Transcriptomic and proteomic strategies to reveal the mechanism of Gymnocypris przewalskii scale development.

BACKGROUND: Fish scales are typical products of biomineralization and play an important role in the adaptation of fish to their environment. The Gymnocypris przewalskii scales are highly specialized, with scales embedded in only specific parts of the dermis, such as the areas around the anal fin and branchiostegite, making G. przewalskii an ideal material for biomineralization research. In this study, we aimed to unveil genes and pathways controlling scale formation through an integrated analysis of both transcriptome and proteome, of which G. przewalskii tissues of the dorsal skin (no scales) and the rump side skin (with scales) were sequenced. The sequencing results were further combined with cellular experiments to clarify the relationship between genes and signaling pathways. RESULTS: The results indicated the following: (1) a total of 4,904 differentially expressed genes were screened out, including 3,294 upregulated genes and 1,610 downregulated genes (with a filtering threshold of |log2Fold-Change|> 1 and p-adjust < 0.05). The identified differentially expressed genes contained family members such as FGF, EDAR, Wnt10, and bmp. (2) A total of 535 differentially expressed proteins (DEPs) were filtered out from the proteome, with 204 DEPs downregulated and 331 DEPs upregulated (with a filtering threshold of |Fold-Change|> 1.5 and p < 0.05). (3) Integrated analyses of transcriptome and proteome revealed that emefp1, col1a1, col6a2, col16a1, krt8, and krt18 were important genes contributing to scale development and that PI3K-AKT was the most important signaling pathway involved. (4) With the use of the constructed G. przewalskii fibroblast cell line, emefp1, col1a1, col6a2, col16a1, krt8, and krt18 were confirmed to be positively regulated by the PI3K-AKT signaling pathway. CONCLUSION: This study provides experimental evidence for PI3K-AKT controlled scale development in G. przewalskii and would benefit further study on stress adaptation, scale biomineralization, and the development of skin appendages.

Thermobacterium salinum gen. nov., sp. nov., a novel member of the family Flavobacteriaceae isolated from a hydrothermal zone.

A Gram-stain-negative, aerobic, non-motile and rod-shaped bacterial strain, designated as strain TK19130T, was isolated from the Lonqi hydrothermal zone in the Southwest Indian Ridge. Growth occurred with 1-12 % (w/v) NaCl (optimum, 2-4 %), at 10-40 °C (optimum, 30-35 °C) and at pH 6.0-9.0 (optimum, pH 7.0-8.0). The genome of strain TK19130T was 3.15 Mb, with a DNA G+C content of 41.35 %. Based on the results of 16S rRNA gene sequence analysis, strain TK19130T was affiliated with the family Flavobacteriaceae, in which the highest similarity was 90.54 % to Aureisphaera salina A6D-50T, under the genus demarcation boundary (94.50 %). Average nucleotide identity values between strain TK19130T and adjacent strains were 67.17-72.00 %, lower than the recommended threshold of 73.98 % for genus delineation. The predominant respiratory quinone of strain TK19130T was menaquinone 6. Major polar lipids were phosphatidylethanolamine, three aminolipids and one unidentified polar lipid. Major fatty acids were detected as iso-C15 : 1 G, iso-C15 : 0 and iso-C17 : 0 3-OH. Based on the polyphasic taxonomic evidence presented above, strain TK19130T formed an independent branch representing a new species of a novel genus within the family Flavobacteriaceae, for which the name Thermobacterium salinum gen. nov., sp. nov. is proposed. The type strain is TK19130T (=CGMCC 1.18993T=JCM 35842T=MCCC M28200T).

Bacterial communities associated with mushrooms in the Qinghai-Tibet Plateau are shaped by soil parameters.

