Two H3K36 methyltransferases differentially associate with transcriptional activity and enrichment of facultative heterochromatin in rice blast fungus.

Di- and tri-methylation of lysine 36 on histone H3 (H3K36me2/3) is catalysed by histone methyltransferase Set2, which plays an essential role in transcriptional regulation. Although there is a single H3K36 methyltransferase in yeast and higher eukaryotes, two H3K36 methyltransferases, Ash1 and Set2, were present in many filamentous fungi. However, their roles in H3K36 methylation and transcriptional regulation remained unclear. Combined with methods of RNA-seq and ChIP-seq, we revealed that both Ash1 and Set2 are redundantly required for the full H3K36me2/3 activity in Magnaporthe oryzae, which causes the devastating worldwide rice blast disease. Ash1 and Set2 distinguish genomic H3K36me2/3-marked regions and are differentially associated with repressed and activated transcription, respectively. Furthermore, Ash1-catalysed H3K36me2 was co-localized with H3K27me3 at the chromatin, and Ash1 was required for the enrichment and transcriptional silencing of H3K27me3-occupied genes. With the different roles of Ash1 and Set2, in H3K36me2/3 enrichment and transcriptional regulation on the stress-responsive genes, they differentially respond to various stresses in M. oryzae. Overall, we reveal a novel mechanism by which two H3K36 methyltransferases catalyze H3K36me2/3 that differentially associate with transcriptional activities and contribute to enrichment of facultative heterochromatin in eukaryotes. Supplementary Information: The online version contains supplementary material available at 10.1007/s42994-023-00127-3.

Yttrium chloride induces ferroptosis in cardiomyocytes via iron accumulation and triggers cardiac lipid peroxidation and inflammation that cause heart adverse events in mice.

The growing presence of yttrium (Y) in the environment raises concern regarding its safety and toxicity. However, limited toxicological data are available to determine cardiotoxicity of Y and its underlying mechanisms. In the present study, yttrium chloride (YCl3) intervention with different doses was performed in male Kunming mice for the toxicological evaluation of Y in the heart. After 28 days of intragastric administration, 500 mg/kg·bw YCl3 induces iron accumulation in cardiomyocytes, and triggers ferroptosis through the glutathione peroxidase 4 (GPX4)/glutathione (GSH)/system Xc- axis via the inhibition of Nrf2 signaling pathway. This process led to cardiac lipid peroxidation and inflammatory response. Further RNA sequencing transcriptome analysis found that many genes involved in ferroptosis and lipid metabolism-related pathways were enriched. The ferroptosis induced by YCl3 in cardiomyocytes ultimately caused cardiac injury and dysfunction in mice. Our findings assist in the elucidation of the potential subacute cardiotoxicity of Y3+ and its underlying mechanisms.

Transcriptional Regulation of Autophagy-Related Genes by Sin3 Negatively Modulates Autophagy in Magnaporthe oryzae.

Autophagy is a conserved degradation and recycling pathway in eukaryotes and is important for their normal growth and development. An appropriate status of autophagy is crucial for organisms which is tightly regulated both temporally and continuously. Transcriptional regulation of autophagy-related genes (ATGs) is an important layer in autophagy regulation. However, the transcriptional regulators and their mechanisms are still unclear, especially in fungal pathogens. Here, we identified Sin3, a component of the histone deacetylase complex, as a transcriptional repressor of ATGs and negative regulator of autophagy induction in the rice fungal pathogen Magnaporthe oryzae. A loss of SIN3 resulted in upregulated expression of ATGs and promoted autophagy with an increased number of autophagosomes under normal growth conditions. Furthermore, we found that Sin3 negatively regulated the transcription of ATG1, ATG13, and ATG17 through direct occupancy and changed levels of histone acetylation. Under nutrient-deficient conditions, the transcription of SIN3 was downregulated, and the reduced occupancy of Sin3 from those ATGs resulted in histone hyperacetylation and activated their transcription and in turn promoted autophagy. Thus, our study uncovers a new mechanism of Sin3 in modulating autophagy through transcriptional regulation. IMPORTANCE Autophagy is an evolutionarily conserved metabolic process and is required for the growth and pathogenicity of phytopathogenic fungi. The transcriptional regulators and precise mechanisms of regulating autophagy, as well as whether the induction or repression of ATGs is associated with autophagy level, are still poorly understood in M. oryzae. In this study, we revealed that Sin3 acts as a transcriptional repressor of ATGs to negatively regulate autophagy level in M. oryzae. Under the nutrient-rich conditions, Sin3 inhibits autophagy with a basal level through directly repressing the transcription of ATG1-ATG13-ATG17. Upon nutrient-deficient treatment, the transcriptional level of SIN3 would decrease and dissociation of Sin3 from those ATGs associates with histone hyperacetylation and activates their transcriptional expression and in turn contributes to autophagy induction. Our findings are important as we uncover a new mechanism of Sin3 for the first time to negatively modulate autophagy at the transcriptional level in M. oryzae.

