Molecular Mechanism of pH-Induced Protrusion Configuration Switching in Piscine Betanodavirus Implies a Novel Antiviral Strategy.

Many viruses contain surface spikes or protrusions that are essential for virus entry. These surface structures can thereby be targeted by antiviral drugs to treat viral infections. Nervous necrosis virus (NNV), a simple nonenveloped virus in the genus of betanodavirus, infects fish and damages aquaculture worldwide. NNV has 60 conspicuous surface protrusions, each comprising three protrusion domains (P-domain) of its capsid protein. NNV uses protrusions to bind to common receptors of sialic acids on the host cell surface to initiate its entry via the endocytic pathway. However, structural alterations of NNV in response to acidic conditions encountered during this pathway remain unknown, while detailed interactions of protrusions with receptors are unclear. Here, we used cryo-EM to discover that Grouper NNV protrusions undergo low-pH-induced compaction and resting. NMR and molecular dynamics (MD) simulations were employed to probe the atomic details. A solution structure of the P-domain at pH 7.0 revealed a long flexible loop (amino acids 311-330) and a pocket outlined by this loop. Molecular docking analysis showed that the N-terminal moiety of sialic acid inserted into this pocket to interact with conserved residues inside. MD simulations demonstrated that part of this loop converted to a ß-strand under acidic conditions, allowing for P-domain trimerization and compaction. Additionally, a low-pH-favored conformation is attained for the linker connecting the P-domain to the NNV shell, conferring resting protrusions. Our findings uncover novel pH-dependent conformational switching mechanisms underlying NNV protrusion dynamics potentially utilized for facilitating NNV entry, providing new structural insights into complex NNV-host interactions with the identification of putative druggable hotspots on the protrusion.

Comparable cognitive impairment was detected in MACS and CS and alleviated after remission of hypercortisolism in MACS.

Context: Few studies have directly compared the cognitive characteristics of patients with mild autonomous cortisol secretion (MACS) and Cushing's syndrome (CS). The effect of surgical or conservative treatment on cognitive function in patients with MACS is still unclear. Objective: To compare the differences in cognitive function between patients with MACS and CS and evaluate the effect of surgery or conservative treatment on cognitive function. Methods: We prospectively recruited 59 patients with nonfunctional adrenal adenoma (NFA), 36 patients with MACS, and 20 patients with adrenal CS who completed the global cognition and cognitive subdomains assessments. Seventeen MACS patients were re-evaluated for cognitive function after a 12-month follow-up period; of these, eleven underwent laparoscopic adrenalectomy and six received conservative treatment. Results: Patients with MACS and CS performed worse in the global cognition and multiple cognitive domains than those with NFA (all P<0.05). No statistical difference was found in cognitive functions between patients with MACS and CS. Logistic regression analysis showed that patients with MACS (odds ratio [OR]=3.738, 95% confidence intervals [CI]: 1.329-10.515, P=0.012) and CS (OR=6.026, 95% CI: 1.411-25.730, P=0.015) were associated with an increased risk of immediate memory impairment. Visuospatial/constructional, immediate and delayed memory scores of MACS patients were significantly improved at 12 months compared with pre-operation in the surgical treatment group (all P<0.05), whereas there was no improvement in the conservative treatment group. Conclusion: Patients with MACS have comparable cognitive impairment as patients with CS. Cognitive function was partially improved in patients with MACS after adrenalectomy. The current data support the inclusion of cognitive function assessment in the clinical management of patients with MACS.

Novel kinase 1 regulates CD8+T cells as a potential therapeutic mechanism for idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a rare, chronic and progressively worsening lung disease that poses a significant threat to patient prognosis, with a mortality rate exceeding that of some common malignancies. Effective methods for early diagnosis and treatment remain for this condition are elusive. In our study, we used the GEO database to access second-generation sequencing data and associated clinical information from IPF patients. By utilizing bioinformatics techniques, we identified crucial disease-related genes and their biological functions, and characterized their expression patterns. Furthermore, we mapped out the immune landscape of IPF, which revealed potential roles for novel kinase 1 and CD8+T cells in disease progression and outcome. These findings can aid the development of new strategies for the clinical diagnosis and treatment of IPF.

Unveiling the hidden impact: Subclinical hypercortisolism and its subtle influence on bone health.

