Role of Jak/Stat pathway in the pathogenesis of breast cancer

The Jak/Stat signaling cascade mediates cell proliferation, differentiation, survival, apoptosis and immune responses. Aberrant activation of this pathway mediates neoplastic transformation and abnormal growth of many malignancies including breast cancer, the most common cancer among women, and the second leading cause of cancer deaths in women in United States. The mechanism by which the Jak/Stat pathway modulates the pathogenesis of breast cancer is unclear. This dissertation elucidates roles of Jak/Stat members that mediate the pathogenesis of breast cancer. For these studies, we used 4T1 mouse mammary tumor cells as a model which mimics human breast cancer. First, we investigated the role of Tyk2 tyrosine kinase in the pathogenesis of breast cancer. Here we show for the first time that compared with wild type mice, Tyk2 -/- mice show increased tumor growth rate as well as metastatic disease and splenomegaly when inoculated with 4T1 breast cancer cells. Such increased tumorigenicity was associated with a significant decrease of IFNg production in 4T1 tumor-bearing Tyk2 deficient mice T cells compared with wild type (WT) mice. We demonstrated that NK cells or CD8+ T cells control tumor growth in both Tyk2-/- and WT mice, but neither Tyk2-/- NK cells alone nor Tyk2-/- CD8+ T cells alone do not contribute to enhanced tumor growth and metastatic disease of Tyk2-/- mice. Tumor-bearing Tyk2-/- mice have increased level of myeloid-derived suppression cells than tumor-bearing mice. Tyk2-/- MDSCs have a slight increase in suppression of T cell proliferation. Since elevated phosphorylation of Stat3 has been seen in human and murine breast cancer, and expression of Stat3 in the mitochondria (mitoStat3) appears to have important affects on cell growth, we studied the ability of Stat3 targeted to the mitochondria (MLS Stat3) to influence growth and metastasis of 4T1 cells. We show that a serine mutant of Stat3 expressed in the mitochondria (Stat3 S727A) inhibits the ability of 4T1 tumor cells to grow and metastasize. In contrast, a serine to aspartic acid mutant of Stat3 (S727D) enhances tumorigenesis. We found that expression of mitochondrial-targeted Stat3 does not affect cell growth rate in cell culture under normal conditions, however in low glucose, the serine to alanine mutant shows reduced growth rate and ability to invade. Moreover, we found that expression of mitochondrial-targeted Stat3 protects cells from hypoxia. Our data indicate that serine phosphorylation of mitochondrial-localized Stat3 is required for cell transformation. In summary, our studies provided new insights into the role of Stat3 in breast cancer and suggest new therapeutic targets for the treatment of this disease

Elastic Modulus Calculation Model of a Soil-Rock Mixture at Normal or Freezing Temperature Based on Micromechanics Approach

Considering rock wrapped by soil in the mesoscopic structure of soil-rock mixture at normal temperature, a two-layer embedded model of single inclusion composite material was established to obtain the elastic modulus of soil-rock mixture. Given an interface ice interlayer attached between the soil and rock interface in the mesoscopic structure of soil-rock mixture at freezing temperature, a three-layer embedded model of double inclusion composite material and multistep multiphase micromechanics model was established to obtain the elastic modulus of a frozen soil-rock mixture. With the effect of structure pore with soil-rock mixture at normal temperature taken into consideration, its elastic modulus was calculated with the three-layer embedded model. An experimental comparison found that the predicted effect of the three-layer embedded model on the soil-rock mixture was better than that of the two-layer embedded model. The elastic modulus of soil-rock mixture gradually increased with the increase in rock content regardless of temperature. The increase rate of the elastic modulus of the soil-rock mixture increased quickly especially when the rock content is between 50% and 70%. The elastic modulus of the frozen soil-rock mixture is close to four times higher than that of the soil-rock mixture at a normal temperature

The effects of co-colonising ectomycorrhizal fungi on mycorrhizal colonisation and sporocarp formation in Laccaria japonica colonising seedlings of Pinus densiflora