Changes in the skin characteristics associated with dehydration and rehydration.

The present study aimed to test the hypothesis that changes in the dermal tissue dielectric constant (TDC) and biomechanical properties of the skin would be correlated with the indicators related to dehydration. Ten healthy adult men were enrolled in three trials: no fluid intake (DEH), ad libitum fluid intake (AL-HYD), and programmed fluid intake (P-HYD) after exercise in a randomised crossover design. The participants performed a pedalling exercise at 60% heart rate reserve until 2% body mass loss. At 120 min after exercise, an incremental exercise test was carried out. Aerobic capacity, body composition, TDC, biomechanical properties of the skin (pliability, viscoelasticity, and total recovery), and indicators related to dehydration in the serum and urine were measured before and 120 min after exercise. Higher values of the pliability and viscoelasticity, and lower value of the total recovery on the hand were demonstrated in the P-HYD trial compared to the DEH trial (all P < 0.05). Changes in the TDC were significantly correlated with changes in body mass, total body water, serum osmolarity, and hematocrit (all P < 0.05). Changes in the biomechanical properties of the hand were significantly correlated with changes in body mass, hematocrit, and urine specific gravity (all P < 0.05). The present study showed that the changes in skin characteristics correlated with the body water and dehydration-associated indicators in the serum and urine, thus suggesting that skin characteristics may be useful in the assessment of dehydration.HighlightsThis study was the first to investigate the effect of dehydration and rehydration on the TDC and biomechanical properties of the skin upon instrumental measure, and not manual testing.This study confirmed the decline in aerobic capacity by dehydration and immediate recovery with sufficient rehydration.Changes in the TDC and the biomechanical properties of the skin correlated with the body water and dehydration-associated indicators in the serum and urine.Skin characteristics may be useful in the assessment of dehydration.

A Dual-Modal Approach Using Electromyography and Sonomyography Improves Prediction of Dynamic Ankle Movement: A Case Study.

For decades, surface electromyography (sEMG) has been a popular non-invasive bio-sensing technology for predicting human joint motion. However, cross-talk, interference from adjacent muscles, and its inability to measure deeply located muscles limit its performance in predicting joint motion. Recently, ultrasound (US) imaging has been proposed as an alternative non-invasive technology to predict joint movement due to its high signal-to-noise ratio, direct visualization of targeted tissue, and ability to access deep-seated muscles. This paper proposes a dual-modal approach that combines US imaging and sEMG for predicting volitional dynamic ankle dorsiflexion movement. Three feature sets: 1) a uni-modal set with four sEMG features, 2) a uni-modal set with four US imaging features, and 3) a dual-modal set with four dominant sEMG and US imaging features, together with measured ankle dorsiflexion angles, were used to train multiple machine learning regression models. The experimental results from a seated posture and five walking trials at different speeds, ranging from 0.50 m/s to 1.50 m/s, showed that the dual-modal set significantly reduced the prediction root mean square errors (RMSEs). Compared to the uni-modal sEMG feature set, the dual-modal set reduced RMSEs by up to 47.84% for the seated posture and up to 77.72% for the walking trials. Similarly, when compared to the US imaging feature set, the dual-modal set reduced RMSEs by up to 53.95% for the seated posture and up to 58.39% for the walking trials. The findings show that potentially the dual-modal sensing approach can be used as a superior sensing modality to predict human intent of a continuous motion and implemented for volitional control of clinical rehabilitative and assistive devices.

