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Biomedical subjects

Jia Lu

Publications and source records attributed to Jia Lu.

At least 19 recordsLinked to original sources

Machine learning identifies ac4C-related prognostic signature and TUBA1C as therapeutic target in COAD.

To explore the role of N4-acetylcytidine (ac4C)-related genes (acRGs) in colon adenocarcinoma (COAD) and identify reliable prognostic biomarkers and potential therapeutic targets. Multi-source transcriptomic datasets (TCGA-COAD, GSE39582, GSE17536) and single-cell RNA-seq data were analyzed. Ten machine learning algorithms were integrated to construct an acRG-based prognostic signature (acRGBS). Immune microenvironment (TME) and genomic profiling were performed, with in vitro functional experiments validating TUBA1C's role. acRGBS, comprising four hub genes (SARAF, CDC42SE2, TSPYL2, TUBA1C), effectively stratified COAD patients into high- and low-risk groups with distinct survival outcomes and was an independent prognostic factor. High-risk patients exhibited increased genomic instability and immunosuppressive TME, while low-risk patients had favorable immunotherapy response. TUBA1C was overexpressed in COAD cells, and its knockdown inhibited proliferation/migration and induced apoptosis. The acRGBS is a robust prognostic tool for COAD, and TUBA1C serves as a candidate therapeutic target, providing new insights for personalized COAD management.

Humans↗

Isolation, identification, and genomic characterization of Staphylococcus aureus phage vB_SauL_202595 and its bacteriostatic application in dairy products.

Staphylococcus aureus is an important pathogen associated with bovine mastitis and dairy product contamination, posing economic and public health risks through the food chain. In this study, a temperate phage, vB_SauL_202595, was isolated from a dairy farm environmental sample using S. aureus SHZ-0127 as the host, and its biological characteristics, genomic features, and antibacterial activity in dairy matrices were evaluated. vB_SauL_202595 lysed 18 of 66 tested S. aureus strains, with a lysis susceptibility rate of 27.3%, including 5 highly susceptible strains, indicating a relatively limited host range. The optimal multiplicity of infection was 0.01, the latent period was approximately 30 min, and the burst size was approximately 316 PFU/cell. The phage remained stable at 4°C-37°C and pH 6-10. Genome analysis showed that vB_SauL_202595 belongs to the class Caudoviricetes, has a genome of 44,503 bp with 33.59% GC content, and encodes 63 predicted proteins. No typical antibiotic resistance genes or major virulence factors were detected; however, integrase and repressor genes were identified, supporting its temperate nature. vB_SauL_202595 inhibited S. aureus SHZ-0127 growth, reduced mature biofilm biomass, and decreased viable bacterial counts in milk and yogurt, with reductions of 1.23 and 1.42 log10 CFU/mL under representative conditions, respectively. From a One Health perspective, these findings provide foundational evidence for reducing S. aureus contamination and related antimicrobial resistance risks along the dairy chain. Overall, vB_SauL_202595 represents a candidate phage resource for dairy-associated S. aureus biocontrol research, but its limited host range and lysogeny-related genes require further safety assessment before food-related applications.IMPORTANCEStaphylococcus aureus is a major pathogen associated with bovine mastitis and a common contaminant in dairy products, causing economic losses and public health risks through the food chain. Although phage-based biocontrol has emerged as a promising strategy for controlling S. aureus contamination in dairy products, systematic evidence regarding phage activity in actual dairy matrices remains limited. In this study, we isolated and characterized a dairy farm environment-derived temperate phage, vB_SauL_202595, and evaluated its biological characteristics, genomic features, host range, stability, biofilm removal ability, and antibacterial performance in milk and yogurt. These findings provide foundational experimental evidence for phage-based dairy biocontrol against S. aureus. However, due to its limited host range and lysogeny-related genomic features, vB_SauL_202595 should be considered a candidate phage resource for further study. Broader validation, including phage-cocktail testing, long-term storage assays, product quality assessment, and regulatory safety evaluation, is needed before practical application.