In recent years, advancements in imaging technologies have led to an increased detection rate of adrenal incidentalomas (AI), with age demonstrating a significant correlation with their incidence. Among the various forms of functional adrenal incidentalomas, subclinical hypercortisolism (SH) stands out as a predominant subtype. Despite the absence of typical symptoms associated with Cushing's syndrome, both domestic and international research consistently establishes a robust link between SH and diverse metabolic irregularities, including hypertension, lipid metabolism disorders, glucose metabolism abnormalities, and disruptions in bone metabolism. Individuals with SH face an elevated risk of cardiovascular events and mortality, highlighting the clinical significance of addressing this condition. Prolonged exposure to elevated cortisol levels poses a significant threat to bone health, contributing to bone loss, alterations in bone microstructure, and an increased susceptibility to fractures. However, comprehensive reviews addressing bone metabolism changes and associated mechanisms in SH patients are currently lacking. Furthermore, the profound impact of concurrent SH on the overall health of the elderly cannot be overstated. A comprehensive understanding of the skeletal health status in elderly individuals with concomitant SH is imperative. This article aims to fill this gap by offering a detailed review of bone metabolism changes and associated mechanisms in SH patients arising from AI. Additionally, it provides a forward-looking perspective on research concerning skeletal health in elderly individuals with concurrent SH.

Co-transcriptional folding of the glmS ribozyme enables a rapid response to metabolite.

The glmS ribozyme riboswitch, located in the 5' untranslated region of the Bacillus subtilis glmS messenger RNA (mRNA), regulates cell wall biosynthesis through ligand-induced self-cleavage and decay of the glmS mRNA. Although self-cleavage of the refolded glmS ribozyme has been studied extensively, it is not known how early the ribozyme folds and self-cleaves during transcription. Here, we combine single-molecule fluorescence with kinetic modeling to show that self-cleavage can occur during transcription before the ribozyme is fully synthesized. Moreover, co-transcriptional folding of the RNA at a physiological elongation rate allows the ribozyme catalytic core to react without the downstream peripheral stability domain. Dimethyl sulfate footprinting further revealed how slow sequential folding favors formation of the native core structure through fraying of misfolded helices and nucleation of a native pseudoknot. Ribozyme self-cleavage at an early stage of transcription may benefit glmS regulation in B. subtilis, as it exposes the mRNA to exoribonuclease before translation of the open reading frame can begin. Our results emphasize the importance of co-transcriptional folding of RNA tertiary structure for cis-regulation of mRNA stability.

Structural insights into the role of N-terminal integrity in PhoSL for core-fucosylated N-glycan recognition.

PhoSL (Pholiota squarrosa Lectin) has an exceptional binding affinity for biomolecules with core-fucosylated N-glycans. This modification involves the addition of fucose to the inner N-acetylglucosamine within the N-glycan structure and is known to influence many physiological processes. Nevertheless, the molecular interactions underlying high-affinity binding of native PhoSL to core-fucosylated N-glycans remain largely unknown. In this study, we devised a strategy to produce PhoSL with the essential structural characteristics of the native protein (n-PhoSL). To do so, a fusion protein was expressed in E. coli and purified. Then, enzymatic cleavage and incubation with glutathione were utilized to recapitulate the native primary structure and disulfide bonding pattern. Subsequently, we identified the residues crucial for n-PhoSL binding to core-fucosylated chitobiose (N2F) via NMR spectroscopy. Additionally, crystal structures were solved for both apo n-PhoSL and its N2F complex. These analyses suggested a pivotal role of the N-terminal amine in maintaining the integrity of the binding pocket and actively contributing to core-fucose recognition. In support of this idea, the inclusion of additional residues at the N-terminus considerably reduced binding affinity and PhoSL cytotoxicity toward breast cancer cells. Taken together, these findings can facilitate the utilization of PhoSL in basic research, diagnostics and therapeutic strategies.

Granulomatous lobular mastitis co-existing with ductal carcinoma in situ: Report of three cases and review of the literature.

Granulomatous lobular mastitis (GLM) is a benign and infrequent chronic breast ailment. Although this lesion can be clinically and radiographically mistaken for early-onset breast cancer, it is a rare occurrence for the two to coexist. This report describes three such cases. In all three patients, the primary signs and symptoms were related to the formation of diffuse breast masses or abscesses. Breast ultrasound and MRI revealed glandular edema and dilated breast ducts. The biopsies of all lesions exhibited both granulomatous inflammation confined to the lobules of the breast, abundant interstitial inflammatory cell infiltrates, and apparently cancerous cells located in dilated ducts with intact basement membranes. The surgically excised specimens confirmed the diagnosis of GLM and ductal carcinoma in situ (DCIS) in all three patients who underwent breast mass resection. By clinical imaging and clinical manifestations, GLM may obscure a concurrent DCIS, as highlighted by the cases reported herein.