Fungi capable of producing fruit bodies are essential food and medicine resources. Despite recent advances in the study of microbial communities in mycorrhizospheres, little is known about the bacterial communities contained in fruit bodies. Using high-throughput sequencing, we investigated the bacterial communities in four species of mushrooms located on the alpine meadow and saline-alkali soil of the Qinghai-Tibet Plateau (QTP). Proteobacteria (51.7% on average) and Actinobacteria (28.2% on average) were the dominant phyla in all of the sampled fairy ring fruit bodies, and Acidobacteria (27.5% on average) and Proteobacteria (25.7% on average) dominated their adjacent soils. For the Agria. Bitorquis, Actinobacteria was the dominant phylum in its fruit body (67.5% on average) and adjacent soils (65.9% on average). The alpha diversity (i.e., Chao1, Shannon, Richness, and Simpson indexes) of the bacterial communities in the fruit bodies were significantly lower than those in the soil samples. All of the fungi shared more than half of their bacterial phyla and 16.2% of their total operational taxonomic units (OTUs) with their adjacent soil. Moreover, NH4+ and pH were the key factors associated with bacterial communities in the fruit bodies and soils, respectively. These results indicate that the fungi tend to create a unique niche that selects for specific members of the bacterial community. Using culture-dependent methods, we also isolated 27 bacterial species belonging to three phyla and five classes from fruit bodies and soils. The strains isolated will be useful for future research on interactions between mushroom-forming fungi and their bacterial endosymbionts.

Heterozygosity for a Pathogenic Variant in SLC12A3 That Causes Autosomal Recessive Gitelman Syndrome Is Associated with Lower Serum Potassium.

BACKGROUND: Potassium levels regulate multiple physiologic processes. The heritability of serum potassium level is moderate, with published estimates varying from 17% to 60%, suggesting genetic influences. However, the genetic determinants of potassium levels are not generally known. METHODS: A whole-exome sequencing association study of serum potassium levels in 5812 subjects of the Old Order Amish was performed. A dietary salt intervention in 533 Amish subjects estimated interaction between p.R642G and sodium intake. RESULTS: A cluster of variants, spanning approximately 537 kb on chromosome 16q13, was significantly associated with serum potassium levels. Among the associated variants, a known pathogenic variant of autosomal recessive Gitelman syndrome (p.R642G SLC12A3) was most likely causal; there were no homozygotes in our sample. Heterozygosity for p.R642G was also associated with lower chloride levels, but not with sodium levels. Notably, p.R642G showed a novel association with lower serum BUN levels. Heterozygotes for p.R642G had a two-fold higher rate of self-reported bone fractures and had higher resting heart rates on a low-salt diet compared with noncarriers. CONCLUSIONS: This study provides evidence that heterozygosity for a pathogenic variant in SLC12A3 causing Gitelman syndrome, a canonically recessive disorder, contributes to serum potassium concentration. The findings provide insights into SLC12A3 biology and the effects of heterozygosity on electrolyte homeostasis and related subclinical phenotypes that may have implications for personalized medicine and nutrition.

Epigenetics Variation and Pathogenesis in Diabetes.

PURPOSE OF REVIEW: Great strides have recently been made in elucidating the role of genetic sequence variation in diabetes pathogenesis. Increasingly, studies are focusing on other factors that may contribute to the pathogenesis of diabetes, such as epigenetics, a term "traditionally" encompassing changes to the DNA that do not alter sequence and are heritable (primary methylation and histone modification) but often expanded to include microRNAs. This review summarizes latest findings on the role of epigenetics in diabetes pathogenesis. RECENT FINDINGS: Recent studies illustrate roles for methylation changes, histone modification, imprinting, and microRNAs across several diabetes types and complications. Notably, methylation changes in the human leukocyte antigen (HLA) region have been found to precede the development of type 1 diabetes. In type 2 diabetes, lifestyle factors appear to interact with epigenetic mechanisms in pathogenesis. Emerging technologies have allowed increasingly comprehensive descriptive analysis of the role of epigenetic mechanisms in diabetes pathogenesis which have yielded meaningful insights into effects on expression of relevant genes. These findings have the potential to inform future development of predictive testing to enable primary prevention and further work to uncover the complex pathogenesis of diabetes.

miR-598 inhibits metastasis in colorectal cancer by suppressing JAG1/Notch2 pathway stimulating EMT.