Forest trees are colonised by different species of ectomycorrhizal (ECM) fungi that interact competitively or mutualistically with one another. Most ECM fungi can produce sporocarps. To date, the effects of co-colonising fungal species on sporocarp formation in ECM fungi remain unknown. In this study, we examined host plant growth, mycorrhizal colonisation, and sporocarp formation when roots of Pinus densiflora are colonised by Laccaria japonica and three other ECM fungal species (Cenococcum geophilum, Pisolithus sp., and Suillus luteus). Sporocarp numbers were recorded throughout the experimental period. The biomass, photosynthetic rate, and mycorrhizal colonisation rate of the seedlings were also measured at 45days, 62days, and 1year after seedlings were transplanted. Results indicated that C. geophilum and S. luteus may negatively impact mycorrhizal colonisation and sporocarp formation in L. japonica. Sporocarp formation in L. japonica was positively correlated with conspecific mycorrhizal colonisation but negatively correlated with the biomass of seedlings of P. densiflora. The co-occurring ECM fungi largely competed with L. japonica, resulting in various effects on mycorrhizal colonisation and sporocarp formation in L. japonica. A variety of mechanisms may be involved in the competitive interactions among the different ECM fungal species, including abilities to more rapidly colonise root tips, acquire soil nutrients, or produce antibiotics. These mechanisms need to be confirmed in further studies.Peer reviewe

Research progress of esketamine and postoperative delirium

Postoperative delirium (POD) is a common complication in elderly patients after surgery, significantly affecting prognosis and increasing mortality rates. The underlying mechanisms of POD remain unclear, with diverse risk factors making prevention difficult and treatment outcomes unsatisfactory. Esketamine is a high-affinity N-methyl-D-aspartate (NMDA) receptor antagonist known for its anesthetic and analgesic properties. Besides its widespread use in perioperative anesthesia and pain management, esketamine has shown promising clinical applications across various disciplines including psychiatry and critical care. This review summarizes recent advances and mechanisms of esketamine in preventing and treating POD, offering new insights for clinical practice

Optimal planning for partially self-sufficient microgrid with limited annual electricity exchange with distribution grid

Existing research on on-grid microgrid planning is carried out with a free trading assumption and without considering the limitation of annual electricity exchange. Therefore, the existing planning and sizing scheme may be not viable for the application of partially self-sufficient microgrid (PSSMG) with a limited amount of electricity exchange. To address this issue, a new planning method for PSSMG is proposed in this paper considering the limited annual electricity exchanging amount (AEEA). The sizing model and energy management are linearized and simultaneously integrated into one model, which could be solved in polynomial time. In order to effectively reduce the number of variables of a full year horizon and to cope with the uncertainty both of DGs and loads, a data-driven method based on K-means algorithm is utilized to choose a set of typical days that are representative of historical data of one full year. Finally, the validity and effectiveness of the proposed model are verified by comparative numerical simulations, and the sensitivity of limited AEEA to the planning scheme is analyzed

MDM2 promotes cancer cell survival through regulating the expression of HIF-1α and pVHL in retinoblastoma

Hypoxia is an important tumor feature and hypoxia-inducible factor 1 (HIF-1) is a master regulator of cell response to hypoxia. Mouse double minute 2 homolog (MDM2) promotes cancer cell survival in retinoblastoma (RB), with the underlying mechanism remaining elusive. In this study, we investigated the role of MDM2 and its relation to HIF-1α in RB. Expression analysis on primary human RB samples showed that MDM2 expression was positively correlated with that of HIF-1α while negatively correlated with von Hippel-Lindau protein (pVHL), the regulator of HIF-1α. In agreement, RB cells with MDM2 overexpression showed increased expression of HIF-1α and decreased expression of pVHL, while cells with MDM2 siRNA knockdown or MDM2-specific inhibitor showed the opposite effect under hypoxia. Further immuno-precipitation analysis revealed that MDM2 could directly interact with pVHL and promotes its ubiquitination and degradation, which consequently led to the increase of HIF-1α. Inhibition of MDM2 and/or HIF-1α with specific inhibitors induced RB cell death and decreased the stem cell properties of primary RB cells. Taken together, our study has shown that MDM2 promotes RB survival through regulating the expression of pVHL and HIF-1α, and targeting MDM2 and/or HIF-1α represents a potential effective approach for RB treatment

Molecular tracing of a suspected foodborne disease event caused by Bacillus cereus

ObjectiveTo trace Bacillus cereus （B. cereus） from foodborne disease outbreaks toidentify pathogens and cut off transmission.MethodsPulsed-field gel electrophoresis （PFGE） was performed. Furthermore， 12 isolates of B. cereus were subjected to PFGE. Subsequently， whole-genome sequencing （WGS） analysis was conducted on ten of these isolates. The WGS data were analyzed and assembled using BioNumerics software. Multilocus sequence typing （MLST）， virulence gene profiles， and single nucleotide polymorphisms （SNPs） were analyzed using assembled sequences.ResultsPFGE analysis classified the 12 B. cereus strains into nine pulsotypes. The three B. cereus isolates with the same PFGE pattern belonged to ST1435， and there were only three SNPs in the three ST1435 strains. The two B. cereus isolates with the same PFGE patterns were ST24 with one SNP between them， and the two ST24 isolates harbored hlbACD. These results indicate that the B. cereus isolates belonged to the same clone. The remaining three B. cereus strains also contained hlbACD.ConclusionFood-borne illness events caused by B. cereus are complex and are sources of contamination. Therefore， it will be necessary to strengthen the hygiene surveillance of food sources and workers and to pay more attention to cleaning and disinfecting environments and facilities， which will be important for preventing and controlling foodborne diseases

