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This study observed the effects of treadmill running on adipose tissue browning and lipolysis in rats with induced heart failure and elucidated the possible mechanism. Rats underwent abdominal aortic constriction as a model of heart failure. Cardiac function was detected by echocardiography. We detected serum levels of norepinephrine and interleukin 6, cardiac atrial natriuretic peptide and brain natriuretic peptide and marker genes of browning, white adipose tissue (WAT), and lipolysis in adipose tissue. Rats with heart failure showed typical symptoms such as increased heart weight and mRNA levels of atrial natriuretic peptide and brain natriuretic peptide and decreased left ventricular ejection fraction. Exercise partially improved left ventricular diastolic function and significantly decreased atrial natriuretic peptide expression. Rats with heart failure showed significantly reduced body weight and ratios of muscle and fat weight to body weight. Exercise significantly increased body weight and the ratio of muscle weight to body weight. Heart failure stimulated the expression of proliferator-activated receptor-gamma coactivator-1-alpha and uncoupling protein 1 in epididymal WAT, inguinal WAT, and brown adipose tissue but decreased that of adiponectin and leptin in inguinal WAT. Lipolysis, characterized by high adipose triglyceride lipase and hormone-sensitive lipase expression, was activated in all adipose tissues. Exercise reduced browning and lipolysis in adipose tissues. Rats with heart failure had abnormally high levels of serum norepinephrine and interleukin 6, which could be suppressed by exercise. Exercise may improve cardiac cachexia and inhibit the browning and lipolysis of adipose tissue by downregulating sympathetic nervous system activity and inflammation.

Animals utilize specialized sensory neurons enabling the detection of a wide range of environmental stimuli from the presence of toxic chemicals to that of touch. However, how these neurons discriminate between different kinds of stimuli remains poorly understood. By combining in vivo calcium imaging and molecular genetic manipulation, here we investigate the response patterns and the underlying mechanisms of the C. elegans phasmid neurons PHA/PHB to a variety of sensory stimuli. Our observations demonstrate that PHA/PHB neurons are polymodal sensory neurons which sense harmful chemicals, hyperosmotic solutions and mechanical stimulation. A repulsive concentration of IAA induces calcium elevations in PHA/PHB and both OSM-9 and TAX-4 are essential for IAA-sensing in PHA/PHB. Nevertheless, the PHA/PHB neurons are inhibited by copper and post-synaptically activated by copper removal. Neuropeptide is likely involved in copper removal-induced calcium elevations in PHA/PHB. Furthermore, mechanical stimulation activates PHA/PHB in an OSM-9-dependent manner. Our work demonstrates how PHA/PHB neurons respond to multiple environmental stimuli and lays a foundation for the further understanding of the mechanisms of polymodal signaling, such as nociception, in more complex organisms.

Protein lysine lactylation (Kla) is a novel protein acylation reported in recent years, which plays an important role in the development of several diseases with pathologically elevated lactate levels, such as tumors. The concentration of lactate as a donor is directly related to the Kla level. High-intensity interval training (HIIT) is a workout pattern that has positive effects in many metabolic diseases, but the mechanisms by which HIIT promotes health are not yet clear. Lactate is the main metabolite of HIIT, and it is unknown as to whether high lactate during HIIT can induce changes in Kla levels, as well as whether Kla levels differ in different tissues and how time-dependent Kla levels are. In this study, we observed the specificity and time-dependent effects of a single HIIT on the regulation of Kla in mouse tissues. In addition, we aimed to select tissues with high Kla specificity and obvious time dependence for lactylation quantitative omics and analyze the possible biological targets of HIIT-induced Kla regulation. A single HIIT induces Kla in tissues with high lactate uptake and metabolism, such as iWAT, BAT, soleus muscle and liver proteins, and Kla levels peak at 24 h after HIIT and return to steady state at 72 h. Kla proteins in iWAT may affect pathways related to glycolipid metabolism and are highly associated with de novo synthesis. It is speculated that the changes in energy expenditure, lipolytic effects and metabolic characteristics during the recovery period after HIIT may be related to the regulation of Kla in iWAT.

