted a replication analysis using data from another GWAS study on epilepsy to validate our findings. The final results were analyzed using five MR methods, with the inverse-variance weighted (IVW) method as the primary outcome. We applied methods such as radial MR, MR pleiotropy residual and outlier test and MR Steiger filters to exclude outliers. Sensitivity analyses were also conducted to assess heterogeneity and pleiotropy. RESULTS: Our analysis found no evidence of a causal relationship between epilepsy and TL (all p-values >0.05). The sensitivity analysis confirms the robustness of these results. SIGNIFICANCE: In summary, our study contradicts existing observational reports by not finding any evidence to support a causal relationship between epilepsy and TL. Further research is necessary to determine the underlying mechanism behind the association observed in observational studies.

Association between housework and the risk of dementia among older Chinese adults: a prospective cohort study.

Objectives: Physical activity (PA) is known to improve physical functioning and mental health and to reduce the incidence of dementia. However, studies of the effects of non-recreational PA on the incidence of dementia, especially in East Asian populations, remain limited. In this study, we evaluate the association of doing housework with the risk of dementia among participants in the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Methods: The analysis was conducted with data from 7,237 CLHLS participants age over 65 obtained in 2008/2009, 2011/2012, 2014, and 2018. The frequency of housework performance was classified into four groups. A Cox proportional-hazards model was used to examine the association of the baseline housework frequency with the incidence of dementia, with adjustment for demographic and socioeconomic characteristics and lifestyle and health conditions. Results: The adjusted multivariate model showed that the incidence of dementia was lower among participants who did housework almost every day than among those who rarely or never did housework (hazard ratio = 0.49; 95% confidence interval, 0.39-0.61). The subgroup and sensitivity analyses yielded similar results. Conclusion: A high frequency of housework performance was associated with a reduced incidence of dementia among older Chinese adults, especially those who did not exercise regularly. The encouragement of engagement in housework would be a cost-effective measure promoting healthy aging in the Chinese population.

YY2-DRP1 Axis Regulates Mitochondrial Fission and Determines Cancer Stem Cell Asymmetric Division.

Cancer stem cells (CSCs) are associated with tumor progression, recurrence, and therapeutic resistance. To maintain their pool while promoting tumorigenesis, CSCs divide asymmetrically, producing a CSC and a highly proliferative, more differentiated transit-amplifying cell. Exhausting the CSC pool has been proposed as an effective antitumor strategy; however, the mechanism underlying CSC division remains poorly understood, thereby largely limiting its clinical application. Here, through cross-omics analysis, yin yang 2 (YY2) is identified as a novel negative regulator of CSC maintenance. It is shown that YY2 is downregulated in stem-like tumor spheres formed by hepatocarcinoma cells and in liver cancer, in which its expression is negatively correlated with disease progression and poor prognosis. Furthermore, it is revealed that YY2 overexpression suppressed liver CSC asymmetric division, leading to depletion of the CSC pool and decreased tumor-initiating capacity. Meanwhile, YY2 knock-out in stem-like tumor spheres caused enrichment in mitochondrial functions. Mechanistically, it is revealed that YY2 impaired mitochondrial fission, and consequently, liver CSC asymmetric division, by suppressing the transcription of dynamin-related protein 1. These results unravel a novel regulatory mechanism of mitochondrial dynamic-mediated CSCs asymmetric division and highlight the role of YY2 as a tumor suppressor and a therapeutic target in antitumor treatment.

YY2/PHGDH axis suppresses tumorigenesis by inhibiting tumor cell de novo serine biosynthesis.

Metabolic reprogramming is one of the key features of tumors facilitating their rapid proliferation and adaptation to harsh microenvironments. Yin Yang 2 (YY2) has recently been reported as a tumor suppressor downregulated in various types of tumors; however, the molecular mechanisms underlying its tumor-suppressive activity remain poorly understood. Furthermore, the involvement of YY2 in tumor cell metabolic reprogramming remains unclear. Herein, we aimed to elucidate the novel regulatory mechanism of YY2 in the suppression of tumorigenesis. Using transcriptomic analysis, we uncovered an unprecedented link between YY2 and tumor cell serine metabolism. YY2 alteration could negatively regulate the expression level of phosphoglycerate dehydrogenase (PHGDH), the first enzyme in the serine biosynthesis pathway, and consequently, tumor cell de novo serine biosynthesis. Mechanistically, we revealed that YY2 binds to the PHGDH promoter and suppresses its transcriptional activity. This, in turn, leads to decreased production of serine, nucleotides, and cellular reductants NADH and NADPH, which subsequently suppresses tumorigenic potential. These findings reveal a novel function of YY2 as a regulator of the serine metabolic pathway in tumor cells and provide new insights into its tumor suppressor activity. Furthermore, our findings suggest the potential of YY2 as a target for metabolic-based antitumor therapeutic strategies.

