Effects of acute- and long-term aerobic exercises at different intensities on bone in mice.

INTRODUCTION: Exercise intensity determines the benefits of aerobic exercise. Our objectives were, in aerobic exercise at different intensities, to determine (1) changes in bone metabolism-related genes after acute exercise and (2) changes in bone mass, strength, remodeling, and bone formation-related proteins after long-term exercise. MATERIALS AND METHODS: Total 36 male C57BL/6J mice were divided into a control group and exercise groups at 3 different intensities: low, moderate, or high group. Each exercise group was assigned to acute- or long-term exercise groups. Tibias after acute exercise were evaluated by real-time PCR analysis. Furthermore, hindlimbs of long-term exercise were assessed by micro-CT, biomechanical, histological, and immunohistochemical analyses. RESULTS: Acute moderate-intensity exercise decreased RANKL level as bone resorption marker, whereas low- and high-intensity exercise did not alter it. Additionally, only long-term exercise at moderate intensity increased bone mass and strength. Moderate-intensity exercise promoted osteoblast activity and suppressed osteoclast activity. After low- and high-intensity exercise, osteoblast and osteoclast activity were unchanged. An increase in the number of ß-catenin-positive cells and a decrease in sclerostin-positive cells were observed in the only moderate group. CONCLUSION: These results showed that moderate-intensity exercise can inhibit bone resorption earlier, and long-term exercise can increase bone mass and strength through promoted bone formation via the Wnt/ß-catenin activation. High-intensity exercise, traditionally considered better for bone, may fail to stimulate bone remodeling, leading to no change in bone mass and strength. Our findings suggest that moderate-intensity exercise, neither too low nor high, can maintain bone health.

Effects of different exercise modes and intensities on cognitive performance, adult hippocampal neurogenesis, and synaptic plasticity in mice.

Exercise can induce beneficial improvements in cognition. However, the effects of different modes and intensities of exercise have yet to be explored in detail. This study aimed to identify the effects of different exercise modes (aerobic and resistance) and intensities (low and high) on cognitive performance, adult hippocampal neurogenesis and synaptic plasticity in mice. A total of 40 C57BL/6J mice were randomised into 5 groups (n = 8 mice per group): control, low-intensity aerobic exercise, high-intensity aerobic exercise, low-intensity resistance exercise, and high-intensity resistance exercise. The aerobic exercise groups underwent treadmill training, while the resistance exercise groups underwent ladder climbing training. At the end of the exercise period, cognitive performance was assessed by the Y-maze and Barnes maze. In addition, adult hippocampal neurogenesis was evaluated immunohistochemically by 5-bromo-2'-deoxyuridine (BrdU)/ neuronal nuclei (NeuN) co-labeling. The levels of synaptic plasticity-related proteins in the hippocampus, including synaptophysin (SYP) and postsynaptic density protein 95 (PSD-95), were analyzed by western blotting. Our results showed no significant differences in cognitive performance among the groups. However, high-intensity aerobic exercise significantly increased hippocampal adult neurogenesis relative to the control. A trend towards increased adult neurogenesis was observed in the low-intensity aerobic group compared to the control group. No significant changes in synaptic plasticity were observed among all groups. Our results indicate that high-intensity aerobic exercise may be the most potent stimulator of adult hippocampal neurogenesis.

Effects of uphill and downhill walking on post-traumatic osteoarthritis development in mice.

Using destabilization of the medial meniscus (DMM) to induce models of osteoarthritis (OA), we sought to clarify how flat, uphill and downhill walking affects OA-related inflammation and articular cartilage degeneration. Thirty-two male C57BL/6J mice 7 weeks old underwent DMM surgery in their right knee and sham surgery in their left knee, and were then assigned to either the no walking after DMM group or the flat, uphill or downhill walking after DMM group (n = 8/group). After creating the knee OA model, the mice in the walking groups were subjected to treadmill walking 1 day after surgery, which included walking at 12 m/min for 30 min/day, 7 days/week, at inclines of 0, 20, or -20 degrees. Knee joints were harvested at the end of the intervention period. Non-demineralized frozen sections were prepared and samples were examined histologically. Osteoarthritis Research Society International scores were significantly decreased in both the uphill and flat-walking groups, compared with the no-walking group. Immunohistochemical staining showed increased levels of aggrecan and Sry-related high-mobility group box9; conversely, decreased levels of matrix metalloproteinase-13 and A disintegrin and metalloproteinase with thrombospondin motifs-5 in both the uphill and flat-walking groups. Micro-CT results showed a higher bone-volume fraction in the uphill and flat-walking groups than that in the no-walking group. Our findings indicate that flat and uphill walking may prevent the progression of OA. KEY POINTS: Flat and uphill treadmill walking can prevent the development of post-traumatic osteoarthritis in mice. Flat and uphill walking increases anabolic proteins and decreases catabolic proteins and inflammatory cytokines in articular cartilage, resulting in protection against cartilage degeneration. Downhill walking increases catabolic proteins and inflammatory cytokines in cartilage, which has negative effects on articular cartilage.