MicroRNAs (miRNAs) are a class of endogenous, evolutionarily conserved small non-coding RNA molecules that mediate the posttranscriptional process of target gene, leading to translational repression or degradation of target mRNAs. A series of studies have indicated that miRNAs play an important role in tumor initiation, development and progression. In this study, we found that down regulation of miR-598 was a frequent event in CRC tissues compared to the paracarcinoma tissues. And the study demonstrated that miR-598 was implicated in CRC metastasis. Transwell migration assay revealed that elevated miR-598 expression reduces CRC cell migration. Moreover, our study showed that suppression of miR-598 expression induces CRC cell epithelialmesenchymal transition(EMT) and overexpression of miR-598 inhibits CRC cell EMT. In addition, bioinformatics target prediction identified JAG1 as a putative target of miR-598. Knockdown of miR-598 was shown to upregulate JAG1 expression. Furthermore, overexpression of miR-598 suppressed the expression of JAG1. Consistent results were also obtained when the regulation of JAG1 expression by miR-598 was further specified in CRC tissues. Moreover, overexpression of JAG1 induces epithelialmesenchymal transition(EMT) and promotes the metastasis of CRC cells. Decreased Notch2 expression suppresses CRC cells metastasis and EMT. Together, these results indicate that miR-598 is a novel regulator of colorectal cancer metastasis. Our data suggest miR-598 is implicated in regulating Epithelial-mesenchymal transitions by directly suppressing its downstream target gene JAG1 to inactivate Notch signaling pathway.

Human germline and pan-cancer variomes and their distinct functional profiles.

Identification of non-synonymous single nucleotide variations (nsSNVs) has exponentially increased due to advances in Next-Generation Sequencing technologies. The functional impacts of these variations have been difficult to ascertain because the corresponding knowledge about sequence functional sites is quite fragmented. It is clear that mapping of variations to sequence functional features can help us better understand the pathophysiological role of variations. In this study, we investigated the effect of nsSNVs on more than 17 common types of post-translational modification (PTM) sites, active sites and binding sites. Out of 1 705 285 distinct nsSNVs on 259 216 functional sites we identified 38 549 variations that significantly affect 10 major functional sites. Furthermore, we found distinct patterns of site disruptions due to germline and somatic nsSNVs. Pan-cancer analysis across 12 different cancer types led to the identification of 51 genes with 106 nsSNV affected functional sites found in 3 or more cancer types. 13 of the 51 genes overlap with previously identified Significantly Mutated Genes (Nature. 2013 Oct 17;502(7471)). 62 mutations in these 13 genes affecting functional sites such as DNA, ATP binding and various PTM sites occur across several cancers and can be prioritized for additional validation and investigations.

[Outcomes and prognostic factors of distant metastasis in patients with advanced cervical squamous cell carcinoma treated with concurrent chemoradiotherapy].

OBJECTIVE: To evaluate the outcomes and prognostic factors of distant metastasis in patients with advanced cervical squamous cell carcinoma treated with concurrent chemoradiotherapy (CCRT). METHODS: A total of 118 patients with International Federation of Gynecology and Obstetrics (FIGO, 2009 version) stage II b-IVa cervical squamous cell carcinoma treated with CCRT between 2006 and 2010 in the Second Affiliated Hospital of Dalian Medical University were analyzed. Their median age was 48 years (range, 23-70 years). FIGO stages were as follows: IIb stage 56 cases, IIIa stage 6 cases, IIIb stage 52 cases, and IVa stage 4 cases. Of the all patients, 55 cases showed bulkly tumor (tumor size >4 cm) and 35 cases were pelvic lymph node positive. Forty patients had pretreatment hemoglobin (Hb) levels no greater than 110 g/L. Patients with elevated squamous cell carcinoma antigen (SCC- Ag) >1.5 µg/L before CCRT and at one month after CCRT were 91 cases and 34 cases, respectively. Kaplan-Meier method was used to estimate survival. For the analysis of prognostic factors affecting distant metastasis, log- rank test was used for univariate analysis, and Cox proportional hazard model was used for multivariate analysis. RESULTS: Thirty- seven patients were diagnosed with recurrence, 19 cases of whom developed distant metastasis, 13 cases developed loco-regional recurrence and 5 cases had both distant and loco-regional recurrence. The 5- year overall survival rates and distant disease- free survival of all patients were 64.0% and 78.8% , respectively. Two patients had grade 3 acute gastrointestinal toxicity (mainly diarrhea) and 20 cases had grade 3 to 4 hematologic toxicity. Seven patients experienced grade 3 to 4 late toxicity, 5 cases of them were gastrointestinal and 2 cases were genitourinary toxicity. Univariate analysis showed that FIGO stages, SCC-Ag level at one month after treatment, pretreatment hemoglobin level, and pelvic lymph node metastasis were significantly correlated with distant metastasis (all P < 0.05). Multivariate analysis showed that FIGO stage, SCC- Ag level at one month after treatment, and pelvic lymph node metastasis were independent prognostic factors for distant metastasis (all P < 0.05). CONCLUSIONS: For stage IIb-IVa cervical squamous cell carcinoma, the regimen of CCRT was efficacious and safe. The predictive factors for distant metastasis in patients with IIb-IVa stage squamous cell carcinoma of cervix treated with CCRT included FIGO stage, SCC- Ag level at one month after treatment, and pelvic lymph node metastasis. New treatment strategies should be considered to control distant metastasis for these patients.