Radiation therapy (RT) has been employed as a tumoricidal modality for more than 100 years and on 470,000 patients each year in the United States. The ionizing radiation causes genetic changes and results in cell death. However, since the biological mechanism of radiation remains unclear, there is a pressing need to understand this mechanism to improve the killing effect on tumors and reduce the side effects on normal cells. DNA break and epigenetic remodeling can be induced by radiotherapy. Hence the modulation of histone modification enzymes may tune the radiosensitivity of cancer cells. For instance, histone deacetylase (HDAC) inhibitors sensitize irradiated cancer cells by amplifying the DNA damage signaling and inhibiting double-strand DNA break repair to influence the irradiated cells’ survival. However, the combination of epigenetic drugs and radiotherapy has only been evaluated in several ongoing clinical trials for limited cancer types, partly due to a lack of knowledge on the potential mechanisms on how radiation induces epigenetic regulation and chromatin remodeling. Here, we review recent advances of radiotherapy and radiotherapy-induced epigenetic remodeling and introduce related technologies for epigenetic monitoring. Particularly, we exploit the application of fluorescence resonance energy transfer (FRET) biosensors to visualize dynamic epigenetic regulations in single living cells and tissue upon radiotherapy and drug treatment. We aim to bridge FRET biosensor, epigenetics, and radiotherapy, providing a perspective of using FRET to assess epigenetics and provide guidance for radiotherapy to improve cancer treatment. In the end, we discuss the feasibility of a combination of epigenetic drugs and radiotherapy as new approaches for cancer therapeutics.

Numerous taste receptors and related molecules have been identified in vertebrates and invertebrates. Otopetrin1 has recently been identified as mammalian sour taste receptor which is essential for acid sensation. However, whether other Otopetrin proteins are involved in PH-sensing remains unknown. In C. elegans , there are eight otopetrin homologous genes but their expression patterns and functions have not been reported so far. Through heterologous expression in HEK293T cells, we found that ceOTOP1a can be activated by acid in NMDG + solution without conventional cations, which generated inward currents and can be blocked by zinc ions. Moreover, we found that Otopetrin channels are widely expressed in numerous tissues, especially in sensory neurons in the nematode. These results suggest that the biophysical characteristics of the Otopetrin channels in nematodes are generally conserved. However, a series of single gene mutations of otopetrins, which were constructed by CRISPR-Cas9 method, did not affect either calcium responses in ASH polymodal sensory neurons to acid stimulation or acid avoidance behaviors, suggesting that Otopetrin channels might have diverse functions among species. This study reveals that nematode Otopetrins are evolutionarily conserved acid-sensitive proton channels, and provides a framework for further revealing the function and mechanisms of Otopetrin channels in both invertebrates and vertebrates.

Synaptic vesicles (SV) store various neurotransmitters that are released at the synapse. The molecular mechanisms of biogenesis, exocytosis, and endocytosis for SV, however, remain largely elusive. In this study, using Complex Object Parametric Analysis and Sorter (COPAS) to monitor the fluorescence of synapto-pHluorin (SpH), we performed a whole-genome RNAi screen in to identify novel genetic modulators in SV cycling. One hundred seventy six genes that up-regulating SpH fluorescence and 96 genes that down-regulating SpH fluorescence were identified after multi-round screen. Among these genes, encodes ortholog of mammalian C2H2 zinc-finger protein BuGZ/ZNF207, which is a spindle assembly checkpoint protein essential for mitosis in human cells. Combining electrophysiology, imaging and behavioral assays, we reveal that depletion of BuGZ-1 results in defects in locomotion. We further demonstrate that BuGZ-1 promotes SV recycling by regulating the expression levels of endocytosis-related genes such as rab11.1. Therefore, we have identified a bunch of potential genetic modulators in SV cycling, and revealed an unexpected role of BuGZ-1 in regulating synaptic transmission.

Mechanotransduction channels are widely expressed in both vertebrates and invertebrates, mediating various physiological processes such as touch, hearing and blood-pressure sensing. While previously known mechanotransduction channels in metazoans are primarily cation-selective, we identified Anoctamin-1 (ANOH-1), the C. elegans homolog of mammalian calcium-activated chloride channel ANO1/TMEM16A, as an essential component of a mechanosensory channel complex that contributes to the nose touch mechanosensation in C. elegans . Ectopic expression of either C. elegans or human Anoctamin-1 confers mechanosensitivity to touch-insensitive neurons, suggesting a cell-autonomous role of ANOH-1/ANO1 in mechanotransduction. Additionally, we demonstrated that the mechanosensory function of ANOH-1/ANO1 relies on CIB (calcium- and integrin- binding) proteins. Thus, our results reveal an evolutionarily conserved chloride channel involved in mechanosensory transduction in metazoans, highlighting the importance of anion channels in mechanosensory processes. Mechanotransduction channels play key roles in various sensory processes. Here, the authors identify the chloride channel ANOH-1/ANO1 as a core component of a mechanosensory channel complex, highlighting its evolutionary conservation.