Fluorescence detection of the human angiotensinogen protein by the G-quadruplex aptamer.

Noncanonical G-quadruplex nucleic acid structures can be used as probes in biosensors for the detection of metal ions, proteins and nucleic acids. Angiotensinogen (AGT) is a glycosylated globulin found in serum, which can regulate blood pressure and body fluid homeostasis. AGT is an important part of the renin-angiotensin system (RAS) and can be potentially used as a biomarker of diseases with RAS alterations. G-quadruplex based biosensors can detect targets with high accuracy and speed and low cost. Employing the magnetic bead enrichment method we constructed a reliable and efficient fluorescent biosensor platform for G-quadruplex based detection of the human AGT protein. The primary antibody in our biosensor is recognized by fluorescently labeled secondary antibodies, which leads to the detection of AGT captured by the G-quadruplex aptamer coupled magnetic beads. This G-quadruplex based fluorescent biosensor designed with a detection limit of 5 × 10-5 mg mL-1 was used for the successful detection of AGT at the cellular level. Our G-quadruplex based fluorescent biosensor will contribute to the more reliable and efficient detection of AGT.

The impact mitigation of a heterojunction nanotube-water system: behavior and mechanism.

A novel nanofluidic impact protection system is introduced in this paper, consisting of hydrophobic heterojunction carbon nanotubes (HCNTs) and water molecules. When the capillary resistance of the nanopores is overcome, water molecules can infiltrate into nanopores such as to convert external impact energy into excessive surface energy. A model of a single HCNT with water molecules in a reservoir is established and validated. The effects of several dominant parameters (e.g., nanopore size, impact velocity) are evaluated, and the potential mechanism is illustrated. The effect of the carbon nanotube structure on the nanofluidic behavior of the HCNT-water system is investigated. Results reveal that the segment of carbon nanotubes close to the water reservoir determines the energy absorption efficiency of the system.

Promotion of colorectal cancer by transcription factor BHLHE40 involves upregulation of ADAM19 and KLF7.

BHLHE40 is a transcription factor, whose role in colorectal cancer has remained elusive. We demonstrate that the BHLHE40 gene is upregulated in colorectal tumors. Transcription of BHLHE40 was jointly stimulated by the DNA-binding ETV1 protein and two associated histone demethylases, JMJD1A/KDM3A and JMJD2A/KDM4A, which were shown to also form complexes on their own and whose enzymatic activity was required for BHLHE40 upregulation. Chromatin immunoprecipitation assays revealed that ETV1, JMJD1A and JMJD2A interacted with several regions within the BHLHE40 gene promoter, suggesting that these three factors directly control BHLHE40 transcription. BHLHE40 downregulation suppressed both growth and clonogenic activity of human HCT116 colorectal cancer cells, strongly hinting at a pro-tumorigenic role of BHLHE40. Through RNA sequencing, the transcription factor KLF7 and the metalloproteinase ADAM19 were identified as putative BHLHE40 downstream effectors. Bioinformatic analyses showed that both KLF7 and ADAM19 are upregulated in colorectal tumors as well as associated with worse survival and their downregulation impaired HCT116 clonogenic activity. In addition, ADAM19, but not KLF7, downregulation reduced HCT116 cell growth. Overall, these data have revealed a ETV1/JMJD1A/JMJD2A→BHLHE40 axis that may stimulate colorectal tumorigenesis through upregulation of genes such as KLF7 and ADAM19, suggesting that targeting this axis represents a potential novel therapeutic avenue.