Synthesis and structures of mono- and di-nuclear aluminium and zinc complexes bearing α-diimine and related ligands, and their use in the ring opening polymerization of cyclic esters.

A series of organoaluminium imino-amido complexes of the type {[ArNC(Me2)C(Me)[double bond, length as m-dash]NAr]AlMe2} (Ar = 2,6-iPr2C6H3 (1), Ar = 2,6-Et2C6H3 (2); Ar = 2,6-Me2C6H3 (3) have been prepared via reaction of AlR3 and the respective α-diimine. Similar reaction of the bis(α-diimine) [ArN[double bond, length as m-dash]C(Me)C(Me)[double bond, length as m-dash]N-]2 (Ar = 2,6-iPr2C6H3) with AlMe3 afforded the bimetallic complex [ArN-C(Me)2C(Me)[double bond, length as m-dash]NAlMe2]2 (4), whilst reaction of the acetyl-imino compound [O[double bond, length as m-dash]C(Me)C(Me)[double bond, length as m-dash]NAr] (Ar = 2,6-Et2C6H3) with AlMe3 afforded the bimetallic complex {[OCMe2CH(Me)[double bond, length as m-dash]NAr]AlMe2}2 (5). In related organozinc chemistry, we have isolated {[ArNC(Me)(Et)C(Me)[double bond, length as m-dash]NAr]ZnEt} (Ar = 2,6-iPr2C6H3, 6) and the trinuclear complex {[ArN[double bond, length as m-dash]C(Me)COCHCO(Me)C(Me)[double bond, length as m-dash]NAr][OCH(Me)C(Me)[double bond, length as m-dash]NAr](ZnEt)3} (Ar = 2,6-iPr2C6H3, 7) from reactions of ZnEt2 with ArN[double bond, length as m-dash]C(Me)C(Me)[double bond, length as m-dash]NAr or [O[double bond, length as m-dash]C(Me)C(Me)[double bond, length as m-dash]NAr], respectively. Reaction of the bis(α-diimine), LiPr-N2-ArCH2Ar-N2, derived from 4,4'-methylenebis(2,6-diisopropylaniline), with ZnCl2 affords [LiPr-N2-ArCH2Ar-N2(ZnCl2)2] (8). The molecular structures of complexes 1-8 are reported. Preliminary results of the ability of 1-8, along with the previously reported metal-metal bonded complex {[ArN[double bond, length as m-dash]C(Me)C(Me)[double bond, length as m-dash]NAr]Al(THF)}2 (9), to act as catalysts for the ring opening polymerization (ROP) of the cyclic esters ε-caprolactone (ε-CL), δ-valerolactone (δ-VL) and rac-lactide (r-LA) are presented. For ε-CL and δ-VL, best results were obtained using the metal-metal bonded complex 9. For r-LA, the Al-based systems exhibited moderate activity affording only liquid oligomers, whilst the Zn-based systems performed better affording at 80 °C isotactic PLA with Mnca. 10 kDa with conversions of up to 66%. The co-polymerization of ε-CL with δ-VL was also examined, and differing preferences were noted for monomer incorporation.

Mono-oxo molybdenum(vi) and tungsten(vi) complexes bearing chelating aryloxides: synthesis, structure and ring opening polymerization of cyclic esters.

