Crosstalk between transcription factors and microRNAs in human protein interaction network

<p>Abstract</p> <p>Background</p> <p>Gene regulatory networks control the global gene expression and the dynamics of protein output in living cells. In multicellular organisms, transcription factors and microRNAs are the major families of gene regulators. Recent studies have suggested that these two kinds of regulators share similar regulatory logics and participate in cooperative activities in the gene regulatory network; however, their combinational regulatory effects and preferences on the protein interaction network remain unclear.</p> <p>Methods</p> <p>In this study, we constructed a global human gene regulatory network comprising both transcriptional and post-transcriptional regulatory relationships, and integrated the protein interactome into this network. We then screened the integrated network for four types of regulatory motifs: single-regulation, co-regulation, crosstalk, and independent, and investigated their topological properties in the protein interaction network.</p> <p>Results</p> <p>Among the four types of network motifs, the crosstalk was found to have the most enriched protein-protein interactions in their downstream regulatory targets. The topological properties of these motifs also revealed that they target crucial proteins in the protein interaction network and may serve important roles of biological functions.</p> <p>Conclusions</p> <p>Altogether, these results reveal the combinatorial regulatory patterns of transcription factors and microRNAs on the protein interactome, and provide further evidence to suggest the connection between gene regulatory network and protein interaction network.</p

Reduction in antioxidant enzyme expression and sustained inflammation enhance tissue damage in the subacute phase of spinal cord contusive injury

<p>Abstract</p> <p>Background</p> <p>Traumatic spinal cord injury (SCI) forms a disadvantageous microenvironment for tissue repair at the lesion site. To consider an appropriate time window for giving a promising therapeutic treatment for subacute and chronic SCI, global changes of proteins in the injured center at the longer survival time points after SCI remains to be elucidated.</p> <p>Methods</p> <p>Through two-dimensional electrophoresis (2DE)-based proteome analysis and western blotting, we examined the differential expression of the soluble proteins isolated from the lesion center (LC) at day 1 (acute) and day 14 (subacute) after a severe contusive injury to the thoracic spinal cord at segment 10. In situ apoptotic analysis was used to examine cell apoptosis in injured spinal cord after adenoviral gene transfer of antioxidant enzymes. In addition, administration of chondroitinase ABC (chABC) was performed to analyze hindlimb locomotor recovery in rats with SCI using Basso, Beattie and Bresnahan (BBB) locomotor rating scale.</p> <p>Results</p> <p>Our results showed a decline in catalase (CAT) and Mn-superoxide dismutase (MnSOD) found at day 14 after SCI. Accordingly, gene transfer of SOD was introduced in the injured spinal cord and found to attenuate cell apoptosis. Galectin-3, β-actin, actin regulatory protein (CAPG), and F-actin-capping protein subunit β (CAPZB) at day 14 were increased when compared to that detected at day 1 after SCI or in sham-operated control. Indeed, the accumulation of β-actin⁺immune cells was observed in the LC at day 14 post SCI, while most of reactive astrocytes were surrounding the lesion center. In addition, chondroitin sulfate proteoglycans (CSPG)-related proteins with 40-kDa was detected in the LC at day 3-14 post SCI. Delayed treatment with chondroitinase ABC (chABC) at day 3 post SCI improved the hindlimb locomotion in SCI rats.</p> <p>Conclusions</p> <p>Our findings demonstrate that the differential expression in proteins related to signal transduction, oxidoreduction and stress contribute to extensive inflammation, causing time-dependent spread of tissue damage after severe SCI. The interventions by supplement of anti-oxidant enzymes right after SCI or delayed administration with chABC can facilitate spinal neural cell survival and tissue repair.</p

Reduction in antioxidant enzyme expression and sustained inflammation enhance tissue damage in the subacute phase of spinal cord contusive injury

