Miracle-dz/UniFAR-FTUs huggingface dataset:
Negative regulation of CDK6 expression by microRNA‐126‐5p and its influence on the proliferation and invasion of esophageal cancer cells

The present study aimed to investigate the expression of cyclin‐dependent kinase 6 (CDK6) and microRNA‐126‐5p (miR‐126‐5p) in esophageal cancer tissues and cells, and their effect on esophageal cancer cell proliferation and invasion, and to explore the potential molecular mechanisms. The relative expression levels of CDK6 and miR‐126‐5p in esophageal cancer tissue, paracancerous tissue, and HEEC and EC109 cells were determined and compared using reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR). A miR‐126‐5p overexpression vector was constructed and a stable EC109 cell line expressing miR‐126‐5p was established. The EC109 cell line was transfected with a CDK6 small interfering RNA sequence. The rate of cell proliferation was determined using the WST‐8 method, and cell invasion was determined using a Transwell assay. In addition, the relative expression levels of genes were determined using RT‐qPCR; the relative expression levels of proteins were determined by western blot analysis; the binding sites of CDK6 and miR‐126‐5p were analyzed using TargetScan software; and the interaction of CDK6 and miR‐126‐5p was verified using dual‐fluorescence reporter gene expression. Esophageal tissues and EC109 cells expressed higher levels of CDK6 but significantly lower levels of miR‐126‐5p compared with adjacent tissues and HEEC cells, and their correlation coefficient between esophageal tissues and matched adjacent tissues was −7.526. The overexpression of miR‐126‐5p and CDK6 knockdown in the EC109 cell line inhibited cell proliferation and invasion compared with the control and NC (negative control) groups. miR‐126‐5p overexpression reduced the relative expression level of CDK6, and CDK6 knockdown by siRNA increased the expression of miR‐126‐5p. miR‐126‐5p regulated CDK6 expression by binding to the 3′‐untranslated region of its mRNA. Overexpression miR‐126‐5p inhibited the proliferation and migration of esophageal cancer cells by targeting CDK6 and negatively regulating its expression. These findings contribute to the understanding of the underlying molecular mechanism of esophageal cancer.
PITHD1 is a proteasome-interacting protein essential for male fertilization

The proteasome is a protein-degrading molecular complex that is necessary for protein homeostasis and various biological functions, including cell cycle regulation, signal transduction, and immune response. Proteasome activity is finely regulated by a variety of proteasome-interacting molecules. PITHD1 is a recently described molecule that has a domain putatively capable of interacting with the proteasome. However, it is unknown whether PITHD1 can actually bind to proteasomes and what it does in vivo. Here we report that PITHD1 is detected specifically in the spermatids in the testis and the cortical thymic epithelium in the thymus. Interestingly, PITHD1 associates with immunoproteasomes in the testis, but not with thymoproteasomes in the thymus. Mice deficient in PITHD1 exhibit severe male infertility accompanied with morphological abnormalities and impaired motility of spermatozoa. Furthermore, PITHD1 deficiency reduces proteasome activity in the testis and alters the amount of proteins that are important for fertilization capability by the sperm. However, the PITHD1-deficient mice demonstrate no detectable defects in the thymus, including T cell development. Collectively, our results identify PITHD1 as a proteasome-interacting protein that plays a nonredundant role in the male reproductive system.
LncRNA PTENP1 inhibits cervical cancer progression by suppressing miR-106b