Staphylococcus aureus↗

2', 3'-Cyclic nucleotide 3'-phosphodiesterase cells derived from transplanted marrow stromal cells and host tissue contribute to perineurial compartment formation in injured rat spinal cord.

Transdifferentiation of transplanted marrow stromal cells (MSCs) and reactive changes of glial cells in a completely transected rat spinal cord were examined. Marrow stromal cells exhibited 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) at the plasma membrane and this has allowed their identification after transplantation by immunoelectron microscopy. In the control rats, the lesion site showed activated microglia/neural macrophages and some elongated cells, whose cytoplasm was immunoreactive for CNP. Cells designated as CNP1 and apparently host-derived expressed CXCR4. In experimental rats receiving MSCs transplantation, CNP1 cells were increased noticeably. This was coupled with the occurrence of a different subset of CNP cells whose plasma membrane was CNP-immunoreactive and expressed CXCR4. These cells, designated as CNP2, enclosed both myelinated and unmyelinated neurites thus assuming a spatial configuration resembling that of Schwann cells. A remarkable feature was the extensive ramifications of CNP1 cells with long filopodia processes delineating the CNP2 cells and their associated neurites, forming many perineurial-like compartments. Present results have shown that CNP2 cells considered to be MSCs-derived can transform into cells resembling Schwann cells based on their spatial relation with the regenerating nerve fibers, whereas the CNP1 glial cells participate in formation of perineurial compartments, probably serving as conduits to guide the nerve fiber growth. The chemotactic migration of CNP cells either derived from host tissue or MSCs bearing CXCR4 may be attracted by stromal derived factor-1alpha (SDF-1alpha) produced locally. The coordinated cellular interaction between transplanted MSCs and local glial cells may promote the growth of nerve fibers through the lesion site.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

Nonlinear anisotropic stress analysis of anatomically realistic cerebral aneurysms.

BACKGROUND: Static deformation analysis and estimation of wall stress distribution of patient-specific cerebral aneurysms can provide useful insights into the disease process and rupture. METHOD OF APPROACH: The three-dimensional geometry of saccular cerebral aneurysms from 27 patients (18 unruptured and nine ruptured) was reconstructed based on computer tomography angiography images. The aneurysm wall tissue was modeled using a nonlinear, anisotropic, hyperelastic material model (Fung-type) which was incorporated in a user subroutine in ABAQUS. Effective material fiber orientations were assumed to align with principal surface curvatures. Static deformation of the aneurysm models were simulated assuming uniform wall thickness and internal pressure load of 100 mm Hg. RESULTS: The numerical analysis technique was validated by quantitative comparisons to results in the literature. For the patient-specific models, in-plane stresses in the aneurysm wall along both the stiff and weak fiber directions showed significant regional variations with the former being higher. The spatial maximum of stress ranged from as low as 0.30 MPa in a small aneurysm to as high as 1.06 MPa in a giant aneurysm. The patterns of distribution of stress, strain, and surface curvature were found to be similar. Sensitivity analyses showed that the computed stress is mesh independent and not very sensitive to reasonable perturbations in model parameters, and the curvature-based criteria for fiber orientations tend to minimize the total elastic strain energy in the aneurysms wall. Within this small study population, there were no statistically significant differences in the spatial means and maximums of stress and strain values between the ruptured and unruptured groups. However, the ratios between the stress components in the stiff and weak fiber directions were significantly higher in the ruptured group than those in the unruptured group. CONCLUSIONS: A methodology for nonlinear, anisotropic static deformation analysis of geometrically realistic aneurysms was developed, which can be used for a more accurate estimation of the stresses and strains than previous methods and to facilitate prospective studies on the role of stress in aneurysm rupture.

Anisotropy↗

An experimentally derived stress resultant shell model for heart valve dynamic simulations.

