The roles of nuclear orphan receptor NR2F6 in anti-viral innate immunity.

Proper transcription regulation by key transcription factors, such as IRF3, is critical for anti-viral defense. Dynamics of enhancer activity play important roles in many biological processes, and epigenomic analysis is used to determine the involved enhancers and transcription factors. To determine new transcription factors in anti-DNA-virus response, we have performed H3K27ac ChIP-Seq and identified three transcription factors, NR2F6, MEF2D and MAFF, in promoting HSV-1 replication. NR2F6 promotes HSV-1 replication and gene expression in vitro and in vivo, but not dependent on cGAS/STING pathway. NR2F6 binds to the promoter of MAP3K5 and activates AP-1/c-Jun pathway, which is critical for DNA virus replication. On the other hand, NR2F6 is transcriptionally repressed by c-Jun and forms a negative feedback loop. Meanwhile, cGAS/STING innate immunity signaling represses NR2F6 through STAT3. Taken together, we have identified new transcription factors and revealed the underlying mechanisms involved in the network between DNA viruses and host cells.

Dyadic coping and associated factors in women with high-risk pregnancy and their spouses: Do they interact?

OBJECTIVE: The objective of this study was to examine the present situation of dyadic coping in pregnant women with high-risk pregnancy and their spouses, as well as the relevant factors and the interactions between partners. METHODS: From October 2022 to September 2023, a cross-sectional survey was undertaken, involving 460 pairs of pregnant women with high-risk pregnancy who were hospitalized for childbirth and their accompanying spouses. These participants completed self-assessments on dyadic coping, marital satisfaction, perceived stress, and self-efficacy through the completion of paper questionnaires. The collected data was then subjected to analysis utilizing correlation analysis and multiple linear regression. The actor-partner interdependence model (APIM) was then developed using the structural equation modeling(SEM) to test the binary association. FINDINGS: Pregnant women preferred to utilize stressful communication, whereas their spouses employed supportive and delegated coping. Both external (such as education level, employment status, and medical insurance) and internal (such as marital satisfaction, perceived stress, and self-efficacy) factors were associated with pregnant women's dyadic coping. Education level and internal factors were also associated with the spouses' dyadic coping. In contrast to spouses, who can only have a partner effect on pregnant women through marriage satisfaction, all pregnant women's internal elements played the partner effect on the spouses' dyadic coping. IMPLICATIONS: The study's findings help identify populations with inadequate coping ability. Promoting marital satisfaction, self-efficacy, and reducing perceived stress are associated with enhancing the dyadic coping ability of pregnant women with high-risk pregnancy and their spouses. It also suggests that antenatal care should intervene with pregnant women with high-risk pregnancy and their spouses as a whole, and emphasize collaborative coping and effective mutual support between couples rather than spousal support alone.

CFTR dysfunction leads to defective bacterial eradication on cystic fibrosis airways.

Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel by genetic mutations causes the inherited disease cystic fibrosis (CF). CF lung disease that involves multiple disorders of epithelial function likely results from loss of CFTR function as an anion channel conducting chloride and bicarbonate ions and its function as a cellular regulator modulating the activity of membrane and cytosol proteins. In the absence of CFTR activity, abundant mucus accumulation, bacterial infection and inflammation characterize CF airways, in which inflammation-associated tissue remodeling and damage gradually destroys the lung. Deciphering the link between CFTR dysfunction and bacterial infection in CF airways may reveal the pathogenesis of CF lung disease and guide the development of new treatments. Research efforts towards this goal, including high salt, low volume, airway surface liquid acidosis and abnormal mucus hypotheses are critically reviewed.

Candida parapsilosis bone marrow infection in an immunocompetent patient.

Background: We discuss a case of an immunocompetent patient who presented with fever and tachypnoea, found to have Candida parapsilosis bone marrow infection, cultured on bone marrow aspirate sample. Candida parapsilosis is an opportunistic yeast pathogen that typically affects immunocompromised individuals, or occurs in patients with apparent introduced source; neither of these factors were present for this case. Bone marrow aspirates and trephines are not regular investigations for fever; however they can be useful diagnostic aids as evidenced in this case. Case report: An 83-year-old woman presenting with fevers and tachypnoea was being treated for a systemic bacterial infection, however was unresponsive to empirical antibiotic therapy. To exclude an occult malignancy, an 18-fluorodeoxyglucose positron emission tomography scan was conducted. Significant bone marrow uptake was noted, prompting a bone marrow aspirate and trephine to investigate for a hematological malignancy. While the trephine biopsy was benign, a culture of the aspirate grew Candida parapsilosis. Intravenous antifungal therapy was initiated; however, the patient did not improve despite targeted therapy likely due to delays in diagnosis, and was palliated. Conclusion: Our case seeks to demonstrate a novel case whereby a bone marrow aspirate culture provided a conclusive diagnosis of invasive Candida parapsilosis bone marrow infection, and guided treatment in an immunocompetent patient. It is important for clinicians to consider invasive fungal infections in febrile patients regardless of immune status. Additionally, when performing a bone marrow aspirate and trephine on a febrile patient, we recommend including aspirate fungal cultures to investigate for an invasive fungal infection.