Abstract LncRNA PTENP1 is a competitive endogenous RNA (ceRNA) involved in decoying miR-106b in multiple diseases. This study investigates the interaction of PTENP1 and miR-106b in cell proliferation, apoptosis and epithelial–mesenchymal transition (EMT) in cervical cancer. The expressions of PTENP1, miR-106b and PTEN were determined in cervical cancer tissues, adjacent normal tissues, cervical cancer cells (HeLa, SiHa, C33A and CasKi) and normal cervical epithelial H8 cells. Up-regulation of PTENP1 and down-regulation of miR-106b were conducted in HeLa and CasKi cells by transfecting cells with corresponding miRNA mimics and inhibitors. Bioinformatics analysis, luciferase reporter assay and RNA-pull down assay were performed to verify the association of miR-106b, PTEN, and PTENP1. Cell growth and cell apoptosis were determined by CCK-8 and flow cytometry analysis. It was found that the expressions of PTENP1 and PTEN were up-regulated and that of miR-106b were down-regulated in cervical cancer tissues and cells. PTENP1 localized in cytoplasm and competitively bound to miR-106b. Up-regulation of PTENP1 and down-regulation of miR-106b contributed to increased expressions of PTEN and E-cadherin. Decreased expression of miR-106b, ZEB1, Snail and Vimentin, resulted in inhibiting cell proliferation and promoting cell apoptosis. Over-expression of PTENP1 and miR-106b accelerated cell proliferation and slowed down cell apoptosis. miR-106b inhibited the expression of PTEN. Our results suggest that LncRNA PTENP1 inhibits cervical cancer progression by competitively binding to miR-106b, leading to promote PTEN expression, inhibit cell proliferation and EMT and induce cell apoptosis in cervical cancer cells
The VR23 Antitumor Compound Also Shows Strong Anti-Inflammatory Effects in a Human Rheumatoid Arthritis Cell Model and Acute Lung Inflammation in Mice

Key Points Anticancer VR23 also effectively downregulates inflammatory cytokines in monocytes. VR23 effectively downregulates MCP-1, IL-6, and cell migration in human synoviocytes. VR23 effectively downregulates lung inflammation caused by LPS in mice. Visual Abstract We previously found that the novel VR23 proteasome inhibitor not only possesses an effective antitumor activity without causing any ill effects to animals but also reduces side effects caused by a partner drug when used in combination. In this article, we report that VR23, unlike other proteasome inhibitors, exhibits potent anti-inflammatory activity. In the LPS-induced THP-1 monocyte model, VR23 downregulates proinflammatory cytokines IL-1β, TNF-α, IL-6, and IL-8 at a similar efficacy to dexamethasone. In contrast, two well-known proteasome inhibitors, bortezomib and carfilzomib, do not effectively downregulate these proinflammatory cytokines. Data from a study with SW982 synovial cell line and primary human synoviocytes showed that VR23 not only effectively downregulates IL-6 but also inhibits cell migration. Interestingly, the IL-6 downregulation by VR23 was significantly more pronounced in the primary synovial cells from rheumatoid arthritis patients than those from healthy donors, suggesting that VR23 can be selective against rheumatoid arthritis. Finally, VR23 effectively reduces neutrophil migration, TNF-α secretion, and tissue inflammation in mice (female BALB/c strain) with an LPS-induced acute lung injury. Thus, our current data indicate that VR23 can be effective on both acute and chronic inflammatory conditions. Taken together with our previous work, VR23 is not only effective on inflammatory conditions but also applicable to different aspects of cancer control, including the treatment and prevention of tumor development by chronic inflammatory responses.
Fluid Shear Stress Suppresses Osteoclast Differentiation in RAW264.7 Cells through Extracellular Signal-Regulated Kinase 5 (ERK5) Signaling Pathway

Background Although extracellular signal-regulated kinase 5 (ERK5) is known to be critical for osteoclast differentiation, there are few studies on how fluid shear stress (FSS) regulates osteoclast differentiation through the ERK5 signaling pathway. We examined the expression of nuclear factor of activated T cells c1 (NFATc1) in RAW264.7 cells and its downstream factors, including cathepsin K (CTSK), tartrate-resistant acid phosphatase (TRAP), matrix metalloproteinases-9 (MMP-9) and their relationship with ERK5. Material/Methods RAW264.7 cells were treated with RANKL, XMD8-92 (ERK5 inhibitor), and then loaded onto 12 dyn/cm2 FSS for 4 days. Endpoints measured were osteoclast differentiation, bone resorption, and TRAP activity. Cell viability was detected by using the Cell Counting Kit-8 (CCK-8) assay. Western blot was used to analyze protein expression of phosphorylated-ERK5 (p-ERK5), NFATc1, CTSK, TRAP, and MMP-9. Results FSS inhibited osteoclast differentiation and expression of NFATc1, CTSK, TRAP, and MMP-9; cell viability was not affected. ERK5 expression increased by FSS but not by RANKL, and it was blocked by XMD8-92. Furthermore, FSS suppressed osteoclast differentiation in RAW264.7 cells through ERK5 pathway. Conclusions Our findings demonstrated that FSS inhibited osteoclast differentiation in RAW264.7 cells via the ERK5 pathway through reduced NFATc1 expression and its downstream factors MMP-9, CTSK, and TRAP.
BHBA treatment improves cognitive function by targeting pleiotropic mechanisms in transgenic mouse model of Alzheimer's disease