Bamboo, a non-timber grass species, known for exceptionally fast growth is a commercially viable crop. Long terminal repeat (LTR) retrotransposons, the main class I mobile genetic elements in plant genomes, are highly abundant (46%) in bamboo, contributing to genome diversity. They play significant roles in the regulation of gene expression, chromosome size and structure as well as in genome integrity. Due to their random insertion behavior, interspaces of retrotransposons can vary significantly among bamboo genotypes. Capitalizing this feature, inter-retrotransposon amplified polymorphism (IRAP) is a high-throughput marker system to study the genetic diversity of plant species. To date, there are no transposon based markers reported from the bamboo genome and particularly using IRAP markers on genetic diversity. Phyllostachys genus of Asian bamboo is the largest of the Bambusoideae subfamily, with great economic importance. We report structure-based analysis of bamboo genome for the LTR-retrotransposon superfamilies, Ty3-gypsy and Ty1-copia, which revealed a total of 98,850 retrotransposons with intact LTR sequences at both the ends. Grouped into 64,281 clusters/scaffold using CD-HIT-EST software, only 13 clusters of retroelements were found with more than 30 LTR sequences and with at least one copy having all intact protein domains such as gag and polyprotein. A total of 16 IRAP primers were synthesized, based on the high copy numbers of conserved LTR sequences. A study using these IRAP markers on genetic diversity and population structure of 58 Asian bamboo accessions belonging to the genus Phyllostachys revealed 3340 amplicons with an average of 98% polymorphism. The bamboo accessions were collected from nine different provinces of China, as well as from Italy and America. A three phased approach using hierarchical clustering, principal components and a model based population structure divided the bamboo accessions into four sub-populations, PhSP1, PhSP2, PhSP3 and PhSP4. All the three analyses produced significant sub-population wise consensus. Further, all the sub-populations revealed admixture of alleles. The analysis of molecular variance (AMOVA) among the sub-populations revealed high intra-population genetic variation (75%) than inter-population. The results suggest that Phyllostachys bamboos are not well evolutionarily diversified, although geographic speciation could have occurred at a limited level. This study highlights the usability of IRAP markers in determining the inter-species variability of Asian bamboos.

Histone acetylation is an important epigenetic modification that governs gene expression, chromatin changes in stress response, and cell fate transition. FRET biosensors have been developed for various epigenetic events to enable spatiotemporal tracking of sub-cellular signaling events. Previously reported histone H3 acetylation biosensor recognizing two acetyl residues lacked specificity. In this study, using a single bromodomain of the BRD4, we have developed a genetically encoded H3K9ac biosensor. We systematically investigated different combinations of the BET family protein as binding domains and performed site-saturated mutagenesis to optimize the biosensor, achieving a dynamic FRET change up to 30% under TSA treatment. With the application of the optimized H3K9ac biosensor, we revealed different basal active chromatin architectures in invasive tumor cells compared to benign tumor cells. Furthermore, we found that H3K9ac level increased dramatically when cancer cells passed through microchannels, which models the physical constraints and mechanical microenvironmental conditions that cancer cells encounter when passing through narrow spaces within the body. This result highlights the chromatin plasticity in response to external mechanical stresses. In summary, our H3K9ac biosensor provides a versatile tool for mechanistic investigation of cell fate transition in cancer and mechanotransduction. Graphical Abstract Highlights A genetically encoded H3K9ac FRET biosensor, with a single bromodomain, was developed for live-cell imaging. New biosensor detects different basal H3K9ac levels in highly-invasive tumor cells compared to less invasive tumor cells. The acetylation level increases when cancer cells undergo external mechanical stresses.

On-device training has become an increasingly popular approach to machine learning, enabling models to be trained directly on mobile and edge devices. However, a major challenge in this area is the limited memory available on these devices, which can severely restrict the size and complexity of the models that can be trained. In this systematic survey, we aim to explore the current state-of-the-art techniques for breaking on-device training memory walls, focusing on methods that can enable larger and more complex models to be trained on resource-constrained devices. Specifically, we first analyze the key factors that contribute to the phenomenon of memory walls encountered during on-device training. Then, we present a comprehensive literature review of on-device training, which addresses the issue of memory limitations. Finally, we summarize on-device training and highlight the open problems for future research. By providing a comprehensive overview of these techniques and their effectiveness in breaking memory walls, we hope to help researchers and practitioners in this field navigate the rapidly evolving landscape of on-device training.