Structural basis of transcriptional activation by the OmpR/PhoB-family response regulator PmrA.

PmrA, an OmpR/PhoB-family response regulator, triggers gene transcription responsible for polymyxin resistance in bacteria by recognizing promoters where the canonical-35 element is replaced by the pmra-box, representing the PmrA recognition sequence. Here, we report a cryo-electron microscopy (cryo-EM) structure of a bacterial PmrA-dependent transcription activation complex (TAC) containing a PmrA dimer, an RNA polymerase σ70 holoenzyme (RNAPH) and the pbgP promoter DNA. Our structure reveals that the RNAPH mainly contacts the PmrA C-terminal DNA-binding domain (DBD) via electrostatic interactions and reorients the DBD three base pairs upstream of the pmra-box, resulting in a dynamic TAC conformation. In vivo assays show that the substitution of the DNA-recognition residue eliminated its transcriptional activity, while variants with altered RNAPH-interacting residues resulted in enhanced transcriptional activity. Our findings suggest that both PmrA recognition-induced DNA distortion and PmrA promoter escape play crucial roles in its transcriptional activation.

Human mobility and disease prevalence.

We examine the effect of human mobility on disease prevalence by studying the dependence of the total infected population at endemic equilibria with respect to population diffusion rates of a diffusive epidemic model. For small diffusion rates, our results indicate that the total infected population size is strictly decreasing with respect to the ratio of the diffusion rate of the infected population over that of the susceptible population. Moreover, when the disease local reproductive function is spatially heterogeneous, we found that: (i) for large diffusion rate of the infected population, the total infected population size is strictly maximized at large diffusion rate of the susceptible population when the recovery rate is spatially homogeneous, while it is strictly maximized at intermediate diffusion rate of the susceptible population when the difference of the transmission and recovery rates are spatially homogeneous; (ii) for large diffusion rate of the susceptible population, the total infected population size is strictly maximized at intermediate diffusion rate of the infected population when the recovery rate is spatially homogeneous, while it is strictly minimized at large diffusion rate of the infected population when the difference of the transmission and recovery rates is spatially homogeneous. Numerical simulations are provided to complement the theoretical results. Our studies may provide some insight into the impact of human mobility on disease outbreaks and the severity of epidemics.

Co-phase separation of Y14 and RNA in vitro and its implication for DNA repair.

The multifunctional RNA recognition motif-containing protein Y14/RBM8A participates in mRNA metabolism and is essential for the efficient repair of DNA double-strand breaks (DSBs). Y14 contains highly charged, low-complexity sequences in both the amino- and carboxy-terminal domains. The feature of charge segregation suggests that Y14 may undergo liquid-liquid phase separation (LLPS). Recombinant Y14 formed phase-separated droplets, which were sensitive to pH and salt concentration. Domain mapping suggested that LLPS of Y14 involves multivalent electrostatic interactions and is partly determined by the net charge of its low-complexity regions. Phospho-mimicry of the carboxy-terminal arginine-serine dipeptides of Y14 suppressed phase separation. Moreover, RNA could phase separate into Y14 droplets and modulate Y14 LLPS in a concentration-dependent manner. Finally, the capacity of Y14 in LLPS and coacervation with RNA in vitro correlated with its activity in DSB repair. These results reveal a molecular rule for LLPS of Y14 in vitro and an implication for its co-condensation with RNA in genome stability.

A West Nile virus nonlocal model with free boundaries and seasonal succession.

The paper deals with a West Nile virus (WNv) model, in which the nonlocal diffusion characterizes the long-range movement of birds and mosquitoes, the free boundaries describe their spreading fronts, and the seasonal succession accounts for the effect of the warm and cold seasons. The well-posedness of the mathematical model is established, and its long-term dynamical behaviours, which depend upon the generalized eigenvalues of the corresponding linearized differential operator, are investigated. For both spatially independent and nonlocal WNv models with seasonal successions, the generalized eigenvalues are studied and applied to determine whether the spreading or vanishing occurs. Our results extend those for the case with nonlocal diffusion but no free boundary and those for the case with free boundary but local diffusion, respectively. The generalized eigenvalues reveal that there exists positive correlation between the duration of the warm season and the risk of infection. Moreover, the initial infection length, the initial infection scale and the spreading ability to new areas all play important roles for the long time behaviors of the time dependent solutions.

Dynamic network biomarker factors orchestrate cell-fate determination at tipping points during hESC differentiation.