Accumulation of amyloid β (Aβ) peptide, inflammation, and oxidative stress contribute to Alzheimer's disease (AD) and trigger complex pathogenesis. The ketone body β‐hydroxybutyrate (BHBA) is an endogenous metabolic intermediate that protects against stroke and neurodegenerative diseases, but the underlying mechanisms are unclear. The present study aims to elucidate the protective effects of BHBA in the early stage of AD model and investigate the underlying molecular mechanisms. Three‐and‐half‐month‐old double‐transgenic mice (5XFAD) overexpressing β‐amyloid precursor protein (APP) and presenilin‐1 (PS1) were used as the AD model. The 5XFAD mice received 1.5 mmol/kg/d BHBA subcutaneously for 28 days. Morris water maze test, nest construction, and passive avoidance experiments were performed to assess the therapeutic effects on AD prevention in vivo, and brain pathology of 5XFAD mice including amyloid plaque deposition and microglia activation were assessed. Gene expression profiles in the cortexes of 5XFAD‐ and BHBA‐treated 5XFAD mice were performed with high‐throughput sequencing and bioinformatic analysis. Mouse HT22 cells were treated with 2 mM BHBA to explore its in vitro protective effects of BHBA on hippocampal neurons against Aβ oligomer toxicity, ATP production, ROS generation, and mitochondrial aerobic respiratory function. APP, BACE1, and neprilysin (NEP) expression levels were evaluated in HT22 cells following treatment with BHBA by measuring the presence or absence of G protein‐coupled receptor 109A (GPR109A). BHBA improved cognitive function of 5XFAD mice in Morris water maze test, nesting construction and passive avoidance experiments, and attenuated Aβ accumulation and microglia overactivation in the brain. BHBA also enhanced mitochondrial respiratory function of hippocampal neurons and protected it from Aβ toxicity. The enzymes, APP and NEP were regulated by BHBA via G‐protein‐coupled receptor 109A (GPR109A). Furthermore, RNA sequencing revealed that BHBA‐regulated genes mainly annotated in aging, immune system, nervous system, and neurodegenerative diseases. Our data suggested that BHBA confers protection against the AD‐like pathological events in the AD mouse model by targeting multiple aspects of AD and it may become a promising candidate for the prevention and treatment of AD.
Review of digital technologies to improve productivity of New Zealand construction industry

The New Zealand construction industry continues to face pressures to improve productivity and lower construction costs. With the need to build more houses and infrastructure, quicker, to high quality and on time, there is a need to upscale the use of advanced technologies. Going digital is a solution that can transform the construction industry by improving productivity measures. The objectives of this paper are to: 1 Identify the availability of transformative technologies and their potential impact on productivity improvement across the construction life cycle and, 2. To investigate the benefits and barriers to technology-uptake in New Zealand construction. This paper is a review of digital technologies which analyzes their impact on productivity across the construction life cycle. As a basis for analysis, the digital technologies are isolated into three key productivity improvement functions: (1) Ubiquitous Digital Access, (2) Whole Building Whole-of-Life (WBWOL) decision making, and (3) Cost Reduction Engineering. This study is a literature-based theoretical exploration, aimed at signifying digitization as a function of productivity performance in the New Zealand construction industry. From a practical perspective, clients and contractors may be convinced to invest in digital technologies, increasing or accelerating uptake and more fully realizing the benefits digital technologies could add to productivity performance, growth and long-term success. This study may provide useful information for researchers regarding the development of case studies by analyzing organizations that implement technological innovations, their successful actions/processes, barriers overcoming actions, and sources of new ideas.
Circadian disruption by shifting the light‐dark cycle negatively affects bone health in mice