Partial GCK gene deletion mutations causing maturity-onset diabetes of the young.

AIMS: Maturity-onset diabetes of the young (MODY) is an autosomal dominant monogenic form of diabetes, and glucokinase-maturity-onset diabetes of the young (GCK-MODY), or MODY 2, being the most prevalent type. However, the presence of copy number variants (CNVs) may lead to misdiagnoses, as genetic testing for MODY is typically reliant on sequencing techniques. This study aimed to describe the process of diagnosis in a Chinese pedigree with an exon 8-10 deletion of the GCK gene. METHODS: This study collected clinical data and medical history through direct interviews with the patient and reviewing relevant medical records. Sanger sequencing and whole exome sequencing (WES) were conducted over years of follow up. WES-based CNV sequencing technology was used to detect CNVs and the results were validated by multiplex ligation-dependent amplification dosage assay (MLPA). Additionally, we reviewed the previously reported cases caused by heterozygous exon deletion of the GCK gene. RESULTS: WES-based CNV detection revealed a heterozygous exon 8-10 deletion in the GCK gene within this particular pedigree after Sanger sequencing and WES failed to find causal variants in single nucleotide variations (SNVs) and small indels. The deletion was considered pathogenic according to ACMG/AMP and ClinGen guidelines. Most of the previously reported cases caused by heterozygous exon deletion or whole gene deletion of the GCK gene present similarly to GCK-MODY caused by SNVs and small indels. CONCLUSIONS: This study contributed to progress in our comprehension of the mutation spectrum of the GCK gene and underscored the significance of CNV detection in the genetic testing of MODY.

In Vitro Functional Analysis Can Aid Precision Diagnostics of HNF1B-MODY.

Precision medicine relies on accurate and consistent classification of sequence variants. A correct diagnosis of hepatocyte nuclear factor (HNF) 1B maturity-onset diabetes of the young, caused by pathogenic variants in the HNF1B gene, is important for optimal disease management and prognosis, and it has implications for genetic counseling and follow-up of at-risk family members. We hypothesized that the functional characterization could provide valuable information to assist the interpretation of pathogenicity of HNF1B variants. Using different in vitro functional assays, variants identified among 313 individuals, suspected to have monogenic diabetes with or without kidney disease, were characterized. The data from the functional assays were subsequently conjugated with obtained clinical, biochemical, and in silico data. Two variants (p.A167P, p.H336Pfs∗22) showed severe loss of function due to impaired transactivation, reduced DNA binding (p.A167P), and mRNA instability (p.A167P). Although both these variant carriers were diagnosed with diabetes, the p.H336Pfs∗22 carrier also had congenital absence of a kidney, which is a characteristic trait for HNF1B maturity-onset diabetes of the young. Functional analysis of the p.A167P variant revealed damaging effects on HNF-1B protein function, which may warrant imaging of the kidneys and/or pancreas. In addition, the current study has generated important data, including evidence supporting the benign functional impact of five variants (p.D82N, p.T88A, p.N394D, p.V458G, and p.T544A), and piloting new approaches that will prove critical for the growth of HNF1B-diabetes diagnosis.

Progress and prospects in stem cell therapy.

In the past few years, progress being made in stem cell studies has incontestably led to the hope of developing cell replacement based therapy for diseases deficient in effective treatment by conventional ways. The induced pluripotent stem cells (iPSCs) are of great interest of cell therapy research because of their unrestricted self-renewal and differentiation potentials. Proof of principle studies have successfully demonstrated that iPSCs technology would substantially benefit clinical studies in various areas, including neurological disorders, hematologic diseases, cardiac diseases, liver diseases and etc. On top of this, latest advances of gene editing technologies have vigorously endorsed the possibility of obtaining disease-free autologous cells from patient specific iPSCs. Here in this review, we summarize current progress of stem cell therapy research with special enthusiasm in iPSCs studies. In addition, we compare current gene editing technologies and discuss their potential implications in clinic application in the future.