Integrated proteomic profiling identifies amino acids selectively cytotoxic to pancreatic cancer cells.

Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers, characterized by extremely limited therapeutic options and a poor prognosis, as it is often diagnosed during late disease stages. Innovative and selective treatments are urgently needed, since current therapies have limited efficacy and significant side effects. Through proteomics analysis of extracellular vesicles, we discovered an imbalanced distribution of amino acids secreted by PDAC tumor cells. Our findings revealed that PDAC cells preferentially excrete proteins with certain preferential amino acids, including isoleucine and histidine, via extracellular vesicles. These amino acids are associated with disease progression and can be targeted to elicit selective toxicity to PDAC tumor cells. Both in vitro and in vivo experiments demonstrated that supplementation with these specific amino acids effectively eradicated PDAC cells. Mechanistically, we also identified XRN1 as a potential target for these amino acids. The high selectivity of this treatment method allows for specific targeting of tumor metabolism with very low toxicity to normal tissues. Furthermore, we found this treatment approach is easy-to-administer and with sustained tumor-killing effects. Together, our findings reveal that exocytosed amino acids may serve as therapeutic targets for designing treatments of intractable PDAC and potentially offer alternative treatments for other types of cancers.

PLA2G12A protects against diet-induced obesity and insulin resistance by enhancing energy expenditure and clearance of circulating triglycerides.

Secreted phospholipase A2s are involved in the development of obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease, which have become serious and growing health concerns worldwide. Integration of genome-wide association study and gene co-expression networks analysis showed that the secreted phospholipase A2 group XIIA (PLA2G12A) may participate in hepatic lipids metabolism. Nevertheless, the role of PLA2G12A in lipid metabolism and its potential mechanism remain elusive. Here, we used AAV9 vector carrying human PLA2G12A gene to exogenously express hPLA2G12A in the liver of mice. We demonstrated that the overexpression of hPLA2G12A resulted in a significant decrease in serum lipid levels in wild-type mice fed with chow diet or high-fat diet (HFD). Moreover, hPLA2G12A treatment protected against diet-induced obesity and insulin resistance in mice fed a HFD. Notably, we found that hPLA2G12A treatment confers protection against obesity and hyperlipidemia independent of its enzymatic activity, but rather by increasing physical activity and energy expenditure. Furthermore, we demonstrated that hPLA2G12A treatment induced upregulation of ApoC2 and Cd36 and downregulation of Angptl8, which contributed to the increase in clearance of circulating triglycerides and hepatic uptake of fatty acids without affecting hepatic de novo lipogenesis, very low-density lipoprotein secretion, or intestinal lipid absorption. Our study highlights the potential of PLA2G12A gene therapy as a promising approach for treating obesity, insulin resistance and T2DM.

PD-1/CD80+ small extracellular vesicles from immunocytes induce cold tumours featured with enhanced adaptive immunosuppression.

Only a minority of cancer patients benefit from immune checkpoint blockade therapy. Sophisticated cross-talk among different immune checkpoint pathways as well as interaction pattern of immune checkpoint molecules carried on circulating small extracellular vesicles (sEV) might contribute to the low response rate. Here we demonstrate that PD-1 and CD80 carried on immunocyte-derived sEVs (I-sEV) induce an adaptive redistribution of PD-L1 in tumour cells. The resulting decreased cell membrane PD-L1 expression and increased sEV PD-L1 secretion into the circulation contribute to systemic immunosuppression. PD-1/CD80+ I-sEVs also induce downregulation of adhesion- and antigen presentation-related molecules on tumour cells and impaired immune cell infiltration, thereby converting tumours to an immunologically cold phenotype. Moreover, synchronous analysis of multiple checkpoint molecules, including PD-1, CD80 and PD-L1, on circulating sEVs distinguishes clinical responders from those patients who poorly respond to anti-PD-1 treatment. Altogether, our study shows that sEVs carry multiple inhibitory immune checkpoints proteins, which form a potentially targetable adaptive loop to suppress antitumour immunity.