The past decade, it has become evident that circadian rhythms within metabolically active tissues are very important for physical health. However, although shift work has also been associated with an increased risk of fractures, circadian rhythmicity has not yet been extensively studied in bone. Here, we investigated which genes are rhythmically expressed in bone, and whether circadian disruption by shifts in light‐dark cycle affects bone turnover and structure in mice. Our results demonstrate diurnal expression patterns of clock genes (Rev‐erbα, Bmal1, Per1, Per2, Cry1, Clock), as well as genes involved in osteoclastogenesis, osteoclast proliferation and function (Rankl, Opg, Ctsk), and osteocyte function (c‐Fos) in bone. Weekly alternating light‐dark cycles disrupted rhythmic clock gene expression in bone and caused a reduction in plasma levels of procollagen type 1 amino‐terminal propeptide (P1NP) and tartrate‐resistant acidic phosphatase (TRAP), suggestive of a reduced bone turnover. These effects coincided with an altered trabecular bone structure and increased cortical mineralization after 15 weeks of light‐dark cycles, which may negatively affect bone strength in the long term. Collectively, these results show that a physiological circadian rhythm is important to maintain bone health, which stresses the importance of further investigating the association between shift work and skeletal disorders.
The History of Alloplastic Ear Reconstruction for Microtia

Abstract Microtia reconstruction is a unique and challenging field in reconstructive surgery. In the early 20th century, many different alloplastic materials have been used in an attempt to recreate the fibrocartilaginous framework of the native ear. These materials include celluloid, tantalum wire cage, nylon mesh, polyethylene, and acrylic. The first standard for alloplastic microtia reconstruction, silicone, is one fraught with complications and failures. This alloplastic material is walled off by the host and prone to scar tissue formation and extrusion. Alloplastic microtia reconstruction largely shifts to porous polyethylene, where the results are markedly superior. This is attributed to the porous structure of porous polyethylene, which allows tissue ingrowth. Moreover, the use of the temporoparietal fascia flap for total coverage of the implant has impressively lowered the risk of implant extrusion. However, there is paucity in the literature regarding the evolution of alloplastic microtia reconstruction, especially characterizing historical mistakes, significant technique evolutions, and drawbacks/advantages of materials. This review serves as a guide both to avoid repeating mistakes and to improve outcomes.
Epitranscriptomic profiling in human placenta: N6‐methyladenosine modification at the 5′‐untranslated region is related to fetal growth and preeclampsia

Intracellular mRNA levels are not always proportional to their respective protein levels, especially in the placenta. This discrepancy may be attributed to various factors including post‐transcriptional regulation, such as mRNA methylation (N6‐methyladenosine: m6A). Here, we conducted a comprehensive m6A analysis of human placental tissue from neonates with various birth weights to clarify the involvement of m6A in placental biology. The augmented m6A levels at the 5′‐untranslated region (UTR) in mRNAs of small‐for‐date placenta samples were dominant compared to reduction of m6A levels, whereas a decrease in m6A in the vicinity of stop codons was common in heavy‐for‐date placenta samples. Notably, most of these genes showed similar expression levels between the different birth weight categories. In particular, preeclampsia placenta samples showed consistently upregulated SMPD1 protein levels and increased m6A at 5′‐UTR but did not show increased mRNA levels. Mutagenesis of adenosines at 5′‐UTR of SMPD1 mRNAs actually decreased protein levels in luciferase assay. Collectively, our findings suggest that m6A both at the 5′‐UTR and in the vicinity of stop codon in placental mRNA may play important roles in fetal growth and disease.
Effects of culturing technique on human peripheral blood lymphocytes response to proton and X-ray radiation

Abstract Purpose: The main aim of this study was to comparatively investigate the effects of culturing methods on the response of human peripheral blood lymphocytes to irradiation exposure. Materials and methods: Whole blood and isolated lymphocytes were ex vivo exposed to two radiation sources (60 MeV proton or 250 kV X-ray radiation) with different doses (0.3, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, and 4.0 Gy), and genotoxic markers were subsequently assayed. The observed effects were compared as dose–response relationships using two end points (CBMN and PCC tests) and different biomarkers (NDI, PCC index, MNi frequency and excess PCC fragments). Results and conclusions: The results showed different effects of the culturing techniques on the response of human peripheral blood lymphocytes to radiation. The MNi frequency and excess PCC fragments were significantly higher when lymphocytes were cultured after being isolated. After irradiation, no differences were seen in the NDI between the lymphocytes of the two culturing techniques; however, there were differences in the PPC index. When planning or performing cytogenetic studies, the possibility of such effects and their potential to impact the variability of the results of human biomonitoring studies should be considered important and taken into account.
Advanced fluorescence imaging of in situ protein aggregation