A Chinese family with cat eye syndrome and abnormality of eye movement: First case report.

Background: Cat eye syndrome (CES) is a rare disease with a wide spectrum of phenotypic variability that is observed in 1:150,000 newborns. CES is characterized clinically by the combination of iris coloboma, anal atresia, and preauricular tags and/or pits. Many eye malformations have been reported to be associated with CES, such as iris and chorioretinal coloboma. However, an abnormality of eye movement has not been previously reported. Case presentation: We report on a Chinese family carrying a 22q11.1-q11.21 duplication of 1.7Mb tetrasomy (chr22:16,500,000-18,200,000, hg38) in two generations. Based on the proband and her father's clinical manifestations, including ophthalmological examination, cytogenetic analysis, FISH, CNV-seq, and WES, the diagnosis of CES with an abnormality of eye movement was made. Conclusion: Our findings broadened the symptom spectrum of CES syndrome and laid the foundation for pathogenesis, diagnostic targets, and drug research on the abnormality of eye movement, and were helpful for early diagnosis and intervention of CES.

Phase Change Composite Microcapsules with Low-Dimensional Thermally Conductive Nanofillers: Preparation, Performance, and Applications.

Phase change materials (PCMs) have been extensively utilized in latent thermal energy storage (TES) and thermal management systems to bridge the gap between thermal energy supply and demand in time and space, which have received unprecedented attention in the past few years. To effectively address the undesirable inherent defects of pristine PCMs such as leakage, low thermal conductivity, supercooling, and corrosion, enormous efforts have been dedicated to developing various advanced microencapsulated PCMs (MEPCMs). In particular, the low-dimensional thermally conductive nanofillers with tailorable properties promise numerous opportunities for the preparation of high-performance MEPCMs. In this review, recent advances in this field are systematically summarized to deliver the readers a comprehensive understanding of the significant influence of low-dimensional nanofillers on the properties of various MEPCMs and thus provide meaningful enlightenment for the rational design and multifunction of advanced MEPCMs. The composition and preparation strategies of MEPCMs as well as their thermal management applications are also discussed. Finally, the future perspectives and challenges of low-dimensional thermally conductive nanofillers for constructing high performance MEPCMs are outlined.

Radiotherapy dosimetry and radiotherapy related complications of immediate implant-based reconstruction after breast cancer surgery.

Backgrounds: The impact of immediate implant-based breast reconstruction (IBBR) on the delivery of radiotherapy plans remains controversial. This study aimed to compare the differences in radiotherapy dosimetry, complications of radiotherapy, and quality of life in patients who underwent modified radical mastectomy combined with or without IBBR. Methods: We retrospectively collected 104 patients with breast cancer who underwent intensity-modulated radiation therapy after modified radical mastectomy with IBBR (n =46) or not (n =58) from January 2017 to December 2021. The dosimetric differences in radiotherapy of planning target volume (PTV) and organs at risk and the differences in complications of radiotherapy between the two groups were compared. We also applied the functional assessment of cancer therapy-breast cancer (FACT-B) score to compare the difference in quality of life. The chi-square test and independent samples t-test were used to analyze the above data. Results: IBBR group was associated with higher PTV volumes, PTV D98, V95, and lower PTV Dmean, D2 compared with the non-reconstruction group (P<0.05). IBBR group also had lower radiotherapy dosimetric parameters in the ipsilateral lung and the heart of left breast cancer patients. The differences in the rates of radiation pneumonia (RP) and radiation dermatitis (RD) between the two groups were not statistically significant (P > 0.05). Moreover, FACT-B scores at 6 months after radiotherapy in patients with IBBR were higher than those without reconstruction (P < 0.05). Conclusion: Patients with IBBR achieved better radiation dosimetry distribution and higher quality of life without more complications of radiotherapy.

Fabricating Well-Dispersed Poly(Vinylidene Fluoride)/Expanded Graphite Composites with High Thermal Conductivity by Melt Mixing with Maleic Anhydride Directly.