In order to achieve a more realistic and accurate computational simulation of native and bioprosthetic heart valve dynamics, a finite shell element model was developed. Experimentally derived and uncoupled in-plane and bending behaviors were implemented into a fully nonlinear stress resultant shell element. Validation studies compared the planar biaxial extension and three-point bending simulations to the experimental data and demonstrated excellent fidelity. Dynamic simulations of a pericardial bioprosthetic heart valve with the developed shell element model showed significant differences in the deformation characteristics compared to the simulation with an assumed isotropic bending model. The new finite shell element model developed in the present study can also incorporate various types of constitutive models and is expected to help us to understand the complex dynamics of native and bioprosthetic heart valve function in physiological and pathological conditions.

Animals↗

Transient expression of endothelins in the amoeboid microglial cells in the developing rat brain.

Amoeboid microglial cells (AMC) which transiently exist in the corpus callosum in the postnatal rat brain expressed endothelins (ETs), specifically endothelin-1 (ET-1) and ET3 as revealed by real time RT-PCR. ET immunoreactive AMC occurred in large numbers at birth, but were progressively reduced with age and were undetected in 14 days. In rats subjected to hypoxia exposure, ET immunoexpression in AMC was reduced but the incidence of apoptotic cells was not increased when compared with the control suggesting that this was due to its downregulation that may help regulate the constriction of blood vessels bearing ET-A receptor. AMC were endowed ET-B receptor indicating that ET released by the cells may also act via an autocrine manner. In microglia activated by lipopolysaccharide (LPS), ET-1 mNA expression coupled with that of monocyte chemoattractant protein (MCP-1) and stromal derived factor-1 (SDF-1) was markedly increased; ET-3 mRNA, however, remained unaffected. AMC exposed to oxygen glucose deprivation (OGD) in vitro resulted in increase in both ET-1 and ET-3 mRNA expression. It is suggested that the downregulated ETs expression in vivo of AMC subjected to hypoxia as opposed to its upregulated expression in vitro may be due to the complexity of the brain tissue. Furthermore, the differential ET-1 and ET-3 mRNA expression in LPS and OGD treatments may be due to different signaling pathways independently regulating the two isoforms. The present novel finding has added microglia as a new cellular source of ET that may take part in multiple functions including regulating vascular constriction and chemokines release.

Animals↗

Hydrogen sulfide and its possible roles in myocardial ischemia in experimental rats.

The role of hydrogen sulfide (H(2)S) in myocardial infarction (MI) has not been previously studied. We therefore investigated the effect of H(2)S in a rat model of MI in vivo. Animals were randomly divided into three groups (n = 80) and received either vehicle, 14 micromol/kg of sodium hydrosulfide (NaHS), or 50 mg/kg propargylglycine (PAG) everyday for 1 wk before surgery, and the treatment was continued for a further 2 days after MI when the animals were killed. The mortality was 35% in vehicle-treated, 40% in PAG-treated, and 27.5% in NaHS-treated (P < 0.05 vs. vehicle) groups. Infarct size was 52.9 +/- 3.5% in vehicle-treated, 62.9 +/- 7.6% in PAG-treated, and 43.4 +/- 2.8% in NaHS-treated (P < 0.05 vs. vehicle) groups. Plasma H(2)S concentration was significantly increased after MI (59.2 +/- 7.16 microM) compared with the baseline concentration (i.e., 38.2 +/- 2.07 microM before MI; P < 0.05). Elevated plasma H(2)S after MI was abolished by treatment of animals with PAG (39.2 +/- 5.02 microM). We further showed for the first time cystathionine-gamma-lyase protein localization in the myocardium of the infarct area by using immunohistochemical staining. In the hypoxic vascular smooth muscle cells, we found that cell death was increased under the stimuli of hypoxia but that the increased cell death was attenuated by the pretreatment of NaHS (71 +/- 1.2% cell viability in hypoxic vehicle vs. 95 +/- 2.3% in nonhypoxic control; P < 0.05). In conclusion, endogenous H(2)S was cardioprotective in the rat model of MI. PAG reduced endogenous H(2)S production after MI by inhibiting cystathionine-gamma-lyase. The results suggest that H(2)S might provide a novel approach to the treatment of MI.