Current management of intracerebral haemorrhage in China: a national, multi-centre, hospital register study

<p>Abstract</p> <p>Background</p> <p>We aimed to examine current practice of the management and secondary prevention of intracerebral haemorrhage (ICH) in China where the disease is more common than in Western populations.</p> <p>Methods</p> <p>Data on baseline characteristics, management in-hospital and post-stroke, and outcome of ICH patients are from the ChinaQUEST (QUality Evaluation of Stroke Care and Treatment) study, a multi-centre, prospective, 62 hospital registry in China during 2006-07.</p> <p>Results</p> <p>Nearly all ICH patients (n = 1572) received an intravenous haemodiluting agent such as mannitol (96%) or a neuroprotectant (72%), and there was high use of intravenous traditional Chinese medicine (TCM) (42%). Neurosurgery was undertaken in 137 (9%) patients; being overweight, having a low Glasgow Coma Scale (GCS) score on admission, and Total Anterior Circulation Syndrome (TACS) clinical pattern on admission, were the only baseline factors associated with this intervention in multivariate analyses. Neurosurgery was associated with nearly three times higher risk of death/disability at 3 months post-stroke (odd ratio [OR] 2.60, p < 0.001). Continuation of antihypertensives in-hospital and at 3 and 12 months post-stroke was reported in 732/935 (78%), 775/935 (83%), and 752/935 (80%) living patients with hypertension, respectively.</p> <p>Conclusions</p> <p>The management of ICH in China is characterised by high rates of use of intravenous haemodiluting agents, neuroprotectants, and TCM, and of antihypertensives for secondary prevention. The controversial efficacy of these therapies, coupled with the current lack of treatments of proven benefit, is a call for action for more outcomes based research in ICH.</p

Disruption of splicing-regulatory elements using CRISPR/Cas9 to rescue spinal muscular atrophy in human iPSCs and mice

We here report a genome-editing strategy to correct spinal muscular atrophy (SMA). Rather than directly targeting the pathogenic exonic mutations, our strategy employed Cas9 and guide-sgRNA for the targeted disruption of intronic splicing-regulatory elements. We disrupted intronic splicing silencers (ISSs, including ISS-N1 and ISS + 100) of survival motor neuron (SMN) 2, a key modifier gene of SMA, to enhance exon 7 inclusion and full-length SMN expression in SMA iPSCs. Survival of splicing-corrected iPSC-derived motor neurons was rescued with SMN restoration. Furthermore, co-injection of Cas9 mRNA from Streptococcus pyogenes (SpCas9) or Cas9 from Staphylococcus aureus (SaCas9) alongside their corresponding sgRNAs targeting ISS-N1 into zygotes rescued 56% and 100% of severe SMA transgenic mice (Smn , SMN2 ). The median survival of the resulting mice was extended to >400 days. Collectively, our study provides proof-of-principle for a new strategy to therapeutically intervene in SMA and other RNA-splicing-related diseases. -/- tg/

Discriminating physiological from non-physiological interfaces in structures of protein complexes: A community-wide study

Reliably scoring and ranking candidate models of protein complexes and assigning their oligomeric state from the structure of the crystal lattice represent outstanding challenges. A community-wide effort was launched to tackle these challenges. The latest resources on protein complexes and interfaces were exploited to derive a benchmark dataset consisting of 1677 homodimer protein crystal structures, including a balanced mix of physiological and non-physiological complexes. The non-physiological complexes in the benchmark were selected to bury a similar or larger interface area than their physiological counterparts, making it more difficult for scoring functions to differentiate between them. Next, 252 functions for scoring protein-protein interfaces previously developed by 13 groups were collected and evaluated for their ability to discriminate between physiological and non-physiological complexes. A simple consensus score generated using the best performing score of each of the 13 groups, and a cross-validated Random Forest (RF) classifier were created. Both approaches showed excellent performance, with an area under the Receiver Operating Characteristic (ROC) curve of 0.93 and 0.94, respectively, outperforming individual scores developed by different groups. Additionally, AlphaFold2 engines recalled the physiological dimers with significantly higher accuracy than the non-physiological set, lending support to the reliability of our benchmark dataset annotations. Optimizing the combined power of interface scoring functions and evaluating it on challenging benchmark datasets appears to be a promising strategy