Higher-intensity ultrasound accelerates fracture healing via mechanosensitive ion channel Piezo1.

Osteoporosis-related fractures are a major public health problem. Mechanobiological stimulation utilizing low-intensity pulsed ultrasound (LIPUS) is the most widely accepted modality for accelerating fracture healing. However, recent evidence has demonstrated the ineffectiveness of LIPUS, and the biophysical mechanisms of ultrasound-induced bone formation also remain elusive. Here, we demonstrate that ultrasound at a higher intensity than LIPUS effectively accelerates fracture healing in a mouse osteoporotic fracture model. Higher-intensity ultrasound promoted chondrogenesis and hypertrophic differentiation of chondrocytes in the fracture callus. Higher-intensity ultrasound also increased osteoblasts and newly formed bone in the callus, resulting in accelerated endochondral ossification during fracture healing. In addition, we found that accelerated fracture healing by ultrasound exposure was attenuated when the mechanosensitive ion channel Piezo1 was inhibited by GsMTx4. Ultrasound-induced new bone formation in the callus was attenuated in fractured mice treated with GsMTx4. Similar results were also confirmed in a 3D osteocyte-osteoblast co-culture system, where osteocytic Piezo1 knockdown attenuated the expression of osteoblastic genes after ultrasound exposure. Together these results demonstrate that higher-intensity ultrasound than clinically used LIPUS can accelerate endochondral ossification after fractures. Furthermore, our results suggest that mechanotransduction via Piezo1 mediates ultrasound-stimulated fracture healing and bone formation.

A NIR-Activated and Mild-Temperature-Sensitive Nanoplatform with an HSP90 Inhibitor for Combinatory Chemotherapy and Mild Photothermal Therapy in Cancel Cells.

Mild photothermal therapy (PTT) shows great potential to treat cancers while avoiding unwanted damage to surrounding normal cells. However, the efficacy of mild PTT is normally moderate because of the low hyperthermia temperature and limited light penetration depth. Chemotherapy has unlimited penetration but often suffers from unsatisfactory efficacy in view of the occurrence of drug resistance, suboptimal drug delivery and release profile. As a result, the combinatory of chemotherapy and mild PTT would integrate their advantages and overcome the shortcomings. Herein, we synthesized an NIR-activatable and mild-temperature-sensitive nanoplatform (BDPII-gel@TSL) composed of temperature-sensitive liposomes (TSL), heat shock protein 90 (HSP90) inhibitor (geldanamycin) and photothermal agent (BDPII), for dual chemotherapy and mild PTT in cancer cells. BDPII, constructed with donor-acceptor moieties, acts as an excellent near-infrared (NIR) photothermal agent (PTA) with a high photothermal conversion efficiency (80.75%). BDPII-containing TSLs efficiently produce a mild hyperthermia effect (42 °C) under laser irradiation (808 nm, 0.5 W cm-2). Importantly, the phase transformation of TSL leads to burst release of geldanamycin from BDPII-gel@TSL, and this contributes to down-regulation of the overexpression of HSP90, ensuring efficient inhibition of cancer cell growth. This research provides a dual-sensitive synergistic therapeutic strategy for cancer cell treatment.

Effects of different modes and intensities of exercise on longevity proteins in middle-aged mouse skeletal muscle.

Physical exercise represents one of the most effective approaches to anti-aging. The goal of this study was to verify the effects of different modes and intensities of exercise on longevity proteins in the skeletal muscle in midlife. Middle-aged mice were trained in aerobic or resistance exercise for 8 weeks, and the changes in sirtuin 1 (SIRT1), adenosine monophosphate-activated kinase (AMPK), and mammalian target of rapamycin (mTOR) pathways in the skeletal muscle were evaluated by western blotting. Long-term exercise had no effects on skeletal muscle SIRT1 abundance, whereas high-intensity aerobic exercise increased AMPK phosphorylation and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Low-intensity resistance exercise facilitated Akt/mTOR/p70 ribosomal protein kinase S6 (p70S6K) signaling but did not induce muscle hypertrophy. Conversely, high-intensity resistance exercise stimulated muscle hypertrophy without phosphorylation of mTOR signaling-related proteins. These results suggest the importance of setting exercise modes and intensities for anti-aging in midlife.