Target organ damage in untreated hypertensive patients with primary aldosteronism.

An increased risk of target organ damage (TOD) has been reported in patients with primary aldosteronism (PA). However, there is relatively little related research on the correlation between the degree of TOD and those with and without PA in newly diagnosed hypertensive patients. The aim of this study was to assess the association between PA and TOD among patients with newly diagnosed hypertension. Newly diagnosed hypertensive patients were consecutively recruited from January 2015 to June 2020 at the University of Hong Kong-Shenzhen Hospital. Patients were stratified into those with and without PA. Data for left ventricular mass index (LVMI), carotid intima-media thickness (CIMT) and plaque, and microalbuminuria were systematically collected. A total of 1044 patients with newly diagnosed hypertension were recruited, 57 (5.5%) of whom were diagnosed with PA. Patients with PA had lower blood pressure, serum lipids, body mass index, and plasma renin activity and a higher incidence of hypokalemia than those without PA. In contrast, the prevalence of left ventricular hypertrophy, increased CIMT, and microalbuminuria was higher in patients with PA than in those without PA. Multivariable regression analysis demonstrated that PA was independently associated with increased LVMI, CIMT and microalbuminuria. Among patients with newly diagnosed hypertension, those with PA had more severe TOD, including a higher LVMI, CIMT and microalbuminuria, than those without PA. These findings emphasize the need for screening TOD in newly diagnosed hypertension due to underlying PA.

Detection of maize stem diameter by using RGB-D cameras' depth information under selected field condition.

Stem diameter is a critical phenotypic parameter for maize, integral to yield prediction and lodging resistance assessment. Traditionally, the quantification of this parameter through manual measurement has been the norm, notwithstanding its tedious and laborious nature. To address these challenges, this study introduces a non-invasive field-based system utilizing depth information from RGB-D cameras to measure maize stem diameter. This technology offers a practical solution for conducting rapid and non-destructive phenotyping. Firstly, RGB images, depth images, and 3D point clouds of maize stems were captured using an RGB-D camera, and precise alignment between the RGB and depth images was achieved. Subsequently, the contours of maize stems were delineated using 2D image processing techniques, followed by the extraction of the stem's skeletal structure employing a thinning-based skeletonization algorithm. Furthermore, within the areas of interest on the maize stems, horizontal lines were constructed using points on the skeletal structure, resulting in 2D pixel coordinates at the intersections of these horizontal lines with the maize stem contours. Subsequently, a back-projection transformation from 2D pixel coordinates to 3D world coordinates was achieved by combining the depth data with the camera's intrinsic parameters. The 3D world coordinates were then precisely mapped onto the 3D point cloud using rigid transformation techniques. Finally, the maize stem diameter was sensed and determined by calculating the Euclidean distance between pairs of 3D world coordinate points. The method demonstrated a Mean Absolute Percentage Error (MAPE) of 3.01%, a Mean Absolute Error (MAE) of 0.75 mm, a Root Mean Square Error (RMSE) of 1.07 mm, and a coefficient of determination (R²) of 0.96, ensuring accurate measurement of maize stem diameter. This research not only provides a new method of precise and efficient crop phenotypic analysis but also offers theoretical knowledge for the advancement of precision agriculture.

Low caveolin-1 levels and symptomatic intracranial haemorrhage risk in large-vessel occlusive stroke patients after endovascular thrombectomy.

BACKGROUND AND PURPOSE: Caveolin-1 (Cav-1) is reported to mediate blood-brain barrier integrity after ischaemic stroke. Our purpose was to assess the role of circulating Cav-1 levels in predicting symptomatic intracranial haemorrhage (sICH) amongst ischaemic stroke patients after endovascular thrombectomy (EVT). METHODS: Patients with large-vessel occlusive stroke after EVT from two stroke centres were prospectively included. Serum Cav-1 level was tested after admission. sICH was diagnosed according to the Heidelberg Bleeding Classification. RESULTS: Of 325 patients (mean age 68.6 years; 207 men) included, 47 (14.5%) were diagnosed with sICH. Compared with patients without sICH, those with sICH had a lower concentration of Cav-1. After adjusting for potential confounders, multivariate regression analysis demonstrated that the increased Cav-1 level was associated with a lower sICH risk (odds ratio 0.055; 95% confidence interval 0.005-0.669; p = 0.038). Similar results were obtained when Cav-1 levels were analysed as a categorical variable. Using a logistic regression model with restricted cubic splines, a linear and negative association of Cav-1 concentration was found with sICH risk (p = 0.001 for linearity). Furthermore, the performance of the conventional risk factors model in predicting sICH was substantially improved after addition of the Cav-1 levels (integrated discrimination index 2.7%, p = 0.002; net reclassification improvement 39.7%, p = 0.007). CONCLUSIONS: Our data demonstrate that decreased Cav-1 levels are related to sICH after EVT. Incorporation of Cav-1 into clinical decision-making may help to identify patients at a high risk of sICH and warrants further consideration.