The aggregation of intrinsically disordered proteins is a hallmark of neurodegenerative diseases, such as Alzheimer’s, Parkinson’s and Huntington’s disease. Although we currently have a good molecular level understanding on how protein aggregation occurs in vitro, the details of its self-assembly in live cells are still mainly unknown. During the last ten years, we have witnessed the rapid development of advanced imaging techniques, especially super-resolution and fluorescence lifetime-based microscopy, in different areas of cell biology. These methods have been revolutionising our understanding of how proteins aggregate, providing unprecedented high spatial-temporal resolution which permits us to capture the kinetics of aggregate seeding and expansion, the motion and distribution of individual aggregates within the cells, and its structural change. In this article, we will review the study of in situ protein aggregation using advanced imaging techniques, with the focus on protein aggregate structure and its assembly dynamics.
Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer

Background: A recently published randomized controlled trial compared single-dose psilocybin with single-dose niacin in conjunction with psychotherapy in participants with cancer-related psychiatric distress. Results suggested that psilocybin-assisted psychotherapy facilitated improvements in psychiatric and existential distress, quality of life, and spiritual well-being up to seven weeks prior to the crossover. At the 6.5-month follow-up, after the crossover, 60–80% of participants continued to meet criteria for clinically significant antidepressant or anxiolytic responses. Methods: The present study is a long-term within-subjects follow-up analysis of self-reported symptomatology involving a subset of participants that completed the parent trial. All 16 participants who were still alive were contacted, and 15 participants agreed to participate at an average of 3.2 and 4.5 years following psilocybin administration. Results: Reductions in anxiety, depression, hopelessness, demoralization, and death anxiety were sustained at the first and second follow-ups. Within-group effect sizes were large. At the second (4.5 year) follow-up approximately 60–80% of participants met criteria for clinically significant antidepressant or anxiolytic responses. Participants overwhelmingly (71–100%) attributed positive life changes to the psilocybin-assisted therapy experience and rated it among the most personally meaningful and spiritually significant experiences of their lives. Conclusion: These findings suggest that psilocybin-assisted psychotherapy holds promise in promoting long-term relief from cancer-related psychiatric distress. Limited conclusions, however, can be drawn regarding the efficacy of this therapy due to the crossover design of the parent study. Nonetheless, the present study adds to the emerging literature base suggesting that psilocybin-facilitated therapy may enhance the psychological, emotional, and spiritual well-being of patients with life-threatening cancer.
Prevalence of Trachoma in Pakistan: Results of 42 Population-Based Prevalence Surveys from the Global Trachoma Mapping Project

ABSTRACT Purpose: Previous phases of trachoma mapping in Pakistan completed baseline surveys in 38 districts. To help guide national trachoma elimination planning, we set out to estimate trachoma prevalence in 43 suspected-endemic evaluation units (EUs) of 15 further districts. Methods: We planned a population-based trachoma prevalence survey in each EU. Two-stage cluster sampling was employed, using the systems and approaches of the Global Trachoma Mapping Project. In each EU, residents aged ≥1 year living in 30 households in each of 26 villages were invited to be examined by trained, certified trachoma graders. Questionnaires and direct observation were used to evaluate household-level access to water and sanitation. Results: One EU was not completed due to insecurity. Of the remaining 42, three EUs had trichiasis prevalence estimates in ≥15-year-olds ≥0.2%, and six (different) EUs had prevalence estimates of trachomatous inflammation—follicular (TF) in 1–9-year-olds ≥5%; each EU requires trichiasis and TF prevalence estimates below these thresholds to achieve elimination of trachoma as a public health problem. All six EUs with TF prevalences ≥5% were in Khyber Pakhtunkhwa Province. Household-level access to improved sanitation ranged by EU from 6% to 100%. Household-level access to an improved source of water for face and hand washing ranged by EU from 37% to 100%. Conclusion: Trachoma was a public health problem in 21% (9/42) of the EUs. Because the current outbreak of extremely drug-resistant typhoid in Pakistan limits domestic use of azithromycin mass drug administration, other interventions against active trachoma should be considered here.