Methylation of the epigenetic JMJD2D protein by SET7/9 promotes prostate tumorigenesis.

How the function of the JMJD2D epigenetic regulator is regulated or whether it plays a role in prostate cancer has remained elusive. We found that JMJD2D was overexpressed in prostate tumors, stimulated prostate cancer cell growth and became methylated by SET7/9 on K427. Mutation of this lysine residue in JMJD2D reduced the ability of DU145 prostate cancer cells to grow, invade and form tumors and elicited extensive transcriptomic changes. This included downregulation of CBLC, a ubiquitin ligase gene with hitherto unknown functions in prostate cancer, and upregulation of PLAGL1, a transcription factor with reported tumor suppressive characteristics in the prostate. Bioinformatic analyses indicated that CBLC expression was elevated in prostate tumors. Further, downregulation of CBLC largely phenocopied the effects of the K427 mutation on DU145 cells. In sum, these data have unveiled a novel mode of regulation of JMJD2D through lysine methylation, illustrated how this can affect oncogenic properties by influencing expression of the CBLC gene, and established a pro-tumorigenic role for CBLC in the prostate. A corollary is that JMJD2D and CBLC inhibitors could have therapeutic benefits in the treatment of prostate and possibly other cancers.

Deep learning for microscopic examination of protozoan parasites.

The infectious and parasitic diseases represent a major threat to public health and are among the main causes of morbidity and mortality. The complex and divergent life cycles of parasites present major difficulties associated with the diagnosis of these organisms by microscopic examination. Deep learning has shown extraordinary performance in biomedical image analysis including various parasites diagnosis in the past few years. Here we summarize advances of deep learning in the field of protozoan parasites microscopic examination, focusing on publicly available microscopic image datasets of protozoan parasites. In the end, we summarize the challenges and future trends, which deep learning faces in protozoan parasite diagnosis.

Multiplex Biosensing for Simultaneous Detection of Mutations in SARS-CoV-2.

COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has become the world's largest public health emergency of the past few decades. Thousands of mutations were identified in the SARS-CoV-2 genome. Some mutants are more infectious and may replace the original strains. Recently, B.1.1.7(Alpha), B1.351(Beta), and B.1.617.2(Delta) strains, which appear to have increased transmissibility, were detected. These strains accounting for the high proportion of newly diagnosed cases spread rapidly over the world. Particularly, the Delta variant has been reported to account for a vast majority of the infections in several countries over the last few weeks. The application of biosensors in the detection of SARS-CoV-2 is important for the control of the COVID-19 pandemic. Due to high demand for SARS-CoV-2 genotyping, it is urgent to develop reliable and efficient systems based on integrated multiple biosensor technology for rapid detection of multiple SARS-CoV-2 mutations simultaneously. This is important not only for the detection and analysis of the current but also for future mutations. Novel biosensors combined with other technologies can be used for the reliable and effective detection of SARS-CoV-2 mutants.

A survey of municipal solid waste landfills in Beijing during 2009-2011.

The investigation of municipal solid waste (MSW) treatment in China is rare due to its sensitivity and difficulty in terms of access. We chose Beijing, the capital of China, as an example to identify the characteristics of MSW landfill treatments using a 2-month investigation with 20 participants. MSW landfill treatments account for nearly 70% of the annual MSW disposal in Beijing; the landfill processes are equipped with many kinds of technologies and consume a large amount of energy and produce a variety of contaminants. The cover method (the most obvious difference in landfill tamping) mainly includes high-density polyethylene (HDPE) geomembranes with loess and soil alone (i.e., loess or sandy soil). We investigated the actual conditions of landfills and collected data on leachate and landfill gas (LFG) emissions and energy consumption during 2009-2011. The results indicated that the cover method employed by landfills was related to treatment quantity, operation, and especially landfill location. Early large-scale landfills located in plains were covered with HDPE geomembranes, and newly built landfills covered with soil tended to be equipped with HDPE covers. Using HDPE cover also contributed greatly to LFG production due to its impermeability but had no remarkable effect on leachate yield reduction due to the dry climate in Beijing. The potential was reinforced by the potentials of decrement and reuse. The disposal method of LFG can be optimized, and the power generated by the LFG process can meet the landfill demand. The gray water recycled from the leachate could be used in the landfill process.