Draconibacterium aestuarii sp.nov., a Glycolipid-Producing Bacterium Isolated from Tidal Flat Sediment and Emended Description of the Genus Draconibacterium.

A facultatively anaerobic, Gram-negative, curved rod-shaped bacterium (4.0-17.0 µm long, 0.6-0.9 µm wide), designated Z1-6T, was obtained from tidal flat sediment collected from YueAo village in Zhoushan, Zhejiang, People's Republic of China. Strain Z1-6T occurred at 15-45 °C (optimum 28-32 °C), pH 6.0-9.0 (optimum 7.0-7.5), and in the presence of 1-5% (w/v) NaCl (optimum 1-2%). The strain contained iso-C15:0 and antesio-C15:0 as the major fatty acids. An unsaturated menaquinone with seven isoprene units (MK-7) was the predominant respiratory quinone. The polar lipids included phosphatidylethanolamine (PE), one aminophospholipid (APL), two phospholipids (PL1 and PL2), three glycolipids (GL1, GL2, and GL3), and two unidentified lipids (L1 and L2). The genomic DNA G+C content of strain Z1-6T was 39.2%, and the genome size was 6.4 Mb. The strain showed the highest average nucleotide identity (ANI) value of 73.5-74.6%, digital DNA-DNA hybridization (dDDH) value of 19.3-20%, average amino acid identity (AAI) value of 72.0-73.1% with the members of genus Draconibacterium. Phylogenetic analysis based on 16S rRNA gene sequences and genome revealed that strain Z1-6T formed a distinct branch in the clade of the genus Draconibacterium. Based on the phenotypic, phylogenetic, chemotaxonomic analyses and genomic data, strain Z1-6T represents a novel species of the genus Draconibacterium, for which the name Draconibacterium aestuarii sp. nov. (The type strain Z1-6T = MCCC 1K07533T = KCTC 92310T) is proposed.

Comparative efficacy of immune checkpoint inhibitors combined with chemotherapy in patients with advanced driver-gene negative non-small cell lung cancer: A systematic review and network meta-analysis.

Objective: To evaluate the efficacy of different combinations of immune checkpoint inhibitors (ICIs) and chemotherapy (CT) in the treatment of advanced non-small cell lung cancer (NSCLC). Methods: We obtained relevant randomized controlled trials (RCTs) from databases such as PubMed, Embase, Web of Science, and The Cochrane Library up to May 31, 2023. The analysis of clinical prognostic factors was performed using R 4.2.3 and STATA 15.0. The main outcomes measured were overall survival (OS) and progression-free survival (PFS), while secondary outcomes included the objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events of grade 3-5 severity (Grade ≥3 TRAE). Results: A total of 17 randomized controlled trials (RCTs) were conducted between 2012 and 2023, involving 7792 patients. These trials evaluated 11 different treatment methods. The results of these trials showed that in terms of overall survival (OS) and progression-free survival (PFS), the combination of tislelizumab with chemotherapy and the combination of camrelizumab with chemotherapy were particularly effective. Moreover, when compared with other combination therapies, pembrolizumab combined with chemotherapy showed superiority in terms of disease control rate (DCR) and objective response rate (ORR). Subgroup analyses further demonstrated that the addition of immune checkpoint inhibitors (ICIs) to chemotherapy significantly improved PFS and OS in patients without liver metastasis and in those with brain metastasis. Additionally, carboplatin-based combination therapy was found to confer favorable survival benefits in terms of PFS, while cisplatin-based combination therapy showed the most favorable outcomes in terms of OS. The results of subgroup analyses for overall survival (OS) showed that the combination of immunotherapy and chemotherapy yielded positive outcomes in specific subgroups. These subgroups were characterized by PD-L1 Tumor Proportion Score (TPS) of 50 % or higher, usage of anti-PD-1 medications, age below 65, male gender, smoking history, and non-squamous cell carcinoma histology. Superior effectiveness was demonstrated only in extending the progression-free survival (PFS) of female patients and patients with squamous carcinoma. Meanwhile, other patient cohorts did not show the same level of improvement. Conclusions: Tislelizumab, camrelizumab or pembrolizumab combined with chemotherapy may be the optimal first-line treatment strategies for NSCLC.