The generation of ectoderm, mesoderm, and endoderm layers is the most critical biological process during the gastrulation of embryo development. Such a differentiation process in human embryonic stem cells (hESCs) is an inherently nonlinear multi-stage dynamical process which contain multiple tipping points playing crucial roles in the cell-fate decision. However, the tipping points of the process are largely unknown, letting alone the understanding of the molecular regulation on these critical events. Here by designing a module-based dynamic network biomarker (M-DNB) model, we quantitatively pinpointed two tipping points of the differentiation of hESCs toward definitive endoderm, which leads to the identification of M-DNB factors (FOS, HSF1, MYCN, TP53, and MYC) of this process. We demonstrate that before the tipping points, M-DNB factors are able to maintain the cell states and orchestrate cell-fate determination during hESC (ES)-to-ME and ME-to-DE differentiation processes, which not only leads to better understanding of endodermal specification of hESCs but also reveals the power of the M-DNB model to identify critical transition points with their key factors in diverse biological processes, including cell differentiation and transdifferentiation dynamics.

Impaired Cognitive Function in Patients With Autonomous Cortisol Secretion in Adrenal Incidentalomas.

CONTEXT: Glucocorticoids have potent effects on the central nervous system. However, while patients with Cushing syndrome frequently report impairments in cognitive function, studies investigating cognitive function in patients with autonomous cortisol secretion (ACS) in adrenal incidentalomas (AIs) are scarce. OBJECTIVE: The aim of the present study was to evaluate neurocognitive function in patients with ACS. METHODS: We prospectively recruited 63 patients with AI, 36 patients with nonfunctional adrenal adenoma (NFA) (46.5 ± 10.5 years), and 27 patients with ACS (48.6 ± 9.1 years); these patients underwent a battery of validated neuropsychological tests. ACS was diagnosed when serum cortisol levels after a 1-mg dexamethasone suppression test (cortisol1 mg DST) ≥ 50 nmol/L. RESULTS: Patients with ACS had higher frequency of subjective memory complaints (40.7% vs 13.9%, P < 0.05) and higher proportion of mild cognitive impairment (22.2% vs 2.8%, P < 0.05) than patients with NFA. Furthermore, patients with ACS had worse performance on working memory and the visuospatial/constructional domain than patients with NFA (all P < 0.05). Serum cortisol1 mg DST was negatively correlated with working memory and visuospatial/constructional domains (r = -0.307 and -0.306, respectively, all P < 0.05). Performance on working memory and visuospatial/constructional domains gradually deteriorated with increases in serum cortisol1 mg DST (all P values for trend < 0.05). Multivariate linear regression analysis showed that serum cortisol1 mg DST was a significant risk factor for impairment of working memory and visuospatial/constructional domains (B = -0.006 and -0.043, respectively, all P < 0.05). CONCLUSION: This study is the first to report that ACS is accompanied by impaired cognitive function. Consequently, cognitive function assessment should be incorporated into the clinical evaluation of patients with ACS. CLINICAL TRIAL REGISTRATION NUMBER: NCT05357456.

Ferroptosis: A new strategy for traditional Chinese medicine treatment of stroke.

Stroke is a serious threat to human survival and health due to its high morbidity and mortality. The pathological mechanism of stroke is complex and involves various regulated cell death (RCD) modalities such as autophagy, apoptosis and necroptosis. ferroptosis, a novel form of RCD characterised by iron-dependent accumulation of lipid peroxides and reactive oxygen radicals, has been found to be closely associated with the prognosis and outcome of stroke. At the same time, ferroptosis is also associated with other forms of RCD with varying degrees of crosstalk. Traditional Chinese medicine(TCM), with its multi-component, multi-pathway and multi-target action characteristics, has unique advantages and good prospects for application in stroke prevention and treatment. Using ferroptosis and its crosstalk with other forms of RCD as an entry point, we review the research on TCM with anti-stroke effects discovered in the past 10 years, with a view to providing reference for further scientific development and application of anti-stroke therapeutic drugs.

Correlation between serum laminin levels and prognosis of acute myocardial infarction.