The mono-oxo aryloxide complexes [M(O)(L1)2] (M = Mo (1·hexane), W(2·2MeCN)) have been prepared from [Mo(O)(Cl)4] or [W(O)(Ot-Bu)4] and two equivalents of the di-phenol 2,2'-ethylidenebis(4,6-di-tert-butylphenol) L1H2, respectively. Use of in situ generated [Mo(O)(Ot-Bu)4] with two equivalents of L1H2 also led to the isolation of 1·2MeCN. In the presence of adventitious oxygen, attempts to generate in situ [Mo(O)(Ot-Bu)4] and reaction with one equivalent of L1H2 afforded the bi-metallic complex [Mo(O)(L1)(µ-O)Li(THF)(MeCN)]2·2MeCN (3·2MeCN). Use of the tetra-phenol α,α,α',α'-tetrakis(3,5-di-tert-butyl-2-hydroxyphenyl)-p-xyleneH4 (L2H4) with [Mo(O)(Oi-Pr)4] led to the isolation of {[Mo(O)]L2}2 (4), whilst the analogous tungsten complex {[W(O)]L2}2 (5) was isolated from the reaction of L2H4 with [W(O)(Ot-Bu)4]. Similar reaction of p-tert-butylcalix[4]areneH4 (L3H4) with [Mo(O)(Oi-Pr)4] afforded ([Mo(O)L3(NCMe)]·3MeCN (6). Modifications of known routes were employed to access complexes [W(Cl)2L3]·3.5MeCN (7·3.5MeCN) and [W(O)L3(NCMe)] (8), whilst use of [WO(Ot-Bu)4] with L3H4 unexpectedly afforded [W(Ot-Bu)2L3]·MeCN (9·MeCN). The molecular crystal structures for 1-9 are reported, and the ability of these complexes to act as catalysts for the ring opening polymerization (ROP) of ε-caprolactone (ε-CL), δ-valerolactone (δ-VL) and ω-pentadecalactone (ω-PDL) has been investigated. The molybdenum complexes 1 and 4 were the best performers for ε-Cl and δ-VL, but all complexes exhibited poor control and were also inactive toward the ROP of PDL.

Sub-optimally Solving Actuator Redundancy in a Hybrid Neuroprosthetic System with a Multi-layer Neural Network Structure.

Functional electrical stimulation (FES) has recently been proposed as a supplementary torque assist in lower-limb powered exoskeletons for persons with paraplegia. In the combined system, also known as a hybrid neuroprosthesis, both FES-assist and the exoskeleton act to generate lower-limb torques to achieve standing and walking functions. Due to this actuator redundancy, we are motivated to optimally allocate FES-assist and exoskeleton torque based on a performance index that penalizes FES overuse to minimize muscle fatigue while also minimizing regulation or tracking errors. Traditional optimal control approaches need a system model to optimize; however, it is often difficult to formulate a musculoskeletal model that accurately predicts muscle responses due to FES. In this paper, we use a novel identification and control structure that contains a recurrent neural network (RNN) and several feedforward neural networks (FNNs). The RNN is trained by supervised learning to identify the system dynamics, while the FNNs are trained by a reinforcement learning method to provide sub-optimal control actions. The output layer of each FNN has its unique activation functions, so that the asymmetric constraint of FES and the symmetric constraint of exoskeleton motor control input can be realized. This new structure is experimentally validated on a seated human participant using a single joint hybrid neuroprosthesis.

Analysis of the complex formation, interaction and electron transfer pathway between the "open" conformation of NADPH-cytochrome P450 reductase and aromatase.

The complex structure of human aromatase (CYP19) and the open form of ΔTGEE mutant NADPH-cytochrome P450 reductase (mCPR) was constructed using template-based protein alignment method. Dynamic simulation of formed complex was performed on NAMD 2.9, in which CHARMm all 27_prot_lipid_na force field and an explicit TIP3P water solvent model were applied. The result showed mCPR in its open conformation could steadily combine with aromatase from the proximal face. Data analysis indicates hydrogen bonds and four salt bridges on the binding surface enhance the interaction between the two protein molecules. Amino acid, Lys108 plays a key role in aromatase activity through the formation of a salt bridge with Asp147 and two hydrogen bonds with Asp147 and Gln150 in mCPR. The optimal pathway for the first electron transfer from CPR to aromatase was revealed and calculated using HARLEM software. The rates for solvent mediated and non-solvent mediated electron transfer from FMNH2 to heme were determined as 1.04×10(6)s(-)(1) and 4.86×10(5)s(-)(1) respectively, which indicates the solvent water can facilitate the electron transfer from FMNH2 to heme. This study presents a novel strategy for the study of the protein-protein interactions based on the template-based protein alignment, which may help new aromtase development targeting the electron transfer between mCPR and aromatase.