Innervation of nociceptor neurons in the spleen promotes germinal center responses and humoral immunity.

Peripheral sensory neurons widely innervate various tissues to continuously monitor and respond to environmental stimuli. Whether peripheral sensory neurons innervate the spleen and modulate splenic immune response remains poorly defined. Here, we demonstrate that nociceptive sensory nerve fibers extensively innervate the spleen along blood vessels and reach B cell zones. The spleen-innervating nociceptors predominantly originate from left T8-T13 dorsal root ganglia (DRGs), promoting the splenic germinal center (GC) response and humoral immunity. Nociceptors can be activated by antigen-induced accumulation of splenic prostaglandin E2 (PGE2) and then release calcitonin gene-related peptide (CGRP), which further promotes the splenic GC response at the early stage. Mechanistically, CGRP directly acts on B cells through its receptor CALCRL-RAMP1 via the cyclic AMP (cAMP) signaling pathway. Activating nociceptors by ingesting capsaicin enhances the splenic GC response and anti-influenza immunity. Collectively, our study establishes a specific DRG-spleen sensory neural connection that promotes humoral immunity, suggesting a promising approach for improving host defense by targeting the nociceptive nervous system.

A wearable flexible triboelectric nanogenerator for bio-mechanical energy harvesting and badminton monitoring.

Recently, textile materials used for wearable flexible sensors have received much attention. Wearable textile based triboelectric nanogenerator (TENG) not only has unique advantages in mechanical energy harvesting, but also has application value in the direction of motion sensing. Here, we proposed a non-woven fabric triboelectric nanogenerator (NW-TENG) for mechanical energy harvesting and badminton monitoring. The non-woven fabric play the role of positive triboelectric, and the fluffy fiber structure endows NW-TENG with a sensitive response to pressure. The pressure sensing sensitivity of NW-TENG sensor can reach 1.22 V N-1 (Pressure range: 0-7 N) and 0.18 V N-1 (Pressure range: 8 N-55 N). Furthermore, the NW-TENG can be installed on the body joints of badminton players for analyzing joint movements, thereby achieving data-driven badminton training and facilitating the evaluation of training effectiveness. This research provide a new path to promote TENG to the badminton monitoring field.

Stem Cell-Derived Extracellular Vesicles: Promising Therapeutic Opportunities for Diabetic Wound Healing.

Wound healing is a sophisticated and orderly process of cellular interactions in which the body restores tissue architecture and functionality following injury. Healing of chronic diabetic wounds is difficult due to impaired blood circulation, a reduced immune response, and disrupted cellular repair mechanisms, which are often associated with diabetes. Stem cell-derived extracellular vesicles (SC-EVs) hold the regenerative potential, encapsulating a diverse cargo of proteins, RNAs, and cytokines, presenting a safe, bioactivity, and less ethical issues than other treatments. SC-EVs orchestrate multiple regenerative processes by modulating cellular communication, increasing angiogenesis, and promoting the recruitment and differentiation of progenitor cells, thereby potentiating the reparative milieu for diabetic wound healing. Therefore, this review investigated the effects and mechanisms of EVs from various stem cells in diabetic wound healing, as well as their limitations and challenges. Continued exploration of SC-EVs has the potential to revolutionize diabetic wound care.

The dyadic associations among self-efficacy, dyadic coping, and health-related quality of life between high-risk pregnant women and spouses: a cross-sectional study.

AIM: Health-related quality of life(HRQoL) is essential for high-risk pregnant women and their spouses. This study aimed to explore the dyadic associations (including actor and partner effects) among self-efficacy, dyadic coping, and HRQoL of high-risk pregnant women and their spouses and examine the mediating effect of dyadic coping. METHODS: This cross-sectional study recruited participants from two Grade A tertiary hospitals in China from October 2022 to September 2023. A questionnaire including the Chinese version of the General Self-Efficacy Scale, Dyadic Coping Inventory, and 12 Short Form Health Survey Scales was used for the survey. The actor-partner interdependence mediation model was constructed to test dyadic associations and mediating effects. RESULTS: In the actor effects, self-efficacy was positively associated with dyadic coping and HRQoL (P < 0.05). Regarding partner effects, pregnant women's self-efficacy was positively associated with spouses' dyadic coping and physical health (P < 0.05). Dyadic coping partially mediated the relationship between self-efficacy and HRQoL for both groups(P < 0.05). CONCLUSION: The HRQoL of high-risk pregnant women and their spouses requires urgent attention. Enhancing self-efficacy and dyadic coping in these couples is related to their improved physical and mental health. Healthcare professionals should consider interactions between couples and include them together in perinatal care. Intervention programs for couples or families based on existing positive psychology and dyadic interventions may work together to improve the HRQoL of couples.