Maleic anhydride (MA) is introduced to fabricate poly(vinylidene fluoride)/expanded graphite (PVDF/EG) composites via one-step melt mixing. SEM micrographs and WAXD results have demonstrated that the addition of MA helps to exfoliate and disperse the EG well in the PVDF matrix by promoting the mobility of PVDF molecular chains and enhancing the interfacial adhesion between the EG layers and the PVDF. Thus, much higher thermal conductivities are obtained for the PVDF/MA/EG composites compared to the PVDF/EG composites that are lacking MA. For instance, The PVDF/MA/EG composite prepared with a mass ratio of 93:14:7 exhibits a high thermal conductivity of up to 0.73 W/mK. It is 32.7% higher than the thermal conductivity of the PVDF/EG composite that is prepared with a mass ratio of 93:7. Moreover, the introduction of MA leads to an increased melting peak temperature and crystallinity due to an increased nucleation site provided by the uniformly dispersed EG in the PVDF matrix. This study provides an efficient preparation method for PVDF/EG composites with a high thermal conductivity.

Prevalence and associated factors of inappropriate hospital admissions and days of children in a secondary hospital in Shanghai, China.

BACKGROUND: Although the appropriateness of hospital utilization of adults and the elderly in China was audited by several studies, the appropriateness of hospital use by children in Shanghai remains to be determined. This study aims to assess the level of inappropriate hospital admissions and hospital days, to detect factors associated with inappropriateness, and to elucidate reasons for inappropriateness. METHODS: A retrospective review of the records of 291 admissions and 1449 hospital days of children inpatients from a secondary hospital in Shanghai was performed by two reviewers using the Chinese version Pediatric Appropriateness Evaluation Protocol (C-PAEP). Demographics, socio-economic characteristics, and other admission- or hospital stay-related information were collected and analyzed to determine factors associated with inappropriateness utilizing multivariate regression models. RESULTS: 38.5% (n = 112) of admissions and 9.5% (n = 137) of hospital days were categorized as inappropriate, according to the C-PAEP. Children who were non-Shanghai residents (p < 0.001), admitted through the emergency sector (p = 0.030), and/or received services in a surgical ward (p < 0.001) had a higher risk of being admitted inappropriately. Payment method (p = 0.006), service type (p < 0.001), comorbidity (p = 0.016), length of stay (p = 0.007), and appropriateness of admission (p < 0.001) were found to be associated with prevalence of inappropriate hospital days. Approximately three-fourths of the inappropriate admissions were premature admissions (75.9%, n = 85). The most frequent reasons for inappropriate hospital days were awaiting test results (34.3%, n = 47), awaiting surgery (19.7%, n = 27), awaiting test execution (10.9%, n = 15), and family unprepared for home care (10.9%, n = 15). CONCLUSIONS: Although the extent of inappropriate hospital days was moderate compared with that found by previous investigations, the prevalence of inappropriateness of admission was considerable. To enhance the appropriateness of hospital care for children, interventions could be implemented according to the associated factors and identified causes.

Sensitization of cervical cancer cells to radiation by the cyclin-dependent kinase inhibitor dinaciclib.

Dinaciclib is a selective cyclin-dependent kinase inhibitor, but its radiosensitizing effect remains unclear. The aim of this study is to investigate the radiosensitizing effect of Dinaciclib on cervical cancer cells. Two cervical cancer cell lines, Hela and Siha, were selected, and the IC50 was determined by CCK8. The radiosensitizing effect of Dinaciclib was verified by plate cloning assay, and the G2/M phase arrest and apoptosis of IR cells were verified by flow cytometry. Immunofluorescence assay was used to verify the formation of γH2AX foci following DNA damage. Western blot was performed to detect cell cycle, apoptosis, autophagy, and DNA damage-related pathways. Dinaciclib increased the cell sensitivity to IR. IR induced G2/M phase arrest and apoptosis, and Dinaciclib enhanced this effect. Further, Dinaciclib delayed DNA repair, including non-homologous end joining repair and homologous recombination repair, and reduced the expression of DNA repair proteins Ku80 (SiHa cells), Ku70, and RAD51, as well as the expression of apoptotic marker Bcl-2. The expression of autophagy marker Beclin1 induced tumor cell death and increased the formation of DNA damage marker γH2AX foci. Dinaciclib improves the sensitivity of cervical cancer cells to IR by inducing cell cycle arrest, delaying DNA repair, and increasing apoptosis. However, further research is needed to unravel the complexity of DNA repair pathways.