<p>Abstract</p> <p>Background</p> <p>Traumatic spinal cord injury (SCI) forms a disadvantageous microenvironment for tissue repair at the lesion site. To consider an appropriate time window for giving a promising therapeutic treatment for subacute and chronic SCI, global changes of proteins in the injured center at the longer survival time points after SCI remains to be elucidated.</p> <p>Methods</p> <p>Through two-dimensional electrophoresis (2DE)-based proteome analysis and western blotting, we examined the differential expression of the soluble proteins isolated from the lesion center (LC) at day 1 (acute) and day 14 (subacute) after a severe contusive injury to the thoracic spinal cord at segment 10. In situ apoptotic analysis was used to examine cell apoptosis in injured spinal cord after adenoviral gene transfer of antioxidant enzymes. In addition, administration of chondroitinase ABC (chABC) was performed to analyze hindlimb locomotor recovery in rats with SCI using Basso, Beattie and Bresnahan (BBB) locomotor rating scale.</p> <p>Results</p> <p>Our results showed a decline in catalase (CAT) and Mn-superoxide dismutase (MnSOD) found at day 14 after SCI. Accordingly, gene transfer of SOD was introduced in the injured spinal cord and found to attenuate cell apoptosis. Galectin-3, β-actin, actin regulatory protein (CAPG), and F-actin-capping protein subunit β (CAPZB) at day 14 were increased when compared to that detected at day 1 after SCI or in sham-operated control. Indeed, the accumulation of β-actin⁺immune cells was observed in the LC at day 14 post SCI, while most of reactive astrocytes were surrounding the lesion center. In addition, chondroitin sulfate proteoglycans (CSPG)-related proteins with 40-kDa was detected in the LC at day 3-14 post SCI. Delayed treatment with chondroitinase ABC (chABC) at day 3 post SCI improved the hindlimb locomotion in SCI rats.</p> <p>Conclusions</p> <p>Our findings demonstrate that the differential expression in proteins related to signal transduction, oxidoreduction and stress contribute to extensive inflammation, causing time-dependent spread of tissue damage after severe SCI. The interventions by supplement of anti-oxidant enzymes right after SCI or delayed administration with chABC can facilitate spinal neural cell survival and tissue repair.</p

Non-prompt surgery for patients with acute type A aortic dissection without pre-operative shock and malperfusion

BackgroundAcute type A aortic dissection (ATAAD) requires urgent surgical treatment. However, during daily practice, there were some patients with ATAAD sought for medical attention several days after symptoms occurred and some other patients hesitated to receive aortic surgery after the diagnosis of ATAAD was made. This study aims to investigate the surgical outcomes of non-prompt aortic surgery (delayed diagnosis caused by the patient or delayed surgery despite immediate diagnosis) for ATAAD patients.MethodsFrom November 2004 to June 2020, of more than 200 patients with ATAAD patients who underwent aortic surgery at our hospital, there were 30 patients without pre-operative shock and malperfusion who sought for medical attention with symptoms for several days or delayed aortic surgery several days later despite ATAAD was diagnosed. Of the 30 patients (median age 60.9, range 33.4~82.5 years) in the study group, there were 18 patients undergoing surgery when they arrived at our hospital (delayed diagnosis by the patient) and 12 patients receiving surgery days later (delayed surgery despite immediate diagnosis). Patients with prompt surgery after symptom onset (control group) were matched from our database by propensity score matching. The surgical mortality rate and post-operative morbidities were compared between the study group and control group.ResultsThe in-hospital mortality was 3.3% for the study group and 6.7% for the control group (p = non-significant). The incidence of post-operative cerebral permanent neurological defect was 0% for the study group and 13.3% for the control group (p = 0.112). There were three patients receiving aortic re-intervention or re-do aortic surgery during follow-up for the study group and two patients for the control group.ConclusionPrompt surgery for ATAAD is usually a good choice if everything is well prepared. Besides, urgent but non-prompt aortic surgery could also provide acceptable surgical results for ATAAD patients without pre-operative shock and malperfusion who did not seek medical attention or who could not make their minds to undergo surgery immediately after symptom onset. Hospitalization with intensive care is very important for pre-operative preparation and monitoring for the patients who decline prompt aortic surgery

Multimodality imaging and mathematical modelling of drug delivery to glioblastomas

MAJC would like to thank the Isaac Newton Institute for Mathematical Sciences for its hospitality during the programme “Coupling Geometric PDEs with Physics for Cell Morphology, Motility and Pattern Formation” supported by EPSRC Grant Number EP/K032208/1.Patients diagnosed with glioblastoma, an aggressive brain tumour, have a poor prognosis, with a median overall survival of less than 15 months. Vasculature within these tumours is typically abnormal, with increased tortuosity, dilation and disorganization and they typically exhibit a disrupted blood brain barrier. Although it has been hypothesized that the “normalization” of the vasculature resulting from anti-angiogenic therapies could improve drug delivery through improved blood flow, there is also evidence that suggests that the restoration of blood brain barrier integrity might limit the delivery of therapeutic agents and hence their effectiveness. In this paper we apply mathematical models of blood flow, vascular permeability and diffusion within the tumour microenvironment to investigate the effect of these competing factors on drug delivery. Preliminary results from the modelling indicate that all three physiological parameters investigated – flow rate, vessel permeability, and tissue diffusion coefficient – interact nonlinearly to produce the observed average drug concentration in the microenvironment.PostprintPeer reviewe