The causal effect of serum 25-hydroxyvitamin D levels on epilepsy: A two-sample Mendelian randomization study.

OBJECTIVE: Observational studies have shown an association between 25-hydroxyvitamin D (25 (OH) D) and epilepsy, but it is unclear whether the association is causal. Therefore, we applied Mendelian randomization (MR) analysis to determine the causal relationship between serum 25 (OH) D levels and epilepsy. METHODS: We conducted a two-sample Mendelian randomization (TSMR) study to investigate the association between serum 25 (OH) D levels and epilepsy using pooled statistics from genome-wide association studies (GWAS). Data for 25 (OH) D came from a GWAS comprising 417,580 participants, and data for epilepsy were obtained from the International League Against Epilepsy (ILAE) consortium. Five methods were used to analyze TSMR, including the inverse variance weighting method, MR Egger method, weighted median method, simple model, and weighted model. In the sensitivity analysis, MR Egger and MR PRESSO methods were used to test for pleiotropy, inverse variance weighting and MR Egger in Cochran's Q statistics were used to test for heterogeneity. RESULTS: MR analyzed the relationship between 25 (OH) D and different types of epilepsy, and the results showed that a 1 standard deviation increase in natural log-transformed serum 25 (OH) D levels was associated with reduced risk for juvenile absence epilepsy (IVW OR = 0.985; 95% confidence interval [CI]: 0.971-0.999; P-value = 0.038). There was no apparent heterogeneity and horizontal gene pleiotropy. SIGNIFICANCE: Higher serum levels of 25 (OH) D were a protective factor for adolescent absence epilepsy, but had no effect on other types of epilepsy.

Personality characteristics, defense styles, borderline symptoms, and non-suicidal self-injury in first-episode major depressive disorder.

Background: Non-suicidal self-injury (NSSI) is commonly seen in adolescents with depression and is a high-risk factor leading to suicide. The psychological mechanisms underlying depression with NSSI are still unclear. The purpose of this study was to explore the differences in personality traits, defensive styles, and borderline symptoms among first-episode youth patients with depression and self-injury compared with patients with depression without self-injury and healthy populations. Methods: The current study recruited 188 participants, including 64 patients with depression and NSSI, 60 patients with depression without NSSI, and 64 healthy control subjects. Eysenck Personality Questionnaire, the Defense Style Questionnaire, the short version of the Borderline Symptom List, the Beck Depression Inventory, and the Ottawa Self-Injury Inventory were used to assess all participants. Results: Patients with depression and NSSI showed more psychoticism than patients with depression without NSSI and healthy control subjects. Patients with depression and NSSI presented more intermediate defense styles than healthy control subjects. In the patients with depression and NSSI group, the frequency of self-injury in the last week was negatively correlated with mature defense styles and positively correlated with depressive symptoms and borderline symptoms. Further regression analysis showed that EPQ-psychoticism and depressive symptoms were independent risk factors for NSSI in patients with depression. Conclusion: This study found that patients with depression and self-injury presented more neuroticism, introversion, EPQ-psychoticism, immature defenses, intermediate defenses, and borderline symptoms. Self-injury frequency was negatively correlated with mature defense styles and positively correlated with depressive symptoms and borderline symptoms. EPQ-Psychoticism and depressive symptoms are risk factors for predicting non-suicidal self-injury in patients with depression.

Effectiveness of acupuncture in migraine rats: A systematic review.