Background: Acute myocardial infarction (AMI) is a critical cardiovascular disease (CVD). Laminin (LN) is involved in the process of myocardial fibrosis and ventricular remodeling observed in AMI; however, there are currently no studies on the correlation between LN and AMI prognosis. Purpose: To explore the predictive value of serum LN levels for major adverse cardiovascular events (MACE) in patients, 6 months after an acute myocardial infarction. Methods: A total of 202 AMI patients who were hospitalized in the Department of Cardiology of the Second Affiliated Hospital of Nantong University between December 2019 and December 2020 were included. The observation endpoint was the occurrence of MACE. Univariate and multivariate logistic analyses were used to evaluate the relationships between the variables and endpoint. The predictive value of LN for MACE in AMI patients was assessed using receiver operating characteristic (ROC) analysis. Results: A total of 47 patients developed MACE. Univariate logistic analysis showed that smoking, emergency percutaneous coronary intervention (EPCI), age, cardiac troponin I (c-TNI) levels, N-terminal prohormone brain natriuretic peptide (NT-proBNP) levels, and LN levels were associated with the occurrence of MACE (p < 0.05). Multivariate logistic analysis showed that LN was an independent predictor of MACE (odds ratio [OR] = 1.021, 95%CI: 1.014-1.032, p < 0.001). According to the ROC curve, LN can be used as an effective predictor of MACE (AUC = 0.856, 95%CI: 0.794-0.918, p < 0.001). According to the cutoff value, LN>58.80 ng/ml (sensitivity = 83.00%, specificity = 76.80%) or LN>74.15 ng/ml (sensitivity = 76.6%, specificity = 83.2%) indicate a poor prognosis for AMI. Different cut-off values are selected according to the need for higher sensitivity or specificity in clinical applications. Conclusions: LN may be a predictor of MACE following AMI in patients and could be utilized as a novel substitute marker for the prevention and treatment of AMI.

Total biomass of a single population in two-patch environments.

For the two-patch logistic model, we study the effect of dispersal intensity and dispersal asymmetry on the total population abundance and its distribution. Two complete classifications of the model parameter space are given: one concerning when dispersal causes smaller or larger total biomass than no dispersal, and the other addressing how the total biomass changes with dispersal intensity and dispersal asymmetry. The dependencies of the population abundance of each individual patch on dispersal intensity and dispersal asymmetry are also fully characterized. In addition, the maximal and minimal total population sizes induced by dispersal are determined for the logistic model with an arbitrary number of patches, and a weak order-preserving result correlated the local population abundances with and without dispersal is established.

Expression and clinical significance of VISTA and PD-L1 in adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis and challenging management. The present study aimed to investigate the expression of programmed death ligand-1 (PD-L1) and V-domain Ig-containing suppressor of T cell activation (VISTA) in ACC and their associations with clinicopathological features and survival outcomes. Immunohistochemistry was performed on formalin-fixed paraffin-embedded specimens from 54 ACC patients. Chi-square/Fisher's exact tests or independent samples t/Mann-Whitney U tests were performed to assess correlations between immunoscores and clinicopathological parameters. The Kaplan-Meier method and Cox regression were conducted for survival analysis and to identify independent predictors of overall (OS) and disease-free (DFS) survival. Results showed that VISTA was expressed in tumor cells (TCs) and tumor-infiltrating immune cells (TICs) in 81.5% (44/54) and 40.7% (22/54) of the patients, respectively. PD-L1 positivity was found in either TCs or TICs in 11.1% (6/54) of the patients. Patients with positive VISTA expression in TCs had a higher tumor stage (56.9% vs 20%, P = 0.036) and Ki-67 index (30.50 ± 23.51% vs 14.76 ± 11.75%, P = 0.006). However, PD-L1 positivity in either TCs or TICs had no association with patient clinicopathological features. A higher VISTA expression intensity, a larger area and a higher immunoscore were associated with increased risks of disease progression and overall mortality, but PD-L1 expression in TCs or TICs was not associated with OS or DFS. In conclusion, positive TC VISTA expression was correlated with pathological parameters related to malignancy in ACC patients. This finding provides novel evidence of the value of VISTA, in addition to PD-L1, as an immunotherapeutic target in ACC.

Global dynamics of a generalist predator-prey model in open advective environments.

This paper deals with a system of reaction-diffusion-advection equations for a generalist predator-prey model in open advective environments, subject to an unidirectional flow. In contrast to the specialist predator-prey model, the dynamics of this system is more complex. It turns out that there exist some critical advection rates and predation rates, which classify the global dynamics of the generalist predator-prey system into three or four scenarios: (1) coexistence; (2) persistence of prey only; (3) persistence of predators only; and (4) extinction of both species. Moreover, the results reveal significant differences between the specialist predator-prey system and the generalist predator-prey system, including the evolution of the critical predation rates with respect to the ratio of the flow speeds; the take-over of the generalist predator; and the reduction in parameter range for the persistence of prey species alone. These findings may have important biological implications on the invasion of generalist predators in open advective environments.