Cyclic Alopecia and Abnormal Epidermal Cornification in Zdhhc13-Deficient Mice Reveal the Importance of Palmitoylation in Hair and Skin Differentiation

Many biochemical pathways involved in hair and skin development have not been investigated. Here, we reported on the lesions and investigated the mechanism underlying hair and skin abnormalities in Zdhhc13skc4 mice with a deficiency in DHHC13, a palmitoyl-acyl transferase encoded by Zdhhc13. Homozygous affected mice showed ragged and dilapidated cuticle of the hair shaft (CUH, a hair anchoring structure), poor hair anchoring ability, and premature hair loss at early telogen phase of the hair cycle, resulting in cyclic alopecia. Furthermore, the homozygous affected mice exhibited hyperproliferation of the epidermis, disturbed cornification, fragile cornified envelope (CE, a skin barrier structure), and impaired skin barrier function. Biochemical investigations revealed that cornifelin, which contains five palmitoylation sites at cysteine residues (C58, C59, C60, C95, and C101), was a specific substrate of DHHC13 and that it was absent in the CUH and CE structures of the affected mice. Furthermore, cornifelin levels were markedly reduced when two palmitoylated cysteines were replaced with serine (C95S and C101S). Taken together, our results suggest that DHHC13 is important for hair anchoring and skin barrier function and that cornifelin deficiency contributes to cyclic alopecia and skin abnormalities in Zdhhc13skc4 mice

Inner sense of rhythm: percussionist brain activity during rhythmic encoding and synchronization

IntroductionThe main objective of this research is to explore the core cognitive mechanisms utilized by exceptionally skilled percussionists as they navigate complex rhythms. Our specific focus is on understanding the dynamic interactions among brain regions, respectively, related to externally directed cognition (EDC), internally directed cognition (IDC), and rhythm processing, defined as the neural correlates of rhythm processing (NCRP).MethodsThe research involved 26 participants each in the percussionist group (PG) and control group (CG), who underwent task-functional magnetic resonance imaging (fMRI) sessions focusing on rhythm encoding and synchronization. Comparative analyses were performed between the two groups under each of these conditions.ResultsRhythmic encoding showed decreased activity in EDC areas, specifically in the right calcarine cortex, left middle occipital gyrus, right fusiform gyrus, and left inferior parietal lobule, along with reduced NCRP activity in the left dorsal premotor, right sensorimotor cortex, and left superior parietal lobule. During rhythmic synchronization, there was increased activity in IDC areas, particularly in the default mode network, and in NCRP areas including the left inferior frontal gyrus and bilateral putamen. Conversely, EDC areas like the right dorsolateral prefrontal gyrus, right superior temporal gyrus, right middle occipital gyrus, and bilateral inferior parietal lobule showed decreased activity, as did NCRP areas including the bilateral dorsal premotor cortex, bilateral ventral insula, bilateral inferior frontal gyrus, and left superior parietal lobule.DiscussionPG’s rhythm encoding is characterized by reduced cognitive effort compared to CG, as evidenced by decreased activity in brain regions associated with EDC and the NCRP. Rhythmic synchronization reveals up-regulated IDC, down-regulated EDC involvement, and dynamic interplay among regions with the NCRP, suggesting that PG engages in both automatic and spontaneous processing simultaneously. These findings provide valuable insights into expert performance and present opportunities for improving music education

Serotonin receptor HTR6-mediated mTORC1 signaling regulates dietary restriction-induced memory enhancement

Dietary restriction (DR; sometimes called calorie restriction) has profound beneficial effects on physiological, psychological, and behavioral outcomes in animals and in humans. We have explored the molecular mechanism of DR-induced memory enhancement and demonstrate that dietary tryptophan-a precursor amino acid for serotonin biosynthesis in the brain-and serotonin receptor 5-hydroxytryptamine receptor 6 (HTR6) are crucial in mediating this process. We show that HTR6 inactivation diminishes DR-induced neurological alterations, including reduced dendritic complexity, increased spine density, and enhanced long-term potentiation (LTP) in hippocampal neurons. Moreover, we find that HTR6-mediated mechanistic target of rapamycin complex 1 (mTORC1) signaling is involved in DR-induced memory improvement. Our results suggest that the HTR6-mediated mTORC1 pathway may function as a nutrient sensor in hippocampal neurons to couple memory performance to dietary intake