A hierarchical system of covalent and dual non-covalent crosslinks promotes the toughness and self-healing properties of polymer hydrogels.

While it is challenging to simultaneously achieve both high mechanical performance and self-healing ability within one polymer hydrogel network, we, herein, synthesized a novel class of hydrogels based on a combination of chemical and dual non-covalent crosslinks via micellar polymerization of 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate, end-capped by 2-hydroxyethyl methacrylate (IPDI-HEMA), with acrylamide (AM). The prepared hydrogels were demonstrated to possess a tensile elongation at a break of at least 1900%, a fracture energy of 138.4 kJ m-3, and remarkable self-healing behaviors (e.g., a strong self-healing ability achieved at ambient temperature without the need for any stimulus or healing agent). The multiple crosslinks developed in this study for one polymer hydrogel network are significant steps to construct the desired functional hydrogels with excellent self-healing and mechanical properties.

PPARγ/LXRα axis mediated phenotypic plasticity of lung fibroblasts in silica-induced experimental silicosis.

Silicosis is a disease mainly caused by pulmonary interstitial fibrosis caused by long-term inhalation of dust with excessively high content of free SiO2. Transdifferentiation of lung fibroblasts into myofibroblasts is an important cellular basis for silicosis, but the key transcription factors (TFs) involved in this process are still unclear. In order to explore the biological regulation of transcription factor PPARγ/LXRα in silica-induced pulmonary fibrosis, this study explored the molecular mechanism of PPARγ/LXRα involved in regulating transcription factors related to SiO2-induced lung injury at the cellular level and in animal models. ChIP-qPCR detected that PPARγ directly regulated the transcriptional activity of the LXRα gene promoter, while the PPARγ agonist RSG increased the expression of LXRα. In addition, we demonstrated in the cell model that upregulation of LXRα can inhibit silica-mediated fibroblast transdifferentiation, accompanied by an increase in the expression of SREBF1, PLTP and ABCA1. The results of LXRα silencing experiment matched those of overexpression experiment. These studies explored the role of LXRα in plasticity and phenotypic transformation between lung fibroblasts and myofibroblasts. Therefore, inhibiting or reversing the transdifferentiation of lung fibroblasts to myofibroblasts by intervening PPARγ/LXRα may provide a new therapeutic target for the treatment of silicosis.

Levetiracetam alleviates cognitive decline in Alzheimer's disease animal model by ameliorating the dysfunction of the neuronal network.

Background: Patients with Alzheimer's disease (AD) have a significantly higher risk of seizures than other individuals in an age-matched population, suggesting a close association between epilepsy and AD. We aimed to examine the effects of levetiracetam (LEV)-a drug for treating seizures-on learning and memory and the neuropathological features of AD. Methods: We crossbred APP23 mice with microtubule-associated protein tau (MAPT) transgenic mice to generate APP23/MAPT mice. These mice were treated with different concentrations of LEV in the presence of kainic acid (KA) for 3 months. Results: Low doses of LEV alleviated the effects of KA on memory defects in APP23/MAPT mice. Mechanistic investigations showed that low concentrations of LEV decreased tau phosphorylation by reducing the activities of cyclin-dependent kinase 5 and glycogen synthase kinase 3α/ß, thus rescuing neurons from synaptic dystrophy and apoptosis. Low doses of LEV inhibited the effects of KA (i.e., inducing neuroinflammation and impairing the autophagy of amyloid ß-peptide), thus improving cognitive decline. High concentrations of LEV decreased the production and deposition of amyloid ß-peptide (Aß) by reducing the expression of ß-site APP-cleaving enzyme 1 and presenilin 1. However, high concentrations of LEV also induced neuronal apoptosis, decreased movement ability in mice, and did not alleviate cognitive decline in AD mice. Conclusion: Our results support the hypothesis that aberrant network activity contributes to the synaptic and cognitive deficits in APP23/MAPT mice. A low concentration of LEV may help ameliorate abnormalities of AD; however, a high LEV concentration did not induce similar results.