CRF08_BC subtype is more prone to ART failure and new generation NNRTI-resistance under long-term first line ART.

OBJECTIVE: To investigate the characteristics of drug resistance mutations (DRMs) and their contextual influence on drug susceptibility in CRF07_BC and CRF_08BC subtypes. METHODS: Patients with virological failure were genotyped using phylogenetic analysis. DRMs and susceptibility to antiretroviral drugs were analyzed using the Stanford University HIV Drug Resistance Database. RESULTS: Six HIV subtypes were identified among 1296 successfully amplified sequences, with the CRF07_BC subtype prevailing at a rate of 91.7%, followed by CRF08_BC. Overall, the CRF07_BC and CRF08_BC subtypes were similar in the distribution and frequency of DRMs, the most common DRMs were K103N and M184V. However, among patients with ART duration of ≥3 years who developed resistance, CRF08_BC exhibited a higher mutation frequency at sites 184, 138, 221, and 188 (Chi-square test, p<0.05), and compared with CRF07_BC, patients with CRF08_BC had higher prevalence of abacavir, emtricitabine, lamivudine, doravirine, etravirine, and rilpivirine resistance. Moreover, there was an increased prevalence of cross-resistance between efavirenz/nevirapine and new generation NNRTIs in patients with CRF08_BC; doravirine (r=1.0), rilpivirine (r=0.93), and etravirine (r=0.86) resistance highly correlated with efavirenz/nevirapine. CONCLUSIONS: The present study provides valuable insights into the profile of DRMs and resistance patterns in patients with CRF07_BC and CRF08_BC experiencing treatment failure in Butuo. These findings have the potential to contribute to future strategies for HIV control and treatment.

Nonlinear dynamics in phosphoinositide metabolism.

Phosphoinositides broadly impact membrane dynamics, signal transduction and cellular physiology. The orchestration of signaling complexity by this seemingly simple metabolic pathway remains an open question. It is increasingly evident that comprehending the complexity of the phosphoinositides metabolic network requires a systems view based on nonlinear dynamics, where the products of metabolism can either positively or negatively modulate enzymatic function. These feedback and feedforward loops may be paradoxical, leading to counterintuitive effects. In this review, we introduce the framework of nonlinear dynamics, emphasizing distinct dynamical regimes such as the excitable state, oscillations, and mixed-mode oscillations-all of which have been experimentally observed in phosphoinositide metabolisms. We delve into how these dynamical behaviors arise from one or multiple network motifs, including positive and negative feedback loops, coherent and incoherent feedforward loops. We explore the current understanding of the molecular circuits responsible for these behaviors. While mapping these circuits presents both conceptual and experimental challenges, redefining cellular behavior based on dynamical state, lipid fluxes, time delay, and network topology is likely essential for a comprehensive understanding of this fundamental metabolic network.

Functional and structural investigation of a broadly neutralizing SARS-CoV-2 antibody.

Since its emergence, SARS-CoV-2 has been continuously evolving, hampering the effectiveness of current vaccines against COVID-19. mAbs can be used to treat patients at risk of severe COVID-19. Thus, the development of broadly protective mAbs and an understanding of the underlying protective mechanisms are of great importance. Here, we isolated mAbs from donors with breakthrough infection with Omicron subvariants using a single-B cell screening platform. We identified a mAb, O5C2, which possesses broad-spectrum neutralization and antibody-dependent cell-mediated cytotoxic activities against SARS-CoV-2 variants, including EG.5.1. Single-particle analysis by cryo-electron microscopy revealed that O5C2 targeted an unusually large epitope within the receptor-binding domain of spike protein that overlapped with the angiotensin-converting enzyme 2 binding interface. Furthermore, O5C2 effectively protected against BA.5 Omicron infection in vivo by mediating changes in transcriptomes enriched in genes involved in apoptosis and interferon responses. Our findings provide insights into the development of pan-protective mAbs against SARS-CoV-2.