Alkynes↗

Mice with targeted disruption of neurofilament light subunit display formation of protein aggregation in motoneurons and downregulation of complement receptor type 3 alpha subunit in microglia in the spinal cord at their earlier age: a possible feature in pre-clinical development of neurodegenerative diseases.

The pathogenesis of neurodegenerative diseases prior to the onset of symptoms is generally not clear. The present study has employed a mouse model with a lack of the low-molecular-weight neurofilament subunit (NFL-/-), in which formation of protein aggregates occurs in neurons, to investigate glial cellular reactions in the lumbar cord segments of NFL-/- mice at ages from 1 to 6 months. Age-matched C57BL/6 mice serve as the control. Apparent neurofilament positive aggregates in the cytoplasm of motoneurons have been observed in NFL-/- mice. However, there were no noticeable changes in microglial numbers and GFAP staining of astrocytes. Unexpectedly, a downregulation in expression of complement receptor type 3 alpha subunit (CD11b) was detected in the spinal cord of NFL-/- mice, while there was no obvious difference between NFL-/- and C57BL/6 mice in the CD11b staining intensity of macrophages from livers and spleens. In addition, retardation in morphological transformation from activated to amoeboid microglia in response to sciatic nerve injury, differential expressions of some cytokines in the lumbar cord segments and induction of Iba-1 (ionized calcium-binding adaptor molecule-1) expression in microglia were observed in NFL-/- mice. Our results suggest not only the existence of an inhibitory niche for CD11b expression in microglia in the lumbar cord segments of NFL-/- mice but also differential microglial reactions between earlier and later stages of neuropathogenesis. Although the real cause for such inhibition is still unknown, this effect might play a particular role in the survival of the abnormal protein aggregate-bearing motoneurons in the early development stage of neurodegeneration in the NFL-/- mice.

Age Factors↗

Inverse elastostatic stress analysis in pre-deformed biological structures: Demonstration using abdominal aortic aneurysms.

In stress analysis of membrane-like biological structures, the geometry constructed from in vivo image, which often corresponds to a deformed state, is routinely taken as the initial stress-free geometry. In this paper, we show that this limitation can be completely removed using an inverse elastostatic approach, namely, a method for finding the initial geometry of an elastic body from a given deformed state. We demonstrate the utility of the inverse approach using a patient-specific abdominal aortic aneurysm model, and identify the scope of error in stress estimation in the conventional approach within a realistic range of material parameter variations.

Aortic Aneurysm, Abdominal↗

Preprotachykinin-A gene products are key mediators of lung injury in polymicrobial sepsis.

Preprotachykinin-A (PPT-A) gene products substance P and neurokinin-A have been shown to play an important role in neurogenic inflammation. To investigate the role of PPT-A gene products in lung injury in sepsis, polymicrobial sepsis was induced by cecal ligation and puncture in PPT-A gene-deficient mice (PPT-A(-/-)) and the wild-type control mice (PPT-A(+/+)). PPT-A gene deletion significantly protected against mortality, delayed the onset of lethality, and improved the long-term survival following cecal ligation and puncture-induced sepsis. PPT-A(-/-) mice also had significantly attenuated inflammation and damage in the lungs. The data suggest that deletion of the PPT-A gene may have contributed to the disruption in recruitment of inflammatory cells resulting in protection against tissue damage, as in these mice the sepsis-associated increase in chemokine levels is significantly attenuated.

Animals↗

Protease activity of Blastocystis hominis.