OBJECTIVE: To systematically evaluate the effectiveness and potential underlying mechanisms of acupuncture in the treatment of experimental model of migraine in rats. METHODS: Nine electronic databases, including CNKI (China National Knowledge Infrastructure), WanFang, VIP (Chinese Scientific Journals Database), Sinomed, PubMed, Cochrane Library, Web of Science and EBSCO, were searched for randomized experimental studies on migraine in rats involving acupuncture intervention. The search period ranged from inception to June 2022. The methodological quality was assessed using the SYRCLE's risk of bias tool for animal studies. Data were analyzed using the Revman 5.3 software. RESULTS: A total of 13 studies were included in this analysis. Findings from the available experimental studies documented that acupuncture significantly reduced behavior scores of rats with migraine (MD = -15.01, 95%CI = [-18.01, -12.01], P<0.00001) and downregulated the expression of calcitonin gene-related peptide (CGRP) (MD = -16.14, 95%CI = [-21.45, -10.83], P<0.00001), substance P (SP) (MD = -11.47, 95%CI = [-15.97, -6.98], P<0.00001) and nitric oxide (NO) (MD = -3.02, 95%CI = [-3.79, -2.26], P<0.00001) in serum, and stimulatory G protein (Gsa) (MD = -62.90, 95%CI = [-69.88, -55.92], P<0.00001) in brainstem. Acupuncture also significantly increased the content of inhibitory G protein (Gia) (MD = 24.01, 95%CI = [20.10, 27.92], P<0.00001) in brainstem and 50% paw withdrawal threshold (50%PWT) (MD = 1.96, 95%CI = [1.15, 2.77], P<0.00001). CONCLUSION: Acupuncture can effectively improve the behavioral performance of rates with migraine, and its mechanism of action might involve the inhibition of meningeal vasodilation and inflammatory factors, and the reduction of neurogenic inflammation.

Thermo-sensitive amylase-starch double-layer polymer nanoparticles with self-polishing and protein corona-free property for drug delivery applications.

Protein corona formation can lead to obstructive screening of targeting groups of nanoparticles (NPs). Also, the targeting groups are subjected to physiochemical interactions when exposed to solvents. Here, these two factors can influence NP targeting efficiency. Therefore, it is necessary to prepare a general method of preparing an anti-fouling NPs with protected targeting groups. Here, we designed α-amylase-starch double-layer coated poly (methyl methacrylate-co-acrylic acid) NPs (α-ams-SCMMA NPs), functionalized with aptamer targeting groups and doped with Tetrakis(para-hydraoxylphenyl) porphyrin (TPPOH) as a payload drug. Natural polysaccharide starch and enzyme α-amylase were applied here for thermo-sensitive activation of starch hydrolyzation in order to render the NPs' self-polishing from protein corona effects. During incubation with serum media, the protein corona was formed at the exterior shell of NPs, while the self-polishing process was activated to remove the "protein fouling" when the incubation temperature increased to 37 °C (body temperature). Mechanistically, the starch layer of α-ams-SCMMA NPs was readily hydrolysed by α-amylase, whereby the adsorbed protein corona could be efficiently eliminated and the targeting groups were then presented. With this unique self-polishing NP design, we believe our method can be applied for potential NP applications in cancer therepy due to excellent antifouling property and protected targeting groups.

B cell expansion hinders the stroma-epithelium regenerative cross talk during mucosal healing.

Therapeutic promotion of intestinal regeneration holds great promise, but defining the cellular mechanisms that influence tissue regeneration remains an unmet challenge. To gain insight into the process of mucosal healing, we longitudinally examined the immune cell composition during intestinal damage and regeneration. B cells were the dominant cell type in the healing colon, and single-cell RNA sequencing (scRNA-seq) revealed expansion of an IFN-induced B cell subset during experimental mucosal healing that predominantly located in damaged areas and associated with colitis severity. B cell depletion accelerated recovery upon injury, decreased epithelial ulceration, and enhanced gene expression programs associated with tissue remodeling. scRNA-seq from the epithelial and stromal compartments combined with spatial transcriptomics and multiplex immunostaining showed that B cells decreased interactions between stromal and epithelial cells during mucosal healing. Activated B cells disrupted the epithelial-stromal cross talk required for organoid survival. Thus, B cell expansion during injury impairs epithelial-stromal cell interactions required for mucosal healing, with implications for the treatment of IBD.

The Correlations Between Serum Hcy Level and Seizures and Cognitive Function in Patients After Stroke.