Parasite-derived proteases are important for the parasite life cycle and the pathogenesis of the disease they produce. Proteases of intestinal protozoan parasite Blastocystis hominis were studied for the first time with azocasein assays and gelatin SDS-PAGE analysis. Parasitic lysates were found to have high protease activity and nine protease bands of low (20-33 kDa) and high (44-75 kDa) molecular weights were reported. Proteases were found to be pH-dependent and highest proteolytic activity was observed at neutral pH. Inhibition studies showed that B. hominis isolate B, like many other protozoan parasites, contains mainly cysteine proteases.

Animals↗

Adult bone marrow cells differentiate into neural phenotypes and improve functional recovery in rats following traumatic brain injury.

This study aims to investigate the therapeutic potential of adult bone marrow stromal cells (BMSCs). Exposed to a cocktail of induction medium, some BMSCs could differentiate into cell types with phenotypes of neural lineages in vitro. These cells expressed neural markers nestin, GFAP, 68-kDa neurofilament and beta-tubulin III as detected by immunohistochemistry and RT-PCR. Fluorescence-labeled cells were injected intravenously at 72 h after traumatic brain injury. Transplanted cells survived and migrated to the ipsilateral cerebral cortex at different time points after injection. They were immunopositive for neuronal marker MAP-2, oligodendrocyte marker CNPase, astrocytic maker GFAP or microglial marker OX-42 in vivo. In rats receiving BMSC transplants, there were significant improvements in motor and neurological functions when compared with the control groups. Hence, the therapeutic potential of BMSCs for traumatic brain injury is further amplified.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

Dynamic simulation pericardial bioprosthetic heart valve function.

While providing nearly trouble-free function for 10-12 years, current bioprosthetic heart valves (BHV) continue to suffer from limited long-term durability. This is usually a result of leaflet calcification and/or structural degeneration, which may be related to regions of stress concentration associated with complex leaflet deformations. In the current work, a dynamic three-dimensional finite element analysis of a pericardial BHV was performed with a recently developed FE implementation of the generalized nonlinear anisotropic Fung-type elastic constitutive model for pericardial BHV tissues (W. Sun and M.S. Sacks, 2005, [Biomech. Model. Mechanobiol., 4(2-3), pp. 190-199]). The pericardial BHV was subjected to time-varying physiological pressure loading to compute the deformation and stress distribution during the opening phase of the valve function. A dynamic sequence of the displacements revealed that the free edge of the leaflet reached the fully open position earlier and the belly region followed. Asymmetry was observed in the resulting displacement and stress distribution due to the fiber direction and the anisotropic characteristics of the Fung-type elastic constitutive material model. The computed stress distribution indicated relatively high magnitudes near the free edge of the leaflet with local bending deformation and subsequently at the leaflet attachment boundary. The maximum computed von Mises stress during the opening phase was 33.8 kPa. The dynamic analysis indicated that the free edge regions of the leaflets were subjected to significant flexural deformation that may potentially lead to structural degeneration after millions of cycles of valve function. The regions subjected to time varying flexural deformation and high stresses of the present study also correspond to regions of tissue valve calcification and structural failure reported from explanted valves. In addition, the present simulation also demonstrated the importance of including the bending component together with the in-plane material behavior of the leaflets towards physiologically realistic deformation of the leaflets. Dynamic simulations with experimentally determined leaflet material specification can be potentially used to modify the valve towards an optimal design to minimize regions of stress concentration and structural failure.

Animals↗

Blastocystis ratti induces contact-independent apoptosis, F-actin rearrangement, and barrier function disruption in IEC-6 cells.