BACKGROUNDS: Post-stroke cognitive dysfunction (PSCI), a set of illnesses ranging from moderate cognitive impairment to dementia, which is one of the most prevalent consequences following a stroke. Homocysteine (Hcy) has been related to a number of neurological and systemic diseases. It's also a known risk factor for cardiovascular disease and systemic atherosclerosis (CVD). The link between Hcy and PSCI, on the other hand, is unknown. METHODS: Our hospital evaluated 325 patients with acute cerebral infarction between January 1, 2018 and December 1, 2021. There are biological markers and baseline data available. Patients were divided into two groups based on the results of the Montreal Cognitive Assessment (MoCA). The researchers performed logistic regression analysis to find variables that may be linked to PSCI. RESULTS: HCY levels were significantly higher in PSCI patients than in non-PSCI patients. Age, education, seizure manifestation, and income level were all shown to be independent risk variables for PSCI in a multivariate logistic analysis. Hcy levels in PSCI patients differed considerably between the high and low groups. The high and low Hcy levels groups had significantly varied hypertension histories and urine levels. Hcy levels in PSCI patients differed considerably between the high and low groups. The high and low Hcy levels groups had significantly varied hypertension histories and urine levels. CONCLUSION: Serum Hcy levels have been linked to PSCI in post-stroke patients, and researchers believe that serum Hcy levels will diminish PSCI.

Methods to evaluate the impact of SARS-CoV-2 nucleocapsid mutations on antigen detection by rapid diagnostic tests.

Mutations in the nucleocapsid of SARS-CoV-2 may interfere with antigen detection by diagnostic tests. We used several methods to evaluate the effect of various SARS-CoV-2 nucleocapsid mutations on the performance of the Panbio™ and BinaxNOW™ lateral flow rapid antigen tests and a prototype high-throughput immunoassay that utilizes Panbio antibodies. Variant detection was also evaluated by immunoblot and BIAcore™ assay. A panel of 23 recombinant nucleocapsid antigens (rAgs) were produced that included mutations found in circulating SARS-CoV-2 variants, including variants of concern. All mutant rAgs were detected by all assays, at a sensitivity equivalent to wild-type control (Wuhan strain). Thus, using a rAg approach, we found that the SARS-CoV-2 nucleocapsid mutations examined do not directly impact antigen detection or antigen assay performance.

Interleukin-10 regulates goblet cell numbers through Notch signaling in the developing zebrafish intestine.

Cytokines are immunomodulatory proteins that orchestrate cellular networks in health and disease. Among these, interleukin (IL)-10 is critical for the establishment of intestinal homeostasis, as mutations in components of the IL-10 signaling pathway result in spontaneous colitis. Whether IL-10 plays other than immunomodulatory roles in the intestines is poorly understood. Here, we report that il10, il10ra, and il10rb are expressed in the zebrafish developing intestine as early as 3 days post fertilization. CRISPR/Cas9-generated il10-deficient zebrafish larvae showed an increased expression of pro-inflammatory genes and an increased number of intestinal goblet cells compared to WT larvae. Mechanistically, Il10 promotes Notch signaling in zebrafish intestinal epithelial cells, which in turn restricts goblet cell expansion. Using murine organoids, we showed that IL-10 modulates goblet cell frequencies in mammals, suggesting conservation across species. This study demonstrates a previously unappreciated IL-10-Notch axis regulating goblet cell homeostasis in the developing zebrafish intestine and may help explain the disease severity of IL-10 deficiency in the intestines of mammals.

Spliced or Unspliced, That Is the Question: The Biological Roles of XBP1 Isoforms in Pathophysiology.

X-box binding protein 1 (XBP1) is a member of the CREB/ATF basic region leucine zipper family transcribed as the unspliced isoform (XBP1-u), which, upon exposure to endoplasmic reticulum stress, is spliced into its spliced isoform (XBP1-s). XBP1-s interacts with the cAMP response element of major histocompatibility complex class II gene and plays critical role in unfolded protein response (UPR) by regulating the transcriptional activity of genes involved in UPR. XBP1-s is also involved in other physiological pathways, including lipid metabolism, insulin metabolism, and differentiation of immune cells. Its aberrant expression is closely related to inflammation, neurodegenerative disease, viral infection, and is crucial for promoting tumor progression and drug resistance. Meanwhile, recent studies reported that the function of XBP1-u has been underestimated, as it is not merely a precursor of XBP1-s. Instead, XBP-1u is a critical factor involved in various biological pathways including autophagy and tumorigenesis through post-translational regulation. Herein, we summarize recent research on the biological functions of both XBP1-u and XBP1-s, as well as their relation to diseases.