Blastocystis is an enteric protozoan purportedly associated with numerous clinical cases of diarrhea, flatulence, vomiting, and other gastrointestinal symptoms. Despite new knowledge of Blastocystis cell biology, genetic diversity, and epidemiology, its pathogenic potential remains controversial. Numerous clinical and epidemiological studies either implicate or exonerate the parasite as a cause of intestinal disease. Therefore, the aim of this study was to investigate the pathogenic potential of Blastocystis by studying the interactions of Blastocystis ratti WR1, an isolate of zoonotic potential, with a nontransformed rat intestinal epithelial cell line, IEC-6. Here, we report that B. ratti WR1 induces apoptosis in IEC-6 cells in a contact-independent manner. Furthermore, we found that B. ratti WR1 rearranges F-actin distribution, decreases transepithelial resistance, and increases epithelial permeability in IEC-6 cell monolayers. In addition, we found that the effects of B. ratti on transepithelial electrical resistance and epithelial permeability were significantly abrogated by treatment with metronidazole, an antiprotozoal drug. Our results suggest for the first time that Blastocystis-induced apoptosis in host cells and altered epithelial barrier function might play an important role in the pathogenesis of Blastocystis infections and that metronidazole has therapeutic potential in alleviating symptoms associated with Blastocystis.

Actins↗

Determination of pyridostigmine bromide and its metabolites in biological samples.

Pyridostigmine bromide (PB) is a quartenary ammonium compound that inhibits the hydrolysis of acetylcholine by competitive reversible binding to acetylcholinesterase. PB is used for the symptomatic treatment of myasthenia gravis and has been applied as a prophylaxis against nerve agents. Many studies on PB have involved the reliance on techniques that extract and quantify PB in biological samples. This article presents an overview of the currently applied methodologies for the determination of PB and its metabolites in various biological samples. Articles published from January 1975 to the July 2005 were taken into consideration for the discussion of the metabolism and analytical method of PB. HPLC and GC methods have been used and discussed in most of the references cited in this review. Other methods such as RIA and CE that have been recently reported are also mentioned in this article. Basic information about the type of sample used for analysis, sample preparation, chromatographic column, mobile phase, detection mode and validation data are summarized in a table.

Animals↗

Degradation of human secretory immunoglobulin A by Blastocystis.

Microbial immunoglobulin A (IgA) proteases cleave human secretory IgA, promoting the mucosal adhesion of pathogens. To investigate if the enteric protozoan Blastocystis degrades human secretory IgA, cell lysate and conditioned medium from two species were exposed to immunoglobulin A. Secretory IgA was cleaved by both cell lysate and conditioned medium with mainly cysteine proteinase activity in B. hominis B isolate and aspartic proteinase activity in B. ratii WR1 isolate. These findings suggest that Blastocystis proteases may play a role in parasite survival in vivo.

Animals↗

Structure-based design, synthesis, and study of potent inhibitors of beta-ketoacyl-acyl carrier protein synthase III as potential antimicrobial agents.

Fatty acid biosynthesis is essential for bacterial survival. Components of this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. FabH, beta-ketoacyl-ACP synthase III, is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and -negative bacteria. Small molecules that inhibit FabH enzymatic activity have the potential to be candidates within a novel class of selective, nontoxic, broad-spectrum antibacterials. Using crystallographic structural information on these highly conserved active sites and structure based drug design principles, a benzoylaminobenzoic acid series of compounds was developed as potent inhibitors of FabH. This inhibitor class demonstrates strong antibacterial activity against Gram-positive and selected Gram-negative organisms.

3-Oxoacyl-(Acyl-Carrier-Protein) Synthase↗

In vitro and in vivo characterization of MEMS microneedles.

Transdermal drug delivery TDD systems have many advantages but are conventionally limited by the low permeability of skin. The idea of using microneedles to painlessly penetrate the topmost impermeable stratum corneum has previously been put forward. In this paper, the fabrication of solid and hollow silicon microneedles with straight side-walls and with the following dimensions: 20-100 microm in diameter and 100-150 microm in length is described. In vitro tests demonstrate that with prior solid microneedle application, transdermal drug transport is significantly increased by 10-20 times, with the degree of enhancement being related to needle diameter. In vivo tests in diabetic animals, however, were unable to demonstrate any delivery of insulin through the hollow microneedles. It is proposed that two factors, microneedle length and tip sharpness, have to be improved for systemic drug delivery to be seen in vivo.

Administration, Cutaneous↗